Efnocar MX 40-25 Tablets

Efonidipine Hydrochloride Ethanolate (IR) & S (-) Metoprolol (PR) Modified Release Tablets [40 mg+25 mg]

Each modified release uncoated bilayered tablet contains :

Efonidipine Hydrochloride Ethanolate 40 mg

(as immediate release)

S (-) Metoprolol Succinate

equivalent to S (-) Metoprolol Tartrate 25 mg

(as prolonged release)

Excipients q.s.

Colour : Iron Oxide Yellow

Tablet Efonidipine Hydrochloride and S (-) Metoprolol Succinate [40 mg + 25 mg]

4.1 Therapeutic indication

It is indicated for the management of hypertension.

4.2 Posology and method of administration

Adult : The usual recommended dose is 1 tablet daily. It may be increased to 2 tablets per day depending upon the blood pressure control.

4.3 Contraindications

• In patients who are hypersensitive to any component of this product
• Severe bradycardia.
• Second or third degree heart block.
• Cardiogenic shock.
• Decompensated cardiac failure.
• Sick sinus syndrome (unless a permanent pacemaker is in place).

4.4 Warning and precautions

Efonidipine

• Should be administered with caution in patients with hepatic impairment
• Dose adjustment may be required in elderly as hypotension can occur
• Efonidipine may worsen clinical condition in patients with sinus bradycardia, sinus arrest or sinus node dysfunction.
• As dizziness can occur due to hypotensive action, one should be careful while operating machines, with aerial work platforms and driving of a motor vehicle.
• Drug should not be stopped abruptly. Discontinuation should be gradual and under supervision of a qualified Physician.

S (-) Metoprolol

• If an asthmatic uses a β-2 agonist when initiating metoprolol treatment, the dose of the β-2 agonist must be controlled and increased if necessary.
• Metoprolol may reduce the effect of diabetes treatment and mask the symptoms of hypoglycemia
• When prescribing metoprolol to patients with a pheochromocytoma, an alpha blocker must be used before initiating treatment and during the metoprolol treatment.
• Metoprolol treatment may possibly mask the symptoms of thyrotoxicosis.
• In patients with Prinzmetal's angina, β1-selective agents should be used with care, because they may increase the number and duration of angina attacks.
• It is not recommended to discontinue β-blocker treatment during a surgical procedure.
• Metoprolol may also increase both the sensitivity to allergens and the severity of anaphylactic reactions. Adrenalin treatment does not always give the desired therapeutic effect in individuals receiving β-blockers.
• Beta blockers may trigger or exacerbate psoriasis. In the case of increasing bradycardia, the dosage should be reduced, or treatment gradually discontinued.

4.5 Drug interactions

Efonidipine

• Other anti-hypertensive agents : Efonidipine enhances the antihypertensive action additively and may produce hypotension and shock. Blood pressure should be monitored regularly to adjust dose of concomitant drugs.
• Cimetidine : Cimetidine inhibits CYP450 enzymes involved in metabolism of CCBs. Blood concentration of Calcium channel antagonists increase leading to higher incidence of side effects (hot flushes).
• Grapefruit juice : Grapefruit juice suppresses enzymes metabolizing Calcium channel antagonists (Cytochrome P450) and reduces the clearance. Thus, there is a possibility that blood concentration of the drug may increase and the anti-hypertensive effect is enhanced.
• Tacrolimus : Efonidipine inhibits metabolic enzymes involved in Tacrolimus metabolism and reduces its clearance. So, increase in blood concentration of Tacrolimus can occur.

