Angiotensin II AT1 Receptor Blocker
Action And Clinical Pharmacology: Valsartan is an orally active angiotensin II AT1 receptor blocker.
Valsartan acts selectively on AT1, the receptor subtype that mediates the known cardiovascular actions of angiotensin II, the primary vaso-active hormone of the renin-angiotensin-system. The AT2 receptor subtype, found in tissues such as brain, endometrium, myometrium and fetal kidney and adrenals, plays no known role in cardiovascular homeostasis to date. Valsartan does not exhibit any partial AT1 receptor agonist activity and has essentially no activity at the AT2 receptor. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The primary metabolite, valeryl 4-hydroxy valsartan, is essentially inactive.
Angiotensin II has a wide variety of physiological effects; many are either directly or indirectly involved in blood pressure regulation. A potent vasoconstrictor, angiotensin II exerts a direct pressor response. In addition, it promotes sodium retention and aldosterone secretion.
Blockade of angiotensin II AT1 receptors results in 2- to 3-fold increase in plasma renin and angiotensin II plasma concentrations in hypertensive patients. Long-term effects of increased AT2 receptor stimulation by angiotensin II are unknown.
Valsartan does not inhibit angiotensin converting enzyme (ACE), also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin.
Pharmacokinetics: Since its pharmacokinetics are linear in the 80 to 320 mg dose range, valsartan does not accumulate appreciably in plasma following repeated administration. Plasma concentrations are similar in males and females.
The mean absolute bioavailability of valsartan is about 23%, but with high variability. Peak plasma concentration is reached 2 to 4 hours after dosing.
Giving valsartan with food reduces the area under the valsartan plasma concentration curve (AUC) by 48%. After about 8 hours however, plasma valsartan concentrations are similar in the fed and fasted state.
Valsartan is 94 to 97% bound to serum protein, mainly serum albumin. Steady-state volume of distribution is about 17 L, indicating that valsartan does not distribute into tissues extensively.
Following administration of an oral solution of 4 labelled valsartan, 83% of absorbed valsartan is excreted in the feces and 13% in the urine, mainly as unchanged compound. Valsartan biotransformation does not seem to involve the cytochrome P450 system. The enzyme(s) responsible for valsartan metabolism have not been identified.
On average, patients with mild to moderate chronic liver disease have twice the exposure to valsartan of healthy volunteers as measured by AUC and Cmax (see Precautions, Impaired Liver Function and Dosage).
Renal clearance accounts for only 30% of total plasma clearance. There is no apparent correlation between renal function and exposure to valsartan, as measured by AUC and Cmax, in patients with different degrees of renal impairment. In patients with renal failure undergoing hemodialysis, limited information showed that exposure to valsartan is comparable to that in patients with creatinine clearance >10 mL/min.
Valsartan is not removed from plasma by dialysis.
Exposure to valsartan is about 50% higher as measured by AUC and Cmax and the half life is longer in elderly subjects than in young subjects. However, this difference has not been shown to have any clinical significance.
Pharmacodynamics: Valsartan inhibits the pressor effect of an angiotensin II infusion. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours.
After a single oral dose, the antihypertensive activity of valsartan has an onset within approximately 2 hours and peaks within 4 to 6 hours in most patients.
The antihypertensive effect of valsartan persists for 24 hours after dosing. Trough/peak ratio ranges from 0.54 to 0.76. Valsartan reduces blood pressure in hypertensive patients without affecting pulse rate.
During repeated dosing, the maximum blood pressure reduction with any dose is generally attained within 4 weeks, and is sustained during long-term therapy. Combinations with hydrochlorothiazide produce additional reduction in blood pressure.
There is no apparent rebound effect after abrupt withdrawal of valsartan therapy.
Although data available to date indicate a similar pharmacodynamic effect of valsartan in black and white hypertensive patients, this should be viewed with caution since antihypertensive drugs that affect the renin-angiotensin system, such as ACE inhibitors and angiotensin II AT1 receptor blockers, have generally been found to be less effective in low-renin hypertensives (frequently blacks).
