Aviptadil Injection 150 µg/10 ml

Each ml contains :

Aviptadil 15 µg

Water for Injections IP q.s.

Injection 150 µg / 10 ml

4.1 Therapeutic indication

For treatment of patients with severe COVID-19 with Acute Respiratory Distress Syndrome (ARDS).

4.2 Posology and method of administration

Aviptadil intravenous infusion is administered by infusion pump in escalating doses for 3 successive days

• Day 1 : Aviptadil 0.166 mcg/kg/hr (equivalent to 1 vial of Aviptadil Injection)
• Day 2 : Aviptadil 0.332 mcg/kg/hr (equivalent to 2 vials of Aviptadil Injection)
• Day 3 : Aviptadil 0.498 mcg/kg/hr (equivalent to 3 vials of Aviptadil Injection)

Duration of infusion depends on the patient's body weight

• Body weight < 60 kg - 14 hour infusions of Aviptadil at escalating doses on 3 successive days.
• Body weight 60 - 90 kg - 12 hour infusions of Aviptadil at escalating doses on 3 successive days.
• Body weight > 90 kg - 10 hour infusions of Aviptadil at escalating doses on 3 successive days.

4.3 Contraindications

Aviptadil is contraindicated in patients who are hypersensitive to any component of this product.

4.4 Special warnings and precautions for use

Mild transient flushing of the face or trunk occurs commonly. This is rarely associated with discomfort and palpitations or tachycardia in which cases patients may be withdrawn from treatment. Aviptadil must be used with caution in patients with severe cardiovascular or cerebrovascular conditions.

4.5 Drugs interactions

No clinically relevant interaction was observed concomitantly to anti-hypertensive drugs or other cardiovascular drugs.

4.6 Use in special populations

No specific studies in special patient populations have been performed so far

4.7 Effects on ability to drive and use machines

No trials on the effect on the ability to drive a car or use machines have been carried out

4.8 Undesirable effects

Gastrointestinal Disorders e.g. Diarrhea, Vascular disorders - Hypotension, cutaneous flushing, facial flushing and Infusion related reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

4.9 Overdose

No case of overdose has been reported

5.1 Mechanism of action

Aviptadil is a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP). VIP is highly concentrated in the lung and it blocks apoptosis, caspase-3 activation in the lung, inhibits inflammatory cytokines like IL6 and TNF alpha production and reverses CD4/CD8 ratio. VIP increases surfactant production by up regulation of choline phosphate cytidylyltransferase, which increase the incorporation of methyl choline to phosphatidylcholine, the major components of pulmonary surfactant. It also up regulate C Fos protein expression in type II alveolar cells, which increase the synthesis of pulmonary surfactant phospholipids and induce surfactant protein A expression. VIP reduces ischemia-reperfusion injury in animal models. It reduces cell death by inhibiting activation induced perforin, granzyme B and caspase activity. VIP reduces pulmonary inflammation by reducing the production of pro inflammatory cytokines. It inhibits the synthesis and activation of NF-kB, which block the production of TNF alpha. In addition to that VIP blocks SARS-CoV-2 replication in the lungs and monocyte. VIP and pituitary adenylate cyclase activating polypeptide (PACAP) inhibit SARS CoV-2 RNA synthesis in human lung epithelial cell (by 41%) and human primary monocytes (by 33-45%). It also blocks viral cytopathic effect demonstrated by reduced LDH release (by 40%). SARS CoV-2 attack mainly type II cells and results in the death of alveolar type II (AT 11) cells which produces surfactant, resulting in profound defect in oxygenation, leading to hypoxia. Aviptadil a synthetic form of VIP results in rapid clinical recovery in patients with SARS-CoV-2 infection.

5.2 Pharmacodynamic properties

Pulmonary circulation

After intravenous infusion of Aviptadil an increase of heart rate, stroke volume and cardiac output was reported. Right atrial and pulmonary wedge pressure remained unchanged while pulmonary vascular resistance significantly decreased as well as pulmonary arterial systolic pressure. Aviptadil vasodilating properties are 50 times more potent than prostacyclin and independent of the endothelium.

Immunotolerogenic response

In Pulmonary Sarcoidosis, the presumed primary therapeutic mechanism of action of inhaled Aviptadil is a combination of anti-inflammatory properties and induction of tolerogenic immune response of immune cells localized in the lungs.

Systemic circulation

In healthy volunteers intravenous Aviptadil reduced systemic vascular resistance due to its potent vasodilatory effects, followed by increase of heart rate and decrease of blood pressure.

Airway responses

During intravenous infusion (20 ng Aviptadil /kg/min, 30 min), ventilation - perfusion relationships of the lungs (VA/Q) were significantly changed. VA/Q distributions determined by inert gas elimination technique

were shifted to lower values but arterial oxygen tension remained unchanged. Therefore, Aviptadil alters the ventilation - perfusion distributions but generates no shunt and does not cause hypoxia.

5.3 Pharmacokinetic properties

Absorption

Studies with radiolabeled Aviptadil (single intravenous bolus injection of 300 pmol [1 µg]) demonstrate that after the initial rapid clearance from the circulation, the lung is the primary site of peptide binding. Within 30 min., about 45% of the radioactivity is found in the lungs. Only minimal activity was found in the gastrointestinal tract, and almost no activity was seen in normal liver or spleen during the observation period of 24 hours. The radioactivity in the lungs decreased at 4 hours to 25%, and after 24 hours to 10%. Radioactivity was excreted into the urine (35% of the injected dose after 4 hours, and 90% after 24 hours). Half-life of Aviptadil in blood was 1 minute, the metabolic clearance rate was 9 ml/kg/min and the apparent volume of distribution for Aviptadil was about 14 ml/kg.

Distribution

Aviptadil binding to its receptors occurs in discrete locations within the gastrointestinal, respiratory, and genital tracts. Aviptadil is localized on respiratory epithelium, smooth muscles of the airways, blood vessels and alveolar walls.

Elimination

After injection of 1 µg radioactively labelled Aviptadil as bolus to patients a very rapid tissue distribution was observed. Within 30 minutes about 45% of the radioactivity was found in the lungs. Over an observation period of 24 hours only minimal activity was detected in the gastrointestinal tract and almost no activity was found in the liver or spleen. Radioactivity in the lungs decreased within four hours to 25% and within 24 hours to 10%. The half-life of Aviptadil in plasma is about 1-2 minutes. After injection of radiolabelled Aviptadil radioactivity was almost completely eliminated by the kidneys, 35% within 4 hours, and 90% within 24 hours.

6.1 Animal toxicology or pharmacology

In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs and functional behavioural assays in rats, no adverse side effects were observed with NAP concentrations that were ∼ 500-fold higher than the biologically active dose.

Effect of aviptadil on fertility and early embryonal development

• Aviptadil infusions in rabbits can increase plasma progesterone from both the basal levels of estrus and from the peak levels preceding ovulation.

• Infusions of Aviptadil at the time of the preovulatory steroid surge or during ovulation have little effect upon fertility or gamete transport in the rabbit.

• Endogenous VIP may play a role in the regulation of progesterone secretion in the rabbit.

Effect of aviptadil on embryogenesis

In rats, Aviptadil binding sites in the embryo were analysed during embryonic days E10-E13. Aviptadil binding was almost exclusively located to the brain and spinal cord. The investigation of expression of Aviptadil mRNA from embryo in this stage (E11) revealed totally negative results, indicating extraembryonic, maternal Aviptadil supply to the embryo. Indeed, beginning at day E9, there is an enormous increase of Aviptadil concentration in maternal blood, 6-10 times greater than later on during pregnancy. Data indicate that Aviptadil from maternal tissues may be the source of Aviptadil acting on the embryonic tissues, transferred to the embryo undegraded. On day E17, Aviptadil mRNA expression was easily detectable all over the embryo, and maternal Aviptadil concentration in the blood decreased to very low levels. Aviptadil is required for embryonic development.

Genotoxicity

No evidence of genotoxic potential has been found in in vitro and in vivo studies.

Non-proprietary name : Aviptadil

Other name : VIP (Vasoactive Intestinal Peptide)

Structure of Aviptadil

Aviptadil (VIP) is a linear, 28-AA peptide with an amidated C-terminus. All amino acids of Aviptadil are in Lconfiguration.

Chemical name : H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-ValLys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2

Molecular formula : C₁₄₇H₂₃₈N₄₄O₄2S

Molecular weight : 3325.8 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A vial of 10 ml.

8.4 Storage and handing instructions

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep out of reach of children.

Do not use in case any foreign particulate matter is observed inside the vial.

Olmesartan Medoxomil and Chlorthalidone tablets 20mg/12.5mg, 40mg/12.5mg

Olbet-CT 20 Tablets

Each film coated bilayered tablets contains:

Olmesartan Medoxomil IP ………. 20mg

Chlorthalidone IP …………………………..12.5 mg

Excipients……………………………………..q.s.

Olbet-CT 40 Tablets

Each film coated bilayered tablets contains:

Olmesartan Medoxomil IP ………. 40mg

Chlorthalidone IP ………………………..12.5 mg

Excipients……………………………………..q.s.

Film-coated tablet.

4.1 Therapeutic Indication

For the treatment of essential hypertension

4.2 Posology and method of administration

The dose of Olbet-CT is one tablet once daily.

Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 20-60 ml/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group.

Olbet-CT is not recommended in patients with severe renal failure.

Hepatic impairment

Mild hepatic impairment:

No dose adjustment. Should be used with caution due to the chlorthalidone component, as in patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma.

Moderate hepatic impairment:

An initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. Should be used with caution.

Severe hepatic impairment:

NOT recommended in this patient group.

Olmesartan medoxomil should not be used in patients with biliary obstruction.

Elderly patients

No adjustment of dosage is generally required in elderly people. If up-titration of Olmesartan medoxomil to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Paediatric population

Safety and effectiveness of Olbet CT in children have not been established.

4.3 Contraindications

• Hypersensitivity to Olmesartan medoxomil, chlorthalidone or other sulfonamide-derived drugs
• Pregnancy
• Biliary obstruction
• The concomitant use of Olmesartan Tablets with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2)
• Anuria

4.4 Special warnings and precautions for use

Olmesartan medoxomil

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of olmesartan medoxomil.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation

When olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 20 ml/min) (see sections 4.2 and 5.2). There is no experience of the administration of olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 ml/min).

Hepatic impairment

There is no experience in patients with severe hepatic impairment and therefore use of olmesartan medoxomil in this patient group is not recommended (see section 4.2 for dosage recommendations in patients with mild or moderate hepatic impairment).

Hyperkalaemia

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

The risk, that may be fatal, is increased in elderly, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated and other alternatives considered. (see also below section “Dual blockade of the renin-angiotensin-aldosterone system (RAAS)”).

The main risk factors for hyperkalaemia to be considered are:

-Diabetes, renal impairment, age (> 70 years)

-Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Some medicinal products or therapeutic class of medicinal products may provoke a hyperkalaemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptors antagonists, non steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor as ciclosporin or tacrolimus, trimethoprim

-Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extended trauma).

Close-monitoring of serum potassium in at risk patients is recommended

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Lithium

As with other angiotensin-II receptor antagonists, the combination of lithium and olmesartan medoxomil is not recommended.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil is not recommended in such patients.

Sprue-like enteropathy

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Chlorthalidone

Hypotension

Chlorthalidone may cause symptomatic hypotension. Patients with impaired sympathetic response, volume-depletion or who are salt restricted may be at increased risk for developing hypotension. If hypotension occurs, place the patient in the supine position and, if necessary, give intravenous normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Impaired Renal Function

Changes in renal function including acute renal failure can be caused by diuretics. Patients with chronic kidney disease, heart failure, or volume depletion may be at particular risk of developing acute renal failure on Chlorthalidone. Monitor renal function periodically. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Chlorthalidone.

Electrolyte Abnormalities

Chlorthalidone can cause hypokalemia, hyponatremia, hypochloremic alkalosis, and hypomagnesemia.

Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.

If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations),

Chlorthalidone should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

Metabolic Disturbances

Chlorthalidone may alter glucose tolerance.

Chlorthalidone may raise serum levels of cholesterol and triglycerides.

Chlorthalidone may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

Chlorthalidone decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Chlorthalidone

4.5 Drugs interactions

Olmesartan medoxomil

Other antihypertensive medications:

The blood pressure lowering effect of olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.

ACE-inhibitors, angiotensin II receptor blockers or aliskiren

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent

Potassium supplements and potassium sparing diuretics:

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. Such concomitant use is therefore not recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs):

NSAIDs (including acetylsalicylic acid at doses> 3 g/day and also COX-2 inhibitors) and angiotensin II receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient.

Additionally, concomitant treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy.

Bile acid sequestering agent colesevelam

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered.

Other compounds:

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed. Coadministration of warfarin and digoxin had no effect on the pharmacokinetics of olmesartan.

Effects of olmesartan medoxomil on other medicinal products:

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and angiotensin II antagonists. Therefore, use of olmesartan medoxomil and lithium in combination is not recommended. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Other compounds:

Compounds which have been investigated in specific clinical studies in healthy volunteers include warfarin, digoxin, an antacid (magnesium aluminium hydroxide), hydrochlorothiazide and pravastatin. No clinically relevant interactions were observed and in particular olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Olmesartan had no clinically relevant inhibitory effects on in vitro human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and had no or minimal inducing effects on rat cytochrome P450 activities. Therefore, in vivo interaction studies with known cytochrome P450 enzyme inhibitors and inducers were not conducted, and no clinically relevant interactions between olmesartan and drugs metabolised by the above cytochrome P450 enzymes are expected.

Chlorthalidone

Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Chlorthalidone and related drugs may increase the responsiveness to tubocurarine. Lithium renal clearance is reduced by chlorthalidone, increasing the risk of lithium toxicity. Monitor serum lithium levels during concomitant use.

4.6 Use in special populations

Pregnancy

Use of Olbet CT is Not recommended in pregnancy.

Breast-feeding

Use of Olbet CT is Not recommended in breast-feeding.

4.7 Effects on ability to drive and use machines

Olmesartan medoxomil has minor or moderate influence on the ablility to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ablility to react.

4.8 Undesirable effects

Olmesartan medoxomil

The most commonly reported adverse reactions during treatment with olmesartan are headache (7.7%), influenza-like symptoms (4.0%) and dizziness (3.7%).

In placebo-controlled monotherapy studies, the only adverse drug reaction that was unequivocally related to treatment was dizziness (2.5% incidence on olmesartan medoxomil and 0.9% on placebo).

The incidence was also somewhat higher on olmesartan medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).

