Valsaram

Amlodipine besylate, valsartan.

Valsaram Tablet 5 mg/80 mg: Amlodipine besylate 6.94 mg, Valsartan 80 mg.
Valsaram Tablet 5 mg/160 mg: Amlodipine besylate 6.94 mg, Valsartan 160 mg.
Valsaram Tablet 10 mg/160 mg: Amlodipine besylate 13.87 mg, Valsartan 160 mg.

Pharmacology: Toxicology: In embryonic and fetal toxicity study of rat and animal test performed with rat and marmoset for 13 weeks, there was no toxicological finding which may be considered meaningful in human.
As a result of oral administration in rat for 13 weeks, proventricular inflammation was observed in male administered with over 3/48mg/kg/day but not observed in female rat. These results were not found in any doses of marmoset but colitis was observed upon high dose administration (No influence was found in less than 5/80mg/kg/day). Occurrence of gastrointestinal system adverse reaction observed on drug administration was similar with that observed on single administration in clinical studies.

It is indicated for the treatment of essential hypertension. It may be used as an initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals. The choice of Amlodipine besylate + Valsartan (Valsaram) as an initial therapy for hypertension should be based on an assessment of potential benefits and risks.

The recommended dose is one tablet daily and it can be taken along with water, regardless meal. If possible, it is recommended to take at the same time (i.e. morning) every day. It is also recommended to adjust a dose with individual component (amlodipine or valsartan) before taking this medication however, in case that blood pressure is not controlled by monotherapy of the individual components follows, it can be considered to switch to combination therapy with Amlodipine besylate + Valsartan (Valsaram).
5 mg/80 mg: It is administered to a patient whose blood pressure is not adequately controlled on monotherapy of Amlodipine 5 mg or Valsartan 80 mg.
5 mg/160 mg: It is administered to a patient whose blood pressure is not adequately controlled on monotherapy of Amlodipine 5 mg or Valsartan 160 mg.
10 mg/160 mg: It is administered to a patient whose blood pressure is not adequately controlled on monotherapy of Amlodipine 10 mg or Valsartan 160 mg.
In case of a patient taking Valsartan and Amlodipine concurrently, it can be switched to this medicine (combination medication of which individual active ingredient is same) for the sake of convenience.
Patients with renal impairment: No initial dosage adjustment is required for patients with mild or moderate renal impairment (creatinine clearance ≤10 mL/min) but this medicine should not be administered to patients with severe renal impairment (creatinine clearance ≥10 mL/min) and patients undergoing dialysis. In case of patients with moderate renal impairment, it is recommended to monitor potassium level and creatinine.
Patients with hepatic disorder: In case of patients with mild and moderate hepatic disorder, Valsartan daily dose should not exceed 80 mg. This medicine should not be administered to patient with severe hepatic impairment, with biliary cirrhotic liver and with biliary obstruction-cholestasis.
Elderly over 65 years old: Care should be taken upon dosage increase.
Children: It is not recommended to administer this medicine since safety, and efficacy are not established for children below 18 years old.

No overdosage has been experienced. 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 may occur. Clinically significant hypotension due to the combination of Amlodipine and Valsartan 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 hemodialysis. If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of activated charcoal immediately or up to two hours after ingestion of Amlodipine can significantly decrease Amlodipine absorption.

The combination of Amlodipine and Valsartan is contraindicated in: Patients with hypersensitivity to active ingredients of this medicine and dihydropyridine derivatives.
Pregnant or potentially pregnant female, and lactating women.
Patients with severe renal impairment (creatinine clearance ≤10 mL/min) (no experience in use).
Patients with hepatic insufficiency, biliary cirrhosis or cholestasis.
Co-administration with Aliskiren preparations in patients with diabetes or moderate-severe renal impairment (Glomerular filtration rate <60mL/min/1.73 m²).
Patients with hereditary angioedema or with angioedema history when treating with ACE inhibitor or Angiotensin II receptor blocker.
Patients with idiopathic primary aldosteronism (As renin-angiotensin-aldosterone system is not activated in patients with idiopathic primary aldosteronism, this drug is not medicated).
Patients with severe aortic stenosis.
Shock patients.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy increases fetal and neonatal morbidity and death.
Therefore, when pregnancy is detected, discontinue this medicine as soon as possible. (See Use in Pregnancy & Lactation).

