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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 ACEIs
Tekamlo is contraindicated in patients with diabetes who are receiving ARBs or ACEIs because of the increased risk of renal impairment, hyperkalemia, and hypotension. In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with creatinine clearance (CrCl) less than 60 mL/min [see CONTRAINDICATIONS, DRUG INTERACTIONS and Clinical Studies].
Anaphylactic Reactions And Head And Neck Angioedema
Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis and/or larynx have 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 ACEIs or angiotensin receptor antagonists. Anaphylactic reactions have been reported from postmarketing experience with unknown frequency. 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 and appropriate monitoring measures since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and measures to ensure a patent airway may be necessary.
Symptomatic hypotension may occur after initiation of treatment with Tekamlo in patients with marked volume depletion, patients with salt depletion, or with combined use of aliskiren and other agents acting on the reninangiotensin-aldosterone system (RAAS). The volume or salt depletion should be corrected prior to administration of Tekamlo, or the treatment should start 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.
Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.
Risk Of Myocardial Infarction Or Increased Angina
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 RAAS. Patients whose renal function may depend in part on the activity of the RAAS (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or nonsteroidal anti-inflammatory drug (NSAID, including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors), therapy may be at particular risk for developing acute renal failure on Tekamlo [see Renal Impairment/Hyperkalemia/Hypotension When Tekamlo Is Given In Combination With ARBs Or ACEIs, DRUG INTERACTIONS, Use In Specific Populations, and Clinical Studies]. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function [see DOSAGE AND ADMINISTRATION].
Cyclosporine Or Itraconazole
When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or itraconazole [see DRUG INTERACTIONS].
Monitor serum potassium periodically in patients receiving aliskiren. Drugs that affect the RAAS can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEI [see CONTRAINDICATIONS, Renal Impairment/Hyperkalemia/Hypotension When Tekamlo Is Given In Combination With ARBs Or ACEIs, and Clinical Studies], NSAIDs, including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors), or potassium supplements or potassium-sparing diuretics.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION)
Inform female patients of childbearing age about the consequences of exposure to Tekamlo during pregnancy. Discuss treatment options with women planning to become pregnant. Advise patients to report pregnancies to their physician as soon as possible.
Advise nursing women that breastfeeding is not recommended during treatment with Tekamlo [see Use In Specific Populations].
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.
Anaphylactic Reactions And Angioedema
Advise patients to immediately report any signs or symptoms suggesting a severe allergic reaction (difficulty breathing or swallowing, tightness of the chest, hives, general rash, swelling, itching, dizziness, vomiting, or abdominal pain) or 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. Angioedema, including laryngeal edema, may occur at any time during treatment with Tekamlo.
Tell patients receiving Tekamlo not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
Relationship To Meals
Advise patients to establish a routine pattern for taking Tekamlo with regard to meals. High-fat meals decrease absorption substantially.
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 1 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 MRHD (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 MRHD 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 2 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 MRHD of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about twice the MRHD.
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
Tekamlo can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the reninangiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. 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. When pregnancy is detected, discontinue Tekamlo as soon as possible.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively.
Disease-associated Maternal And/Or Embryo/Fetal Risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Fetal/Neonatal Adverse Reactions
Use of drugs that act on the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, oligohydramnios, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. 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.
In patients taking Tekamlo during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. 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. If oliguria or hypotension occur in neonates with a history of in utero exposure to Tekamlo, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.
No reproductive toxicity studies have been conducted with the combination of aliskiren and amlodipine besylateHowever, these studies have been conducted for aliskiren and amlodipine besylate alone.
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.
No evidence of teratogenicity or embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
These animal studies were conducted according to the standards of the time.
There is no information regarding the presence of Tekamlo or aliskiren in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that amlodipine is present in human milk. However, there is insufficient information to determine the effects of amlodipine on the breastfed infant. There is no available information on the effects of amlodipine on milk production. Because of the potential for serious adverse reactions, including hypotension, hyperkalemia and renal impairment in nursing infants, advise a nursing woman that breastfeeding is not recommended during treatment with Tekamlo.
Safety and effectiveness of Tekamlo in pediatric patients have not been established.
Preclinical studies indicate a potential for substantial increase in exposure to aliskiren in pediatric patients [see Nonclinical Toxicology].
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.
Exposure to aliskiren and amlodipine is increased in patients age 65 years and older. Consider starting with the lowest available dose of amlodipine. The lowest strength of Tekamlo contains 5 mg of amlodipine [see CLINICAL PHARMACOLOGY].
In the short-term controlled clinical trials of Tekamlo, 17% of patients treated with Tekamlo were 65 years and older. 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.
Exposure to amlodipine is increased in patients with hepatic insufficiency, thus consider using lower doses of Tekamlo [see CLINICAL PHARMACOLOGY].
There is no impact of renal function on the pharmacokinetics of aliskiren and amlodipine. However, safety and effectiveness of Tekamlo in patients with severe renal impairment (creatinine clearance (CrCl) less than 30 mL/min) have not been established as these patients were excluded in clinical trials [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY, and Clinical Studies].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/30/2017
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