Lactitol Monohydrate Syrup 66.67% w/v

Each 15 ml syrup contains:

Lactitol Monohydrate USP 10 g

Benzoic Acid USP 0.0225 g

Syrup

10 g/15ml in 100/200 ml bottles

4.1 Therapeutic indications

Gutclear® Syrup is indicated for treatment of chronic constipation and prevention of hepatic encephalopathy.

4.2 Posology and method of administration

In the treatment of constipation, the recommended dose of Gutclear® Syrup is as follows

Adults:

The recommended adult dosage of Gutclear® Syrup is 30 ml (20 grams) orally once daily, preferably with meals.

Reduce the dosage to 15 ml (10 grams) once daily for persistent loose stools.

Pediatrics: 250-400 mg/kg/day

Gutclear® Syrup is given as a single dose with the morning or evening meal, subsequently adjusted to produce one stool daily.

In the treatment of hepatic encephalopathy, Gutclear® Syrup is given in usual oral doses of 500 to 700 mg/kg daily in 3 divided doses at meal times. The dose is subsequently adjusted to produce 2 soft stools daily.

Administration Instructions

Doses should be mixed with food or liquid, and it is recommended to drink 1 to 2 glasses of liquid with the meal.

Administer other oral medications at least 2 hours before or 2 hours after Gutclear® Syrup.

4.3 Contraindications

Gutclear® Syrup is contraindicated in:

• Patients with the undiagnosed abdominal pain, colic, bleeding or vomiting
• Patients with intestinal obstruction, ileostomy, colostomy, appendicitis or diverticulitis
• Patients with galactosemia
• Patients hypersensitive to the drug or any other component of the formulation

4.4 Special warnings and precautions for use

• It is suggested that individuals taking Gutclear® Syrup have their fluid and salt (electrolyte) balance monitored regularly especially in elderly patients on long term treatment.
• Treatment with Gutclear® Syrup may cause accumulation of hydrogen in the bowel; patient should be advised to have a thorough bowel cleansing with a non-fermentable solution.

4.5 Interaction with other medicinal products and other forms of interaction

Reduced Absorption of Other Oral Medications Gutclear® Syrup may reduce the absorption of concomitantly administered oral medications. Administer oral medications at least 2 hours before or 2 hours after Gutclear® Syrup [see Dosage and Administration] Gutclear® Syrup should not be administered with other laxatives.

Caution may be exercised in using Gutclear® Syrup with drugs causing potassium loss like loop diuretics.

Gutclear® Syrup can increase digitalis toxicity.

Reduction in acidification effect can be observed if broad spectrum antibacterial agents or antacids are administered along with Gutclear® Syrup.

4.6 Pregnancy and lactation

Pregnancy

Lactitol is minimally absorbed systemically following oral administration, and it is unknown whether maternal use will result in fetal exposure to the drug. Available data from case reports on lactitol use in pregnant women are insufficient to evaluate for any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of lactitol to rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Gutclear® Syrup should be prescribed only if the potential benefits outweigh the risks to the fetus.

Animal Data

Reproduction studies have been performed in pregnant rats at oral doses of lactitol up to 2 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area) and in pregnant rabbits at oral doses up to 1 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area) administered during the period of organogenesis. These studies did not reveal any evidence of harm to the fetus due to lactitol.

In a pre-and postnatal development study in rats, lactitol, administered from gestation day 6 to lactation day 20, did not cause any adverse effect on pre and postnatal development up to 2 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area).

Lactation

There are no data on the presence of lactitol in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Lactitol is minimally absorbed systemically following oral administration. It is unknown whether the minimal systemic absorption of lactitol by adults will result in a clinically relevant exposure to breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Gutclear® Syrup and any potential adverse effects on the breastfed infant from Gutclear® Syrup or from the underlying maternal condition.

No studies are available on the secretion of lactitol in breast milk.

4.7 Effects on ability to drive and use machines

Lactulose has no or negligible influence on your ability to drive safely or use machines.

Undesirable effects

The most commonly observed adverse effects with Gutclear® Syrup are abdominal cramps, distensionor flatulence during the first 10 days of treatment which are likely to disappear after continued administration. The other less frequent side effects are abdominal pain, diarrhoea, nausea and vomiting, anal pruritus, borborygmii or steatorrhea.

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

By reporting side effects, you can help provide more information on the safety of this medicine.

