Hybip-165/Hybip-170

Valsartan, amlodipine.

Hybip-165: Each film-coated tablet contains: Valsartan USP 160 mg, Amlodipine Besilate BP Eq. to Amlodipine 5 mg.
Hybip-170: Each film-coated tablet contains: Valsartan USP 160 mg, Amlodipine Besilate BP Eq. to Amlodipine 10 mg.
Excipients: Q.S.

Pharmacology: Amlodipine: Inhibits movement of calcium ions across cell membranes in systemic and coronary vascular smooth muscle.
Valsartan: Antagonizes the effect of angiotensin II (vasoconstriction and aldosterone secretion) by blocking the angiotensin II receptor invascular smooth muscle and the adrenal gland, producing decreased BP.

Treatment of essential hypertension.
Valsartan and Amlodipine Tablets is indicated in adults whose blood pressure is not adequately controlled on amlodipine or valsartan monotherapy.

Posology: The recommended dose of Valsartan and Amlodipine Tablets is one tablet per day.
Valsartan and Amlodipine Tablets 10 mg/160 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 10 mg or valsartan 160 mg alone or with Valsartan and Amlodipine Tablets 5 mg/160 mg.
Valsartan and Amlodipine Tablets can be used with or without food.
Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered.
For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be switched to Valsartan and Amlodipine Tablets containing the same component doses.
Renal impairment: There are no available clinical data in severely renally impaired patients.
No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and creatinine is advised in moderate renal impairment.
Hepatic impairment: Valsartan and Amlodipine Tablets is contraindicated in patients with severe hepatic impairment.
Caution should be exercised when administering Valsartan and Amlodipine Tablets to patients with hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment. When switching eligible hypertensive patients with hepatic impairment to amlodipine or Valsartan and Amlodipine Tablets, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used.
Elderly (age 65 years or over): In elderly patients, caution is required when increasing the dosage. When switching eligible elderly hypertensive patients to amlodipine or Valsartan and Amlodipine Tablets, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used.
Paediatric population: The safety and efficacy of Valsartan and Amlodipine Tablets in children aged below 18 years have not been established. No data are available.
Method of administration: Oral use.
It is recommended to take Valsartan and Amlodipine Tablets with some water.

Symptoms: There is no experience of overdose with Valsartan and Amlodipine Tablets. The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Treatment: If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption. Clinically significant hypotension due to Valsartan and Amlodipine Tablets overdose calls for active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of 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.
Both valsartan and amlodipine are unlikely to be removed by haemodialysis.

Hypersensitivity.
Severe hepatic impairment, biliary cirrhosis or cholestasis.
Concomitant use of Valsartan and Amlodipine Tablets with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²).
Second and third trimesters of pregnancy.
Severe hypotension.
Shock (including cardiogenic shock).
Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high grade aortic stenosis).
Haemodynamically unstable heart failure after acute myocardial infarction.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Sodium- and/or volume-depleted patients: Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Valsartan and Amlodipine Tablets in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to administration of Valsartan and Amlodipine Tablets or close medical supervision at the start of treatment is recommended.
If hypotension occurs with Valsartan and Amlodipine Tablets, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.
Hyperkalaemia: 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.
Renal artery stenosis: Valsartan and Amlodipine Tablets should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.
Kidney transplantation: To date there is no experience of the safe use of Valsartan and Amlodipine Tablets in patients who have had a recent kidney transplantation.
Hepatic impairment: Valsartan is mostly eliminated unchanged via the bile. The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Particular caution should be exercised when administering Valsartan and Amlodipine Tablets to patients with mild to moderate hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.
Renal impairment: No dosage adjustment of Valsartan and Amlodipine Tablets is required for patients with mild to moderate renal impairment (GFR >30 ml/min/1.73 m²). Monitoring of potassium levels and creatinine is advised in moderate renal impairment.
Primary hyperaldosteronism: Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their renin angiotensin system is affected by the primary disease.
Angioedema: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients treated with valsartan. Some of these patients previously experienced angioedema with other medicinal products, including ACE inhibitors. Valsartan and Amlodipine Tablets should be discontinued immediately in patients who develop angioedema and should not be re-administered.
Heart failure/post-myocardial infarction: 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 reninangiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function. In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
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.
Aortic and mitral valve stenosis: As with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or significant aortic stenosis that is not high grade.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE inhibitors, ARBs 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, ARBs 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 ARBs should not be used concomitantly in patients with diabetic nephropathy.
Valsartan and Amlodipine Tablets has not been studied in any patient population other than hypertension.
Use in Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Amlodipine: The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses.
Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.
Valsartan: 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 Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension.
Breast-feeding: No information is available regarding the use of Valsartan and Amlodipine Tablets during breast-feeding, therefore Valsartan and Amlodipine Tablets is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Summary of the safety profile: The safety of Valsartan and Amlodipine Tablets has been evaluated in five controlled clinical studies with 5,175 patients, 2,613 of whom received valsartan in combination with amlodipine. The following adverse reactions were found to be the most frequently occurring or the most significant or severe: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, oedema, pitting oedema, facial oedema, oedema peripheral, fatigue, flushing, asthenia and hot flush.
Additional information on the individual components: Adverse reactions previously reported with one of the individual components (amlodipine or valsartan) may be potential adverse reactions with Valsartan and Amlodipine Tablets as well, even if not observed in clinical trials or during the post-marketing period.
Amlodipine: Common: Somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling.
Uncommon: Insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypoesthesia, visual disturbance (including diplopia), tinnitus, hypotension, dyspnoea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, micturition disorder, increased urinary frequency, impotence, gynaecomastia, chest pain, malaise, weight increase, weight decrease.
Rare: Confusion.
Very rare: Leukocytopenia, thrombocytopenia, allergic reactions, hyperglycaemia, hypertonia, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, hepatic enzymes increased*, angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity.
* mostly consistent with cholestasis.
Exceptional cases of extrapyramidal syndrome have been reported.
Valsartan: Not known: Decrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia, increase of serum potassium, elevation of liver function values including increase of serum bilirubin, renal failure and impairment, elevation of serum creatinine, angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Non-steroidal anti-inflammatory drugs (NSAIDs) may antagonise the antihypertensive effect.
Concurrent use with sympathomimetics may reduce the antihypertensive effects.
Potassium-sparing diuretics: may lead to elevation of serum potassium.
Concurrent administration of sublingual nitroglycerin, long-acting nitrates, beta-blockers or other antianginal agents with amlodipine may produce additive antihypertensive and antianginal effects.

Store at temperatures not exceeding 30°C. Protect from light.

Angiotensin II Antagonists / Calcium Antagonists

C09DB01 - valsartan and amlodipine ; Belongs to the class of angiotensin II receptor blockers (ARBs) and calcium channel blockers. Used in the treatment of cardiovascular disease.

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