Indications And Clinical Uses: For the treatment of mild to moderate essential hypertension.
Valsartan may be administered alone, or concomitantly with thiazide diuretics.
Valsartan should normally be used in those patients in whom treatment with diuretic or beta-blocker was found ineffective or has been associated with unacceptable adverse effects. Valsartan can also be tried as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.
The safety and efficacy of concurrent treatment with Valsartan and angiotensin converting enzyme inhibitors have not been established.
Contra-Indications: In patients who are hypersensitive to any component of this product (see Supplied).
Manufacturers’ Warnings In Clinical States: Pregnancy: Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, valsartan should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.
Mothers whose embryos and fetuses are exposed to an angiotensin II AT1 receptor blocker only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of valsartan as soon as possible.
Rarely (probably less than 1 in every 1 000 pregnancies), no alternative to angiotensin II AT1 receptor blocker will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examinations should be performed to assess intra-amniotic environment.
If oligohydramnios is observed, valsartan should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to an angiotensin II AT1 receptor blocker should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion may be required as a means of reversing hypotension and/or substituting for impaired renal function. Valsartan is not removed from plasma by dialysis.
Animal Data: No teratogenic effects were observed when valsartan was administered orally to pregnant mice and rats at doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/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 orally with valsartan at maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day.
Hypotension: Occasionally, symptomatic hypotension has occurred after administration of valsartan, in some cases after the first dose. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.
Precautions: Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.
Use of valsartan should include appropriate assessment of renal function.
Impaired Liver Function: In general, no dosage adjustment is needed in patients with mild to moderate liver disease. However, care should be exercised in patients with liver disease, especially in those patients with biliary obstructive disorders, as the majority of valsartan is eliminated in the bile. No information is available in patients with severe liver disease (see Pharmacology, Pharmacokinetics).
Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at a particular risk of decreased coronary perfusion, because they do not develop as much afterload reduction.
Lactation: It is not known whether valsartan is excreted in human milk but it was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Children: The safety and effectiveness of valsartan in children have not been established.
Geriatrics: Of the 2 542 patients receiving valsartan monotherapy in placebo-controlled clinical trials, 31% were 65 years and older. No overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out.
Drug Interactions: Diuretics: Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction in blood pressure after initiation of therapy with valsartan. The possibility of symptomatic hypotension with the use of valsartan can be minimized by discontinuing the diuretic prior to initiation of treatment (see Warnings – Hypotension and Dosage). No drug interaction of clinical significance has been identified with thiazide diuretics.
Agents Increasing Serum Potassium: Since valsartan decreases the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution.
Lithium Salts: As with other drugs which eliminate sodium, lithium clearance may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be administered.
Warfarin: Coadministration of valsartan and warfarin over 3 days did not affect the bioavailability of valsartan. Coadministration had no effect on activated partial thromboplastin time (APTT) and resulted in a 12% increase in prothrombin time (PT).
Digoxin: A single dose of digoxin administered with a single dose of valsartan did not result in a clinically significant interaction. No steady-state data are available.
Adverse Reactions: Valsartan has been evaluated for safety in over 4 300 patients treated for hypertension, including more than 600 treated for over 6 months and more than 330 for over 1 year. Of these, 3 634 were treated with valsartan monotherapy in controlled clinical trials.
In controlled clinical trials, discontinuation due to adverse effects occurred in 3.1 and 4.0% of patients treated with valsartan monotherapy and placebo, respectively.
The following potentially serious adverse reactions have been reported rarely with valsartan in controlled clinical trials: syncope, hypotension.
Table I is based on double-blind controlled trials in patients treated with valsartan monotherapy at doses of 80 to 160 mg/day. Table I includes all adverse effects with an incidence of 1% or greater in the valsartan treatment group, irrespective of causal relationship to study drug. No adverse effects appeared to have an incidence related to dose. Therefore, adverse effects are grouped irrespective of dose.