4.8 Overdose

No data on overdosage of Lactitol is available. If a patient consumes large amount of Lactitol, symptoms of abdominal pain and diarrhea may appear. There may also be electrolyte imbalance. There is no specific antidote known for Lactitol over dosage. Gastric lavage may be instituted at the earliest to remove the remnant drug from the stomach. Patient should be treated symptomatically and electrolyte levels should be monitored periodically.

5.1 Pharmacodynamic properties

Mechanism of action

Once ingested, Lactitol is neither hydrolysed nor absorbed in the small intestine. It is passed undigested to the colon and a substantial proportion of orally ingested lactitol becomes substrate for the resident colonic microflora where it is slowly fermented and is converted into short-chain fatty acids (SCFAs). The liberation of short-chain fatty acids causes a fall in pH of the right colon. The fall in pH results in the formation of an acidic media.

The reduction in intra-luminal pH increases the intra-luminal osmolality. This promotes retention of water within the bowel lumen, softening the stool and increasing the bowel volume. Hydration of the gut content and reduction in intra-luminal pH also results in shorter transit time and the establishment of laxation.

Lactitol decreases blood ammonia concentration by inhibiting both the production and the absorption of ammonia by reducing intestinal pH and shortening the residence time of intestinal contents in the intestinal tract and hence improves hepatic encephalopathy. Lactitol also favors the growth of saccharolytic (healthy) bacteria in the gut.

5.2 Pharmacokinetic Properties

Following a single oral dose of 20-gram Lactitol in healthy adult subjects under fed conditions, the mean ± SD peak serum concentration (Cmax) is 776 ± 253 ng/mL, and the mean ± SD area under the curve (AUC) is 6,019 ± 1,771 ng*hr/mL.

Absorption

Lactitol is minimally absorbed systemically following oral administration. The mean ± SD time to reach peak serum concentration (Tmax) is 3.6 ± 1.2 hours following a single oral dose of 20-gram Lactitol in healthy adult subjects under fed conditions.

Effect of Food

Cmax and AUC values increase greater than 2-fold under fasted conditions compared to fed conditions.

Elimination

The mean half-life of lactitol is 2.4 hours.

Excretion

6.1 Preclinical safety data

A perinatal and postnatal study of lactitol, a hepatic encephalopathy drug was conducted in Sprague-Dawley rats. Female rats were given lactitol orally at dose levels of 0 (control), 0.7, 2.65 and 10 g/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats per level were allowed to deliver naturally for postnatal examination of their offspring. The high dose caused diarrhea or soft stool in dams. The high dose suppressed the body weight of dams during the perinatal period. The food consumption of dams decreased in the intermediate and high dose groups. The water consumption of dams increased in the high dose group. The high dose caused enlargement of cecum and increase of weights of cecum in dams. The drug failed to affect the delivery of dams and gestation index. However, high dose caused prolongation of gestation period. Two dams in the high dose group failed to nurse their all newborns during early lactation. The drug did not affect the number of live newborns, birth index, external appearance, body weight, viability index, weaning index, and sex ratio of weanlings. Nor did lactitol have any adverse effect on the postnatal development of the first (F1) generation offspring, such as differentiation, emotionality, motor ability, learning ability or reproductive performance. Nor did lactitol have any adverse effect on the second (F2) generation offspring. The results show that the no-effect dose levels of lactitol are 0.7 g/kg for general toxicity in mother animals, 2.65 g/kg for reproductive function in mother animals, and 10 g/kg for their offspring.

Lactitol is an osmotic laxative for oral use. Lactitol is a simple monosaccharide sugar alcohol. It is a dry, free flowing, white to off-white powder, readily soluble in aqueous solutions. As shown by the structure diagrams, it is an analog of the disaccharide lactulose. Its chemical name is 4-O-β-dGalactopyranosyl-d-glucitol lactitol.

Molecular Formula C₁₂H₂₄O₁₁

Molecular Weight 344.31

Gutclear® Syrup ® (lactitol) for oral solution is available in multi-dose bottles.

8.1 List of excipients

Benzoic Acid and Purified water

8.2 Incompatibilities

Gutclear® Syrup may reduce the absorption of concomitantly administered oral medications. Administer oral medications at least 2 hours before or 2 hours after Gutclear® Syrup

8.3 Shelf life

36 months

8.4 Special precautions for storage

Store below 30°C. Protect from light. Do not freeze

8.5 Nature and contents of container

100 ml or 200 ml filled in amber colour pet bottle of 200 ml with a silver pp cap with ep wad and 15 ml measuring cup. One such pack is placed along with a leaflet in a carton.

8.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Persistent Loose Stools Advise patients to stop Gutclear® Syrup ® Syrup and contact their healthcare provider if they experience persistent loose stools.

