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Clinical Studies Experience
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
- Anaphylactic Reactions and Head and Neck Angioedema [see WARNINGS AND PRECAUTIONS]
- Hypotension [see WARNINGS AND PRECAUTIONS]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
Amturnide has been evaluated for safety in 1155 patients treated with Amturnide, including 182 patients for over 1 year.
In a short-term controlled trial, there were 60.5% males, 84.1% Caucasians, 10% blacks, 6.4% Hispanics, and 19.1% who were 65 years of age and older. In this study, the overall incidence of adverse events on therapy with Amturnide was similar to that observed with the individual components. The overall frequency of adverse events was similar between men and women and black and Caucasian patients. Discontinuation of therapy because of a clinical adverse event in this study occurred in 3.6% of patients treated with Amturnide versus 2.4% in aliskiren/amlodipine, 0.7% in aliskiren/HCTZ, and 2.7% in amlodipine/HCTZ.
Table 1: Adverse Events in a Short-term Controlled
Trial that Occurred in at Least 2% of Patients Treated with Amturnide
In a long-term safety trial, the safety profile was similar to that seen in the short-term controlled trial.
Aliskiren has been evaluated for safety in 6460 patients, including 1740 treated for longer than 6 months, and 1250 for longer than 1 year. In placebo-controlled clinical trials, discontinuation of therapy because of a clinical adverse event, including uncontrolled hypertension, occurred in 2.2% of patients treated with aliskiren, versus 3.5% of patients given placebo. These data do not include information from the ALTITUDE study which evaluated the use of aliskiren in combination with ARBs or ACEIs [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Clinical Studies].
Two cases of angioedema with respiratory symptoms were reported with aliskiren use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%.
In addition, 26 other cases of edema involving the face, hands, or whole body were reported with aliskiren use, including 4 leading to discontinuation.
In the placebo-controlled studies, however, the incidence of edema involving the face, hands, or whole body was 0.4% with aliskiren compared with 0.5% with placebo. In a long-term active-controlled study with aliskiren and HCTZ arms, the incidence of edema involving the face, hands, or whole body was 0.4% in both treatment arms.
Aliskiren produces dose-related gastrointestinal (GI) adverse reactions. Diarrhea was reported by 2.3% of patients at 300 mg, compared to 1.2% in placebo patients. In women and the elderly (age 65 years and older) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg similar to those seen at 300 mg for men or younger patients (all rates about 2%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation.
Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any aliskiren use versus 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the aliskiren arms were about one-third to one-half the rates in the ACE inhibitor arms.
Other adverse reactions with increased rates for aliskiren compared to placebo included rash (1% versus 0.3%), and renal stones (0.2% versus 0%).
Single episodes of tonic-clonic seizures with loss of consciousness were reported in 2 patients treated with aliskiren in the clinical trials. One patient had predisposing causes for seizures and had a negative electroencephalogram (EEG) and cerebral imaging following the seizures; for the other patient, EEG and imaging results were not reported. Aliskiren was discontinued and there was no re-challenge in either case.
No clinically meaningful changes in vital signs or in ECG (including QTc interval) were observed in patients treated with aliskiren.
Amlodipine (Norvasc®) has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Other adverse events that have been reported at less than 1% but greater than 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were:
Psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization
Skin and Appendages: angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular
**These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.
Urinary System: micturition frequency, micturition disorder, nocturia
Autonomic Nervous System: dry mouth, sweating increased
Metabolic and Nutritional: hyperglycemia, thirst
Other events reported with amlodipine at a frequency of less than or equal to 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.
Other adverse reactions not listed above that have been reported with HCTZ, 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
Musculoskeletal: muscle spasm
Nervous System/Psychiatric: restlessness
Special Senses: transient blurred vision, xanthopsia
Clinical Laboratory Test Abnormalities
Clinical laboratory findings for Amturnide in patients with hypertension not concomitantly treated with an ARB or ACEI were obtained in a controlled trial of Amturnide administered at the maximal dose of 300/10/25 mg compared to maximal doses of dual therapies, i.e., aliskiren/amlodipine 300/10 mg, aliskiren/HCTZ 300/25 mg and amlodipine/HCTZ 10/25 mg.
RBC Count, Hemoglobin, and Hematocrit
Small mean changes from baseline were seen in RBC count, hemoglobin and hematocrit in patients treated with Amturnide. This effect is also seen with other agents acting on the renin angiotensin system. In aliskiren monotherapy trials, these decreases led to slight increases in rates of anemia compared to placebo (0.1% for any aliskiren use, 0.3% for aliskiren 600 mg daily, versus 0% for placebo). No patients discontinued Amturnide because of anemia.
Blood Urea Nitrogen (BUN)/Creatinine
No patients with hypertension not concomitantly treated with an ARB or ACEI treated with Amturnide had elevations in BUN greater 40 mg/dL or creatinine greater 2.0 mg/dL.
Liver Function Tests
Occasional elevations (greater than 150% from baseline) in ALT (SGPT) were observed in 2.7% of patients treated with Amturnide, compared with 1.7% to 2.7% in patients treated with the dual combinations. No patients were discontinued due to abnormal liver function tests.
The following adverse reactions have been identified during post-approval use of either aliskiren, amlodipine or HCTZ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure:
Hypersensitivity: anaphylactic reactions and angioedema requiring airway management and hospitalization.
Peripheral edema, severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, urticaria, hepatic enzyme increase with clinical symptoms of hepatic dysfunction, pruritus, erythema, nausea, vomiting.
The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, 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.
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, hyperchloremic 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 Amturnide (aliskiren, amlodipine and hydrochlorothiazide tablets) Side Effects Center for a complete guide to possible side effects
No drug interaction studies have been conducted between Amturnide and other drugs. In a phase III sub-study, there was no clinically relevant change in the exposure of aliskiren, amlodipine, and HCTZ observed with Amturnide compared to the dual combinations of aliskiren and amlodipine, amlodipine and HCTZ, and aliskiren and HCTZ. Studies with the individual aliskiren, amlodipine, and HCTZ components are described below.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 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 agents that affect the RAAS, including aliskiren, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving aliskiren and NSAID therapy.
The antihypertensive effect of aliskiren may be attenuated by NSAIDs.
Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS): The concomitant use of aliskiren with other agents acting on the RAAS such as ACEIs or ARBs is associated with an increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two drugs that inhibit the renin-angiotensin system do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min.
Monitor blood pressure, renal function, and electrolytes in patients on aliskiren and other agents that affect the RAAS [see WARNINGS AND PRECAUTIONS].
The concomitant use of aliskiren with an ARB or an ACEI in diabetic patients is contraindicated r[see CONTRAINDICATIONS].
Furosemide: Oral coadministration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is coadministered with aliskiren.
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.
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 increase the risk of lithium toxicity. Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitoring of serum lithium levels is recommended during concomitant use.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and COX-2 selective agents: When Amturnide and NSAIDs are used concomitantly, observe the patient to determine if the desired effect of the diuretic is obtained.
Ion-exchange Resins: Staggering the dosage of HCTZ and resin (e.g., cholestyramine, colestipol) such that HCTZ 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].
Read the Amturnide Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/3/2016
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