S (-) Metoprolol

• The effects of metoprolol and other antihypertensive drugs on blood pressure are usually additive, and care should be taken to avoid hypotension.
• In the case of the concomitant use of calcium antagonists of the verapamil or diltiazem types, an increase in negative inotropic and chronotropic effects can occur.
• Class I-antiarrhythmic and beta-receptor blockers have additive negative inotropic effects, which can result in serious hemodynamic adverse reactions in patients with impaired left-ventricular function.
• Patients treated with amiodarone can develop severe sinus bradycardia during concomitant treatment with metoprolol.
• NSAID-type antiphlogistics counteract the antihypertensive effect of β-receptor blocking agents.
• CYP2D6 inhibitors such as antidepressants (Fluoxetine, Paroxetine or Bupropion), antipsychotics (Thioridazine), antiarrhythmics (Propafenone), antiretrovirals (Ritonavir), antihistamines (Diphenhydramine), antimalarials (Hydroxychloroquine or Quinidine), antifungals (Terbinafine) and cimetidine increase the plasma concentration of metoprolol.
• Digitalis glycosides in connection with beta-receptor blockers, can increase the atrioventricular conduction time and induce bradycardia.
• MAO inhibitors should be used with caution as concomitant administration with beta-blockers may result in bradycardia and an enhanced hypotensive effect. An increase in the plasma concentrations of metoprolol has been observed when the drug was coadministered with an antacid.

4.6 Special populations

Pregnancy

Efonidipine should not be administered to pregnant women and women suspected of being pregnant. It is recommended that metoprolol should not be administered during pregnancy or lactation unless it is considered that the benefit outweighs the possible risk to the fetus/infant. Should therapy with metoprolol be employed, special attention should be paid to the fetus, neonate and breast fed infant for any undesirable effects such as slowing of the heart rate.

There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Beta blockers reduce placental perfusion and may cause fetal death and premature birth. Intrauterine growth retardation has been observed after long-time treatment of pregnant women with mild to moderate hypertension. β-blockers have been reported to cause bradycardia in the fetus and the newborn child; there are also reports of hypoglycemia and hypotension in newborn children.

Lactation

Administration to lactating women should be avoided unless benefit significantly surpasses the risk to the child. Mothers on Efonidipine treatment should avoid breast feeding. The concentration of metoprolol in breast milk is approximately three times higher than the one in the mother's plasma. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the dr ug. Breastfeeding babies should be monitored for signs of β-blocking if nursing mothers are administered with metoprolol.

4.7 Effects on ability to drive and use machines

Efonidipine / S (-) Metoprolol can have influence on the ability to drive and use machines. Dizziness or drowsiness may occasionally occur when taking Efonidipine / S (-) Metoprolol.

4.8 Undesirable effects

In a double blind, comparative phase III clinical trial conducted on 240 patients, 120 patients were on Efnocar MX 40/25 treatment group and were observed for 3 months. Seven patients of this group experienced mild adverse events like headache, vomiting, fever, hypotension, bradycardia and erythema. All the side effects were resolved without sequelae. Other known side effects observed with the individual ingredients of the formulation are mentioned below :

Efonidipine

Common side effects

The common side effects are hot flushes, palpitations, facial flushing and headache. In addition, elevation in serum total cholesterol, ALT (SGPT), AST (SGOT) and BUN may occur

Uncommon side effects

Hepatobiliary disorders : LDH and alkaline phosphatase, Increase in bilirubin.

Renal and urinary disorders : Serum creatinine rise, Proteinuria, Frequent urination.

Blood and lymphatic system disorders : Decreased hemoglobin, Decreased hematocrit, Decreased red blood cells, Eosinophilia, Leukopenia, Thrombocytopenia.

Hypersensitivity : Rash, Itching

Cardiac disorders : Palpitations, Chest pain, Decreased blood pressure, Bradycardia, Tachycardia, Atrial fibrillation, Premature ventricular contraction, Sick sinus syndrome, Atrioventricular junctional rhythm, Atrioventricular block, Shock.

Nervous system disorders : Sluggishness and light-headedness, Drowsiness, Numbness

Gastrointestinal disorders : Nausea, Stomach discomfort, Abdominal pain, Vomiting, Constipation, Diarrhea, Gingival hyperplasia

Ear and labyrinth disorders : Tinnitus

Investigations : Increased CK (CPK), Increased uric acid and hypokalemia, Increased triglycerides

General : Malaise, Sweating, Edema

S (-) Metoprolol

Since S (-) Metoprolol is the racemic isomer of Metoprolol therefore side effects of Metoprolol may be relevant here

Common side effects

The common side effects are functional dyspnea, fatigue, bradycardia, balance disturbances, palpitations, pronounced blood pressure drop and orthostatic hypotension, very rarely with syncope, cold hands and feet, dizziness, headache, nausea, abdominal pain, diarrhea and constipation. headache, vomiting, fever, low blood pressure, decrease in heartbeat and skin redness

Uncommon side effects

Hepatobiliary disorders : Abnormal LFT values

Metabolism and nutrition disorders : Weight gain

Respiratory, thoracic and mediastinal disorders : Bronchospasms, rhinitis

Endocrine disorders: deterioration of latent diabetes mellitus

Cardiac disorders : Temporary exacerbation of symptoms of heart failure, First-degree atrioventricular block,

Precordial pain, Functional heart symptoms, Heart arrhythmia, Conductivity disturbances.

