Aliskiren / amlodipine / hydrochlorothiazide Side Effects

Some side effects of aliskiren / amlodipine / hydrochlorothiazide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

For the Consumer

Applies to aliskiren / amlodipine / hydrochlorothiazide: oral tablet

Get emergency medical help if you have any of these signs of an allergic reaction while taking aliskiren / amlodipine / hydrochlorothiazide: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using aliskiren, amlodipine, and hydrochlorothiazide and call your doctor at once if you have a serious side effect such as:

• swelling in your hands, ankles, or feet;

• feeling like you might pass out;

• vision problems, eye pain, or seeing halos around lights;

• low potassium (confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling);

• low sodium (headache, slurred speech, hallucinations, vomiting, severe weakness, muscle cramps, loss of coordination, feeling unsteady, seizure, fainting, shallow breathing);

• high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling);

• chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; or

• severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Less serious side effects of aliskiren / amlodipine / hydrochlorothiazide may include:

• mild headache;

• dizziness; or

• stuffy nose, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

For Healthcare Professionals

Applies to aliskiren / amlodipine / hydrochlorothiazide: oral tablet

Cardiovascular

Cardiovascular side effects associated with aliskiren have included rare cases of hypotension (0.1%) and angioedema (0.06%) involving the face, hands, or whole body.

Cardiovascular side effects associated with amlodipine have included palpitation (up to 4.5%). Arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, postural hypotension, tachycardia, and vasculitis have been reported in less than 1% but greater than 0.1% of patients. Cardiac failure, extrasystoles, and pulse irregularity have been reported in less than 0.1% of patients. Angina and myocardial infarction have occasionally been reported; however, these reactions could not be distinguished from coexisting disease states or medications. Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, especially in patients with severe obstructive coronary artery disease.

Cardiac arrhythmias, including ventricular ectopy and complete AV heart block, are associated with hypokalemia and hyponatremia due to HCTZ. Hypotension has been reported in association with HCTZ-induced pulmonary edema. Orthostatic hypotension may occur and may rarely be associated with syncope, particularly in the elderly.

Dermatologic

Dermatologic side effects associated with aliskiren have included rash (1%). Postmarketing reports have included severe cutaneous adverse reactions, including Stevens Johnson syndrome and toxic epidermal necrolysis.

Dermatologic side effects associated with amlodipine have included rash and erythematous rash in up to 2% of patients. Angioedema, erythema multiforme, increased sweating, maculopapular rash, and pruritus have been reported in less than 1% but greater than 0.1% of patients. Alopecia, dermatitis, skin discoloration, skin dryness, and urticaria have been reported in less than 0.1% of patients. Amlodipine-associated lichen planus and telangiectasia have been rarely reported.

Dermatologic reactions associated with HCTZ include case reports of erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus is associated with HCTZ.

Endocrine

Endocrine side effects associated with amlodipine have included gynecomastia during postmarketing experience.

Endocrinologic side effects associated with thiazide diuretics include a single case of recurrent parathyroid adenoma, although the association is probably coincidental.

Gastrointestinal

Gastrointestinal side effects associated with aliskiren appear to be dose related. These have included diarrhea (2.3%), abdominal pain, dyspepsia, and gastroesophageal reflux.

Gastrointestinal side effects associated with amlodipine have included nausea (2.9%), dysphagia (up to 2%), and abdominal pain (1.6%). Anorexia, constipation, diarrhea, dry mouth, dyspepsia, flatulence, gingival hyperplasia, pancreatitis, and vomiting have been reported in less than 1% but greater than 0.1% of patients. Gastritis, increased appetite, loose stools, and taste perversion have been reported in less than 0.1% of patients. At least one case of amlodipine-associated dysgeusia has been reported and confirmed upon rechallenge.

Endocrinologic side effects associated with thiazide diuretics include a single case of recurrent parathyroid adenoma, although the association is probably coincidental.

General

In general, aliskiren is well tolerated with an adverse event profile similar to placebo. Most adverse effects reported were mild to moderate in severity.

Amlodipine is generally well-tolerated at dosages up to 10 mg per day. Most side effects reported were of mild or moderate severity and were dose-related. Headache and edema are the most common side effects. Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Genitourinary

Genitourinary side effects associated with amlodipine have included micturition disorder, micturition frequency, and nocturia in less than 1% but greater than 0.1% of patients. Dysuria and polyuria have been reported in less than 0.1% of patients.

Hematologic

Hematologic side effects associated with amlodipine have included leukopenia, purpura, and thrombocytopenia in less than 1% but greater than 0.1% of patients.

Hematologic side effects are rare. HCTZ Cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been reported.

Hepatic

Hepatic side effects associated with amlodipine have included jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis) during postmarketing experience. In some instances, these cases were severe enough to require hospitalization.

Occasional elevations (greater than 150% from baseline) in ALT (SGPT) were observed in 2.7% of patients treated with aliskiren / amlodipine / hydrochlorothiazide, compared with 1.7-2.7% in patients treated with the dual combinations. No patients were discontinued due to abnormal liver function tests.

