Prescription Drug Information: Amlodipine and Valsartan (Page 4 of 6)

12.3 Pharmacokinetics

Amlodipine

Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.

The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Valsartan

Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2 to 4 hours. Absolute bioavailability is about 25% (range 10% to 35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax ) by about 50%.

The steady state volume of distribution of valsartan after intravenous administration is 17 L indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

Valsartan shows biexponential decay kinetics following intravenous administration with an average elimination half-life of about 6 hours. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.

Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). 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).

Amlodipine and Valsartan

Following oral administration of amlodipine and valsartan in normal healthy adults, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6 to 8 hours, respectively. The rate and extent of absorption of valsartan and amlodipine from amlodipine and valsartan are the same as when administered as individual tablets. The bioavailabilities of amlodipine and valsartan are not altered by the coadministration of food. Amlodipine and valsartan may be administered with or without food.

Specific Populations

Geriatric

Amlodipine : Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma levels, elimination half-life and AUC.

Valsartan : Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary.

Gender

Valsartan: Pharmacokinetics of valsartan does not differ significantly between males and females.

Renal Insufficiency

Amlodipine: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment.

Valsartan: 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. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan.

Hepatic Insufficiency

Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60%.

Valsartan: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease.

Drug Interactions

Amlodipine

In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin and indomethacin.

Impact of other drugs on amlodipine

Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7)].

Impact of amlodipine on other drugs

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone [see Drug Interactions (7)].

Cyclosporine: A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7)].

Tacrolimus: A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5-to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N= 6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7)].

Valsartan

No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.

Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.

Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Amlodipine
Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m2 basis, similar to the MRHD of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about 2.5 the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).
Valsartan
There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at concentrations calculated to provide doses of up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.4 and 6 times, respectively, the MRHD of 320 mg/day on a mg/m2 basis. (Calculations based on 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 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 of up to 200 mg/kg/day. This dose is about 6 times the MRHD on a mg/m2 basis.

14 CLINICAL STUDIES

Amlodipine and valsartan was studied in 2 placebo-controlled and 4 active-controlled trials in hypertensive patients. In a double-blind, placebo-controlled study, a total of 1012 patients with mild-to-moderate hypertension received treatments of 3 combinations of amlodipine and valsartan (5 mg/80 mg, 5 mg/160 mg, 5 mg/320 mg) or amlodipine alone (5 mg), valsartan alone (80 mg, 160 mg, or 320 mg) or placebo. All doses with the exception of the 5 mg/320 mg dose were initiated at the randomized dose. The high dose was titrated to that dose after a week at a dose of 5 mg/160 mg. At week 8, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures.

Table 1: Effect of Amlodipine and Valsartan on Sitting Diastolic Blood Pressure
* Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Diastolic Blood Pressure. Mean baseline diastolic BP was 99.3 mmHg.
Amlodipine dosage Valsartan dosage
0 mg 80 mg 160 mg 320 mg
Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted
0 mg -6.4 -9.5 -3.1 -10.9 -4.5 -13.2 -6.7
5 mg -11.1 -4.7 -14.2 -7.8 -14 -7.6 -15.7 -9.3

Table 2: Effect of Amlodipine and Valsartan on Sitting Systolic Blood Pressure
* Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Systolic Blood Pressure. Mean baseline systolic BP was 152.8 mmHg.
Amlodipine dosage Valsartan dosage
0 mg 80 mg 160 mg 320 mg
Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted
0 mg -6.2 -12.9 -6.8 -14.3 -8.2 -16.3 -10.1
5 mg -14.8 -8.6 -20.7 -14.5 -19.4 -13.2 -22.4 -16.2

In a double-blind, placebo-controlled study, a total of 1246 patients with mild to moderate hypertension received treatments of 2 combinations of amlodipine and valsartan (10 mg/160 mg, 10 mg/320 mg), or amlodipine alone (10 mg), valsartan alone (160 mg or 320 mg) or placebo. With the exception of the 10 mg/320 mg dose, treatment was initiated at the randomized dose. The high dose was initiated at a dose of 5 mg/160 mg and titrated to the randomized dose after 1 week. At week 8, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures.

