Empirical formula is: C24H29N5O3
Molecular weight : 435.53
[Appearance]
Hard capsule with white granules and fine powder
[Pharmacology and Toxicology]
Pharmacology:
Valsartan is an orally effective and specific angiotensin II antagonist acting selectively on the AT1receptor subtype. It blocks the binding of angiotensin II to AT1receptor ( valsartan has an affinity of 20,000-fold for the AT1receptor subtype than for the AT2receptor subtype), so as to suppress both vasoconstriction and the release of aldosterone, to produce anti-hypertensive effect. This product does not act on angiotensin-converting enzyme (ACE), renin and other subtype, or block ion channels known to be important in blood pressure regulation and sodium balance. Since this product is not an ACE inhibitor and does not change the body bradykinin level, the incidence of dry cough is less. Valsartan can reduce the already raised blood pressure, but does not affect heart rate. In most patients, after adminstration of a single oral dose, onset of antihypertensive activity occurs at about 2 hours, and peak reduction of blood pressure is achieved within 4 to 6 hours. The antihypertensive effect also persists for 24 hours after dosing. Optimal effect will be obtained after 2-4 weeks of treatment and the effect will be sustained during long-term therapy. The blood pressure lowering effect of valsartan and thiazide-type diuretics are addictive. Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure ( rebound ) or other side effects.
Valsartan does not affect the level of total cholestrol, triglycerides, serum glucose and uric acid.
Toxicology:
Toxicity of repeated dosing: Rats were administered orally with valsartan containing 60, 200 and 600mg/kg for three consecutive months. In the large dosage group, the water intake and urination were slightly increased. Male rats were found to have a slight glomerulus hyperplasia and increase in killer cells. Female rats were found to have hypertrophy in the small artery at the site of glomerular intake. Abnormality is not seen after the end of the recovery period. In both rats with an oral
intake of 200 mg/kg/day of valsartan for 12 consecutive months (a partial of rats had 6 months only) and monkeys with oral intake of 120 mg/kg/day valsartan for 12 consecutive months, no adverse effect was found.
Mutagenesis:
In bacterial mutagenicity tests (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells and a rat micronucleus test , all test were shown to be negative.
Fertility toxicity:
No tetratogenic effect was observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10mg/kg/day. However,significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral dose of 600 mg/kg/day during organogenesis or late gestationand lactation. In rabbits, fetotoxicity (i.e. Resorptions, Litter loss, abortions and low body weight) associated with maternal toxicity mortality) was observed at doses of 5 and 10 mg/kg/day. No adverse effects were observed at doses of 2, 200 and 600 mg/kg/day in mice; ats and rabbits represent 0.1, 6 and 9 times the maximum recommended human dose (calculations assume an oral dose of 320 mg/day and a 60 kg patient).
Carcinogenesis:
There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose (calculations assume an oral dose of 320 mg/kg/day and a 60 kg patient).
[Pharmacokinetics]
Valsartan is quickly absorbed after oral dose. Peak plasma concentration is reached 2 to 4 hours after dosing. The absolute bioavailability for valsartan is about 25% (range 10% - 35 %). Food reduces the area under the valsartan plasma concentration curve (AUC) by 40% and plasma concentration (Cmax) by about 50%. AUC and Cmax values of valsartan increase linearly with increasing dose over the clinical dosing range. Valsartan does not acculumate in plasma folowing repeated administration. The steady state volume of distribution of valsartan after intravenous adminstration is 17L, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum protein (85%), mainly serum albumin. Valsartan is primarily excreted in feces (about 70% of does) and urine (about 30% of dose), mainly as unchanged drug, with only about 20% of dose excreted as metabolites. The primary metabolite, accounting for 9% of dose, is valeryl 4-hydroxy valsartan. Plasma clearance of valsartan is about 2L/h and its renal clearance is 0.62 L/h. Valsartan shows bi-exponential
decay kinetics following intravenous administration, t1 /2 <1 hour, t1 /2 is about 9 hours.
Pharmacokinetics of special clinical situations:
1. Geriatric:Exposure (measured by AUC) to valsartan is higher by 70% and t1/2 is longer by 35% in the elderly (>65 yrs) than in the young. No dosage adjustment is necessary.
2. Gender : Pharmacokinetics of valsartan does not differ significantly between males and females.
3. Renal insufficiency: Since there is about 30% valsartan being excreted in urine, there is no apparent correlation between renal function to valsartan in patients with renal impairment. Hence, dose adjustment is not required in patients with mild-to-moderate renal dysfunction (for severe renal failure, see contraindication). No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10ml/min). Valsartan is not removed from the plasma by hemodialysis. Therefore, in patients with severe renal disease, exercise care with dosing of valsartan.
4. Impaired hepatic function :About 70% of the valsartan is eliminated unchanged in the bile and is not metabolised. The systemic exposure to valsartan is not correlated with the degree of liver dysfunction. No dose adjustment for valsartan is therefore necessary in patients with hepatic insufficiency of nonbiliary origin and without cholestasis. The AUC of valsartan has been observed to approximately double (see precaution) in patients with biliary cirrhosis or biliary obstruction.