The following terminologies have been used in order to classify the occurrence of adverse reactions very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

• Blood and lymphatic system disorders: Thrombocytopenia (Uncommon)
• Immune system disorders: Anaphylactic reaction (Uncommon)
• Metabolism and nutrition disorders: Hypertriglyceridaemia, Hyperuricaemia (Common), Hyperkalaemia (Rare)
• Nervous system disorders: Dizziness, Headache (Common)
• Ear and labyrinth disorders: Vertigo (Uncommon)
• Cardiac disorders: Angina pectoris (Uncommon)
• Vascular disorders: Hypotension (Rare)
• Respiratory, thoracic and mediastinal disorders: Bronchitis, Pharyngitis, Cough, Rhinitis (Common)
• Gastrointestinal disorders: Gastroenteritis, Diarrhoea, Abdominal pain, Nausea, Dyspepsia (Common), Vomiting (Uncommon), Sprue-like enteropathy (Very rare)
• Skin and subcutaneous tissue disorders: Exanthema, Allergic dermatitis, Urticaria, Rash, Pruritus, (Uncommon), Angioedema (Rare)
• Musculoskeletal and connective tissue disorders: Arthritis, Back pain, Skeletal pain, Myalgia, (Uncommon), Muscle spasm (Rare)
• Renal and urinary disorders: Haematuria, Urinary tract infection (common), Acute renal failure, Renal insufficiency (Rare)
• General disorders and administration site conditions: Pain, Chest pain, Peripheral oedema, Influenza-like symptoms, Fatigue (Common), Face oedema, Asthenia, Malaise (Uncommon), Lethargy (Rare)
• Investigations: Hepatic enzymes increased, Blood urea increased, Blood creatine phosphokinase increased (Common), Blood creatinine increased (Rare)

Chlorthalidone

• Hypotension
• Impaired Renal Function
• Electrolyte Abnormalities
• Metabolic Disturbances (see Warnings and Precautions for more information)

The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency.

Gastrointestinal System Reactions: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis.

Central Nervous System Reactions: dizziness, paresthesias, headache.

Hematologic Reactions: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia.

Dermatologic-Hypersensitivity Reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis).

Cardiovascular Reaction: Orthostatic hypotension.

Other Adverse Reactions: muscle spasm, weakness, restlessness, impotence, xanthopsia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

4.9 Overdose

Olmesartan medoxomil

Only limited information is available regarding overdosage in humans. The most likely effect of overdosage is hypotension. In the event of overdosage, the patient should be carefully monitored and treatment should be symptomatic and supportive.

No information is available regarding the dialysability of olmesartan.

Chlorthalidone

Symptoms of acute overdosage include nausea, weakness, dizziness and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

5.1 Mechanism of Action

Olmesartan medoxomil

Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor.

Chlorthalidone

Chlorthalidone is a long-acting oral diuretic with antihypertensive activity. The diuretic effects of chlorthalidone and the benzothiadiazine (thiazide) diuretics appear to arise from similar mechanisms and the maximal effect of chlorthalidone and the thiazides appear to be similar. The site of the action appears to be the distal convoluted tubule of the nephron. Although the mechanism of action of chlorthalidone and related drugs is not wholly clear, sodium and water depletion appear to provide a basis for its antihypertensive effect.

5.2 Pharmacodynamic properties

Olmesartan medoxomil

The selective antagonism of the angiotensin II (AT1) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

Chlorthalidone

The diuretic action of chlorthalidone commences a mean of 2.6 hours after dosing and continues for up to 72 hours. The drug produces diuresis with increased excretion of sodium and chloride. The diuretic effects of chlorthalidone lead to decreased extracellular fluid volume, plasma volume, cardiac output, total exchangeable sodium, glomerular filtration rate, and renal plasma flow. Chlorthalidone produces dose-related reductions in serum potassium levels, elevations in serum uric acid and blood glucose, and it can lead to decreased sodium and chloride levels.

5.3 Pharmacokinetic properties

Absorption and distribution

Olmesartan medoxomil

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract.

No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6 %.

The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.

Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed. Olmesartan is highly bound to plasma protein (99.7 %), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound coadministered drugs is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 - 29 L).

Chlorthalidone

Absorption of chlorthalidone following oral dosing is consistent but incomplete (approximately 60%) with peak plasma concentrations occurring about 12 hours after dosing. The chlorthalidone blood levels are consistent and subject to little variability. In the blood, approximately 75% of the drug is bound to plasma proteins over a concentration range of 0.2 to 7.7 ug/mL.

Biotransformation and elimination

Olmesartan medoxomil

Total plasma clearance was typically 1.3 L/h (CV, 19 %) and was relatively slow compared to hepatic blood flow (ca 90L/h). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10 - 16 % of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6 %, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40 %) and hepato-biliary excretion (ca 60 %). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.

The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 - 0.7 L/h and was independent of dose.

Chlorthalidone

The mean plasma half-life of chlorthalidone is about 40 to 60 hours. It is eliminated primarily as unchanged drug in the urine.

6.1 Animal Toxicology or Pharmacology

Olmesartan medoxomil

In chronic toxicity studies in rats and dogs, olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: raised blood urea (BUN) and creatinine (through functional changes to the kidneys caused by blocking AT1 receptors); reduction in heart weight; a reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride.

In both species, increased plasma renin activity and hypertrophy/hyperplasia of the juxtaglomerular cells of the kidney were observed. These changes, which are a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, would appear to have no clinical relevance.

Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro. No relevant effects were observed in several in vivo studies using olmesartan medoxomil at very high oral doses of up to 2000 mg/kg. The overall data of a comprehensive genotoxicity testing suggest that olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use.

Olmesartan medoxomil was not carcinogenic, neither in rats in a 2 year study nor in mice when tested in two 6 month carcinogenicity studies using transgenic models.

In reproductive studies in rats, olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced following exposure to olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats, however, there was no indication of a fetotoxic effect.

Chlorthalidone

Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus due to chlorthalidone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No information is available.

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT 1 subtype angiotensin II receptor antagonist. Olmesartan medoxomil, USP is described chemically as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[ p-(o-1 H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.

Chlorthalidone is an antihypertensive/diuretic supplied as 15 mg and 25 mg tablets for oral use. It is a monosulfamyl diuretic that differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is a racemic mixture of 2-chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 blister strips of 10 tablets each

8.8 Storage and handing instructions

Store protected from light & moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

Tablet should be swallowed whole & not to be broken, chewed or crushed.

• Advice patients not to take this medicine, if they are allergic to Olmesartan Medoxomil or Chlorthalidone
• Signs of an allergic reaction include a rash, itching or shortness of breath.
• Symptomatic hypotension and syncope: Advise patients that light headedness can occur, especially during the first days of therapy, and to report this symptom to a healthcare provider. Inform patients that dehydration from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea may lead to an excessive fall in blood pressure. If syncope occurs advise patients, to contact their healthcare provider.
• Pregnancy: Tell female patients Olbet CT should not be given during pregnancy and lactation.
• Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.
• Tell the patients if they get any side effects, talk to the doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
• Advice patients if they have any further questions, ask the doctor or pharmacist.

11/10/2024

Olmesartan Medoxomil Tablets 20 mg/40 mg

OLBET-20

Each film coated tablet contains:

Olmesartan Medoxomil Tablets 20 mg

Excipients q.s.

Colour: Titanium Dioxide IP

OLBET-40

Each film coated tablet contains:

Olmesartan Medoxomil Tablets 40 mg

Excipients q.s.

Colour: Titanium Dioxide IP

Film coated tablet

20/ 40 mg

4.1 Therapeutic Indication

Anti- Hypertension

Olmesartan is indicated for the management of Essential hypertension

4.2 Posology and method of administration

Posology

Adults

The recommended starting dose of olmesartan medoxomil is 10 mg once daily. In patients whose blood pressure is not adequately controlled at this dose, the dose of olmesartan medoxomil may be increased to 20 mg once daily as the optimal dose. If additional blood pressure reduction is required, olmesartan medoxomil dose may be increased to a maximum of 40 mg daily or hydrochlorothiazide therapy may be added.

The antihypertensive effect of olmesartan medoxomil is substantially present within 2 weeks of initiating therapy and is maximal by about 8 weeks after initiating therapy. This should be borne in mind when considering changing the dose regimen for any patient.

Older people (65 years or older)

No adjustment of dosage is generally required in older people (see below for dose recommendations in patients with renal impairment). If up-titration to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Patients with renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 20 – 60 ml/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group. The use of olmesartan medoxomil in patients with severe renal impairment (creatinine clearance < 20 ml/min) is not recommended, since there is only limited experience in this patient group.

Patients with hepatic impairment

No adjustment of dosage recommendations is required for patients with mild hepatic impairment. In patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment, therefore use is not recommended in this patient group. Olmesartan medoxomil should not be used in patients with biliary obstruction.

Paediatric population

Children and adolescents from 6 to less than 18 years of age. The recommended starting dose of olmesartan medoxomil in children from 6 to less than 18 years of age is 10 mg olmesartan medoxomil once daily. In children whose blood pressure is not adequately controlled at this dose, the dose of olmesartan medoxomil may be increased to 20 mg once daily. If additional blood pressure reduction is required, in children who weigh > 35 kg, the olmesartan medoxomil dose may be increased to a maximum of 40 mg. In children who weigh < 35 kg, the daily dose should not exceed 20 mg.

Other paediatric population

The safety and efficacy of olmesartan medoxomil in children aged 1 to 5 years old have not yet been established.

Olmesartan medoxomil should not be used in children below 1 years of age because of safety concerns and lack of data in this age group.

Method of administration

In order to assist compliance, it is recommended that Olmesartan tablets be taken at about the same time each day, with or without food, for example at breakfast time. The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should be swallowed whole without chewing.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Second and third trimesters of pregnancy.
• Biliary obstruction.
• The concomitant use of Olmesartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2)

4.4 Special warnings and precautions for use

Intravascular volume depletion:

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of olmesartan medoxomil.

Other conditions with stimulation of the renin-angiotensin-aldosterone system:

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.

Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation:

When olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 20 ml/min). There is no experience of the administration of olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance <12 ml/min).

Hepatic impairment:

There is no experience in patients with severe hepatic impairment and therefore use of olmesartan medoxomil in this patient group is not recommended.

Hyperkalaemia:

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

The risk, that may be fatal, is increased in older people, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated and other alternatives considered.

The main risk factors for hyperkalaemia to be considered are:

- Diabetes, renal impairment, age (> 70 years).

- Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Some medicinal products or therapeutic class of medicinal products may provoke a hyperkalaemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptors antagonists, non-steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor as ciclosporin or tacrolimus, trimethoprim.

- Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extended trauma).

Close-monitoring of serum potassium in at risk patients is recommended.

Lithium:

As with other angiotensin-II receptor antagonists, the combination of lithium and olmesartan medoxomil is not recommended.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy:

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil is not recommended in such patients.

Sprue-like enteropathy:

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan medoxomil in cases where no other etiology is identified. In cases where symptoms disappear and sprue-like enteropathy is confirmed by biopsy, treatment with olmesartan medoxomil should not be restarted.

Ethnic differences:

As with all other angiotensin II antagonists, the blood pressure lowering effect of olmesartan medoxomil is somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Pregnancy:

Angiotensin II receptor antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.

Other:

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Olmesartan contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Drugs interactions

Paediatric population:

Interaction studies have only been performed in adults.

It is not known if the interactions in children are similar to those in adults.

Effects of other medicinal products on olmesartan medoxomil:

Potassium supplements and potassium sparing diuretics:

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. Such concomitant use is therefore not recommended.

Other antihypertensive medications:

The blood pressure lowering effect of olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.

Non-steroidal anti-inflammatory drugs (NSAIDs):

NSAIDs (including acetylsalicylic acid at doses (> 3 g/day and also COX-2 inhibitors) and angiotensin-II receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient.

Additionally, concomitant treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy.

Bile acid sequestering agent colesevelam:

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered.

Other compounds:

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed. Coadministration of warfarin and digoxin had no effect on the pharmacokinetics of olmesartan.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.

Effects of olmesartan medoxomil on other medicinal products:

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and angiotensin II antagonists. Therefore, use of olmesartan medoxomil and lithium in combination is not recommended. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Other compounds:

Compounds which have been investigated in specific clinical studies in healthy volunteers include warfarin, digoxin, an antacid (magnesium aluminium hydroxide),hydrochlorothiazide and pravastatin. No clinically relevant interactions were observed and in particular olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.Olmesartan had no clinically relevant inhibitory effects on in vitro human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and had no or minimal inducing effects on rat cytochrome P450 activities. Therefore, in vivo interaction studies with known cytochrome P450 enzyme inhibitors and inducers were not conducted, and no clinically relevant interactions between olmesartan and drugs metabolised by the above cytochrome P450 enzymes are expected.

4.6 Use in special populations

Pregnancy

The use of AIIRAs is not recommended during the first trimester of pregnancy. The use of AIIRAs is contraindicated during the second and third trimester of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension.

Breastfeeding

Olmesartan is excreted in the milk of lactating rats but it is not known whether olmesartan is excreted in human milk. Because no information is available regarding the use of Olmesartan during breastfeeding, Olmesartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on ability to drive and use machines

Olmesartan has minor or moderate influence on the ability to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.

4.8 Undesirable effects

Summary of the safety profile:

The most commonly reported adverse reactions during treatmentwith olmesartan medoxomil are headache (7.7%), influenza-like symptoms (4.0%) and dizziness (3.7%).

In placebo-controlled monotherapy studies, the only adverse drug reaction that was unequivocally related to treatment was dizziness (2.5% incidence on olmesartan medoxomil and 0.9% on placebo).

The incidence was also somewhat higher on olmesartan medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).

Tabulated list of adverse reactions:

Adverse reactions from olmesartan medoxomil in clinical trials, post-authorisation safety studies and spontaneous reporting are summarized in the below table.

They are listed by System Organ Class and ranked under headings of frequency using the following convention: very common (≥ 1/10); common (≥ 1/100 to, <1/10); uncommon (≥ 1/1,000 to, <1/100); rare (≥ 1/10,000 to, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).

*Cases of autoimmune hepatitis with a latency of few months to years have been reported post-marketing, that were reversible after the withdrawal of olmesartan.

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.

Additional information on special populations

In older people the frequency of hypotension is slightly increased from rare to uncommon.

Paediatric population:

The safety of olmesartan medoxomil was monitored in 361 children and adolescents, aged 1-17 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

- Epistaxis is a common adverse event in children (i.e. ≥ 1/100 to < 1/10) that has not been reported in adults.