Volume and/or salts depleted patients: In placebo-controlled clinical trials, excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with this medicine. Symptomatic hypotension may occur in patients with activated renin-angiotensin system receiving angiotensin receptor blocker (ARB antagonist) (i.e. volume and/or salts depleted patients taking high doses of diuretics). It is recommended to correct such conditions prior to administration or to closely supervise on initiating treatment with this drug. If hypotension occurs upon drug administration, lay patients down and if necessary, instillate with saline solution. Treatment can be continued after blood pressure is stabilized.
Hyperkalemia: On concomitant therapy with potassium adjuvant, potassium sparing diuretics, salt substitute containing potassium or other drugs (i.e. heparin) which may increase potassium level, attention should be paid and potassium level should be periodically monitored.
Renal artery stenosis: As this drug can increase blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis, or patients with single kidney syndrome who stenosis occurred, it is recommended to monitor in safety aspect.
Kidney transplantation: There is no information which can prove its safety in kidney transplantation patients.
Angioedema: Angioedema (including larynx and glottis swelling) which causes respiratory obstruction and/or swelling of face, mouth and tongue in patients receiving valsartan was reported, some of these patients have experienced angioedema caused by other drugs as same as ACE inhibitors. If angioedema is caused due to this drug, administration should be discontinued immediately and should not be resumed.
Heart failure or myocardial infarction: In general, care should be taken when using calcium channel blockers such as amlodipine to patients with congestive heart failure (NYHA class III or IV stage).
In placebo-control studies (PRAISE-2) with patients with non-ischemic heart failure of NYHA class III or IV, it was reported that amlodipine is associated with increase of pulmonary edema in spite that it remarkably reduces worsening of heart failure. Administration of angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin receptor blocker to patients whose renal function is dependent to activation of renin-angiotensin-aldosterone system is associated with hypouresis and/or progressive azotemia and (rarely) acute renal impairment and/or death. Evaluation on patients after heart failure or myocardial infarction should include renal function evaluation always.
Acute myocardial infarction: Increase of incidence, prevalence period or severity of angina or acute myocardial infarction have been rarely reported in patients (especially, coronary artery disease patients) who start receiving calcium channel blockers (i.e. amlodipine) or increase doses.
Aortic stenosis and mitral stenosis, obstructive cardiomyopathy: As same as any other vasodilators, special care should be taken when treating with amlodipine in patients with aortic or mitral stenosis, or obstructive cardiomyopathy.
Dual renin-angiotensin-aldosterone system (RAAS) blockade: Concomitant therapy with other drugs affecting renin-angiotensin-aldosterone system (RAAS) such as angiotensin receptor blocker (ARB) including Valsartan, ACE inhibitors or Aliskiren is not recommended.
Patients with mild-moderate hepatic impairment (It is adequate not to exceed 80 mg of Valsartan daily dose of this drug components in patients with mild-moderate hepatic impairment).
Valsartan: Since an initial drug administration may cause temporary sudden drop in blood pressure (involved with syncope and decreased consciousness), discontinue drug administration and take an adequate measure in this case. Also, initiate treatment with low dose for the following patients and in case of increasing dose, keep full observation on the patients and slowly increase it: Patients undergoing dialysis; Patients taking diuretics (Especially, as symptomatic hypotension may rarely occur in severe salt- or volume-depleted patients, attention should be paid); Patients under strict salt restriction.
In case of severe salt- or volume-depleted patients due to high doses of diuretics, symptomatic hypotension may rarely arise at the start of treatment. Correction of this condition prior to administration of the combination of amlodipine and valsartan by decreasing diuretic dose. In case of hypotension occurrence, lay patients down and if necessary, instillate with saline solution. Treatment can be continued after blood pressure is stabilized.
Patients with renal artery stenosis: On short term administration to 12 patients with renovascular hypertension involved with second unilateral renal artery stenosis, significant change was not derived in hemodynamics of kidney, serum creatinine and BUN. However, as this drug can increase blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis, it is recommended to monitor in safety aspect. Since this drug may rapidly worsen renal function due to reduction of renal blood flow and decline of glomerular filtration rate in patients with bilateral or unilateral renal artery stenosis, administration should be avoided except for a case that this treatment is unavoidable.
A daily dose of this drug should not exceed 80 mg for patients with mild and moderate hepatic impairment. Since this drug is mostly excreted to bile as an unchanged form and exhibits low clearance in biliary obstructive patients, do not use this drug in such patients. It has been reported that plasma concentration is elevated about 2 times comparing with healthy adults when patients with mild to moderate hepatic impairment administer this drug.
Although this drug decreases blood pressure in most cases of patients after heart failure of myocardial infarction occurrence, it is not necessary to discontinue treatment due to continuous hypotension symptom. When initiating treatment for patients with heart failure or patients after myocardial infarction occurrence, care should be taken.
As a result of renin-angiotensin-aldosterone system inhibition, renal function change is expected in sensitive patients.
Treating with angiotensin-converting enzyme inhibitor (ACE inhibitors) or angiotensin receptor blocker to patients whose renal function is dependent to activation of renin-angiotensin-aldosterone system is associated with hypouresis and/or progressive azotemia and (rarely) acute renal impairment and/or death.
Similar results have been reported in this drug too. Evaluation on patients after heart failure or myocardial infarction should include renal function evaluation always.
Triple therapy of ACE inhibitors, beta blocker and Valsartan are not recommended in patient with heart failure. It is because if beta blocker and ACE inhibitor are concomitantly administered, morbidity and death rates are increased due to heart failure.
In a few patients with heart failure, elevation of BUN, creatinine and potassium level was observed. Such phenomenon is very slight and temporary and may occur mostly in patients with renal injury. Dose decrease of this drug and/or diuretics, and discontinuation should be considered.
As there is a concern that hyperkalemia may be worsened in hyperkalemia patient, administration should be avoided with an exception of inevitability of treatment. Also, serum potassium level should be observed since it may induce hyperkalemia in patients whose serum potassium level easily increases due to renal function disorder and diabetes, etc.
There is no experience in patients receiving kidney transplantation.
Amlodipine: Patients with heart failure: In long term, placebo-control studies (PRAISE-2) with patients with non-ischemic heart failure of NYHA class III or IV, in spite that Amlodipine did not show significant difference in worsening rate of heart failure when compared with placebo, it was associated with increase of pulmonaryedema report.
Patients with hepatic function impairment: As same as all the other calcium antagonists, half-life of Amlodipine was prolonged in patients with hepatic function impairment, and recommendable dose was not established for these patients.
Since gradual hypotensive action is shown even after discontinuation as plasma concentration half-life is long. In case of administering another hypotensive drug after discontinuation, dose and administration interval should be carefully set and administered with care under close medical supervision.
As effect is expressed slowly, effect may not be expected for unstable angina which requires emergency medical treatment.
General Cautions: Caution on driving and operating a machine: A clinical test of influence on driving and operating a machine has not been conducted. It should be considered that dizziness and fatigue may intermittently occur when driving and operating a machine. As same as the other antihypertensive drugs, special care should be taken when driving or operating a machine.
Influence on Clinical Findings: There were only a few patients whose examination value has remarkable changed from basal level among patients with hypertension receiving Valsartan/Amlodipine. Amlodipine/Valsartan concomitant group (5.5%) and Valsartan single group (5.5%) showed higher blood urea nitrogen (BUN) than placebo group (4.5%).
Elevation of hepatic function examination value was occasionally reported upon valsartan administration, it is not high enough to specially monitor clinical findings on patients with essential hypertension taking this drug.
Use in Children: It is not recommended as safety and effectiveness of this drug have not been established in pediatric patients under 18 years old.
Use in the Elderly: When using similar doses both in adults and elderly, excellent tolerability on both components were resulted and therefore, normal dose is recommended.

