Valsartan (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

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, MRHD on a mg/m2 basis (Calculations assume an oral dose of 320 mg/day and a 60-kg patient).

Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the MRHD on a mg/m2 basis (Calculations assume an oral dose of 320 mg/day and a 60-kg patient).

13.2 Animal Toxicology and/or Pharmacology

Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10% of the maximum recommended pediatric dose on a mg/m2 basis) from postnatal day 7 to postnatal day 70 produced persistent, irreversible kidney damage. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans. In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age. It is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney [see Use in Specific Populations (8.4)].

14 CLINICAL STUDIES

14.1 Hypertension

Adult Hypertension

The antihypertensive effects of valsartan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (1 in patients over 65 years) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95 to 115 mmHg. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.

Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of valsartan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.

Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.

The blood pressure-lowering effect of valsartan and thiazide-type diuretics are approximately additive.

The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80 to 160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone.

Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a similar response in both groups.

In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg.

There are no trials of valsartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

Pediatric Hypertension

Children Between 1 to Less Than 6 Years of Age
The antihypertensive effect of valsartan in 290 children aged between 1 to less than 6 years of age has been evaluated in three randomized, double-blind clinical studies. In the first study in 90 patients, patients who weighed less than 18 kg received 5, 20 or 40 mg of valsartan daily (low, medium and high doses), and patients who weighed greater than or equal to 18 kg received 10, 40, and 80 mg of valsartan daily (low, medium and high doses). At the end of 2 weeks, the three dose levels of valsartan (low, medium and high) reduced systolic blood pressure from the baseline by 8.4, 8.3, and 8.6 mmHg, respectively, but a dose response could not be demonstrated. In the second study of 74 patients, higher doses (1 mg/kg and 4 mg/kg daily) of valsartan were associated with numerically greater blood pressure reductions than the lowest dose (0.25 mg/kg) at the end of 6-weeks treatment. The third study was a 6 week, randomized double-blind study to evaluate the dose response of valsartan in 126 children 1 to 5 years of age with hypertension, with or without chronic kidney disease (CKD) randomized to receive either valsartan 0.25 mg/kg or 4 mg/kg daily. At the end of 6 weeks, dose dependent reductions in mean systolic blood pressure (MSBP) were observed. The reduction in MSBP was 8.5 mmHg with valsartan 4 mg/kg and 4.1 mmHg with valsartan 0.25 mg/kg. Similarly, the CKD subgroup showed reductions in MSBP with valsartan 4 mg/kg compared to 0.25 mg/kg (9.2 mmHg vs 1.2 mmHg).
Children Between 6 to 16 Years of Age
In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed less than 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed greater than or equal to 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses). Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by 8, 10, and 12 mm Hg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was 4 and 7 mm Hg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.

14.2 Heart Failure

The Valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF less than 40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years. Although Val-HeFT’s primary goal was to examine the effect of valsartan when added to an ACE inhibitor, about 7% were not receiving an ACE inhibitor. Other background therapy included diuretics (86%), digoxin (67%), and beta-blockers (36%). The population studied was 80% male, 46% 65 years or older and 89% Caucasian. At the end of the trial, patients in the valsartan group had a blood pressure that was 4 mmHg systolic and 2 mmHg diastolic lower than the placebo group. There were two primary end points, both assessed as time to first event: all-cause mortality and heart failure morbidity, the latter defined as all-cause mortality, sudden death with resuscitation, hospitalization for heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours. These results are summarized in the following table.

Placebo Valsartan Hazard Ratio Nominal
(N=2,499) (N=2,511) (95% CI*) p-value
All-cause mortality 484 495 1.02 0.8
(19.4%) (19.7%) (0.90 to 1.15)
HF morbidity 801 723 0.87 0.009
(32.1%) (28.8%) (0.79 to 0.97)
* CI = Confidence Interval

Although the overall morbidity result favored valsartan, this result was largely driven by the 7% of patients not receiving an ACE inhibitor, as shown in the following table.
The modest favorable trend in the group receiving an ACE inhibitor was largely driven by the patients receiving less than the recommended dose of ACE inhibitor. Thus, there is little evidence of further clinical benefit when valsartan is added to an adequate dose of ACE inhibitor.

Secondary end points in the subgroup not receiving ACE inhibitors were as follows.

Placebo (N=181) Valsartan (N=185) Hazard Ratio (95% CI)
Components of HF morbidity
All-cause mortality 49 (27.1%) 32 (17.3%) 0.59 (0.37, 0.91)
Sudden death with resuscitation 2 (1.1%) 1 (0.5%) 0.47 (0.04, 5.20)
CHF therapy 1 (0.6%) 0 (0.0%)
CHF hospitalization 48 (26.5%) 24 (13.0%) 0.43 (0.27, 0.71)
Cardiovascular mortality 40 (22.1%) 29 (15.7%) 0.65 (0.40, 1.05)
Non-fatal morbidity 49 (27.1%) 24 (13.0%) 0.42 (0.26, 0.69)


In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD).
Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor. The number of black patients was small and does not permit a meaningful assessment in this subset of patients.

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