- During the 3 weeks of double blind study, the incidence of treatment emergent dizziness and headache nearly doubled in children 6-17 years of age in the high olmesartan medoxomil dose group.

The overall safety profile for olmesartan medoxomil in paediatric patients does not differ significantly from the safety profile in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to:medico@zuventus.com

Website: https://www.zuventus.co.in/drug-safety-reporting

4.9 Overdose

Only limited information is available regarding overdosage in humans. The most likely effect of overdosage is hypotension. In the event of overdosage, the patient should be carefully monitored and treatment should be symptomatic and supportive.

No information is available regarding the dialysability of olmesartan.

5.1 Mechanism of Action/ Pharmacodynamic properties

Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor.

Clinical efficacy and safety

In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after cessation of therapy.

Once daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24-hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment. When used together with hydrochlorothiazide, the reduction in blood pressure is additive and coadministration is well tolerated.

The effect of olmesartan on mortality and morbidity is not yet known.

The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study in 4447 patients with type 2 diabetes, normo-albuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could delay the onset of microalbuminuria. During the median follow-up duration of 3.2 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.

For the primary endpoint, the study demonstrated a significant risk reduction in the time to onset of microalbuminuria, in favour of olmesartan. After adjustment for BP differences this risk reduction was no longer statistically significant. 8.2% (178 of 2160) of the patients in the olmesartan group and 9.8% (210 of 2139) in the placebo group developed microalbuminuria.

For the secondary endpoints, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates for non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)) and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality with olmesartan was numerically increased (26 patients (1.2%) vs. 15 patients (0.7%)), which was mainly driven by a higher number of fatal cardiovascular events.

The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) investigated the effects of olmesartan on renal and cardiovascular outcomes in 577 randomized Japanese and Chinese type 2 diabetic patients with overt nephropathy. During a median follow-up of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents including ACE inhibitors.

The primary composite endpoint (time to first event of the doubling of serum creatinine, end-stage renal disease, all-cause death) occurred in 116 patients in the olmesartan group (41.1%) and 129 patients in the placebo group (45.4%) (HR 0.97 (95% CI 0.75 to 1.24); p=0.791). The composite secondary cardiovascular endpoint occurred in 40 olmesartan-treated patients (14.2%) and 53 placebo-treated patients (18.7%). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5%) patients receiving olmesartan versus 3 (1.1%) receiving placebo, overall mortality 19 (6.7%) versus 20 (7.0%), non-fatal stroke 8 (2.8%) versus 11 (3.9%) and non-fatal myocardial infarction 3 (1.1%) versus 7 (2.5%), respectively.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Paediatric population:

The antihypertensive effects of olmesartan medoxomil in the paediatric population were evaluated in a randomized, double-blind, placebo-controlled study in 302 hypertensive patients aged 6 to 17 years. The study population consisted of an all-black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The aetiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 mg (low dose) or 20 mg (high dose) of olmesartan medoxomil once daily and patients who weighed ≥ 35 kg were randomized to 5 mg (low dose) or 40 mg (high dose) of olmesartan medoxomil once daily. Olmesartan medoxomil significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Olmesartan medoxomil at both low and high doses significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. This effect was also observed during the 2 weeks randomized withdrawal phase, whereby both mean systolic and diastolic blood pressures demonstrated a statistically significant rebound in the placebo group compared to olmesartan medoxomil group. The treatment was effective in both, paediatric patients with primary and secondary hypertension. As observed in adult populations, the blood pressure reductions were smaller in black patients.

In the same study, 59 patients aged 1 to 5 years who weighed ≥ 5 kg received 0.3 mg/kg of olmesartan medoxomil once daily for three weeks in an open label phase and then were randomized to receiving olmesartan medoxomil or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to olmesartan medoxomil; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).

5.3 Pharmacokinetic properties

Absorption and distribution

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract.

No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%.

The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.

Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.

Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound co-administered drugs is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 – 29 L).

Biotransformation and elimination

Total plasma clearance was typically 1.3 l/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 l/h). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10 - 16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40%) and hepato-biliary excretion (ca 60%). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.

The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 – 0.7 l/h and was independent of dose.

Pharmacokinetics in special populations

Older people (age 65 years or older):

In hypertensive patients, the AUC at steady state was increased by ca 35% in older people (65 – 75 years old) and by ca 44% in very old people (≥ 75 years old) compared with the younger age group. This may be at least in part related to a mean decrease in renal function in this group of patients.

Renal impairment:

In renally impaired patients, the AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls.

Hepatic impairment:

After single oral administration, olmesartan AUC values were 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment was 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC was again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values were similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.

Paediatric population:

The pharmacokinetics of olmesartan was studied in paediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in paediatric patients was similar to that in adult patients when adjusted by the body weight.

There is no pharmacokinetic information available in renally impaired paediatric subjects.

Drug interactions

Bile acid sequestering agent colesevelam:

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmaxand AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half-life of olmesartan was reduced by 50 – 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride.

6.1 Animal Toxicology or Pharmacology

In chronic toxicity studies in rats and dogs, olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: raised blood urea (BUN) and creatinine (through functional changes to the kidneys caused by blocking AT1 receptors); reduction in heart weight; a reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride.

In both species, increased plasma renin activity and hypertrophy/hyperplasia of the juxtaglomerular cells of the kidney were observed. These changes, which are a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, would appear to have no clinical relevance.

Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro. No relevant effects were observed in several in vivo studies using olmesartan medoxomil at very high oral doses of up to 2000 mg/kg. The overall data of a comprehensive genotoxicity testing suggest that olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use.

Olmesartan medoxomil was not carcinogenic, neither in rats in a 2-year study nor in mice when tested in two 6-month carcinogenicity studies using transgenic models.

In reproductive studies in rats, olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced following exposure to olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats, however, there was no indication of a fetotoxic effect.

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist.

Chemical name: 2,3-dihydroxy-2-butenyl 4 (1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-carboxylate, cyclic 2,3-carbonate

Molecular formula: C₂₉H₃₀N₆O₆

Molecular mass: 558.59 g/mol

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store below 25°C. Protected from light & moisture.
• Keep out of reach of children.

• Pregnancy: Advise female patients of childbearing age about the consequences of exposure to Olbet during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.
• Lactation: Advise nursing women not to breastfeed during treatment with Olbet.
• Hyperkalemia: Advise patients not to use potassium supplements or salt substitutes that contain potassium without consulting their healthcare provider.

10/10/2024

Olmesartan Medoxomil, Chlorthalidone and Amlodipine Tablets

Olbet TRIO 20

Each film coated tablet contains:

Olmesartan Medoxomil IP…………….20 mg

Chlorthalidone IP……………………12.5 mg

Amlodipine Besylate IP

equivalent to Amlodipine………………5 mg

Excipients………………………………...q.s.

Olbet TRIO 40

Each film coated tablet contains:

Olmesartan Medoxomil IP…………….40 mg

Chlorthalidone IP……………………12.5 mg

Amlodipine Besylate IP

equivalent to Amlodipine……………………………..5 mg

Excipients…………………………………q.s.

Film-coated tablet. (Olmesartan Medoxomil, Chlorthalidone and Amlodipine)

20mg/12.5mg/5mg, 40mg/12.5mg/5mg.

4.1 Therapeutic Indication

For the treatment of essential hypertension

4.2 Posology and method of administration

Adults

The recommended dose is 1 tablet per day.

Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 30 - 60 mL/min) is Olbet Trio 20 mg/5 mg/12.5 mg, owing to limited experience of the 40 mg Olmesartan Medoxomil dosage in this patient group. Monitoring of serum concentrations of potassium and creatinine is advised in patients with moderate renal impairment.

The use of Olbet Trio in patients with severe renal impairment (creatinine clearance < 30 mL/min) is contraindicated.

Hepatic impairment

In patients with moderate hepatic impairment the maximum dose should not exceed 20 mg/5 mg/12.5 mg once daily.

Method of administration

The table should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day. It can be taken with or without food.

4.3 Contraindications

• Hypersensitivity to Olmesartan medoxomil, chlorthalidone, amlodipine or to any of the excipients.
• Severe renal impairment.
• Refractory hypokalemia, hypercalcemia, hyponatremia and symptomatic hyperuricemia.
• Severe hepatic insufficiency, cholestasis and biliary obstructive disorders.
• Pregnancy.
• Anuria
• Concomitant use of Olbet Trio with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2)
• Due to the Amlodipine component, it is contraindicated in patients with:
  • Shock (including cardiogenic shock).
  • Severe hypotension.
  • Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).
  • Haemodynamically unstable heart failure after acute myocardial infarction.

4.4 Special warnings and precautions for use

Olmesartan medoxomil

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of olmesartan medoxomil.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation

When olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 20 ml/min) (see sections 4.2 and 5.2). There is no experience of the administration of olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 ml/min).

Hepatic impairment

There is no experience in patients with severe hepatic impairment and therefore use of olmesartan medoxomil in this patient group is not recommended (see section 4.2 for dosage recommendations in patients with mild or moderate hepatic impairment).

Hyperkalaemia

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

The risk, that may be fatal, is increased in elderly, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated and other alternatives considered. (see also below section “Dual blockade of the renin-angiotensin-aldosterone system (RAAS)”).

The main risk factors for hyperkalaemia to be considered are:

• Diabetes, renal impairment, age (> 70 years)
• Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Some medicinal products or therapeutic class of medicinal products may provoke a hyperkalaemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptors antagonists, non steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor as ciclosporin or tacrolimus, trimethoprim
• Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extended trauma).

Close-monitoring of serum potassium in at risk patients is recommended

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Lithium

As with other angiotensin-II receptor antagonists, the combination of lithium and olmesartan medoxomil is not recommended.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil is not recommended in such patients.

Sprue-like enteropathy

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Chlorthalidone

Hypotension

Chlorthalidone may cause symptomatic hypotension. Patients with impaired sympathetic response, volume-depletion or who are salt restricted may be at increased risk for developing hypotension. If hypotension occurs, place the patient in the supine position and, if necessary, give intravenous normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Impaired Renal Function

Changes in renal function including acute renal failure can be caused by diuretics. Patients with chronic kidney disease, heart failure, or volume depletion may be at particular risk of developing acute renal failure on Chlorthalidone. Monitor renal function periodically. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Chlorthalidone.

Electrolyte Abnormalities

Chlorthalidone can cause hypokalemia, hyponatremia, hypochloremic alkalosis, and hypomagnesemia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.

If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), Chlorthalidone should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

Metabolic Disturbances

Chlorthalidone may alter glucose tolerance.

Chlorthalidone may raise serum levels of cholesterol and triglycerides.

Chlorthalidone may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

Chlorthalidone decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Chlorthalidone.

Amlodipine

The safety and efficacy of amlodipine in hypertensive crisis has not been established.

Patients with cardiac failure:

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Patients with hepatic impairment:

The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Elderly patients:

In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).

Patients with renal impairment:

Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.

4.5 Drugs interactions

Olmesartan medoxomil

Other antihypertensive medications:

The blood pressure lowering effect of olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.

ACE-inhibitors, angiotensin II receptor blockers or aliskiren

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent

Potassium supplements and potassium sparing diuretics:

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. Such concomitant use is therefore not recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs):

NSAIDs (including acetylsalicylic acid at doses> 3 g/day and also COX-2 inhibitors) and angiotensin II receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient.

Additionally, concomitant treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy.

Bile acid sequestering agent colesevelam

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered.

Other compounds:

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed. Coadministration of warfarin and digoxin had no effect on the pharmacokinetics of olmesartan.

Effects of olmesartan medoxomil on other medicinal products:

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and angiotensin II antagonists. Therefore, use of olmesartan medoxomil and lithium in combination is not recommended. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Other compounds:

Compounds which have been investigated in specific clinical studies in healthy volunteers include warfarin, digoxin, an antacid (magnesium aluminium hydroxide), hydrochlorothiazide and pravastatin. No clinically relevant interactions were observed and in particular olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Olmesartan had no clinically relevant inhibitory effects on in vitro human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and had no or minimal inducing effects on rat cytochrome P450 activities. Therefore, in vivo interaction studies with known cytochrome P450 enzyme inhibitors and inducers were not conducted, and no clinically relevant interactions between olmesartan and drugs metabolised by the above cytochrome P450 enzymes are expected.

Chlorthalidone

Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Chlorthalidone and related drugs may increase the responsiveness to tubocurarine. Lithium renal clearance is reduced by chlorthalidone, increasing the risk of lithium toxicity. Monitor serum lithium levels during concomitant use.

Amlodipine

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.

Tacrolimus

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic Target of Rapamycin (mTOR) Inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Cyclosporin

No drug interaction studies have been conducted with cyclosporin and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporin were observed.

Consideration should be given for monitoring cyclosporin levels in renal transplant patients on amlodipine, and ciclosporin dose reductions should be made as necessary.

Simvastatin

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

4.6 Use in special populations

Pregnancy

Use of Olbet TRIO is Not recommended in pregnancy.

Breast-feeding

Use of Olbet TRIO is Not recommended in breast-feeding.

4.7 Effects on ability to drive and use machines

Olbet-TRIO can have minor or moderate influence on the ability to drive and use machines.

Dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react. Caution is recommended especially at the start of treatment.

4.8 Undesirable effects

Olmesartan medoxomil

The most commonly reported adverse reactions during treatment with olmesartan are headache (7.7%), influenza-like symptoms (4.0%) and dizziness (3.7%).

In placebo-controlled monotherapy studies, the only adverse drug reaction that was unequivocally related to treatment was dizziness (2.5% incidence on olmesartan medoxomil and 0.9% on placebo).

The incidence was also somewhat higher on olmesartan medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).

