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U.S. Department of Health and Human Services

Safety

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Exforge HCT (amlodipine/valsartan/hydrochlorothiazide) tablets

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) 

 

March 2014

Summary View

ADVERSE REACTIONS

Post-Marketing Experience
  • Dermatologic: bullous dermatitis

DRUG INTERACTIONS

  • 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.

 

September 2012 

Summary View

4 CONTRAINDICATIONS

  • Do not use in patients with anuria, hypersensitivity to other sulfonamide-derived drugs or hypersensitivity to any component of this product.

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
5.5 Potassium abnormalities
  • Some patients with heart failure have developed increases in potassium on valsartan. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required.
5.9 Metabolic Imbalances
  • Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
  • Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
  • Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Exforge HCT

6 ADVERSE REACTIONS

6.2 Postmarketing Experience

Valsartan

  • Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experience angioedema with other drugs including ACE inhibitors. Exforge HCT should not be re-administered to patients who have had angioedema.

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.

Valsartan 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 toincreases 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 

8 USE IN SPECIFIC POPULATIONS

8.5 Geriatric Use
  • Exposure to amlodipine is increased in elderly patients, thus consider lower initial doses of Exforge HCT [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment

Amlodipine

Exposure to amlodipine is increased in patients with hepatic insufficiency, thus consider using lower doses of Exforge HCT [see Clinical Pharmacology (12.3)]

Valsartan

No dose adjustment is necessary for patients with mild-to-moderate disease. No dosing recommendations can be provided for patients with severe liver disease

17 PATIENT COUNSELING INFORMATION

Information for Patients/What Should I tell my doctor before taking EXFORGE HCT?

Especially tell your doctor if you take:

  • simvastatin or other cholesterol lowering medicine
  • medicines used to prevent and treat fungal infections (such as ketoconazole,intraconazole)
  • medicines used to treat bacterial infections (such as clarithromycin,telithromycin) 

 

 

February 2012

Summary View

 

WARNINGS AND PRECAUTIONS

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 of developing acute renal failure on Exforge HCT. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Exforge HCT.
 

ADVERSE REACTIONS

Hydrochlorothiazide
  • Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.
  • If hypokalemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG alterations), Exforge HCT should be discontinued. Correction of hypokalemia and any coexisting hypomagnesmia is recommended prior to the initiation of thiazides.
  • Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
  • Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
  • Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Exforge HCT.
Clinical Trials Experience
  • Clinical laboratory test findings for Exforge HCT were obtained in a controlled trial of Exforge HCT administered at the maximal dose of 10/320/25 mg compared to maximal doses of dual therapies…
Post-Marketing Experience
  • The following additional adverse reactions have been reported in post marketing 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.
Hydrochlorothiazide
  • The following additional adverse reactions have been reported in post-marketing 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…
 

DRUG INTERACTIONS

  • Lithium Monitoring of serum lithium concentrations is recommended during concurrent use.
  • Non-steroidal anti-inflammatory drugs...: When Exforge HCT and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of diuretic is obtained.
  • 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 4-6 hours after the administration of resins would potentially minimize the interaction
  • Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.
 

USE IN SPECIFIC POPULATIONS

Pregnancy
Hydrochlorothiazide
  • Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with required concentrations up…
Renal Impairment
  • Safety and effectiveness of Exforge HCT in patients with 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.
Hepatic Impairment
  • Amlodipine. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with impaired hepatic function.
  • Valsartan. No dose adjustment is necessary for patients with mild-to-severe disease.
  • Hydrochlorothiazide. Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
 

PATIENT INFORMATION

What should I tell my doctor before taking EXFORGE HCT?
  • have low levels of potassium (with or without symptoms such as muscle weakness, muscle spasms, abnormal heart rhythm) or magnesium in your
Blood
  • have high levels of calcium in your blood (with or without symptoms such as nausea, vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness and twitching).
  • have high levels of uric acid in the blood.
 
Especially tell your doctor if you take
  • digoxin or other digitalis glycosides (a heart medicine)
  • muscle relaxants (medicines used during operations)
  • certain cancer medicines, like cyclophosphamide or methotrexate

 

December 2011 

Summary View

 

DRUG INTERACTIONS

Valsartan
  • 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.

 

October 2011 

Summary View 

 

DRUG INTERACTIONS

Drug/Drug interactions

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. 

 

June 2011

Summary View

 

* eye problems

 

WARNINGS AND PRECAUTIONS

Acute Myopia and Secondary Angle-Closure Glaucoma
  • Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

PATIENT INFORMATION

What are the possible side effects of Exforge HCT?
  • eye problems. One of the medicines in Exforge HCT can cause eye problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting Exforge HCT.

Tell your doctor right away if you have:

  • decrease in vision
  • eye pain