Due to the mechanism of action of angiotensin II blocker, risk on fetus can't be ruled out. Fetal morbidity and death have been reported in the second and third trimesters of pregnant women who took angiotensin converting enzyme inhibitor (special drug group act on the renin-angiotensin-aldosterone system (RAAS)). And use of ACE inhibitor at the first trimester of pregnancy is associated with potential risk of fetal anomaly. Spontaneous abortion, oligohydramnios and neonatal renal function abnormality have been reported in pregnant women who accidentally took valsartan. Just like other drugs directly action on RAAS, this drug should not be used in case of pregnancy or planning to be pregnant. A medical doctor should explain female with pregnancy potential about potential risk of these drugs during pregnancy when prescribing a drug acting on RAAS. If pregnancy is detected during treatment with this drug, discontinue as soon as possible.
Although human milk secretion of valsartan and/or amlodipine in human has not been known, Valsartan was secreted in rat. Therefore, it is not recommended to use this drug in female in lactation. No clinical study was made on breeding ability in this drug and each single component preparation. Although there is no non-clinical information on breeding ability available, in non-clinical study performed with each Valsartan and Amlodipine separately, no influence on breeding ability was shown.
Others: In embryonic and fetal toxicity study of rat and animal test performed with rat and marmoset for 13 weeks, there was no toxicological finding which may be considered meaningful in human. As a result of oral administration in rat for 13 weeks, proventricular inflammation was observed in male administered with over 3/48mg/kg/day but not observed in female rat. These results were not found in any doses of marmoset but colitis was observed upon high dose administration (No influence was found in less than 5/80mg/kg/day). Occurrence of gastrointestinal system adverse reaction observed on drug administration was similar with that observed on single administration in clinical studies.