The following terminologies have been used in order to classify the occurrence of adverse reactions very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

• Blood and lymphatic system disorders: Thrombocytopenia (Uncommon)
• Immune system disorders: Anaphylactic reaction (Uncommon)
• Metabolism and nutrition disorders: Hypertriglyceridaemia, Hyperuricaemia (Common), Hyperkalaemia (Rare)
• Nervous system disorders: Dizziness, Headache (Common)
• Ear and labyrinth disorders: Vertigo (Uncommon)
• Cardiac disorders: Angina pectoris (Uncommon)
• Vascular disorders: Hypotension (Rare)
• Respiratory, thoracic and mediastinal disorders: Bronchitis, Pharyngitis, Cough, Rhinitis (Common)
• Gastrointestinal disorders: Gastroenteritis, Diarrhoea, Abdominal pain, Nausea, Dyspepsia (Common), Vomiting (Uncommon), Sprue-like enteropathy (Very rare)
• Skin and subcutaneous tissue disorders: Exanthema, Allergic dermatitis, Urticaria, Rash, Pruritus, (Uncommon), Angioedema (Rare)
• Musculoskeletal and connective tissue disorders: Arthritis, Back pain, Skeletal pain, Myalgia, (Uncommon), Muscle spasm (Rare)
• Renal and urinary disorders: Haematuria, Urinary tract infection (common), Acute renal failure, Renal insufficiency (Rare)
• General disorders and administration site conditions: Pain, Chest pain, Peripheral oedema, Influenza-like symptoms, Fatigue (Common), Face oedema, Asthenia, Malaise (Uncommon), Lethargy (Rare)
• Investigations: Hepatic enzymes increased, Blood urea increased, Blood creatine phosphokinase increased (Common), Blood creatinine increased (Rare)

Chlorthalidone

• Hypotension
• Impaired Renal Function
• Electrolyte Abnormalities
• Metabolic Disturbances

(see Warnings and Precautions for more information)

The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency.

• Gastrointestinal System Reactions: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis.
• Central Nervous System Reactions: dizziness, paresthesias, headache.
• Hematologic Reactions: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia.
• Dermatologic-Hypersensitivity Reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis).
• Cardiovascular Reaction: Orthostatic hypotension.
• Other Adverse Reactions: muscle spasm, weakness, restlessness, impotence, xanthopsia.

Amlodipine

The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

The following adverse reactions have been observed and reported during treatment with amlodipine:

• Blood and lymphatic system disorders: Leukocytopenia, thrombocytopenia
• Immune system disorders: Allergic reactions
• Metabolism and nutrition disorders: Hyperglycaemia
• Psychiatric disorders: Depression, mood changes (including anxiety), insomnia, Confusion
• Nervous system disorders: Somnolence, dizziness, headache (especially at the beginning of the treatment), Tremor, dysgeusia, syncope, hypoesthesia, paresthesia, Hypertonia, peripheral neuropathy, Extrapyramidal disorder
• Eye disorders: Visual disturbance (including diplopia)
• Ear and labyrinth disorders: Tinnitus
• Cardiac disorders: Palpitations, Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), Myocardial infarction.
• Vascular disorders: Flushing, Hypotension, Vasculitis
• Respiratory, thoracic and mediastinal disorders: Dyspnoea, Cough, rhinitis.
• Gastrointestinal disorders: Abdominal pain, nausea, dyspepsia, altered bowel habits (including diarrhoea and constipation), Vomiting, dry mouth, Pancreatitis, gastritis, gingival hyperplasia.
• Hepatobiliary disorders: Hepatitis, jaundice, hepatic enzymes increased
• Skin and subcutaneous tissue disorders: Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema, urticaria, Angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity, Toxic Epidermal Necrolysis
• Musculoskeletal and connective tissue disorders: Ankle swelling, muscle cramps, Arthralgia, myalgia, back pain
• Renal and urinary disorders: Micturition disorder, nocturia, increased urinary frequency
• Reproductive system and breast disorders: Impotence, gynaecomastia
• General disorders and administration site conditions: Oedema, Fatigue, asthenia

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

Symptoms:

The most likely effect of Olbet Trio overdosage is hypotension.

The most likely effects of Olmesartan Medoxomil overdosage is hypotension. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension, up to and including shock with fatal outcome, has been reported.

In poisoning due to an overdosage the following signs and symptoms may occur : dizziness, nausea, somnolence, hypovolemia, hypotension and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.

Treatment

In the event of overdosage with Olbet Trio, treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms.

If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of Amlodipine has been shown to reduce substantially the absorption of Amlodipine.

Clinically significant hypotension due to an overdose of Olbet Trio requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous Calcium gluconate may be beneficial in reversing the effects of Calcium channel blockade.

The dialyzability of Olmesartan or Chlorthalidone is unknown. The degree to which Olmesartan and Chlorthalidone are removed by haemodialysis has not been established.

5.1 Mechanism of Action

Olmesartan medoxomil

Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor.

Chlorthalidone

Chlorthalidone is a long-acting oral diuretic with antihypertensive activity. The diuretic effects of chlorthalidone and the benzothiadiazine (thiazide) diuretics appear to arise from similar mechanisms and the maximal effect of chlorthalidone and the thiazides appear to be similar. The site of the action appears to be the distal convoluted tubule of the nephron. Although the mechanism of action of chlorthalidone and related drugs is not wholly clear, sodium and water depletion appear to provide a basis for its antihypertensive effect.

Amlodipine

Amlodipine is a calcium channel blocker that inhibits the transmembrane influx of calcium ions through the potential-dependent L-type channels into the heart and smooth muscle. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth muscle, which leads to a lowering of peripheral resistance and hence of blood pressure.

5.2 Pharmacodynamic properties

Olmesartan medoxomil

The selective antagonism of the angiotensin II (AT1) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

Chlorthalidone

The diuretic action of chlorthalidone commences a mean of 2.6 hours after dosing and continues for up to 72 hours. The drug produces diuresis with increased excretion of sodium and chloride. The diuretic effects of chlorthalidone lead to decreased extracellular fluid volume, plasma volume, cardiac output, total exchangeable sodium, glomerular filtration rate, and renal plasma flow. Chlorthalidone produces dose-related reductions in serum potassium levels, elevations in serum uric acid and blood glucose, and it can lead to decreased sodium and chloride levels.

Amlodipine

In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces an effective reduction in blood pressure in the supine, sitting and standing positions. Chronic use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changing filtration fraction or proteinuria.

5.3 Pharmacokinetic properties

Absorption and distribution

Olmesartan medoxomil

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract.

No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6 %.

The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.

Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed. Olmesartan is highly bound to plasma protein (99.7 %), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound coadministered drugs is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 - 29 L).

Chlorthalidone

Absorption of chlorthalidone following oral dosing is consistent but incomplete (approximately 60%) with peak plasma concentrations occurring about 12 hours after dosing. The chlorthalidone blood levels are consistent and subject to little variability. In the blood, approximately 75% of the drug is bound to plasma proteins over a concentration range of 0.2 to 7.7 ug/mL.

Amlodipine

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The absorption of amlodipine is unaffected by the concomitant intake of food.

Biotransformation and elimination

Olmesartan medoxomil

Total plasma clearance was typically 1.3 L/h (CV, 19 %) and was relatively slow compared to hepatic blood flow (ca 90L/h). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10 - 16 % of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6 %, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40 %) and hepato-biliary excretion (ca 60 %). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.

The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 - 0.7 L/h and was independent of dose.

Chlorthalidone

The mean plasma half-life of chlorthalidone is about 40 to 60 hours. It is eliminated primarily as unchanged drug in the urine.

Amlodipine

The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

6.1 Animal Toxicology or Pharmacology

Olmesartan medoxomil

In chronic toxicity studies in rats and dogs, olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: raised blood urea (BUN) and creatinine (through functional changes to the kidneys caused by blocking AT1 receptors); reduction in heart weight; a reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride.

In both species, increased plasma renin activity and hypertrophy/hyperplasia of the juxtaglomerular cells of the kidney were observed. These changes, which are a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, would appear to have no clinical relevance.

Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro. No relevant effects were observed in several in vivo studies using olmesartan medoxomil at very high oral doses of up to 2000 mg/kg. The overall data of a comprehensive genotoxicity testing suggest that olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use.

Olmesartan medoxomil was not carcinogenic, neither in rats in a 2 year study nor in mice when tested in two 6 month carcinogenicity studies using transgenic models.

In reproductive studies in rats, olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced following exposure to olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats, however, there was no indication of a fetotoxic effect.

Chlorthalidone

Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus due to chlorthalidone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No information is available.

Amlodipine

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

*Based on patient weight of 50 kg

Olbet™ - TRIO tablet contains combination of Olmesartan Medoxomil, Chlorthalidone and Amlodipine.

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT 1 subtype angiotensin II receptor antagonist. Olmesartan medoxomil, USP is described chemically as 2,3-dihydroxy-2-butenyl 4-¬(1-hydroxy-1-methylethyl)-2-propyl-1-[ p-(o-1 H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.

The structural formula for olmesartan medoxomil is:

Chlorthalidone is an antihypertensive/diuretic supplied as 15 mg and 25 mg tablets for oral use. It is a monosulfamyl diuretic that differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is a racemic mixture of 2-chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide.

The structural formula for Chlorthalidone is:

Amlodipine is a Calcium ion influx inhibitor of the Dihydropyridine group (slow channel blocker or calcium ion antagonist). The amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) -1,4-dihydro- 6-methyl- 3,5-pyridine dicarboxylate, monobenzenesulphonate.

The structural formula for amlodipine besylate is:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 blister strips of 10 tablets each

8.4 Storage and handing instructions

Store protected from light & moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

• Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Olbet TRIO during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
• Symptomatic Hypotension: A patient receiving Olbet TRIO should be cautioned that light-headedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs, Olbet TRIO should be discontinued until the physician has been consulted.
• Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of light-headedness and possible syncope

29/11/2024

Amlodipine and Olmesartan Medoxomil Tablets IP

Olbet AM 20

Each film-coated tablet contains:

Amlodipine Besilate IP equivalent to Amlodipine 5 mg

Olmesartan Medoxomil IP 20 mg

Excipients q.s.

Colours: Lake of Quinoline Yellow WS & Titanium Dioxide IP

Olbet-AM 40

Each film-coated tablet contains:

Amlodipine Besilate IP equivalent to Amlodipine 5 mg

Olmesartan Medoxomil IP 40 mg

Excipients q.s.

Colours: Lake of Quinoline Yellow WS & Titanium Dioxide IP

Film-coated tablet.

5mg/20mg and 5mg/40mg

4.1 Therapeutic Indications

Olbet AM 20:

1. For the treatment of mild to moderate hypertension.

Olbet-AM 40:

1. For the treatment of hypertension alone or with other antihypertensive agents
2. To use as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.

4.2 Posology and Method of Administration

Adults

The recommended dosage of Olbet-AM is one tablet per day.

Olbet-AM 5 mg/20 mg may be administered in patients whose blood pressure is not adequately controlled by 20 mg olmesartan medoxomil or 5 mg amlodipine alone.

Olbet-AM 5 mg/ 40 mg may be administered in patients whose blood pressure is not adequately controlled by Olbet-AM 20 mg/5 mg.

A stepwise titration of the dosage of the individual components is recommended before changing to the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered. For convenience, patients receiving olmesartan medoxomil and amlodipine from separate tablets may be switched to Olbet-AM tablets containing the same component doses. Olbet-AM can be taken with or without food.

Older people (age 65 years or over)

No adjustment of the recommended dose is generally required for older people but increase of the dosage should take place with care. Blood pressure should be closely monitored If up titration to the maximum dose of 40 mg olmesartan daily is required.

Renal impairment

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 20 – 60 mL/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group. The use of Olbet-AM in patients with severe renal impairment (creatinine clearance < 20 mL/min) is not recommended. Monitoring of potassium levels and creatinine is advised in patients with moderate renal impairment.

Hepatic impairment

Olbet-AM should be used with caution in patients with mild to moderate hepatic impairment. In patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. As with all calcium antagonists, amlodipine's half life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Olbet-AM should therefore be administered with caution in these patients. Use of Olbet-AM in patients with severe hepatic impairment is contraindicated.

Paediatric population

The safety and efficacy of Olbet-AM in children and adolescents below 18 years has not been established.

Method of administration

The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

4.3 Contraindications

• Hypersensitivity to the active substances, to dihydropyridine derivatives or to any of the excipients
• Second and third trimesters of pregnancy.
• Severe hepatic insufficiency and biliary obstruction.
• The concomitant use of Olbet-AM with aliskiren containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2).

Due to the component amlodipine, Olbet-AM is also contraindicated in patients with:

• Severe hypotension.
• Shock (including cardiogenic shock).
• Obstruction of the outflow tract of the left ventricle (e.g. aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction

4.4 Special Warnings and Precautions for Use

Patients with hypovolaemia or sodium depletion:

Symptomatic hypotension may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, and diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of Olbet-AM or close medical supervision at the start of the treatment is recommended.

Other conditions with stimulation of the renin-angiotensin-aldosterone system:

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system, such as angiotensin II receptor antagonists, has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.

Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation:

When Olbet-AM is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Olbet-AM is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min). There is no experience of the administration of Olbet-AM in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 mL/min).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hepatic impairment:

Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment. Care should be taken when Olbet-AM is administered in patients with mild to moderate hepatic impairment. In moderately impaired patients, the dose of olmesartan medoxomil should not exceed 20 mg. In patients with impaired hepatic function, amlodipine should be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Use of Olbet-AM in patients with severe hepatic impairment is contraindicated.

Hyperkalaemia:

As with other angiotensin II antagonists and ACE inhibitors, hyperkalaemia may occur during treatment, especially in the presence of renal impairment and/or heart failure. Close monitoring of serum potassium levels in at-risk patients is recommended.

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.

Lithium:

As with other angiotensin II receptor antagonists, the concomitant use of Olbet-AM and lithium is not recommended.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy:

Due to the amlodipine component of Olbet-AM, as with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Olbet-AM is not recommended in such patients.

Heart failure:

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the reported incidence of pulmonary oedema was higher in the amlodipine group than in the placebo group. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Sprue-like enteropathy:

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Ethnic differences:

As with all other angiotensin II antagonists, the blood pressure lowering effect of Olbet-AM can be somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Elderly

In the elderly, increase of the dosage should take place with care.

Pregnancy:

Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Other:

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

4.5 Drugs interactions

Potential interactions related to the Olbet-AM combination:

To be taken into account with concomitant use

Other antihypertensive agents:

The blood pressure lowering effect of Olbet-AM can be increased by concomitant use of other antihypertensive medicinal products (e.g. alpha-blockers, diuretics).

Potential interactions related to the olmesartan medoxomil component of Olbet-AM:

Concomitant use not recommended

ACE-inhibitors, angiotensin II receptor blockers or aliskiren:

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.

Medicinal products affecting potassium levels:

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium. If medicinal products, which affect potassium levels, are to be prescribed in combination with Olbet-AM, monitoring of serum potassium levels is recommended.

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II antagonists. Therefore, concomitant use of Olbet-AM and lithium is not recommended. If concomitant use of Olbet-AM and lithium proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs:

When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening of renal function and may lead to an increase in serum potassium. Therefore monitoring of renal function at the beginning of such concomitant therapy is recommended, as well as adequate hydration of the patient.

Bile acid sequestering agent colesevelam:

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered.

Additional information

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.

