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Clinical Studies Experience
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Risk of fetal/neonatal morbidity and mortality [see WARNINGS AND PRECAUTIONS]
- 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.
Tekamlo has been evaluated for safety in more than 2800 patients, including 372 patients for 1 year or longer.
In a placebo-controlled study, there were 51% males, 62% Caucasians, 20% Blacks, 18% Hispanics, and 17% who were over 65 years of age. In this study, the overall incidence of adverse events on therapy with Tekamlo was similar to the individual components. Discontinuation of therapy due to a clinical adverse event in this study occurred in 1.7% of patients treated with Tekamlo (2.2% in the highest dose group) versus 1.5% of patients given placebo.
Peripheral edema is a known, dose-dependent adverse effect of amlodipine. The incidence of peripheral edema for Tekamlo in short-term double-blind placebo-controlled studies was lower than or equal to that of the corresponding amlodipine doses.
The adverse event in a placebo-controlled trial that occurred in at least 2% of patients treated with Tekamlo and at a higher incidence than placebo was peripheral edema (6.2% versus 1.0%). The incidence rate of peripheral edema at high dose was 8.9%.
In a long-term safety trial, the safety profile of adverse events was similar to that seen in the short-term controlled trials.
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 ACEI [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) 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%), elevated uric acid (0.4% versus 0.1%), gout (0.2% versus 0.1%), and renal stones (0.2% versus 0%).
Single episodes of tonic-clonic seizures with loss of consciousness were reported in two 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 rechallenge 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 < 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:
Psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization
**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.
Autonomic Nervous System: dry mouth, sweating increased
Metabolic and Nutritional: hyperglycemia, thirst
Other events 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.
Clinical Laboratory Test Abnormalities
RBC count, hemoglobin and hematocrit: Small mean changes from baseline were seen in RBC count, hemoglobin and hematocrit in patients treated with both Tekamlo and aliskiren monotherapy. 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, vs. 0% for placebo). No patients discontinued due to anemia.
Blood Urea Nitrogen (BUN) / Creatinine: In patients with hypertension not concomitantly treated with an ARB or ACEI, elevations in BUN ( > 40 mg/dL) and creatinine ( > 2.0 mg/dL) in patients treated with Tekamlo were < 1.0%.
Serum Potassium: In patients with hypertension not concomitantly treated with an ARB or ACEI, increases in serum potassium > 5.5 mEq/L were infrequent (0.9% compared to 0.6% with placebo) [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
The following adverse reactions have been identified during postapproval use of either aliskiren or amlodipine. 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: angioedema requiring airway management and hospitalization
Aliskiren: 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
Hypersensitivity: anaphylactic reactions and angioedema requiring airway management and hospitalization
Amlodipine: 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.
Read the Tekamlo (aliskiren and amlodipine tablets) Side Effects Center for a complete guide to possible side effects
No drug interaction studies have been conducted with Tekamlo and other drugs, although studies with the individual aliskiren and amlodipine besylate components are described below.
Cyclosporine: Avoid co-administration of cyclosporine with aliskiren.
Itraconazole: Avoid co-administration of itraconazole with aliskiren [see CLINICAL PHARMACOLOGY].
Non-Steroidal Anti-Inflammatory Agents(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, co-administration of NSAIDs, including selective COX-2 inhibitors with agents that affect the renin-angiotensin-aldosterone system, 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.
Dual Blockade of the renin-angiotensin-aldosterone system: The concomitant use of aliskiren with other agents acting on the renin-angiotensin-aldosterone system 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. Monitor blood pressure, renal function, and electrolytes in patients on aliskiren and other agents that affect the renin-angiotensin-aldosterone system [see WARNINGS AND PRECAUTIONS].
The concomitant use of aliskiren with an ARB or an ACEI in diabetic patients is contraindicated and should be avoided in patients with moderate renal impairment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Furosemide: Oral co-administration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is co-administered with aliskiren.
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 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 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 co-administered with CYP3A4 inducers.
Read the Tekamlo Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/15/2013
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