5,175 patients participated in clinical trials for safety of this drug which was evaluated from 5 controlled clinical studies on which 2,613 of these patients received Amlodipine and Valsartan concomitantly. Adverse reaction is summarized as very commonly (≥1/10,000, <1/1,000), very rarely (<1/10,000) including single report according to incidence frequency. It is also summarized in order that seriousness of adverse reaction is reduced in groups of same frequency. (See Table 1.)

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Valsartan: See Table 2.

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In no association with causality of drug, following symptoms were reported during the clinical studies: Insomnia, sexual desire disorder, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, virus infection. (See Table 3.)

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Additional information on concomitant therapy: In double-blind, drug or placebo controlled clinical trials, incidence frequency of peripheral edema was statistically low in concomitant therapy group (5.8%) in contrast to amlodipine single therapy (9%).
Additional information on each active ingredient: Although it was not observed in the clinical studies and post marketing surveillance, previously reported adverse reactions of each ingredient may occur.
Amlodipine: In no association with causality of drug, adverse reactions reported at amlodipine clinical studies are as follows: See Table 4.

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Post marketing surveillance: As a result of investigation on 859 patients for 6 years for the purpose of re-evaluation, hazardous case occurrence was reported 5.12% (44 patients, 56 cases) irrespective of causal relationship.
Drug hazardous reaction occurrence of which can't rule out causal relationship with this drug was 1.75% (15 patients, 19 cases) in which occurred headache 0.47% (4 patients, 4 cases), dizziness 0.35% (3 patients, 3 cases), pruritus 0.35% (3 patients, 3 cases), peripheral edema 0.23% (2 patients, 2 cases), hypotension 0.23% (2 patients, 2 cases), each 1 case of edema, chest pain, pain, cough and enuresis. Critical hazardous case was not reported regardless causal relationship with this drug. As unexpected hazardous case, there were reported chest discomfort, reflux esophagitis, neck pain, hypercholesterolemia, hypoglycemia and enuresis, 9 cases in total.
As a result of integrated evaluation of local re-evaluation hazardous cases and voluntary side effect report data of this drug comparing with those of all the other marketed drugs, newly confirmed hazardous cases are as follows out of those statistically significant in comparison with hazardous cases reported from all the other drugs. However, this result does not mean that causal relationship between the corresponding ingredients and the following hazardous cases was proven.
General abnormality: Chest pain, weight gain.
Musculoskeletal system: Arthritis, osteocope, rhabdomyolysis.
Mouth: Gingiva hyperplasia.
Gastrointestinal system: Gastritis.
Psychiatric system abnormality.

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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