Potential interactions related to the amlodipine component of Olbet-AM:

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors:

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. There is an increased risk of hypotension. Close observation of patients is recommended and dose adjustment may thus be required.

CYP3A4 inducers:

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other antihypertensive agents.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Cyclosporine: In a prospective study in renal transplant patients, an average 40% increase in trough cyclosporine levels was observed when used concomitantly with amlodipine. The co-administration of Olbet-AM with cyclosporine may increase exposure to cyclosporine. Monitor trough cyclosporine levels during concomitant use and cyclosporine dose reductions should be made as necessary.

4.6 Use in special populations

Pregnancy

There are no data about the use of Olbet-AM in pregnant patients. Animal reproductive toxicity studies with Olbet-AM have not been performed.

Olmesartan medoxomil

The use of angiotensin II antagonists is not recommended during the first trimester of pregnancy. The use of angiotensin II antagonists is contraindicated during the 2nd and 3rd trimesters of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II antagonists therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to angiotensin II antagonists have occurred from the second trimester on, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension.

Amlodipine

Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.

Therefore, Olbet-AM is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.

Breastfeeding

Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk.

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 – 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

During breast-feeding, Olbet-AM is not recommended and alternative treatments with better-established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on Ability to Drive and Use Machines

Olbet-AM can have minor or moderate influence on the ability to drive and use machines.

Dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react. Caution is recommended especially at the start of treatment.

4.8 Undesirable Effects

The most commonly reported adverse reactions during treatment with Olbet AM are peripheral oedema (11.3%), headache (5.3%) and dizziness (4.5%).

The following terminologies have been used in order to classify the occurrence of adverse reactions: Very common (≥ 1/10), Common (≥ 1/100 to <1/10), Uncommon (≥ 1/1,000 to <1/100), Rare (≥ 1/10,000 to <1/1,000), Very rare (<1/10,000), not known (cannot be estimated from the available data)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

Symptoms:

There is no experience of overdose with Olbet-AM. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome has been reported.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Treatment:

If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine.

Clinically significant hypotension due to an overdose of Olbet-AM requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. The dialysability of olmesartan is unknown.

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Angiotensin II antagonists and calcium channel blockers, ATC code C09DB02.

Mechanism of action

Olbet-AM is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a calcium channel blocker, amlodipine besilate. The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

The antihypertensive effect of Olbet-AM was similar irrespective of age and gender, and was similar in patients with and without diabetes.

Olmesartan medoxomil

The olmesartan medoxomil component of Olbet-AM is a selective angiotensin II type 1 (AT1) receptor antagonist. Olmesartan medoxomil is rapidly converted to the pharmacologically active metabolite, olmesartan. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Following once daily administration to patients with hypertension, olmesartan medoxomil produces an effective and smooth reduction in blood pressure over the 24 hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment.

The effect of olmesartan medoxomil on mortality and morbidity is not yet known.

Amlodipine

The amlodipine component of Olbet-AM is a calcium channel blocker that inhibits the transmembrane influx of calcium ions through the potential-dependent L-type channels into the heart and smooth muscle. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth muscle, which leads to a lowering of peripheral resistance and hence of blood pressure.

In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces an effective reduction in blood pressure in the supine, sitting and standing positions. Chronic use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changing filtration fraction or proteinuria.

In haemodynamic studies in patients with heart failure and in clinical studies based on exercise tests in patients with NYHA class II-IV heart failure, amlodipine was found not to cause any clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and clinical signs and symptoms.

5.2 Pharmacokinetic Properties

Olbet-AM

Following oral intake of Olbet-AM, peak plasma concentrations of olmesartan and amlodipine are reached at 1.5 – 2 h and 6 – 8 hours, respectively. The rate and extent of absorption of the two active substances from Olbet-AM are equivalent to the rate and extent of absorption following intake of the two components as separate tablets. Food does not affect the bioavailability of olmesartan and amlodipine from Olbet-AM.

Olmesartan medoxomil

Absorption and distribution:

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract. No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%.

The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.

Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.

Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound coadministered active substances is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 – 29 L).

Biotransformation and elimination:

Total plasma clearance of olmesartan was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10% – 16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40%) and hepato-biliary excretion (ca 60%). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.

The terminal elimination half-life of olmesartan is between 10 and 15 hours after multiple oral dosing. Steady state is reached after the first few doses and no further accumulation is evident after 14 days of repeated dosing. Renal clearance is approximately 0.5 – 0.7 L/h and is independent of dose.

Drug interactions

Bile acid sequestering agent colesevelam:

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half-life of olmesartan was reduced by 50 – 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride.

Amlodipine

Absorption and distribution:

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The absorption of amlodipine is unaffected by the concomitant intake of food.

Biotransformation and elimination:

The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Olmesartan medoxomil and amlodipine

Special populations

Paediatric population (age below 18 years):

No pharmacokinetic data in paediatric patients are available.

Elderly (age 65 years or over):

In hypertensive patients, the olmesartan AUC at steady state is increased by ca 35% in elderly people (65 – 75 years old) and by ca 44% in very elderly people (≥ 75 years old) compared with the younger age group (see section 4.2). This may be at least in part related to a mean decrease in renal function in this group of patients. The recommended dosage regimen for elderly people is, however, the same, although caution should be exercised when increasing the dosage.

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly people. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group in this study.

Renal impairment:

In renally impaired patients, the olmesartan AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls.

Amlodipine is extensively metabolised to inactive metabolites. Ten percent of the substance is excreted unchanged in the urine. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable.

Hepatic impairment:

After single oral administration, olmesartan AUC values are 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment is 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC is again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values are similar in hepatically impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. The clearance of amlodipine is decreased and the half-life is prolonged in patients with impaired hepatic function, resulting in an increase in AUC of about 40% – 60%.

6.1 Animal Toxicology or Pharmacology

Based on the non-clinical toxicity profile of each substance, no exacerbation of toxicities for the combination is expected, because each substance has different targets, i.e. the kidneys for olmesartan medoxomil and the heart for amlodipine. In a 3-month, repeat-dose toxicity study of orally administered olmesartan medoxomil/amlodipine combination in rats, and the following changes were observed:

• Decreases in red blood cell count-related parameters and kidney alterations, which may be attributed to the olmesartan medoxomil component.
• Intestinal changes including luminal dilatation and diffuse mucosal thickening in the ileum and colon, which may be related to the amlodipine component.
• Adrenal alterations, such as hypertrophy of the glomerular cortical cells and vacuolation of the fascicular cortical cells, which could be induced by amlodipine.
• Hypertrophy of the mammary gland ducts, possibly induced by the amlodipine component.

These findings suggest that both components of the combination may contribute to specific organ changes, with olmesartan medoxomil primarily affecting blood cells and kidneys, and amlodipine influencing the intestines, adrenals, and mammary glands.

Amlodipine and Olmesartan Medoxomil Tablets provided, as a tablet for oral administration, is a combination of the calcium channel blocker (CCB) amlodipine besylate and the angiotensin II receptor blocker (ARB) olmesartan medoxomil.

The amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate.

Its empirical formula is C₂₀H₂₅CIN₂O₅•C₆H₆O₃S.

The molecular weight of amlodipine besylate is 567.1.

The structural formula for amlodipine besylate is:

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.

The olmesartan medoxomil is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.

Its empirical formula is C₂₉H₃₀N₆O₆.

The molecular weight of olmesartan medoxomil is 558.59.

The structural formula for olmesartan medoxomil is:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

A Blister strip of 10 tablets each.

8.4 Storage and handing instructions

• Store below 30°C. Protected from light & moisture.
• Keep out of reach of children.

Pregnancy: Advise female patients of childbearing age about the consequences of exposure to Amlodipine and Olmesartan Medoxomil Tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.

Lactation: Advise nursing women not to breastfeed during treatment with Amlodipine and Olmesartan Medoxomil Tablets.

Potassium Supplements: Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider.

29/11/2024

Each film coated tablet contains :

Ofloxacin IP 200 mg

Ornidazole IP 500 mg

Excipients q.s

Colours : Tartrazine & Titanium Dioxide IP

The rationale of combination is based on the fact that quinolones and nitroimidazole derivatives act synergistically. Combinations of fluoroquinolones with other antimicrobial agents have been extensively investigated. Combinations of fluoroquinolones with nitroimidazole,show synergy against Enterobacteriaceae and gram-positive bacteria. Combination covers all treatment related aspects and to widen the spectrum of activity of these two agents.

Pharmacodynamics:

Ofloxacin inhibits bacterial DNA synthesis by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV and shows bactericidal action. Ornidazole is a 5-nitroimidazole derivative active against protozoa and anaerobic bacteria. It is converted to reduction products that interact with DNA to cause destruction of the helical DNA structure and strand, leading to a protein synthesis inhibition and cell death in susceptible organisms.

Microbiology:

Ofloxacin

Therapeutic doses of Ofloxacin are devoid of pharmacological effects on the voluntary or autonomic nervous system. According to DIN 58 940, the following limits apply for Ofloxacin : Susceptible (S)≤ 1 mg/L, Intermediate (I) = 2 mg/L, Resistant (R) ≥ 4 mg/L.

Range of acquired bacterial resistance to Ofloxacin is as follows :

Normally susceptible

Aerobic Gram-positive micro-organisms : S. aureus - methicillin-sensitive (0.3-12.6%), S. pyogenes (2-5%)

Aerobic Gram-negative micro-organisms : Acinetobacter spp (0.3-7.3%), Citrobacter spp. (3-15%), Enterobacter spp. (2-13%), E. coli (1-8%), H. influenzae (1%), Klebsiella spp. (1-10%), Moraxella spp. (0-0.2%), Morganella morganii (0-6.9%), N. gonorrhoeae (25%) Proteus spp. (1-15%), Serratia marcescens (2-2.4%)

Others : Chlamydia spp, L. pneumophila

Intermediately susceptible :

Aerobic Gram-positive micro-organisms : S. pneumoniae (70%), Providentia (17.1%)

Aerobic Gram-negative micro-organisms : E. faecalis (50%), P. aeruginosa (20-30%), Serratia spp. (20-40%)

Ornidazole

Ornidazole is effective against Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia (Giardia intestinalis), and also against certain anaerobic bacteria such as Bacteroides and Clostridium spp., Fusobacterium spp., and anaerobic cocci.

INDICATION :

For treatment of diarrhea of mixed infection in adult only

Contraindications:

Normet is contraindicated in the following situations:

• Known hypersensitivity to nitroimidazoles and/or Ofloxacin, any other fluoroquinolone antibacterial, or to any excipients listed in formulation.

• In patients with a history of epilepsy or an existing central nervous system disorder with a lowered seizure threshold.

• In patients with a history of tendon disorders related to fluoroquinolone administration

• Pregnant or breastfeeding women.

• In patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity because they may be prone to hemolytic reactions when treated with quinolone antibacterial agents.

Dosage and Administration :

One tablet of Normet is recommended as twice-daily therapy.

Use in Special Populations

Hepatic impairment

• Ofloxacin should be used with caution in patients with impaired liver function, as liver damage may occur.In patients with liver cirrhosis, the Ornidazole elimination half-life is longer (22 versus 14 hours) and clearance lower (35 versus 51 ml/min) than in healthy subjects. The dosing interval should be doubled in patients with severe hepatic impairment.Hence,Normet should be used with caution in patients with hepatic impairment.

Renal impairment

• Since Ofloxacin is eliminated primarily via the kidneys, the dose should be adjusted in patients with impaired renal function. The pharmacokinetics of Ornidazole is unaltered in renal impairment.

Drug Interactions:

Warnings and Precautions

Ofloxacin

Methicillin-resistant S. Aureus- Ofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to Ofloxacin

Resistance to fluoroquinolones of E. Coli- Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.

Severe bullous reactions- Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur

Tendonitis- If tendinitis is suspected, treatment with Ofloxacin must be halted immediately, and appropriate treatment must be initiated.

Hypersensitivity- Anaphylactic and anaphylactoid reactions can progress to life-threatening shock

Diseases caused by Clostridium difficile- If pseudo-membraneous colitis is suspected, treatment should be discontinued immediately.

Patients with impaired renal function- Since Ofloxacin is eliminated primarily via the kidneys, the dose should be adjusted in patients with impaired renal function

Patients with history of psychotic disorder- Ofloxacin should be used with caution in patients with a history of psychotic disorder or in patients with psychiatric disease.

Patients with impaired liver function- Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop

Patients treated with vitamin K antagonists- Coagulation tests should be monitored when these drugs are given concomitantly

Myasthenia gravis- not recommended in patients with a known history of myasthenia gravis.

Superinfection- If secondary infection occurs during therapy, appropriate measures be taken

Prevention of photosensitisation- patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays for 48 hours following treatment

QT interval prolongation- Caution with known risk factors for prolongation of the QT interval.

Dysglycaemia- Careful monitoring of blood glucose is recommended.

Peripheral neuropathy- Ofloxacin should be discontinued if the patient experiences symptoms of neuropathy

Interference with laboratory tests- In patients treated with Ofloxacin, determination of opiates or porphyrin levels in urine may give false-positive results.

Vision disorders- If vision becomes impaired, an eye specialist should be consulted immediately

ORNIDAZOLE

Caution should be exercised in patients with diseases of the CNS, e.g. epilepsy or multiple sclerosis. The effect of other medicines can be intensified or impaired.

Adverse Effects :

Ofloxacin

Frequencies are defined using the following convention: uncommon (≥ 1/1,000, < 1/100), rare (≥

1/10,000, < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available

data). * postmarketing experience

Stevens-Johnson syndrome / Toxic epidermal necrolysis is reported adverse drug reaction

associated with the use of Ofloxacin.