In double-blind controlled trials, the following adverse events were reported with valsartan at an occurrence rate of less than 1% regardless of drug relationship: orthostatic effects, chest pain, palpitations, myalgia, asthenia, somnolence, vertigo, impotence, epistaxis, fibrosing alveolitis (1 case), allergic reactions, urticaria, pruritus and rash.
Other adverse reactions reported rarely in postmarketing use include: anaphylaxis (very rarely), angioedema (involving swelling of the face, lips and/or tongue), photosensitivity, increase in blood pressure and taste disorders.
Laboratory Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of valsartan.
Liver Function Tests: In controlled clinical trials, elevations of AST and ALT occurred in 0.8 and 2% of patients treated with valsartan monotherapy compared to 0.8 and 2.0% of patients receiving placebo.
Serum Potassium: Greater than 20% increases in serum potassium were observed in 5% of valsartan treated patients compared to 3% of placebo treated patients. No patient treated with valsartan discontinued therapy due to hyperkalemia.
Creatinine: Minor elevations in creatinine occurred in 1.1% of patients treated with valsartan and 0.8% of patients given placebo in controlled clinical trials.
Hemoglobin and Hematocrit: In controlled clinical trials, greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of patients treated with valsartan compared with 0.1 and 0.1% of patients given placebo. One valsartan patient discontinued treatment for microcytic anemia.
Uric Acid: In placebo-controlled trials, elevations of uric acid levels (baseline vs terminal lab) occurred in 2.6% of patients receiving valsartan monotherapy, 8.2% receiving valsartan and hydrochlorothiazide, 6% receiving hydrochlorothiazide alone and 2.3% receiving placebo.
Neutropenia: Neutropenia was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.
In controlled clinical trials, thrombocytopenia was observed in 0.1% of patients.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Limited data are available in regard to overdosage with valsartan in humans. The most likely manifestations of overdosage would be hypotension and/or tachycardia. If symptomatic hypotension should occur, supportive treatment should be instituted.
Valsartan is not removed from the plasma by dialysis.
Dosage And Administration: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other pertinent clinical factors (see Warnings, Hypotension). The dosage of antihypertensive agents used with valsartan may need to be adjusted.
The recommended dose is 80 mg once daily. The antihypertensive effect is present within 2 weeks and maximal reduction is usually attained within 4 weeks following initiation of therapy. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 160 mg or a thiazide diuretic added.
Valsartan should be administered consistently with or without food (see Pharmacology, Pharmacokinetics).
Hepatic Impairment: No initial dosage adjustment is required in patients with mild to moderate liver disease. Care should be exercised in patients with liver disease (see Pharmacology – Pharmacokinetics and Precautions – Impaired Liver Function).
Renal Impairment: No initial dosage adjustment is required for patients with renal impairment including those patients requiring hemodialysis. Appropriate monitoring of these patients is however recommended (see Pharmacology – Pharmacokinetics and Precautions – Renal Impairment).
Geriatrics: No dosage adjustment is usually necessary (see Precautions, Geriatrics).
Concomitant Diuretic Therapy: In patients receiving diuretics, valsartan therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy. Whenever possible, all diuretics should be discontinued 2 to 3 days prior to the administration of valsartan to reduce the likelihood of hypotension (see Warnings – Hypotension and Precautions – Drug Interactions). If this is not possible because of the patient’s condition, valsartan should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.
Availability And Storage: 80 mg: Each gelatin capsule contains: valsartan 80 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose, povidone compounds and sodium lauryl sulfate; capsule shell: black iron oxide, gelatin, red iron oxide and titanium dioxide. Blister strips of 15, cartons of 2.
160 mg: Each gelatin capsule contains: valsartan 160 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose, povidone compounds and sodium lauryl sulfate; capsule shell: black iron oxide, gelatin, red iron oxide and titanium dioxide. Blister strips of 15, cartons of 2.
Protect from moisture and heat (store at 15 to 30°C).
DIOVAN® Novartis Pharmaceuticals Valsartan Angiotensin II AT1 Receptor Blocker