Nervous system disorders : Paresthesia

Psychiatric disorders : Depression, Concentration problems, Drowsiness or insomnia,

Nightmares, Nervousness, Anxiety

Eye disorders : Visual disturbances, Dry or irritated eyes, Conjunctivitis.

Gastrointestinal disorders : Vomiting, Dryness of mouth

Musculoskeletal and connective tissue disorders : Muscle spasms

General disorders and administration site conditions : Oedema

Reporting of suspected adverse reactions

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

4.9 Overdose

In humans, experience with intentional overdose is limited. Dizziness, nausea, somnolence, hypotension and electrolyte disturbances associated with cardiac arrhythmias, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, asystole, QT-prolongation (isolated cases), poor peripheral perfusion, loss of consciousness (even coma), nausea, vomiting or cyanosis, bronchospasms and muscle spasms are some of the signs and symptoms associated with drug overdose. Respiratory depression, apnea, fatigue, fine tremor, seizures, sweating, paraesthesias, possible oesophageal spasm, hyperglycaemia, hyperkalaemia, renal effects, transient symptoms of myasthenia are other symptoms associated with drug overdose. The symptoms may be exacerbated by concomitant ingestion of alcohol, antihypertensive agents or barbiturates.

Gastric lavage, emesis or activated charcoal should be employed to reduce absorption. Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate. 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. Even apparently well patients who have taken a small overdose should be closely observed for signs of poisoning for at least 4 hours. In case of severe hypotension, bradycardia or in risk of heart failure, the patient could be given a β-1 agonist intravenously at intervals of 2-5 minutes or as continuous infusion until achieving the desired effect. If a selective β-1 agonist is unavailable, dopamine may be used.

5.1 Mechanism of action

Efonidipine, a new generation dihydropyridine (DHP) is a dual Ca2+ channel blocker that blocks both T-type and L-type calcium channels. Apart from being a potent antihypertensive, additional T-type calcium channel inhibition is responsible for its negative chronotropic, renoprotective and cardioprotective effects S (-) Metoprolol antagonizes β-1-adrenergic receptors in the myocardium, thereby reducing the rate and force of myocardial contraction, and consequently a diminished cardiac output. This agent may also reduce the secretion of renin with subsequent reduction in levels of angiotensin II thus decreasing sympathetic activation, including vasoconstriction and aldosterone secretion.

5.2 Pharmacodynamic properties

Efonidipine

Efonidipine blocks both, L and T-type Ca channels and has an excellent clinical profile. Like other dihydropyridine CCBs, Efonidipine exhibits anti-hypertensive action due to the blocking of L-type voltage ++ ++ sensitive calcium channels. These Ca channels mediate the entry of extracellular Ca into vascular ++ smooth muscle in response to electrical depolarization. In both smooth muscle and cardiac myocytes, Ca is a trigger for contraction, albeit by different mechanisms. Apart from being a potent antihypertensive, additional T-type calcium channel inhibition is responsible for its negative chronotropic, renoprotective and cardioprotective effects. Long term therapy with Efonidipine also has protective and reparative effect on the blood vessels.

Efonidipine regulates heart rate (HR) by inhibiting the T-type calcium channels, which are localized primarily in the SA node and are involved in the pacemaker mechanism of the heart. Efonidipine has been reported to have a negative chronotropic effect, which may be involved in controlling tachycardia. Unlike the conventional types of calcium antagonists, Efonidipine potently dilates both afferent and efferent arterioles. It leads to a reduction in glomerular pressure; this effect may be a favourable one in regard to renoprotection. Efonidipine also exhibits reno-protective action in renal impairment or chronic renal parenchymal disease. It has been reported that Efonidipine attenuates proteinuria and serum aldosterone level to a great extent in comparison to amlodipine

