Valsadex-165/Valsadex-170

Valsartan, amlodipine besilate.

Valsadex-165: Each film-coated tablet contains: Valsartan USP 160 mg, amlodipine besilate BP (eq to amlodipine) 5 mg.
Valsadex-170: Each film-coated tablet contains: Valsartan USP 160 mg, amlodipine besilate BP (eq to amlodipine) 10 mg.

Pharmacology: Pharmacodynamics: Valsartan + Amlodipine combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: Amlodipine belongs to the calcium antagonist class and Valsartan to the angiotensin II (Ang II) antagonist class of medicines. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Amlodipine: The Amlodipine component inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of Amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and blood pressure. Experimental data suggest that Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Following administration of therapeutic doses to patients with hypertension, Amlodipine produces vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of Amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with Amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, Amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse experiences on electrocardiographic parameters were observed.
Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.
Valsartan: Valsartan is an orally active, potent, and specific angiotensin II receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of angiotensin II following AT1 receptor blockade with Valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with cough. In clinical trials where Valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P <0.05) lower in patients treated with Valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9% respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving Valsartan and 19.0% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (P <0.05). Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Administration of Valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Abrupt withdrawal of Valsartan has not been associated with rebound hypertension or other adverse clinical events.
In patients with chronic heart failure (NYHA class II-IV), Valsartan has been demonstrated to significantly reduce hospitalizations in patients with chronic heart failure (NYHA class II-IV). The benefits were greatest inpatients not receiving either an ACE inhibitor or a beta blocker. In post-MI patients, Valsartan has also been shown to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
Pharmacokinetics: Linearity: Valsartan and Amlodipine exhibit linear pharmacokinetics.
Amlodipine: Absorption: After oral administration of therapeutic doses of Amlodipine alone, peak plasma concentrations of Amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution: Volume of distribution is approximately 21 L/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins. Amlodipine crosses the placenta and is excreted into breast milk.
Biotransformation: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Elimination: Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady state plasma levels are reached after continuous administration for 7-8 days. 10% of original Amlodipine and 60% of Amlodipine metabolites are excreted in urine.
Valsartan: Absorption: Following oral administration of Valsartan alone, peak plasma concentrations of Valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23%.
Food decreases the exposure (as measured by AUC) to Valsartan by about 40% and peak plasma concentration (C) by about 50%, although from max about 8 h post dosing plasma Valsartan concentrations are similar for the fed and fasted group. This reduction in AUC, however, is not accompanied by a clinically significant reduction in the therapeutic effect, and Valsartan can therefore be given either with or without food.
Distribution: The steady-state volume of distribution of Valsartan after intravenous administration is about 17 liters indicating that Valsartan is not distributed into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation: Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the Valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t_{½ α<1 h} and t_{½ β} about 9 h). Valsartan is primarily eliminated unchanged in feces (about 83% of dose) and urine (about 13% of dose) mainly as unchanged drug. Following intravenous administration, plasma clearance of Valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The half-life of Valsartan is 6 hours.
Valsartan/Amlodipine: Following oral administration of Amlodipine + Valsartan peak plasma concentrations of Amlodipine + Valsartan are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption of Amlodipine + Valsartan are equivalent to the bioavailability of Valsartan and amlodipine when administered as individual tablets.
Special populations: Geriatric patients: 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 patients.
Systemic exposure to Valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to have any clinical significance
Renal impairment: The pharmacokinetics of Amlodipine is not significantly influenced by renal impairment. There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to Valsartan in patients with different degrees of renal impairment.
Patients with mild to moderate renal impairment may therefore receive the usual initial dose.
Hepatic impairment: Patients with hepatic impairment have decreased clearance of Amlodipine with resulting increase in AUC of approximately 40-60%. On average, in patients with mild to moderate chronic liver disease exposure (measured by AUC values) to Valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Care should be exercised in patients with liver disease.

Treatment of essential hypertension.
Valsartan + Amlodipine (Valsadex-165 and Valsadex-170) may be used as initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals. The choice of Valsartan + Amlodipine (Valsadex-165 and Valsadex-170) as initial therapy for hypertension should be based on an assessment of potential benefits and risks.

Posology: The recommended dose of Valsartan and Amlodipine Tablet is one tablet per day.
Valsartan and Amlodipine Tablet 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 Tablet 5 mg/160 mg.
Valsartan and Amlodipine Tablet 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 tablet/capsule may be switched to Valsartan and Amlodipine Tablet containing the same component dose.
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 Tablet is contraindicated in patients with severe hepatic impairment.
Caution should be exercised when administering Valsartan and Amlodipine Tablet to patients with hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is80 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 Tablet, 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 Tablet, the lowest available dose of Amlodipine monotherapy or of the Amlodipine component, respectively, should be used.
Pediatric population: The safety and efficacy of Valsartan and Amlodipine Tablet 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 Tablet with some water.
Or as prescribed by the physician.

Symptoms: There is no experience of overdose with Valsartan and Amlodipine Tablet. 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 Tablet 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 Tablet 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 Tablet 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 Tablet or close medical supervision at the start of treatment is recommended.
If hypotension occurs with Valsartan and Amlodipine Tablet, 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.
Hyperkalemia: 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 under taken with caution and with frequent monitoring of potassium levels.
Renal Artery Stenosis: Valsartan and Amlodipine Tablet 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 Tablet 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 Tablet 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 Tablet is required for patients with mild to moderate renal impairment (GFR >30mL/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 Tablet 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 insusceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin 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 inpatients 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 Tablet 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 fetus.
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.
Breastfeeding: No information is available regarding the use of Valsartan and Amlodipine Tablet during breastfeeding, therefore Valsartan and Amlodipine Tablet is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

Summary of the safety profile: 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 (Valsartan or Amlodipine) may be potential adverse reactions with Valsartan and Amlodipine Tablet 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Non-steroidal anti-inflammatory drugs (NSAIDs) may antagonise the antihypertensive effect concurrent use with sympathomimetics may reduce the antihypertensive effects.
Potassium-sparing diuretic: 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.

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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