Included as part of the PRECAUTIONS section.

Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Tekamlo as soon as possible [see Use In Specific Populations].

Renal Impairment/Hyperkalemia/Hypotension when Tekamlo is given in combination with ARBs or ACEI

Tekamlo is contraindicated in patients with diabetes who are receiving ARBs or ACEI because of the increased risk of renal impairment, hyperkalemia, and hypotension [see CONTRAINDICATIONS and Clinical Trials].

Avoid use of Tekamlo with ARBs or ACEI in patients with moderate renal impairment (GFR < 60 ml/min).

Head and Neck Angioedema

Aliskiren

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACE inhibitors or angiotensin receptor antagonists. If angioedema involves the throat, tongue, glottis or larynx, or if the patient has a history of upper respiratory surgery, airway obstruction may occur and be fatal. Patients who experience these effects, even without respiratory distress, require prolonged observation, since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 ml) and measures to ensure a patent airway may be necessary.

Discontinue Tekamlo immediately in patients who develop angioedema and do not readminister.

Hypotension

In patients with an activated renin-angiotensin-aldosterone system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving reninangiotensin-aldosterone system (RAAS) blockers. Correct these conditions prior to administration of Tekamlo, or start the treatment under close medical supervision.

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Risk of Myocardial Infarction or Increased Angina

Rarely, initiation or change to the dose of a calcium channel blocker has resulted in the development of documented increased frequency, duration or severity of angina or acute myocardial infarction, particularly in patients with severe obstructive coronary artery disease. The mechanism of this effect has not been elucidated.

Impaired Renal Function

Monitor renal function periodically in patients treated with Tekamlo. Changes in renal function, including acute renal failure, can be caused by drugs that affect the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or non-steroidal anti-inflammatory (NSAID) therapy may be at particular risk for developing acute renal failure on Tekamlo [see CONTRAINDICATIONS, Clinical Trials]. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function.

Patients with Hepatic Impairment

Amlodipine besylate

Amlodipine is extensively metabolized by the liver and the plasma elimination half-life is 56 hours in patients with impaired hepatic function, therefore, caution should be exercised when administering Tekamlo to patients with severe hepatic impairment.

Patients with Congestive Heart Failure

Amlodipine besylate

Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction.

Cyclosporine or Itraconazole

Aliskiren

When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or intraconazole [see DRUG INTERACTIONS].

Hyperkalemia

Aliskiren

Monitor serum potassium periodically in patients receiving aliskiren. Drugs that affect the renin-angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEI [see CONTRAINDICATIONS, and Clinical Trials], NSAIDs, or potassium supplements or potassium sparing diuretics.

Patient Counseling Information

See FDA-Approved Patient Labeling (PATIENT INFORMATION)

Healthcare professionals should instruct their patients to read the Patient Package Insert before starting Tekamlo and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

Pregnancy

Female patients of childbearing age should be told about the consequences of exposure to Tekamlo during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physician as soon as possible.

Symptomatic Hypotension

Caution patients receiving Tekamlo that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs, discontinue Tekamlo until the physician has been consulted.

Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Angioedema

Patients should be advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Potassium Supplements

Tell patients receiving Tekamlo not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

Relationship to Meals

Patients should establish a routine pattern for taking Tekamlo with regard to meals. High-fat meals decrease absorption substantially.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Aliskiren hemifumarate and Amlodipine besylate

No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of aliskiren hemifumarate and amlodipine besylate. However, these studies have been conducted for aliskiren hemifumarate and amlodipine besylate alone.

Studies with Aliskiren hemifumarate

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of 750 or more mg/kg/day in both species, with a colonic adenoma identified in one rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC0-24hr) basis, 1500 mg/kg/day in the rat is about 4 times and in the mouse about 1.5 times the maximum recommended human dose (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13-week studies.

Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli, the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo rat bone marrow micronucleus assay.

Fertility of male and female rats was unaffected at doses of up to aliskiren 250 mg/kg/day (8 times the maximum recommended human dose of aliskiren 300 mg/60 kg on a mg/m² basis).

Studies with Amlodipine besylate

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m² basis, similar to the maximum recommended human dose (MRHD) of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m² basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Tekamlo as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the reninangiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Tekamlo, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Tekamlo for hypotension, oliguria, and hyperkalemia [see Use In Specific Populations]

Animal Data

No reproductive toxicity studies have been conducted with the combination of aliskiren and amlodipine besylate. However, these studies have been conducted for aliskiren and amlodipine besylate alone.

Aliskiren

In developmental toxicity studies, pregnant rats and rabbits received oral aliskiren hemifumarate during organogenesis at doses up to 20 and 7 times the maximum recommended human dose (MRHD) based on body surface area (mg/m²), respectively, in rats and rabbits. (Actual animal doses were up to 600 mg/kg/day in rats and up to 100 mg/kg/day in rabbits.) No teratogenicity was observed; however, fetal birth weight was decreased in rabbits at doses 3.2 times the MRHD based on body surface area (mg/m²). Aliskiren was present in placentas, amniotic fluid and fetuses of pregnant rabbits.

Amlodipine

In developmental toxicity studies, pregnant rats and rabbits received oral amlodipine maleate during organogenesis at doses approximately 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area (mg/m²), respectively, in rats and rabbits. (Actual animal doses were up to 10 mg/kg/day.) No evidence of teratogenicity or other embryofetal toxicity was observed. However, litter size was decreased approximately 50% and the number of intrauterine deaths was increased approximately 5-fold for rats receiving amlodipine maleate at doses approximately 10 times the MRHD based on body surface area (mg/m²) for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

Nursing Mothers

It is not known whether aliskiren or amlodipine is excreted in human milk. Both aliskiren and amlodipine are secreted in the milk of lactating rats. Because of the potential for serious adverse reactions in human milk-fed infants from Tekamlo, a decision should be made whether to discontinue nursing or discontinue Tekamlo, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Tekamlo in pediatric patients have not been established.

Neonates with a history of in utero exposure to Tekamlo:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Geriatric Use

Tekamlo

In the short-term controlled clinical trials of Tekamlo, 17% of patients treated with Tekamlo were ≥ 65 years. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Aliskiren

Impact of aging on aliskiren pharmacokinetics has been assessed, when compared to young adults (18-40 years), aliskiren mean AUC and Cmax in elderly subjects ( > 65 years) are increased by 57% and 28%, respectively. However, differences in efficacy and safety between the elderly and younger populations were minor, indicating that differences in exposure due to age do not significantly alter the clinical effect of the drug. Therefore, no starting dose adjustment in geriatric population is required.

Amlodipine

Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40-60%. In general dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Renal impairment

Safety and effectiveness of Tekamlo in patients with severe renal impairment (CrCL < 30 ml/min) have not been established as patients with eGFR < 30ml/min were excluded in clinical trials [see Clinical Trials].

Last reviewed on RxList: 5/2/2012
This monograph has been modified to include the generic and brand name in many instances.