S (-) Metoprolol

Metoprolol is a cardioselective β-adrenergic blocking agent. It has a relatively greater blocking effect on β-1-receptors (i.e. those mediating adrenergic stimulation of heart rate and contractility and release of free fatty acids from fat stores) than on β-2-receptors, which are chiefly involved in broncho and vasodilation. Clinical pharmacology studies have confirmed the β-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia. The relative β-1-selectivity of metoprolol has been confirmed by the following : (1) in normal subjects, metoprolol is unable to reverse the β-2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective β-blockers, which completely reverse the vasodilating effects of epinephrine; (2) in asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a nonselective β-blocker, propranolol, at equivalent β1-receptor blocking doses. S (-) Metoprolol is the chirally pure enantiomer. It is known to exhibit greater affinity and higher β-1 receptor blocking activity than the R isomer with S: R activity ratio being 33:1. The β-1 receptor affinity of S (-) Metoprolol is 500 times greater than that of R (-) Metoprolol.

5.3 Pharmacokinetic properties

Absorption and distribution

Peak plasma concentration of Efonidipine is achieved in about 1.5 - 3.67 h after administration. The bioavailability of Efonidipine is ~ 25% and half-life is ~4h. The dissociation constant of Efonidipine from DHP receptors is very low (0.0042/min/nm), signifying very low dissociation from receptors. This causes long duration of action of Efonidipine.

Metoprolol is completely absorbed after an oral dose, peak plasma concentrations occurring 1.5 - 2 hours after dosing. Concomitant intake of food increases bioavailability to approximately 70%. Peak plasma-metoprolol concentrations at steady state with usual doses have been reported as 20 - 340 ng/ml. Only a small fraction of metoprolol (approx. 5 - 10%) binds to plasma proteins. Metoprolol is widely distributed; it crosses the blood-brain barrier, crosses the placenta, and is found in breast milk.

Metabolism

Efonidipine is primarily metabolized in liver. The important metabolites are N-dephenylated Efonidipine (DPH), deaminated Efonidipine (AL) and N-debenzylated Efonidipine (DBZ). DBZ and DPH exhibit activity as calcium antagonists.

Metoprolol is extensively metabolized in the liver; O-dealkylation followed by oxidation and aliphatic hydroxylation. The rate of hydroxylation to α-hydroxymetoprolol is reported to be determined by genetic polymorphism; the half-life of metoprolol in fast hydroxylators is stated to be 3 - 4 hours, whereas in poor hydroxylators it is about 7 hours.

Elimination

Biliary route is the main pathway of excretion of Efonidipine. Only 1.1% of the dose was excreted as deaminated Efonidipine and 0.5% as a pyridine analogue of deaminated Efonidipine in urine collected for 24 h after oral dosing.

The metabolites of metoprolol are excreted in the urine (> 95%) together with only small amounts of unchanged metoprolol. The elimination half-life of metoprolol in plasma is 3.5 hours on average (interval 1 - 9 hours). Total clearance is ~ 1 L/min. Metoprolol is excreted in breast milk.

6.1 Animal toxicology or pharmacology

No known animal toxicology data

8.1 Incompatibilities

Not applicable

8.2 Shelf life

24 Months

8.3 Packaging information

Alu-Alu blister strip of 10 tablets

8.4 Storage and handing instructions

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

Keep out of reach of children. Tablet should be swallowed whole & not to be broken, crushed or chewed

Do not use Efnocar MX if you are allergic to Efonidipine or S (-) Metoprolol. While you are taking Efnocar MX, do not stop taking your other prescription medicines, including any other blood pressure medicines, without talking to your doctor. If you took too much Efnocar MX, call your doctor or Poison Control Centre, or go to the nearest hospital emergency room right away. Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies.

Tell your doctor if you

• Ever had heart disease
• Ever had liver problems
• Are pregnant, or plan to become pregnant.
• Are breastfeeding. Do not breastfeed while taking Efnocar MX. You can stop breastfeeding or take a different medicine.
• Heart failure patients (if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath).

Patients should be advised

• To avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy with Efnocar MX tablets has been determined.
• To contact the Physician if any difficulty in breathing occurs
• To inform the physician or dentist before any type of surgery that he or she is taking Efnocar MX tablets.