Label Changes for:
Exforge (amlodipine/valsartan) Tablets
Changes have been made to the PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.
Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
- Dermatologic: bullous dermatitis
- Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium angiotensin II receptor antagonists, including valsartan. Monitor serum lithium levels is during concomitant use.
- Do not use in patients with known hypersensitivity to any component
5 WARNINGS AND PRECAUTIONS
5.3 Risk of Myocardial Infarction or Increased Angina
- Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease
5.4 Impaired Renal Function
- Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g. patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk .....
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
- Studies with Exforge: The hazards [see Warnings and Precautions(5)] of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter.
- Clinical Lab Test Findings:
- Creatinine: In hypertensive patients, greater than 50% increases in creatinine occurred in 0.4% of patients receiving .....
6.2 Postmarketing Experience
- Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia
- Renal: Impaired renal function, renal failure
7 DRUG INTERACTIONS
7.1 Drug/Drug Interactions
- 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.
- CYP3A4 Inhibitors: Co-administration with CYP3A4 inhibitors (moderate and strong) result in increased systemic exposure to amlodipine warranting dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors to determine the need for dose adjustment.
- CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be monitored when amlodipine is coadministered with CYP3A4 inducers.
- Potassium: Concomitant use of valsartan with other agents that block the reninangiotensin system, potassium sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium 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.
- CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and co-administered drugs are unlikely because of low extent of metabolism [see Pharmacokinetics, Valsartan (12.3)]
8 USE IN SPECIFIC POPULATIONS
8.6 Renal Impairment
- Safety and effectiveness of Exforge in patients with severe renal impairment (CrCl< 30 mL/min) have not been established. No dose adjustment is required in patients with mild (60-90 mL/min) or moderate (CrCl 30-60) renal impairment.
8.7 Hepatic Impairment
- Exposure to amlodipine is increased in patients with hepatic insufficiency, thus consider using lower doses of Exforge HCT [see Clinical Pharmacology (12.3)]
- No dose adjustment is necessary for patients with mild-to-moderate disease. No dosing recommendations can be provided for patients with severe liver disease
What should I tell my doctor before taking EXFORGE?
- have ever had a reaction called angioedema, to another blood pressure medicine. Angioedema causes swelling of the face, lips, tongue, throat, and may cause difficulty breathing.
Especially tell your doctor if you take:
- simvastatin or other cholesterol lowering medicine
- other medicines for high blood pressure or a heart problem
- water pills (diuretics)
- potassium supplements. Your doctor may check the amount of potassium in your blood periodically.
- a salt substitute. Your doctor may check the amount of potassium in your blood periodically.
- nonsteroidal anti-inflammatory drugs (like ibuprofen or naproxen)
- medicines used to prevent and treat fungal skin infections (such as Ketoconazole, itraconazole)
- medicines used to treat bacterial infections (such as clarithromycin, telithromycin)
Studies with Amlodipine added:
- 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. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
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, co-administration 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.
CYP 450 Interactions
- In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and co-administered drugs are unlikely because of low extent of metabolism
- 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. Co-administration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
PATIENT PACKAGE INFORMATION
What should I tell my doctor before taking Exforge?
- Nonsteroidal anti-inflammatory drugs (like ibuprofen or naproxen)