Blood and lymphatic system disorders : Very rare- Anaemia, Haemolytic anaemia, Leucopenia,

Eosinophilia, Thrombocytopenia, Not known- Agranulocytosis, Bone marrow failure, Pancytopenia

Immune system disorders : Rare- Anaphylactic reaction*, Anaphylactoid reaction*, Angioedema,

Very rare- Anaphylactic shock*, Anaphylactoid shock

Metabolism and Nutrition disorders : Rare- Anorexia, Not known- Hypoglycaemia in diabetics

treated with hypoglycaemic agents, Hyperglycaemia, Hypoglycaemic coma

Psychiatric disorders : Uncommon- Agitation, Sleep disorder, Insomnia, Rare- Psychotic disorder

(for e.g. hallucination), Anxiety, Confusional state, Nightmares, Depression, Not known-

Psychotic disorder and depression with self-endangering behaviour including

suicidal ideation or suicide attempt, Nervousness

Nervous system disorders : Uncommon- Dizziness, Headache, Rare- Somnolence, Paraesthesia,

Dysgeusia, Parosmia, Very rare- Peripheral sensory neuropathy*, Peripheral sensory motor

neuropathy*, Convulsion*,Extra-pyramidal symptoms or other disorders of

muscular coordination, Not known- Tremor, Dykinesia, Ageusia, Syncope

Eye disorders : Uncommon- Eye irritation, Rare- Visual disturbance, Not known- Uveitis

Ear and labyrinth disorders : Uncommon- Vertigo, Very rare- Tinnitus, Hearing loss, Not known-

Hearing impaired

Cardiac disorders : Rare- Tachycardia, Not known- Ventricular arrhythmias and torsades de

pointes, ECG QT prolonged

Vascular disorders : Rare- Hypotension

Respiratory, thoracic and mediastinal disorders : Uncommon- Cough, Nasopharyngitis, Rare-

Dyspnoea, Bronchospasm, Not known- Allergic pneumonitis, Severe dyspnoea

Gastrointestinal disorders : Uncommon- Abdominal pain, Diarrhoea, Nausea, Vomiting, Rare-

Enterocolitis, sometimes haemorrhagic, Very rare- Pseudomembranous colitis*, Not known-

Dyspepsia, Flatulence, Constipation, Pancreatitis

Hepatobiliary disorders : Rare- Hepatic enzymes increased (ALAT, ASAT, LDH, gamma-GT and/or

alkaline phosphatase), Blood bilirubin increased , Very rare- Jaundice cholestatic, Not known-

Hepatitis, which may be severe*, Severe liver injury, including cases with

acute liver failure, sometimes fatal, have been reported with Ofloxacin, primarily in patients

with underlying liver disorders

Skin and subcutaneous tissue disorders : Uncommon- Pruritus, Rash, Rare- Urticaria, Hot

flushes, Hyperhidrosis Pustular rash, Very rare- Erythema multiforme, Toxic epidermal

necrolysis, Photo-sensitivity reaction, Drug eruption, Vascular purpura, Vasculitis, which

can lead in exceptional cases to skin necrosis,Stevens-Johnson syndrome, Acute generalised

exanthemous pustulosis, Drug rash, Stomatitis, Exfoliative dermatitis

Musculoskeletal and connective tissue disorders : Rare- Tendonitis, Very rare- Arthralgia,

Myalgia, Tendon rupture (e.g. Achilles tendon) which may occur within 48 hours of treatment

start and may be bilateral, Not known- Rhabdomyolysis and/or Myopathy, Muscle

tear, Muscle rupture, Ligament rupture, Arthritis

Renal and urinary disorders : Rare- Serum creatinine increased, Very rare- Acute renal failure,

Not known- Acute interstitial nephritis

Congenital, familial and genetic disorders : Not known- Attacks of porphyria in patients with

porphyria

General disorders and administration site conditions : Not known- Asthenia, Pyrexia, Pain

(including pain in back, chest and extremities)

Diseases of the Vascular and Lymph System Rare : leucopaenia

Nervous System Disorders - Very rare : somnolence, headache, dizziness, tremor, rigidity, coordination impairments, seizures, fatigue, vertigo, temporary loss of consciousness and sensory or mixed peripheral neuropathy.

Gastrointestinal Disorders Uncommon : nausea, vomiting, diarrhoea, epigastric discomfort, dry mouth, loss of appetite. Rare: impairment of the sense of taste

Hepatobiliary Diseases Unknown : jaundice, abnormal liver function tests Skin and subcutaneous tissue diseases Rare: pruritus and skin reactions

Ofloxacin

Symptoms : The most important signs to be expected following acute overdose are CNS symptoms such as confusion, dizziness, impairment of consciousness and convulsive seizures increases in QT interval as well as gastrointestinal reactions such as nausea and mucosal erosions.

Management : In the case of overdose steps to remove any unabsorbed Ofloxacin e.g. gastric lavage, administration of adsorbants and sodium sulphate, if possible during the first 30 minutes, are recommended; antacids are recommended for protection of the gastric mucosa. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection of gastric mucosa. A fraction of Ofloxacin may be removed from the body with haemodialysis. Peritoneal dialysis and CAPD are not effective in removing Ofloxacin from the body. No specific antidote exists. Elimination of Ofloxacin may be increased by forced diuresis.

Ornidazole

In cases of overdosage, the symptoms mentioned under undesirable effects occur in a more severe form. No specific antidote is known. The administration of diazepam is recommended if cramps occur

Store at a temperature not exceeding 30°C. Protect from moisture

Keep out of reach of children

A blister strip of 10 tablets.

Ofloxacin & Metronidazole Suspension

Each 5 ml contains :

Ofloxacin IP    100 mg

Metronidazole Benzoate IP

equivalent to Metronidazole    200 mg

Excipients    q.s.

Colour : Quinoline Yellow WS

In a flavoured syrup base

Suspension, Ofloxacin 100 mg and Metronidazole 200 mg

4.1 Therapeutic indication

For the treatment of diarrhea of mixed infection in adult patients only.

4.2 Posology and method of administration

Dose of Ofloxacin is 15 mg/kg/day and that of Metronidazole is 30 mg/kg/day in two divided doses. Therefore, New Normet suspension containing 100 mg of Ofloxacin and 200 mg of Metronidazole in each 5 ml is an appropriate combination.

Dosage: As advised by the physician.

Geriatric Use

• Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as ofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involves the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.
• In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended. Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage.

Pediatric Use

• Safety and effectiveness in pediatric patients and adolescents below the age of 18 years have not been established. Ofloxacin causes arthropathy (arthrosis) and osteochondrosis in juvenile animals of several species.
• Safety and effectiveness of metronidazole in pediatric patients have not been established, except for the treatment of amebiasis.

4.3 Contraindications

• Patients hypersensitivity to any fluoroquinolone antibacterials.
• Patients having history of epilepsy or tendon disorders or CNS disorder with a lowered seizure threshold should be avoided giving ofloxacin formulation.
• Ofloxacin shall not be prescribed to Adolescent, pregnant or breastfeeding women, since animal experiments do not entirely exclude the risk of damage to the growth-plate cartilage.
• In patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity because they more prone to haemolytic reactions when treated with quinolone antibacterial agents.
• Ofloxacin is not the drug of first choice in pneumonia, caused by Streptococcus pneumoniae or Chlamydia pneumonia, Methicillin resistant S. aureus. Ofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to ofloxacin.
• Metronidazole is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
• In patients with trichomoniasis, metronidazole is contraindicated during the first trimester of pregnancy.
• Use of metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks.
• Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole.

4.4 Special warnings and precautions for use

Ofloxacin

Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitisand Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects:

Fluoroquinolones, including ofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting ofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions. Discontinue ofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

Tendinopathy and Tendon Rupture: Fluoroquinolones, including ofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages. Discontinue ofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Peripheral Neuropathy: Fluoroquinolones, including ofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including ofloxacin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible in some patients. Discontinue ofloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ofloxacin, in patients who have previously experienced peripheral neuropathy.

Central Nervous System Effects: Psychiatric Adverse Reactions: Fluoroquinolones, including ofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including toxic psychoses or hallucinations; agitation; delirium, confusion, disorientation, or disturbances in attention; nervousness or restlessness, memory impairment. If these reactions occur in patients receiving ofloxacin, the drug should be discontinued and appropriate measures instituted.

Central Nervous System Adverse Reactions: Fluoroquinolones have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pseudotumor cerebri), lightheadedness, or tremors.The effects of ofloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, ofloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures.

Exacerbation of Myasthenia Gravis: Fluoroquinolones, including ofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis.Avoid ofloxcain in patients with known history of myasthenia gravis.

The safety and efficacy of ofloxacin in pediatric patients and adolescents (under the age of 18 years), pregnant women, and lactating women have not been established.

Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones, including ofloxacin. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. This drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• fever, rash, severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice or any other sign of hypersensitivity and supportive measures instituted.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ofloxacin tablets, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

General:

• Prescribing ofloxacin tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
• Adequate hydration of patients receiving ofloxacin should be maintained to prevent the formation of a highly concentrated urine.
• Administer ofloxacin with caution in the presence of renal or hepatic insufficiency/impairment. In patients with known or suspected renal or hepatic insufficiency/impairment, careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of ofloxacin may be reduced. In patients with impaired renal function (creatinine clearance ≤ 50 mg/mL), alteration of the dosage regimen is necessary.
• Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs.
• As with other quinolones, ofloxacin should be used with caution in any patient with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction).
• A possible interaction between oral hypoglycemic drugs (e.g., glyburide/glibenclamide) or with insulin and fluoroquinolone antimicrobial agents have been reported resulting in a potentiation of the hypoglycemic action of these drugs, sometimes resulting in coma or death. The mechanism for this interaction is not known. If a hypoglycemic reaction occurs in a patient being treated with ofloxacin, discontinue ofloxacin immediately and consult a physician. As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Torsades de pointes

Some quinolones, including ofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving quinolones, including ofloxacin. Ofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine, procainamide), or class III (amiodarone, sotalol) antiarrhythmic agents.

Metronidazole

• Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Metronidazole for more than 10 days is considered to be necessary and patients should be monitored for adverse reactions, such as peripheral or central neuropathy (such as paraesthesia, ataxia, dizziness, convulsive seizures).
• Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.
• Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, the drug should be discontinued.
• Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop taking metronidazole.
• Cases of severe bullous skin reactions such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalised exanthematous pustulosis (AGEP) have been reported with metronidazole. If symptoms or signs of SJS, TEN or AGEP are present, Metronidazole treatment must be immediately discontinued.
• Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of the encephalopathy. Metronidazole should therefore, be administered with caution to patients with hepatic encephalopathy. The daily dosage should be reduced to one third and may be administered once daily.

Psychotic Reaction with Disulfiram

Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks.

Interaction with Alcohol

Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headache, flushing, throbbing headache, rapid heartbeat, palpitation, sweating, thirst, chest pain, lightheadness, blurred vision, dizziness and difficulty in breathing. Rarely more severe reactions may include abnormal heart rhythm, heart attack, heart failure, unconsciousness, convulsions and even death. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole.

Central and Peripheral Nervous System Effects

Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole.

Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy.

Hepatic Impairment

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), a reduced dose of metronidazole is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events.

Renal Impairment

Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended.

Fungal Superinfections

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candidacidal agent.

Use in Patients with Blood Dyscrasias

Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.

Drug-Resistant Bacteria and Parasites

Prescribing metronidazole in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites.

4.5 Drugs interactions

Ofloxacin

Antacids, Sucralfate, Metal Cations, Multivitamins

Quinolones form chelates with alkaline earth and transition metal cations. Administration of quinolones with antacids containing calcium, magnesium, or aluminum, with sucralfate, with divalent or trivalent cations such as iron, or with multivitamins containing zinc or with didanosine, may substantially interfere with the absorption of quinolones resulting in systemic levels considerably lower than desired. These agents should not be taken within the two-hour period before or within the twohour period after ofloxacin administration.

Caffeine

Interactions between ofloxacin and caffeine have not been detected.

Cimetidine

Cimetidine has demonstrated interference with the elimination of some quinolones. This interference has resulted in significant increases in half-life and AUC of some quinolones. The potential for interaction between ofloxacin and cimetidine has not been studied.

Cyclosporine

Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with some other quinolones. The potential for interaction between ofloxacin and cyclosporine has not been studied.

Drugs Metabolized by Cytochrome P450 Enzymes

Most quinolone antimicrobial drugs inhibit cytochrome P450 enzyme activity. This may result in a prolonged half-life for some drugs that are also metabolized by this system (e.g., cyclosporine, theophylline/methylxanthines, warfarin) when co-administered with quinolones. The extent of this inhibition varies among different quinolones.

Non-Steroidal Anti-Inflammatory Drugs

The concomitant administration of a non-steroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of CNS stimulation and convulsive seizures.

Probenecid

The concomitant use of probenecid with certain other quinolones has been reported to affect renal tubular secretion. The effect of probenecid on the elimination of ofloxacin has not been studied.

Theophylline

Steady-state theophylline levels may increase when ofloxacin and theophylline are administered concurrently. As with other quinolones, concomitant administration of ofloxacin may prolong the half life of theophylline, elevate serum theophylline levels, and increase the risk of theophylline-related adverse reactions. Theophylline levels should be closely monitored and theophylline dosage adjustments made, if appropriate, when ofloxacin is co-administered. Adverse reactions (including seizures) may occur with or without an elevation in the serum theophylline level.

Warfarin

Some quinolones have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. Therefore, if a quinolone antimicrobial is administered concomitantly with warfarin or its derivatives, the prothrombin time or other suitable coagulation test should be closely monitored.

Antidiabetic Agents (e.g., insulin, glyburide/glibenclamide)

Since disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concurrently with quinolones and an antidiabetic agent, careful monitoring of blood glucose is recommended when these agents are used concomitantly.

Interaction with Laboratory or Diagnostic

Testing Some quinolones, including ofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specic methods may be necessary.

Metronidazole

Disulfiram

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.

Alcoholic Beverages

Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy.

Warfarin and other Oral Anticoagulants

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When FLAGYL is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored.

Lithium

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.

Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.

Drugs that Inhibit CYP450 Enzymes

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.

Drugs that Induce CYP450 Enzymes

The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.

Drug/Laboratory Test Interactions

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD+ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

4.6 Use in special populations

Pregnancy

• There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
• There are no adequate and well controlled studies of Metronidazole in pregnant women. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the foetus due to metronidazole.

Nursing Mothers

• Because of the potential for serious adverse reactions from ofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
• Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

4.7 Effects on ability to drive and use machines

Since there have been occasional reports of drowsiness/somnolence, impairment of skills, dizziness/vertigo and visual disturbances, which may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery); patients should advised not to drive or operate machinery if these symptoms occur. These effects may be enhanced by alcohol.

4.8 Undesirable effects

Ofloxacin In clinical trials, the following events were considered likely to be drug-related in patients receiving multiple doses of ofloxacin: nausea, insomnia, headache, dizziness, diarrhea, vomiting, rash, pruritus, external genital pruritus in women, vaginitis, dysgeusia.

In clinical trials, the most frequently reported adverse events, regardless of relationship to drug, were: nausea, headache, insomnia, external genital pruritus in women, dizziness, vaginitis, diarrhea, vomiting. In clinical trials, the following events, regardless of relationship to drug, occurred in 1 to 3% of patients: abdominal pain and cramps, chest pain, decreased appetite, dry mouth, dysgeusia, fatigue, flatulence, gastrointestinal distress, nervousness, pharyngitis, pruritus, fever, rash, sleep disorders, somnolence, trunk pain, vaginal discharge, visual disturbances, and constipation.