Hypersensitivity

Hypersensitivity side effects associated with aliskiren have included cases of angioedema involving the face, hands, and body with or without respiratory symptoms. Periorbital edema without respiratory symptoms were also reported as possible angioedema and resulted in discontinuation. There have been postmarketing reports of angioedema requiring airway management and hospitalization associated with aliskiren.

Hypersensitivity side effects associated with amlodipine have included allergic reaction (less than 1% but greater than 0.1%).

Hypersensitivity (usually nausea, vomiting, diarrhea, and rash) has been reported in less than 1% of patients taking HCTZ. Rare cases of acute pulmonary edema, interstitial cystitis, and interstitial nephritis, and anaphylaxis have been reported.

Metabolic

Metabolic side effects associated with aliskiren have included elevated uric acid (0.4%), gout (0.2%), and renal stones (0.2%). There have been postmarketing reports of peripheral edema associated with aliskiren.

Metabolic side effects associated with amlodipine have included hyperglycemia, thirst, weight decrease, and weight gain in less than 1% but greater than 0.1% of patients. New-onset diabetes has been reported. A single case of acute porphyria exacerbation has been associated with the use of amlodipine, and confirmed upon rechallenge in the same patient. Calcium channel blockers have been suggested as possibly unsafe in patients with this condition.

Metabolic side effects are common in patients taking HCTZ, especially when doses greater than 50 mg per day are used. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50% of patients, and may predispose patients to cardiac arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, and elevated serum uric acid levels are also relatively common. Metabolic problems associated with thiazide diuretics also include glucose intolerance and a potentially deleterious effect on the lipid profile (i.e., increased serum cholesterol).

Uric acid increase greater than 50% from baseline was more commonly observed in patients treated with aliskiren / amlodipine / hydrochlorothiazide (4.7%) compared with the dual combinations (0.4-2.8%). Gout was less commonly observed (0.3% in aliskiren / amlodipine / hydrochlorothiazide treated patients) and renal stones were not reported.

Immunologic

Immunologic side effects associated with HCTZ have included case reports of allergic vasculitis and hemolytic anemia. There are numerous case reports of patients developing a rash histologically identical to subacute cutaneous lupus following HCTZ administration.

Nervous system

Nervous system side effects associated with aliskiren have included headache, dizziness, fatigue, and single episodes of tonic-clonic seizures with loss of consciousness.

Nervous system side effects associated with amlodipine have included headache (7.3%), dizziness (up to 3.4%), and somnolence (up to 1.6%). Hypoesthesia, paresthesia, peripheral neuropathy, postural dizziness, syncope, tinnitus, tremor, and vertigo have been reported in less than 1% but greater than 0.1% of patients. Ataxia and migraine have been reported in less than 0.1% of patients. Myoclonus has been reported.

Nervous system side effects including cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction. At least one case of cognitive and neurologic impairment (i.e., confusion, somnolence, feeling dazed) has been reported. Symptoms immediately resolved following discontinuation of hydrochlorothiazide.

Musculoskeletal

Musculoskeletal side effects associated with amlodipine have included myalgia (up to 2%). Arthralgia, arthrosis, and muscle cramps have been reported in less than 1% but greater than 0.1% of patients. Hypertonia, muscle weakness, and twitching have been reported in less than 0.1% of patients.

Musculoskeletal side effects associated with HCTZ are unusual, and include case reports of myalgias, chills, and muscle spasms. Preservation of mineral bone density has also been observed in older patients.

Ocular

Ocular side effects associated with amlodipine have included abnormal vision, conjunctivitis, diplopia, and eye pain in less than 1% but greater than 0.1% of patients. Abnormal visual accommodation and xerophthalmia have been reported in less than 0.1% of patients.

Ocular side effects associated with HCTZ have included transient blurred vision, xanthopsia.

Other

Other side effects associated with aliskiren have included back pain.

Other side effects associated with amlodipine have included edema (up to 14.6%), flushing (up to 4.5%), fatigue (4.5%), back pain (up to 2%), and tinnitus. During studies in patients with documented coronary artery disease, the most common side effect was peripheral edema. Asthenia, hot flushes, malaise, pain, and rigors have been reported in less than 1% but greater than 0.1% of patients. Cold and clammy skin and parosmia have been reported in less than 0.1% of patients.

Renal

Renal side effects associated with amlodipine have been reported rarely. At least one case of interstitial nephritis has been reported.

Renal insufficiency, manifest as an increase in serum creatinine and BUN may occur due to HCTZ-induced intravascular volume depletion. Rare cases of renal failure, renal dysfunction, and interstitial nephritis have been reported.

Respiratory

Respiratory side effects associated with aliskiren have included nasopharyngitis, upper respiratory tract infection, and cough.

Respiratory side effects associated with amlodipine have included epistaxis (up to 2%) and dyspnea (less than 1% but greater than 0.1%). Coughing and rhinitis have been reported in less than 0.1% of patients. Pulmonary edema was reported during a study of patients with NYHA Class III or IV heart failure without clinical symptoms or objective evidence of underlying ischemic disease.

Respiratory side effects associated with HCTZ have included approximately 40 case reports of acute noncardiogenic pulmonary edema. These cases are thought to be due to idiosyncrasy or a hypersensitivity mechanism.

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