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Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
In the controlled trial of Exforge HCT, where only the maximum dose (10/320/25 mg) was evaluated, safety data were obtained in 582 patients with hypertension. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The overall frequency of adverse reactions was similar between men and women, younger ( < 65 years) and older ( ≥ 65 years) patients, and black and white patients. In the active controlled clinical trial, discontinuation because of adverse events occurred in 4.0% of patients treated with Exforge HCT 10/320/25 mg compared to 2.9% of patients treated with valsartan/HCTZ 320/25 mg, 1.6% of patients treated with amlodipine/valsartan 10/320 mg, and 3.4% of patients treated with HCTZ/amlodipine 25/10 mg. The most common reasons for discontinuation of therapy with Exforge HCT were dizziness (1.0%) and hypotension (0.7%).
The most frequent adverse events that occurred in the active controlled clinical trial in at least 2% of patients treated with Exforge HCT are presented in the following table.
|Preferred Term||Aml/Val/HCTZ 10/320/25 mg
|Val/HCTZ 320/25 mg
|Aml/Val 10/320 mg
|HCTZ/Aml 25/10 mg
|Dizziness||48 (8.2)||40 (7.2)||14 (2.5)||23 (4.1)|
|Edema||38 (6.5)||8 (1.4)||65 (11.5)||63 (11.2)|
|Headache||30 (5.2)||31 (5.5)||30 (5.3)||40 (7.1)|
|Dyspepsia||13 (2.2)||5 (0.9)||6 (1.1)||2 (0.4)|
|Fatigue||13 (2.2)||15 (2.7)||12 (2.1)||8 (1.4)|
|Muscle spasms||13 (2.2)||7 (1.3)||7 (1.2)||5 (0.9)|
|Back pain||12 (2.1)||13 (2.3)||5 (0.9)||12 (2.1)|
|Nausea||12 (2.1)||7 (1.3)||10 (1.8)||12 (2.1)|
|Nasopharyngitis||12 (2.1)||13 (2.3)||13 (2.3)||12 (2.1)|
Orthostatic events (orthostatic hypotension and postural dizziness) were seen in 0.5% of patients. Other adverse reactions that occurred in clinical trials with Exforge HCT ( > 0.2%) are listed below. It cannot be determined whether these events were causally related to Exforge HCT.
Cardiac Disorders: tachycardia
Eye Disorders: vision blurred
Infections and Infestations: upper respiratory tract infection, bronchitis, influenza, pharyngitis, tooth abscess, gastroenteritis viral, respiratory tract infection, rhinitis, urinary tract infection
Musculoskeletal and Connective Tissue Disorders: pain in extremity, arthralgia, musculoskeletal pain, muscular weakness, musculoskeletal weakness, musculoskeletal stiffness, joint swelling, neck pain, osteoarthritis, tendonitis
Psychiatric Disorders: anxiety, depression, insomnia
Renal and Urinary Disorders: pollakiuria
Reproductive System and Breast Disorders: erectile dysfunction
Vascular Disorders: hypotension
Amlodipine has been evaluated for safety in more than 11000 patients in US and foreign clinical trials. Other adverse reactions not listed above that have been reported in < 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were:
Central and Peripheral Nervous System: neuropathy peripheral, tremor
General: allergic reaction, hot flushes, malaise, rigors, weight gain
Musculoskeletal System: arthrosis, muscle cramps
Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization
Autonomic Nervous System: sweating increased
Metabolic and Nutritional: hyperglycemia, thirst
Other adverse reactions reported with amlodipine at a frequency of ≤ 0.1% of patients include: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.
Adverse reactions reported for amlodipine for indications other than hypertension may be found in its full prescribing information.
Valsartan has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p < 0.001).
Other adverse reactions, not listed above, occurring in > 0.2% of patients in controlled clinical trials with valsartan are:
Respiratory: sinusitis, pharyngitis
Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan.
Other adverse reactions not listed above that have been reported with hydrochlorothiazide, without regard to causality, are listed below:
Body as a Whole: weakness
Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation
Hypersensitivity: photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions
Metabolic: glycosuria, hyperuricemia
Nervous System/Psychiatric: restlessness
Clinical Laboratory Test Findings
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, i.e., valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, and HCTZ/amlodipine 25/10 mg. Findings for the components of Exforge HCT were obtained from other trials.
Creatinine: In hypertensive patients, greater than 50% increases in creatinine occurred in 2.1% of Exforge HCT patients compared to 2.4% of valsartan/HCTZ patients, 0.7% of amlodipine/valsartan patients, and 1.8% of HCTZ/amlodipine patients.
In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.
Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Exforge HCT-treated patients.
Blood Urea Nitrogen (BUN): In hypertensive patients, greater than 50% increases in BUN were observed in 30% of Exforge HCT-treated patients compared to 29% of valsartan/HCTZ patients, 15.8% of amlodipine/valsartan patients, and 18.5% of HCTZ/amlodipine patients. The majority of BUN values remained within normal limits.
In heart failure patients, greater than 50% increases in BUN were observed in 17% of valsartan-treated patients compared to 6% of placebo-treated patients.
Serum Electrolytes (Potassium): In hypertensive patients, greater than 20% decreases in serum potassium were observed in 6.5% of Exforge HCT-treated patients compared to 3.3% of valsartan/HCTZ patients, 0.4% of amlodipine/valsartan patients, and 19.3% of HCTZ/amlodipine patients. Greater than 20% increases in potassium were observed in 3.5% of Exforge HCT-treated patients compared to 2.4% of valsartan/HCTZ patients, 6.2% of amlodipine/valsartan patients, and 2.2% of HCTZ/amlodipine patients.
In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartantreated patients compared to 5.1% of placebo-treated patients [see WARNINGS AND PRECAUTIONS].
Neutropenia: Neutropenia ( < 1500/L) was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.
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.
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.
The following additional adverse reactions have been reported in postmarketing experience with valsartan or valsartan/hydrochlorothiazide:
Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Exforge HCT 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.
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.
Read the Exforge HCT (amlodipine valsartan hydrochlorothiazide tablets) Side Effects Center for a complete guide to possible side effects
No drug interaction studies have been conducted with Exforge HCT 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, Exforge HCT, and the corresponding 3 double combinations. No clinically relevant interaction was observed.
Simvastatin: Coadministration 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: Coadministration with CYP3A inhibitors (moderate and strong) result in increased systemic exposure to amlodipine warranting dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered 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.
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].
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, 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.
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. Closely monitor blood pressure, renal function, and electrolytes in patients on Exforge HCT and other agents that affect the RAS.
Do not coadminister aliskiren with Exforge HCT in patients with diabetes. Avoid use of aliskiren with Exforge HCT 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 Exforge HCT.
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 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.
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]
Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.
Read the Exforge HCT Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 6/20/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Exforge HCT Information
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