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

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

Glutathione tablet

Each film coated tablet contains

Glutathione……………………………………………500 mg

Tablet 500 mg

4.1 Therapeutic indication

• Alcoholic fatty liver
• Alcoholic liver fibrosis
• Alcoholic liver cirrhosis
• Hepatitis

4.2 Posology and method of administration

Adults: One Maxiliv tablet (500 mg) once or twice daily.

4.3 Contraindications

Patients who show hypersensitivity to reduced glutathione.

4.4 Special warnings and precautions for use

• Administer Maxiliv tablet under the supervision of a doctor.
• Keep out of reach of children.
• If unusual symptoms such as eruption, pale face, blood pressure drop, or difficulty in breathing occur during therapy, discontinue the drug immediately.

4.5 Drugs interactions

Vitamin K, Vitamin B12, Calcium pantothenate and antihistamines can affect the bioavailability of glutathione.

4.6 Use in special populations

Pregnancy and Lactation

Maxiliv tablet should not be administered to a pregnant and lactating woman unless clinical benefit outweighs the risks.

Geriatric

Appropriate dose reduction is required during therapy.

4.7 Effects on ability to drive and use machines

It is not known whether Maxiliv Tablet alters the ability to drive. Do not drive if you experience any symptoms that affect your ability to concentrate and react.

4.8 Undesirable Effects

According to the scientific literature, there are no risks or side effects of oral administration glutathione. However, there have been anecdotal reports of transitory increase in flatulence, gastrointestinal irritation which diminishes after several days of consistent use.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

No specific antidote is available for the treatment of glutathione overdosage. Symptomatic treatment should be provided.

5.1 Mechanism of Action/ Pharmacodynamic properties

Glutathione is an extremely important cell protectant which directly quenches reactive hydroxyl free radicals, other oxygen-centered free radicals, and radical centers on DNA and other biomolecules. It is an essential cofactor for many enzymes which require thiol-reducing equivalents, and helps to keep redox-sensitive active sites on enzymes in the necessary reduced state. Higher-order thiol cell systems like metallothioneins, thioredoxins, and other redox regulator proteins are ultimately regulated by reduced form of glutathione (GSH) levels and the ratio of GSH/GSSG (oxidized GSH).

GSH/GSSG balance is crucial for homeostasis, stabilizing the cellular biomolecular spectrum, and facilitating cellular performance and survival. GSH and its metabolites also interface with energetics and neurotransmitter syntheses, through several prominent metabolic pathways. GSH availability down-regulates the pro-inflammatory potential of leukotrienes and other eicosanoids. Recently discovered S-nitroso metabolites, generated in-vivo from GSH and NO (nitric oxide) further diversify GSH’s impact on metabolism.

5.2 Pharmacokinetic properties

A 6-month randomized, double-blinded, placebo-controlled trial of oral GSH (250 or 1,000 mg/day) on GSH levels in blood, erythrocytes, plasma, lymphocytes and exfoliated buccal mucosal cells was conducted in 54 non-smoking adults.

GSH levels in blood increased after 1, 3 and 6 months versus baseline at both doses. At 6 months, mean GSH levels increased 30-35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells in the high-dose group (P < 0.05). GSH levels increased 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P < 0.05). In most cases, the increases were dose and time dependent, and levels returned to baseline after a 1-month washout period. A reduction in oxidative stress in both GSH dose groups was indicated by decreases in the oxidized to reduced glutathione ratio in whole blood after 6 months.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Glutathione (GSH) is a physiological tripeptide- a chain of three amino acid- cysteine, glycine and glutamic acid. It is used for the detoxification of electrophilic metabolites. It is a very efficient free radical scavenger, preventing damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides.

Chemical Name: (2S)-2-Amino-4-[1-(carboxymethyl)carbamoyl-(2R)-2- sulfanylethylcarbamoyl] butanoic acid.

Molecular Formula: C₁₀H₁₇N₃O₆S

Molecular Weight: 307.32 g/mol

8.1 List of excipients

8.2 Incompatibilities

8.3 Shelf life

8.4 Special precautions for storage

• Inform your doctor if you have past or current history of asthma.
• Seek immediate medical attention if you have difficulty in breathing after taking the drug.
• Tell your doctor if you are or planning to become pregnant or are breastfeeding.
• Do not take if allergic to glutathione, milk protein or any of its ingredients.
• Do not take if patients had organ transplantation.
• Avoid if suffering from asthma.
• Do not take if patient is Pregnant and breastfeeding women.

28.11.2024