Amlodipine, Valsartan and Hydrochlorothiazide (Page 3 of 9)

6.2 Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Amlodipine

With amlodipine, gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

Valsartan

The following additional adverse reactions have been reported in postmarketing experience with valsartan or valsartan/hydrochlorothiazide:

Blood and Lymphatic:

Decrease in hemoglobin, decrease in hematocrit, neutropenia

Hypersensitivity:

There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Amlodipine, valsartan and hydrochlorothiazide should not be re-administered to patients who have had angioedema.

Digestive:

Elevated liver enzymes and very rare reports of hepatitis

Renal:

Impaired renal function, renal failure

Clinical Laboratory Tests:

Hyperkalemia

Dermatologic:

Alopecia, bullous dermatitis

Vascular:

Vasculitis

Nervous System:

Syncope

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Hydrochlorothiazide

The following additional adverse reactions have been reported in postmarketing experience with hydrochlorothiazide:

Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, visual impairment.

Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary.

7 DRUG INTERACTIONS

No drug interaction studies have been conducted with amlodipine, valsartan and hydrochlorothiazide and other drugs, although studies have been conducted with the individual components. A pharmacokinetic drug-drug interaction study has been conducted to address the potential for pharmacokinetic interaction between the triple combination, amlodipine, valsartan and hydrochlorothiazide, and the corresponding 3 double combinations. No clinically relevant interaction was observed.

Amlodipine

Impact of other Drugs on Amlodipine

CYP3A Inhibitors :

Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see CLINICAL PHARMACOLOGY (12.3) ].

CYP3A Inducers:

No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

Sildenafil:

Monitor for hypotension when sildenafil is co-administered with amlodipine [see CLINICAL PHARMACOLOGY (12.2) ].

Impact of Amlodipine on other Drugs

Simvastatin:

Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see CLINICAL PHARMACOLOGY (12.3) ].

Immunosuppressants:

Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see CLINICAL PHARMACOLOGY (12.3) ].

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.

In vitro metabolism studies have indicated that CYP450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism [see Pharmacokinetics – Valsartan, (12.3) ].

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

Potassium

Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including valsartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on amlodipine, valsartan and hydrochlorothiazide and other agents that affect the RAS.

Do not coadminister aliskiren with amlodipine, valsartan and hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with amlodipine, valsartan and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min).

Valsartan-Hydrochlorothiazide

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or thiazides. Monitor lithium levels in patients taking amlodipine, valsartan and hydrochlorothiazide.

Hydrochlorothiazide

When administered concurrently the following drugs may interact with thiazide diuretics:

Antidiabetic drugs (oral agents and insulin)

Dosage adjustment of the antidiabetic drug may be required.

Non-steroidal anti-inflammatory drugs (NSAIDs and COX-2 selective inhibitors )

When amlodipine, valsartan and hydrochlorothiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of diuretic is obtained.

Carbamazepine

May lead to symptomatic hyponatremia.

Ion exchange resins

Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins would potentially minimize the interaction [see CLINICAL PHARMACOLOGY (12.3) ].

Cyclosporine

Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.