[Indication]
Mild-to-moderate hypertension
[Adminstration and Dosage]
The recommended dose of valsartan is 80 mg once daily. Dosage is irrespective of race, age and gender. Valsartan can be taken with food or before meal. It is suggested to take the drug at the same time each day (e.g. breakfast). The antihypertensive effect is present within 2 weeks and maximal effects are seen after 4 weeks. If additional antihypertensive effect is required, the dose may be increased to 160 mg daily or a diuretic drug may be added. No dosage adjustment is required for patients with renal impairment (severe renal failure, see contraindication) and for patients with hepatic insufficiency of nonbiliary origin and without cholestasis. Valsartan can be used in combination with other antihypertensive drugs.
[Adverse Reactions]
Clinical trials indicate that the overall incidence of adverse experiences with valsartan was similar to placebo and was mild. In comparison to an ACE inhibitor, the incidence of dry cough caused by valsartan was less. The major adverse reactions include headache, dizziness, viral infection, upper respiratory infection, diarrhea, fatigue and vertigo. There are rare cases of angioedema, rash, pruritis and other hypersensitivity/allergic reactions including serum sickness and vasculitis. Clinical laboratory test findings showed that some patients may have a decrease in hemoglobin and hematocrit and neutropenia. Occasional elevations of serum creatinine, potassium and total bilirubin and liver function values were found in valsartan-treated patients.
[Contraindications]
Tuoping capsule is contraindicated in patients who are hypersensitive to this medication or any of its ingredients. Patients with severe renal failure (creatinine clearance<10ml/min).
[Precautions]
1. Salt- and/or volume-depletion:
In severely salt- and/or volume-depleted patients (e.g. those receiving high doses of diuretics), symptomatic hypotension may occur in rare cases after initiation therapy with valsartan. Hence, salt- and volume-depletion should be corrected or reducing the diuretic dose before valsartan adminstration. When hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Once the blood pressure has stablized, treatment with valsartan can be continued.
2. Renal artery stenosis :
Short term administration of valsartan to patients with renovascular hypertension secondary to unilateral renal artery stenosis did not find any significant change in renal hemodynamics, serum creatinine or blood urea nitrogen (BUN). Since other drugs that affect the renin-angiotensin-aldosterone system (RAAS) may increase blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis, monitoring is recommended as a safety measure.
3. Impaired renal function :
Patients with mild-to-moderate renal impairment do not need dosage adjustment.
4. Hepatic impairment :
No dosage adjustment is required for patients with hepatic insufficiency. Patients with mild-to-moderate hepatic insufficiency should not exceed 80mg/day of valsartan. Valsartan is mostly eliminated unchanged in the bile and patients with biliary obstructive disorders showed lower valsartan clearance (see pharmacokinetics), and care should be exercised.
5. Same as with other antihypertensive drugs, patients treated with valsartan should be careful at driving and operating machinery.Use in Pregnancy and Lactation :
Fetal renal perfusion, which is dependent upon the development of the (RAAS), begins in the 2nd trimester. If the pregnant women intake drugs that act on the RAAS, it can cause fetal morbidity andmortality. Hence, valsartan should not be taken during pregnancy. When pregnancy is detected, valsartan should be discontinued as soon as possible. Fetuses with previous intrauterine drug exposure should be monitored closely that there is normal urination to prevent hyperkalemia and hypotension. Actions on drug clearance should be taken in emergency cases. Valsartan is found in the breast milk of rabbits. No studies have been made on the effect of valsartan on lactation, so nursing mothers should not use valsartan.
[Pediatric Use]
Safety and effectiveness in pediatrics patients have not been established.
[Geriatric Use]
The overall effect of Valsartan is greater in older patients than younger patients but does not account for any major clinical significance.
[Drug Interaction]
No clinically significant drug interactions were observed. Studies have been made on the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine and glyburide. As valsartan is not metabolised to a significant extent, clinically relevant drug-drug interactions, in the form of metabolic induction or inhibition of the cytochrome P-450 system, are not expected with valsartan. Although valsartan is highly bound to plasma proteins, in vitro studies have not shown any interactions at this level with a range of molecules which are also highly protein bound (eg, diclofenac, furosemide, and warfarin). Concomitant use of potassium-sparing diuretics (eg. Spirolactone, triamterene, amiloride), potassium supplements or salt substitutes containing potassium may lead to increase in serum potassium. If co-medication is considered necessary, caution is advisable.
[Overdose]
Limited data are available related to overdosage in humans. The most likely manifestations of overdose would be hypotension and tachycardia; bracycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Valsartan is not removed from the plasma by hemodialysis.
[Presentation]  Available as 80mg capsule
[Storage]  Sealed and protect from moisture.
[Packing]  In blister pack of 7's , 1x7's.
[Shelf-life]  18 months from the date of manufacture.
[Sanction number]  H20030777
[Manufacturer]  TIANDA PHARMACEUTICALS (ZHUHAI) LTD.
Address : 82 Anlian Road, Lian Tang Industrial Park, Qian Shan, Zhuhai, China. 519070
Overseas Agent : TIANDA PHARMACEUTICALS LIMITED
Address : Suites 2401-2404, 24/F., CITIC Tower, No.1 Tim Mei Avenue, Central, Hong Kong
Tel : 852 2295 0303
Fax : 852 2295 0301
Web-site : http://www.tianda.com