Diovan HCT (valsartan/hydrochlorothiazide) tablets

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – April 2010, June and December 2011, February and August 2012

 

August 2012

Summary View

 

WARNINGS AND PRECAUTIONS

• Monitor renal function and potassium in susceptible patients

Potassium Abnormalities

• Valsartan:Some patients with heart failure have developed increases in potassium with Diovan therapy…

ADVERSE REACTIONS

Postmarketing Experience

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

PATIENT COUNSELING INFORMATION

• Tell your doctor about all your medical conditions including whether you:
• have ever had a reaction called angioedema, to another blood pressure medicine. Angioedema causes swelling of the face, lips, tongue and/or throat, and may cause difficulty breathing.
• 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
• certain antibiotics (rifamycin group), a drug used to protect against transplant rejection (cyclosporin) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs may increase the effect of valsartan.

 

February 2012

Summary View

 

WARNINGS AND PRECAUTIONS

• Hypotension: Correct volume-depletion prior to initiation
• Monitor renal function in susceptible patients

Impaired Renal Function Heading

• 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 arterystenosis, chronic kidney disease, severe congestive heart failure, or volume depletion)may be at particular risk of developing acute renal failure on Diovan 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 Diovan HCT.

Serum Electrolyte Abnormalities

Valsartan – Hydrochlorothiazide:

• In the controlled trials of various doses Diovan HCT the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 3.0%; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%...
• 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), Diovan HCT should be discontinued. Correction of hypokalemia and any coexisting hypomagnesmia is recommended prior to the initiation of thiazides.

Metabolic Disturbances

Hydrochlorothiazide

• 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 Diovan HCT.

 

DRUG INTERACTIONS

• Lithium: risk of lithium toxicity Monitor serum lithium concentrations during concurrent use.
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): May increase risk of renal impairment. Can reduce diuretic, natriuretic and antihypertensive effects of diuretics.
• 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.

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.
• Lithium - Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Diovan HCT. Monitoring of serum lithium concentrations is recommended during concurrent use.
• Nonsteroidal Anti-inflammatory Drug (NSAIDS and COX-2 selective inhibitors)- Diovan HCT and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the 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 4-6 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.
• Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.
• Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives.
• Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity.
• Drugs that alter gastrointestinal motility: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, prokinetic drugs may decrease the bioavailability of thiazide diuretics.
• Cholestyramine: In a dedicated drug interaction study, administration of cholestyramine 2 hours before hydrochlorothiazide resulted in a 70% reduction in exposure to…
• Antineoplastic agents (e.g. cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

 

ADVERSE REACTIONS

Clinical Trials Experience

Hydrochlorothiazide

• Other adverse reactions not listed above that have been reported with hydrochlorothiazide, without regard to causality, are listed below…
• Clinical Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Diovan HCT.
• Creatinine/Blood Urea Nitrogen (BUN): Minor elevations in creatinine and BUN occurred in 2% and 15% respectively, of patients taking Diovan HCT and 0.4% and 6% respectively, given placebo in controlled clinical trials.
• Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in less than 0.1% of Diovan HCT patients, compared with 0% in placebo-treated patients.
• Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan HCT-treated patients.
• Neutropenia: Neutropenia was observed in 0.1% of patients treated with Diovan HCT and 0.4% of patients treated with placebo.

Postmarketing Experience

• The following additional adverse reactions have been reported in valsartan or valsartan/hydrochlorothiazide 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.
• Hypersensitivity: There are rare reports of angioedema;
• Digestive: Elevated liver enzymes and very rare reports of hepatitis;
• Renal: Impaired renal function;
• Clinical Laboratory Tests: Hyperkalemia;
• Dermatologic: Alopecia;
• 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 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, 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.

 

USE IN SPECIFIC POPULATIONS

Pregnancy

 

• Renal Impairment

 

PATIENT INFORMATION

What should I tell my doctor before taking Diovan Hct?

 

• Tell your doctor about all your medical conditions including if you:
  • 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.

Tell your doctor about all the medicines 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

• CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and co-administered drugs are unlikely because of the low extent of metabolism
• 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. Co-administration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to 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…

PATIENT INFORMATION

“Tell your doctor about all the medicines you take”

• like ibuprofen or naproxen

 

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 Diovan HCT?

Eye Problems. One of the medicines in Diovan HCT can cause eye problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting Diovan HCT. Tell your doctor right away if you have:

• decrease in vision
• eye pain 

 

April 2010

Summary View

 

ADVERSE REACTIONS
Postmarketing Experience

• Dermatologic: Alopecia
• Vascular: Vasculitis
• Nervous System: Syncope

DRUG INTERACTIONS

Hydrochlorothiazide

• Carbamazepine: May lead to symptomatic hyponatremia

Valsartan

• 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.
• 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. Co-administration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.