Additional events, occurring in clinical trials at a rate of less than 1%, regardless of relationship to drug, were :

The following laboratory abnormalities appeared in ≥1% of patients receiving multiple doses of ofloxacin. It is not known whether these abnormalities were caused by the drug or the underlying conditions being treated.

In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with other quinolones. The relationship of the drugs to these events is not presently established.

Metronidazole

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

Symptoms-The most important signs to be expected following acute overdose are CNS symptoms such as confusion, dizziness, impairment of consciousness and convulsive seizures increases in QT interval as well as gastrointestinal reactions such as nausea and mucosal erosions.

Management-In the case of overdose steps to remove any unabsorbed ofloxacin e.g. gastric lavage, administration of adsorbants and sodium sulphate, if possible during the first 30 minutes, are recommended; antacids are recommended for protection of the gastric mucosa. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection of gastric mucosa. No specific antidote exists. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.

5.1 Mechanism of Action

Ofloxacin inhibits bacterial DNA replication by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV. The nitro group of metronidazole acts as electron acceptor and is thus reduced to a chemically reactive drug form. This produces biochemical lesions in the cells, thus causing death. The major site of action is believed to be DNA, where it causes loss of the helical structure and inhibits synthesis.

5.2 Pharmacodynamic properties

Ofloxacin

Therapeutic doses of ooxacin are devoid of pharmacological effects on the voluntary or autonomic nervous system. According to DIN 58 940, the following limits apply for ofloxacin:

Susceptible (S)≤ 1 mg/L, Intermediate (I) = 2 mg/L, Resistant (R) ≥ 4 mg/L.

Range of acquired bacterial resistance to ofloxacin is as follows:

Normally susceptible

Aerobic Gram-positive micro-organisms: S. aureus - methicillin-sensitive (0.3-12.6%), S. pyogenes (2-5%)

Aerobic Gram-negative micro-organisms: Acinetobacter spp (0.3-7.3%), Citrobacter spp. (3-15%), Enterobacter spp. (2-13%), E. coli (1-8%), H. influenzae (1%), Klebsiella spp. (1-10%), Moraxella spp. (0-0.2%), Morganella morganii (0- 6.9%), N. gonorrhoeae (25%) Proteus spp. (1-15%), Serratia marcescens (2-2.4%)

Others: Chlamydia spp, L. pneumophila

Intermediately susceptible

Aerobic Gram-positive micro-organisms: S. pneumoniae (70%), Providentia (17.1%)

Aerobic Gram-negative micro-organisms: E. faecalis (50%), P. aeruginosa (20-30%), Serratia spp. (20-40%)

Metronidazole

A potential for development of resistance exists against metronidazole. Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efux pumps, inactivation of the drug, and/or increased DNA damage repair.

Activity in Vitro and in Clinical Infections

• Gram-positive anaerobes: Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species.
• Gram-negative anaerobes: Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Fusobacterium species.

Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC’s) of 8 mcg/mL or less against most (≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

• Gram-negative anaerobes: Bacteroides fragilis group (B. caccae, B. uniformis), Prevotella species (P. bivia, P. buccae, P. disiens)

5.3 Pharmacokinetic properties

6.1 Animal toxicology or pharmacology

Ofloxacin

Preclinical effects in conventional studies of safety pharmacology, acute toxicity, repeated dose toxicity, reproductive studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Joint toxicity was observed at exposure in the human therapeutic range in juvenile rats and dogs. Ofloxacin exhibits a neurotoxic potential and causes reversible testicular alterations at high doses.

Mutagenicity studies showed no evidence for mutagenicity of ofloxacin. However, like some other quinolones Ofloxacin is phototoxic in animals at exposure in the human therapeutic range. The phototoxic, photomutagenic and photocarcinogenic potential of ofloxacin is comparable with that of other gyrase inhibitors.

Preclinical data from conventional genotoxicity studies reveal no special hazard to humans, carcinogen potential has not been investigated.

Reproduction toxicity

Ofloxacin has no effect on fertility, peri- or postnatal development, and therapeutic doses did not lead to any teratogenic or other embryotoxic effects in animals. Ofloxacin crosses the placenta and levels reached in the amniotic fluid are about 30% of the maximal concentrations measured in maternal serum.

Metronidazole

Metronidazole has been shown to be carcinogenic in the mouse and in the rat following chronic oral administration however similar studies in the hamster have given negative results. Epidemiological studies have provided no clear evidence of an increased carcinogenic risk in humans.

Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole, with some studies reporting mutagenic effects, while others studies were negative.

Ofloxacin is a synthetic broad-spectrum second-generation fluoroquinolone antibacterial agent.

Metronidazole Benzoate is the benzoate ester of metronidazole, a synthetic nitroimidazole derivative with antiprotozoal and antibacterial activities.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A bottle of 60 ml.

8.4 Storage and handling instructions

Store below 25°C. Protect from light. Do not freeze.

Keep out of reach of children.

Shake well before use.

• Your medicine contains Ofloxacin and Metronidazole which belong to a group of medicines called antibacterials.
• Do not take this medicine, if you are allergic to ofloxacin or metronidazole. Signs of an allergic reaction include a rash, itching or shortness of breath.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
• If you have any further questions, ask your doctor or pharmacist

24 June 2024

Tolperisone Hydrochloride & Paracetamol Tablets [150 mg + 325 mg]

Each film coated tablet contains :

Tolperisone Hydrochloride JP 150 mg

Paracetamol IP 325 mg

Excipients q.s.

Colour : Titanium Dioxide IP

Film coated tablet [150 mg + 325 mg]

4.1 Therapeutic indication

Symptomatic treatment of post stroke spasticity associated with pain in adults.

4.2 Posology and method of administration

One tablet three times a day is the recommended dose for adults or as directed by the Physician.

4.3 Contraindications

Myotop P is contraindicated in patients :

• History of hypersensitivity to any component of the product.
• Suffering from myasthenia gravis.
• Pregnancy and Breast-Feeding

4.4 Special warnings and precautions for use

Close monitoring of renal parameters in patients with advanced renal disease is advisable. The combination should be used with caution in patients with peptic ulcer disease, gastrointestinal perforation and bleeding. Caution should be exercised when administering this combination in patients chronically treated with NSAIDs and in patients with anemia. Precautions have to be taken when Myotop P is used together with other muscle relaxants.

At very rare occasions, hypersensitivity reactions can occur (pruritis, erythema, exanthema, dyspnea, angioneurotic edema and anaphylactic shock).

4.5 Drugs interactions

No known drug-drug interaction.

4.6 Use in special populations Pregnancy and lactation

Myotop P cannot be given in pregnancy (in the first three months of pregnancy) and during breast-feeding. It should be used in pregnancy only if the benefit justifies the potential risk to the fetus.

Paediatrics

There are no studies evaluating the efficacy of the combination of Tolperisone and Paracetamol in children.

Geriatrics

Can be used in the elderly.

4.7 Effects on ability to drive and use machines

Studies on the effects on the ability to drive and use machines have not been performed.

4.8 Undesirable effects

It may cause muscular weakness, headache, nausea, vomiting and other abdominal complaints. Rarely hypersensitivity reactions (itching, skin rash,dyspnoea, angioneurotic edema and anaphylactic shock) can occur. Paracetamol is generally well-tolerated, but may cause mild nausea, vomiting, dyspepsia, skin rashes, Fixed Drug Eruption (FDE) and hepatic disturbances.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com By reporting side effects, you can help provide more information on the safety of this medicine

4.9 Overdose

No data on overdosage of this combination. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

5.1 Mechanism of action

Tolperisone is a centrally acting muscle relaxant, reducing the muscle tone.

Paracetamol, a para amino phenol derivative has excellent analgesic, antipyretic activity and has relatively little anti-inflammatory activity

5.2 Pharmacodynamic properties

Tolperisone

Being, centrally acting muscle relaxant, Tolperisone acts at the level of spinal cord by blocking sodium and calcium channels. Tolperisone exerts its spinal reflex inhibitory action predominantly via a pre synaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels. Tolperisone increases the blood supply to skeletal muscles; this action is noteworthy since a muscle contracture may compress the small blood vessels and induce an ischemia leading to release of pain stimulating compounds. Tolperisone causes preferential antinociceptive activity against thermal stimulation that is likely to be attributed to its local anesthetic action. Tolperisone causes muscle relaxation by its action on central nervous system. It also leads to membrane stabilization & has analgesic activity. This muscle relaxation is dose dependant.

Paracetamol

Paracetamol has excellent analgesic and antipyretic activity. However, it has negligible anti-inflammatory and anti-rheumatic properties. Paracetamol has been effectively used as an anti-pyretic, analgesic. The mechanism of action of Paracetamol is still not clearly understood. It does not appear to share with NSAIDs the capacity to inhibit peripheral COX activity. There is currently considerable evidence to support the hypothesis of a central anti-nociceptive effect. Experimental evidence suggests that inhibition of prostaglandin biosynthesis contributes to Paracetamol pharmacological actions. The anti-nociceptive action of Paracetamol may be mediated by inhibition of COX-3.

5.3 Pharmacokinetic properties

No Known animal toxicology data.

Ask the patient to report any adverse events

Not to exceed the stated recommended daily dose

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage and handing instructions Store below 25°C. Protect from light & moisture

Keep out of reach of children.

• Ask the patient to report any adverse events.
• Not to exceed the stated recommended daily dose.

24 February 2023

Tolperisone Hydrochloride & Diclofenac Sodium Extended Release Tablets (450 mg + 100 mg)

Each film coated bilayered extended release tablet contains

Tolperisone Hydrochloride 450 mg

Diclofenac Sodium IP 100 mg

Excipients q.s

Colour: Yellow Oxide of Iron

Film coated bilayered extended release tablet

Tolperisone 450 mg + Diclofenac (100 mg) per tablet

4.1 Therapeutic Indication

For the treatment of Patients with acute muscle/musculoskeletal spasm in adult

4.2 Posology and method of administration

In adults, the recommended dosage is one tablet of Myotop-DSR once daily.

Method of administration: Oral

4.3 Contraindications

• Myotop-DSR is contraindicated in patients with history of hypersensitivity to any component of the product
• In patients suffering from myasthenia gravis
• Pregnancy and lactation

4.4 Special warnings and precautions for use

Precautions

• Close monitoring of renal parameters in patients with advanced renal disease is advisable.
• Myotop-DSR should be used with caution in patients with peptic ulcer disease, gastrointestinal perforation or bleeding, impaired renal or liver functions, blood dyscrasias, and hypersensitivity to aspirin or other NSAIDs.
• Caution should be exercised when administering this combination in patients chronically treated with NSAIDs.
• Precautions have to be taken when Myotop-DSR is used together with other muscle relaxants.
• Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible.

Warning

• Rarely, hypersensitivity reactions can occur (pruritis, erythema, exanthema, dyspnea, angioneurotic edema and in single cases anaphylactic shock).

4.5 Drugs interactions

• Concomitant use of Myotop DSR with aspirin, methotrexate, digoxin, cyclosporin, ACE inhibitors, diuretics, lithium and warfarin is not advocated due to possibility of drug interactions with diclofenac.
• Tolperisone (in Myotop DSR) may enhance the effects of other neuromuscular blocking agents.

4.6 Use in special populations

Pregnancy and lactation

Myotop DSR should not be given during pregnancy and lactation

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Most common side effects include gastrointestinal (GI) upset with abdominal pain, heartburn, nausea, vomiting, diarrhea, dyspepsia, flatulence, GI ulcers, bleeding / perforation and dryness of mouth.

Other less common ADRs are abnormal renal function, edema, elevated liver enzymes, anemia, headaches, fatigue, muscle weakness or transient physical asthenia, dizziness, increased bleeding time, pruritus, rashes, arterial hypotension, hypersensitivity and other skin allergic reactions like skin rash, hives.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

Symptoms:

Symptoms include headache, nausea, vomiting, epigastric pain, gastro-intestinal bleeding, diarrhea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, and occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic Measures: Patients should be treated symptomatically as required. Frequent or prolonged convulsions should be treated with intravenous diazepam. Activated charcoal/gastric lavage should be considered within one hour of ingestion of a potentially toxic amount. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Other measures may be indicated by the patient's clinical condition.

5.1 Mechanism of Action

Being, centrally acting muscle relaxant, tolperisone acts at the level of spinal cord by blocking sodium channels and calcium channels.

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities. The mechanism of action of Diclofenac, like that of other NSAIDs, is related to prostaglandin synthesis inhibition.

5.2 Pharmacodynamic properties

Tolperisone exerts its spinal reflex inhibitory action predominantly via a pre synaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels. Tolperisone increases the blood supply to skeletal muscles; this action is noteworthy since a muscle contracture may compress the small blood vessels and induce ischemia leading to release of pain stimulating compounds. Tolperisone causes preferential antinociceptive activity against thermal stimulation that is likely to be attributed to its local anesthetic action. Tolperisone causes muscle relaxation by its action on central nervous system. It also leads to membrane stabilization & has analgesic activity. This muscle relaxation is dose dependant.

Diclofenac reduces inflammation and by extension reduces nociceptive pain and combats fever.

5.3 Pharmacokinetic properties

6.1 Animal Toxicology or Pharmacology

Tolperisone

Tolperisone is a central myorelaxant with solid non-clinical pharmacological and toxicological background. The non-clinical data support the clinical use of tolperisone in the currently approved indication and posology.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Embryo toxic variations were observed in rats at 500 mg/kg body weight and in rabbits at 250 mg/kg body weight oral doses. These doses are several times higher than the human dose-range.

Diclofenac

Carcinogenesis

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.2 times the maximum recommended human dose [MRHD] of Diclofenac Capsules based on body surface area [BSA] comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.014 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.04 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.

Mutagenesis Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalians in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal aberration studies in Chinese hamsters.

Impairment of Fertility

Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.4 times the MRHD based on BSA comparison) did not affect fertility.

Myotop-DSR is a fixed dose combination of a Tolperisone (centrally acting muscle relaxant) and Diclofenac (NSAID).

Tolperisone

Chemical Name: 2,4'-Dimethyl-3-piperidinopropiophenone monohydrochloride

Molecular Formula: C16H24ClNO

Molecular Weight: 281.82

Diclofenac

Chemical Name: 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, monosodium salt.

Molecular Formula: C14H10Cl2NNaO2

Molecular Weight: 318.14

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

A blister strip of 5 tablets.