Table 3: Effect of Amlodipine and Valsartan on Sitting Diastolic Blood Pressure
* Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Diastolic Blood Pressure. Mean baseline diastolic BP was 99.1 mmHg.
Amlodipine dosage Valsartan dosage
0 mg 160 mg 320 mg
Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted
0 mg -8.2 -12.8 - 4.5 -12.8 -4.5
10 mg -15 -6.7 - 17.2 - 9 -18.1 -9.9
Table 4: Effect of Amlodipine and Valsartan on Sitting Systolic Blood Pressure
* Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Systolic Blood Pressure. Mean baseline systolic BP was 156.7 mmHg.
Amlodipine dosage Valsartan dosage
0 mg 160 mg 320 mg
Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted
0 mg -11 -18.1 -7 -18.5 -7.5
10 mg -22.2 -11.2 -26.6 -15.5 -26.9 -15.9

In a double-blind, active-controlled study, a total of 947 patients with mild to moderate hypertension who were not adequately controlled on valsartan 160 mg received treatments of 2 combinations of amlodipine and valsartan (10 mg/160 mg, 5 mg/160 mg) or valsartan alone (160 mg). At week 8, the combination treatments were statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures.

Table 5: Effect of Amlodipine and Valsartan on Sitting Diastolic/Systolic Blood Pressure
* Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 149.5/96.5 (systolic/diastolic) mmHg.** Treatment Difference = difference in mean BP reduction between amlodipine and valsartan and the control group (Valsartan 160 mg).
Treatment Group Diastolic BP Systolic BP
Mean change* Treatment Difference** Mean change* Treatment Difference**
Amlodipine and Valsartan 10 mg/160 mg -11.4 -4.8 -13.9 -5.7
Amlodipine and Valsartan 5 mg/160 mg -9.6 -3.1 -12 -3.9
Valsartan 160 mg -6.6 -8.2

In a double-blind, active-controlled study, a total of 944 patients with mild to moderate hypertension who were not adequately controlled on amlodipine 10 mg received a combination of amlodipine and valsartan (10 mg/160 mg) or amlodipine alone (10 mg). At week 8, the combination treatment was statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures.

Table 6: Effect of Amlodipine and Valsartan on Sitting Diastolic/Systolic Blood Pressure
*Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 147/95.1 (systolic/diastolic) mmHg. **Treatment Difference = difference in mean BP reduction between amlodipine and valsartan and the control group (Amlodipine 10 mg).
Treatment Group Diastolic BP Systolic BP
Mean change* Treatment Difference** Mean change* Treatment Difference**
Amlodipine and Valsartan 10 mg/160 mg -11.8 -1.8 -12.7 -1.9
Amlodipine 10 mg -10 -10.8

Amlodipine and valsartan was also evaluated for safety in a 6-week, double-blind, active-controlled trial of 130 hypertensive patients with severe hypertension (mean baseline BP of 171/113 mmHg). Adverse events were similar in patients with severe hypertension and mild/moderate hypertension treated with amlodipine and valsartan.
A wide age range of the adult population, including the elderly was studied (range 19 to 92 years, mean 54.7 years). Women comprised almost half of the studied population (47.3%). Of the patients in the studied amlodipine and valsartan group, 87.6% were Caucasian. Black and Asian patients each represented approximately 4% of the population in the studied amlodipine and valsartan group.
Two additional double-blind, active-controlled studies were conducted in which amlodipine and valsartan was administered as initial therapy. In 1 study, a total of 572 black patients with moderate to severe hypertension were randomized to receive either combination amlodipine/valsartan or amlodipine monotherapy for 12 weeks. The initial dose of amlodipine/valsartan was 5 mg/160 mg for 2 weeks with forced titration to 10 mg/160 mg for 2 weeks, followed by optional titration to 10 mg/320 mg for 4 weeks and optional addition of hydrochlorothiazide 12.5 mg for 4 weeks. The initial dose of amlodipine was 5 mg for 2 weeks with forced titration to 10 mg for 2 weeks, followed by optional titration to 10 mg for 4 weeks and optional addition of hydrochlorothiazide 12.5 mg for 4 weeks. At the primary endpoint of 8 weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.7/2.8 mmHg.
In the other study of similar design, a total of 646 patients with moderate to severe hypertension (MSSBP of ≥160 mmHg and <200 mmHg) were randomized to receive either combination amlodipine/valsartan or amlodipine monotherapy for 8 weeks. The initial dose of amlodipine/valsartan was 5 mg/160 mg for 2 weeks with forced titration to 10 mg/160 mg for 2 weeks, followed by the optional addition of hydrochlorothiazide 12.5 mg for 4 weeks. The initial dose of amlodipine was 5 mg for 2 weeks with forced titration to 10 mg for 2 weeks, followed by the optional addition of hydrochlorothiazide 12.5 mg for 4 weeks. At the primary endpoint of 4 weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.6/3.9 mmHg.
There are no trials of the amlodipine and valsartan combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the amlodipine component and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.

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