8.4 Storage and handing instructions

• Myotop-DSR Tablet helps relieve pain and muscle spasm that may occur due to strains, sprains, and muscle injuries. It is usually used along with rest and physical therapy.
• Advice patients not to take this medicine, if they are allergic to tolperisone hydrochloride and diclofenac sodium. Signs of an allergic reaction include a rash, itching or shortness of breath.
• Tolperisone is contraindicated in patients suffering from myasthenia gravies.
• Pregnancy: Tell female patients MYOTOP®-DSR should not be given during pregnancy and lactation. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.
• Tell the patients if they get any side effects, talk to the doctor. This includes any possible side effects not listed in this leaflet. Advice patients if they have any further questions, ask the doctor or pharmacist.
• Tablet should be swallowed whole & not to be broken, crushed or chewed. Take it with or after food or a glass of milk.
• Do not stop taking it suddenly without talking to your doctor if you've been on it for a long time.
• Take it with food to avoid an upset stomach.

24/06/2024

Each film coated tablet contains :

Fexofenadine Hydrochloride IP 120 mg

Montelukast Sodium IP equivalent to Montelukast 10 mg

Excipients q.s.

Colours : Lake of Quinoline Yellow & Titanium Dioxide IP

Montefex tablets are a combination of Montelukast Sodium and Fexofenadine Hydrochloride.

Montelukast Sodium

Montelukast Sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.

Chemical Name : [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl]phenyl]-3-[2-(1-hydroxy-1- methylethyl)phenyl]propyl] thio]methyl]cyclopropaneacetic acid, monosodium salt.

Molecular Formula : C₃₅H₃₅ClNNaO₃S

Molecular Weight : 608.18

Fexofenadine Hydrochloride

Fexofenadine Hydrochloride is a histamine H1-receptor antagonist.

Chemical Name : (±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α, α-dimethyl benzeneacetic acid hydrochloride.

Molecular Formula : C₃₂H₃₉NO₄•Hcl

Molecular Weight : 538.13

MECHANISM OF ACTION :

Montelukast Sodium

Pharmacotherapeutic group : Other systemic drugs for obstructive airway diseases, Leukotriene receptor antagonists ATC-code : R03D C03

Mechanism of Action

The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early-and late-phase reactions and are associated with symptoms of allergic rhinitis. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor in preference to other airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.

Fexofenadine Hydrochloride

Pharmacotherapeutic group : Antihistamines for systemic use, ATC code: R06A X26

Mechanism of action

Fexofenadine Hydrochloride is a non-sedating H1 antihistamine. Fexofenadine is a pharmacologically active metabolite of terfenadine.

Clinical efficacy and safety

Human histamine wheal and flare studies following single and twice daily doses of Fexofenadine Hydrochloride demonstrate that the medicinal product exhibits an antihistaminic effect beginning within one hour, achieving maximum at 6 hours and lasting 24 hours. There was no evidence of tolerance to these effects after 28 days of dosing. A positive dose-response relationship between doses of 10 mg to 130 mg taken orally was found to exist. In this model of antihistaminic activity, it was found that doses of at least 130 mg were required to achieve a consistent effect that was maintained over a 24 hour period. Maximum inhibition in skin wheal and flare areas were greater than 80%. Clinical studies conducted in seasonal allergic rhinitis have shown that a dose of 120 mg is sufficient for 24 hour efficacy. No significant differences in QTc intervals were observed in seasonal allergic rhinitis patients given Fexofenadine Hydrochloride up to 240 mg twice daily for 2 weeks when compared to placebo. Also, no significant change in QTc intervals was observed in healthy subjects given Fexofenadine Hydrochloride up to 60 mg twice daily for 6 months, 400 mg twice daily for 6.5 days and 240 mg once daily for 1 year, when compared to placebo. Fexofenadine at concentrations 32 times greater than the therapeutic concentration in man had no effect on the delayed rectifier K+ channel cloned from human heart.

PHARMACOKINETICS :

Montelukast Sodium

Absorption

Montelukast is rapidly absorbed following oral administration. For the 10-mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10-mg film-coated tablet was administered without regard to the timing of food ingestion.

Distribution

Montelukast is >99% bound to plasma proteins. The steady-state volume of distribution of Montelukast averages 8-11 liters. Studies in rats with radiolabeled Montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours post dose were minimal in all other tissues.

Biotransformation

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of Montelukast are undetectable at steady state in adults and children. In vitro studies using human liver microsomes indicate that CYP450 3A4, 2A6 and 2C9 are involved in the metabolism of Montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Montelukast do not inhibit CYP450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of Montelukast is minimal.

Elimination

The plasma clearance of Montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabeled Montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of Montelukast oral bioavailability, this indicates that Montelukast and its metabolites are excreted almost exclusively via the bile. In several studies, the mean plasma half-life of Montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of Montelukast is nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg Montelukast, there is little accumulation of the parent drug in plasma (14%).

Special populations

No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because Montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of Montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9). With high doses of Montelukast (20- and 60-fold the recommended adult dose), decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.

Fexofenadine Hydrochloride

Absorption

Fexofenadine Hydrochloride is rapidly absorbed into the body following oral administration, with Tmax occurring at approximately 1-3 hours post dose. The mean Cmax value was approximately 427 ng/ml following the administration of a 120 mg dose once daily.

Distribution

Fexofenadine is 60-70% plasma protein bound.

Biotransformation and elimination

Fexofenadine undergoes negligible metabolism (hepatic or non-hepatic), as it was the only major compound identified in urine and faeces of animals and man. The plasma concentration profiles of Fexofenadine follow a bi-exponential decline with a terminal elimination half-life ranging from 11 to 15 hours after multiple dosing. The single and multiple dose pharmacokinetics of Fexofenadine are linear for oral doses up to 120 mg BID. A dose of 240 mg BID produced slightly greater than proportional increase (8.8%) in steady state area under the curve, indicating that Fexofenadine pharmacokinetics are practically linear at these doses between 40 mg and 240 mg taken daily. The major route of elimination is believed to be via biliary excretion while up to 10% of ingested dose is excreted unchanged through the urine.

Special populations

Studies in special risk groups (older people, renally or hepatically impaired patients) indicate that it is not necessary to adjust the dose of Fexofenadine Hydrochloride in these patients.

Indications :

For treatment of allergic rhinitis in adults only

Dosage and Method of Administration :

Adults (> 15 yrs) : one tablet once daily

Montelukast Sodium

In rare cases, patients on therapy with anti-asthma agents including Montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated. Treatment with Montelukast does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs.

Neuropsychiatric Events

Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking Montelukast. Post-marketing reports with Montelukast use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving Montelukast appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Montelukast if such events occur.

Eosinophilic Conditions

Patients with asthma on therapy with Montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between Montelukast and these underlying conditions has not been established.

Fexofenadine Hydrochloride

As with most new medicinal products there is only limited data in the older people and renally or hepatically impaired patients. Fexofenadine Hydrochloride should be administered with care in these special groups. Patients with a history of or ongoing cardiovascular disease should be warned that, antihistamines as a medicine class have been associated with the adverse reactions, tachycardia and palpitations.

Effects on ability to drive and use machines

On the basis of the pharmacodynamic profile and reported adverse reactions it is unlikely that Fexofenadine Hydrochloride tablets will produce an effect on the ability to drive or use machines. In objective tests, Fexofenadine has been shown to have no significant effects on central nervous system function. This means that patients may drive or perform tasks that require concentration. Montelukast is not expected to affect a patient's ability to drive a car or operate machinery. However, in very rare cases, individuals have reported drowsiness or dizziness. However, in order to identify sensitive people who have an unusual reaction to medicinal products, it is advisable to check the individual response before driving or performing complicated tasks.

Montelukast Sodium

Very common (≥ 1/10) :Upper respiratory infection

Common (≥ 1/100 to < 1/10) : Diarrhoea, nausea, vomiting, Elevated levels of serum transaminases (ALT, AST), Rash, and Pyrexia.

Uncommon (≥1/1,000 to < 1/100) : Hypersensitivity reactions including anaphylaxis, Dream abnormalities including nightmares, insomnia, somnambulism, irritability, anxiety, restlessness, agitation including aggressive behaviour or hostility, depression, Dizziness, drowsiness paraesthesia/hypoesthesia, seizure, Epistaxis, Dry mouth, dyspepsia Bruising, urticaria, pruritus, Arthralgia, myalgia including muscle cramps, Asthenia/fatigue, malaise, oedema.

Rare (≥ 1/10,000 to < 1/1,000) : Increased bleeding tendency, Tremor, Palpitations, Angiooedema,

Very rare(< 1/10,000) : Hepatic eosinophilic infiltration, Hallucinations, suicidal thinking and behaviour (suicidality), Churg-Strauss Syndrome (CSS), Hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury), Erythema nodosum erythema multiforme.

Fexofenadine Hydrochloride

The following frequency rating has been used, when applicable : Very common ≥1/10 ; Common ≥1/100 and <1/10; Uncommon ≥1/1,000 and <1/100; Rare ≥1/10,000 and <1/1,000; Very rare <1/10,000 and not known (frequency cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. In adults, the following undesirable effects have been reported in clinical trials, with an incidence similar to that observed with placebo :

Common

Nervous system disorders : headache, drowsiness, dizziness

Gastrointestinal disorders : Common: nausea

General disorders and administration site conditions

Uncommon : fatigue In adults, the following undesirable effects have been reported in post-marketing surveillance. The frequency with which they occur is not known (can not be estimated from available data) :

Immune system disorders : Hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnoea, flushing and systemic anaphylaxis

Psychiatric disorders : Insomnia, nervousness, sleep disorders or nightmares/excessive dreaming

Cardiac disorders : Tachycardia, palpitations Gastrointestinal disorders : Diarrhoea

Skin and subcutaneous tissue disorders : Rash, urticaria, pruritus

Montelukast Sodium

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interactions studies, the recommended clinical dose of Montelukast did not have clinically important effects on the pharmacokinetics of the following medicinal products : theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/ norethindrone 35/1), terfenadine, digoxin and warfarin. The area under the plasma concentration curve (AUC) for Montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since Montelukast is metabolised by CYP 3A4, 2C8, and 2C9, caution should be exercised, particularly in children, when Montelukast is co-administered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital and rifampicin. In vitro studies have shown that Montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug-drug interaction study involving Montelukast and Rosiglitazone (a probe substrate representative of medicinal products primarily metabolized by CYP 2C8) demonstrated that Montelukast does not inhibit CYP 2C8 in vivo. Therefore, Montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolised by this enzyme (e.g., Paclitaxel, Rosiglitazone, and Repaglinide.) In vitro studies have shown that Montelukast is a substrate of CYP 2C8, and to a less significant extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving Montelukast and Gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased the systemic exposure of Montelukast by 4.4-fold. No routine dosage adjustment of Montelukast is required upon co-administration with Gemfibrozil or other potent inhibitors of CYP 2C8, but the physician should be aware of the potential for an increase in adverse reactions. Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP 2C8 (e.g., Trimethoprim) are not anticipated. Co-administration of Montelukast Sodium and Fexofenadine Hydrochloride with Itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of Montelukast.

Fexofenadine Hydrochloride

Fexofenadine does not undergo hepatic biotransformation and therefore will not interact with other medicinal products through hepatic mechanisms. Co-administration of Fexofenadine Hydrochloride with Erythromycin or Ketoconazole has been found to result in a 2-3 times increase in the level of Fexofenadine in plasma. The changes were not accompanied by any effects on the QT interval and were not associated with any increase in adverse reactions compared to the medicinal products given singly. Animal studies have shown that the increase in plasma levels of Fexofenadine observed after coadministration of Erythromycin or Ketoconazole appears to be due to an increase in gastrointestinal absorption and either a decrease in biliary excretion or gastrointestinal secretion, respectively. No interaction between Fexofenadine and Omeprazole was observed. However, the administration of antacid containing Aluminium and Magnesium Hydroxide gels 15 minutes prior to Fexofenadine Hydrochloride caused a reduction in bioavailability, most likely due to binding in the gastrointestinal tract. It is advisable to leave 2 hours between administration of Fexofenadine Hydrochloride and Aluminium and Magnesium Hydroxide containing antacids

Pregnancy

Montelukast Sodium : Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/fetal development. Limited data from available pregnancy databases do not suggest a causal relationship between Montelukast and Malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.

Fexofenadine Hydrochloride : There are no adequate data from the use of Fexofenadine Hydrochloride in pregnant women. Limited animal studies do not indicate direct or indirect harmful effects with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development.

Montefex Tablets may be used during pregnancy only if it is considered to be clearly essential.

Lactation

Montelukast Sodium : Studies in rats have shown that Montelukast is excreted in milk. It is not known if Montelukast is excreted in human milk.

Fexofenadine Hydrochloride : There are no data on the content of human milk after administering Fexofenadine Hydrochloride. However, when Terfenadine was administered to nursing mothers, Fexofenadine was found to cross into human breast milk. Therefore Montefex Tablets are not recommended for mothers breast-feeding their babies.

Paediatric Use

The safety and effectiveness of Montefex Tablets in paediatric patients have not been established.

Geriatric Use

There is no data on the geriatric use of this combination. However, the following data is available on the individual components :

Montelukast : No overall differences in safety or effectiveness were observed between the elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but the greater sensitivity of some older individuals cannot be ruled out.

Fexofenadine : In subjects aged 65 years and above, the reported clinical experience has not identified differences in responses between the geriatric and younger subjects. This drug is substantially excreted by the kidneys and, hence, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hypersensitivity to the active substance or to any of the excipients.

Overdose

No published data is available on the overdosage of this combination. However, overdosage has been reported with individual component.

Montelukast Sodium

No specific information is available on the treatment of overdose with Montelukast. In chronic asthma studies, Montelukast has been administered at doses up to 200 mg/day to patients for 22 weeks and in short term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences. There have been reports of acute overdose in post-marketing experience and clinical studies with Montelukast. These include reports in adults and children with a dose as high as 1000 mg (approx. 61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdose reports. The most frequently occurring adverse experiences were consistent with the safety profile of Montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity. It is not known whether Montelukast is dialysable by peritoneal- or haemodialysis.

Fexofenadine Hydrochloride

Dizziness, drowsiness, fatigue and dry mouth have been reported with overdose of Fexofenadine Hydrochloride. Single doses up to 800 mg and doses up to 690 mg twice daily for 1 month or 240 mg once daily for 1 year have been administered to healthy subjects without the development of clinically significant adverse reactions as compared with placebo. The maximum tolerated dose of Fexofenadine Hydrochloride has not been established. Standard measures should be considered to remove any unabsorbed medicinal product. Symptomatic and supportive treatment is recommended. Haemodialysis does not effectively remove Fexofenadine Hydrochloride from blood.

Store protected from light & moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

Presentation:

A blister strip of 10 tablets