aliskiren/amlodipine (Tekamlo)

Dosing and uses of Tekamlo (aliskiren/amlodipine)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

tablet

• 150mg/5mg
• 150mg/10mg
• 300mg/5mg
• 300mg/10mg

 

Hypertension

May switch to aliskiren/amlodipine if patient inadequately controlled with aliskiren alone or amlodipine alone (or another dihydropyridine calcium channel blocker); may use as replacement therapy for patients currently maintained on aliskiren and amlodipine

Initial: 150 mg/5 mg PO qDay

If blood pressure remains uncontrolled after 2-4 weeks, may titrate upward as needed, not to exceed 300 mg/10 mg daily

 

Renal Impairment

<30 mL/min: Dose adjustment not necessary; use caution (monitor for hyperkalemia or renal dysfunction)

>30 mL/min: Dose adjustment not necessary

 

Hepatic Impairment

Use caution; consider lower initial dose; titrate slowly

 

Administration

High fat meals decrease bioavailability substantially

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Geriatric dosage forms and strengths

In the short-term controlled clinical trials, 17% of patients treated were ≥65 yr; no overall differences in safety or effectiveness were observed between these subjects and younger subjects

Aliskiren AUC and Cmax increased by 57% and 28% respectively; no significant effect on clinical efficacy or safety

Amlodipine AUC increased by 40-60% in elderly patients ≥ 65 years and older; consider starting with lowest available dose of amlodipine (5 mg)

 

Tekamlo (aliskiren/amlodipine) adverse (side) effects

Adverse reactions reported with combination product and individual agents

 

>10%

Amlodipine

• Peripheral edema (2-15%)

 

1-10%

Peripheral edema (6.2-8.9%)

Aliskiren

• Diarrhea (2.3%)
• Cough (1.1%)
• Increased creatinine kinase (1%)
• Increased BUN (≤ 7%)
• Hyperkalemia (≤1%)
• Rash (1%)

Amlodipine

• Flushing (1-5%)
• Palpitation (1-5%)
• Dizziness (1-3%)
• Fatigue (5%)
• Somnolence (1-2%)
• Rash (1-2%)
• Pruritus (1-2%)
• Male sexual dysfunction (1-2%)
• Nausea (3%)
• Dyspepsia (1-2%)
• Abdominal pain (1-2%)
• Muscle cramps (1-2%)
• Dyspnea (1-2%)
• Weakness (1-2%)

 

<1%

Angioedema

Increased BUn

Increased creatinine

Hyperkalemia

Hypotension

Aliskiren

• Gastroesophageal reflux
• Periorbital edema
• Toxic epiderma necrolysis
• Increased uric acid
• Severe hypotension
• Stevens Johnson syndrome

Amlodipine

• Abnormal vision
• Arthralgia
• Chest pain
• Abnormal dreams
• Increased apetite
• Acute interstitial nephritis
• Alopecia
• Conjunctivitis
• Cough
• Depression
• Dysphagia
• Flatulence

 

Postmarketing Reports

Nausea/vomiting

 

Warnings

Black box warnings

Discontinue as soon as possible when pregnancy is detected; affects renin-angiotensin system causing oligohydramnios, which may result in fetal injury and/or death

 

Contraindications

Hypersensitivity

Pregnancy (2nd and 3rd trimesters; significant risk of fetal and neonatal morbidity/mortality; see Black box warnings)

Concomitant use with ACEIs or ARBs in patients with diabetes mellitus

 

Cautions

Symptomatic hypotension may occur after initiation of treatment in patients with marked volume depletion, patients with salt depletion, or with combined use of aliskiren and other agents acting on the renin-angiotensin‐ aldosterone system (RAAS); volume or salt depletion should be corrected prior to administration of therapy, or 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 blood pressure has stabilized

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; 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; discontinue therapy immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister

Increased angina or myocardial infarction with calcium channel blockers may occur upon dosage initiation or increased

Renal impairment: Decrease in renal function may be anticipated with susceptible individuals

Titrate slowly in patients with hepatic impairment or heart failure

Cyclosporine or itraconazole increase aliskiren levels; avoid concomitant use

Preclinical studies indicate a potential for substantial increase in exposure to aliskiren in pediatric patients

Patients whose renal function may depend in part on activity of renin-angiotensin‐ aldosterone system (RAAS; e.g., patients with renal artery stenosis, severe heart failure, postmyocardial infarction or volume depletion) or patients receiving ARB, ACE inhibitors or nonsteroidal anti-inflammatory drug (NSAID), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), therapy may be at particular risk of developing acute renal failure; monitor renal function periodically; consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function

Coadministration with ACE inhibitors or ARBs

• When aliskiren was prescribed with ACE inhibitors or angiotensin receptor blockers (ARBs) in the ALTITUDE study, an increased incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension was observed after 18-24 months
• The ALTITUDE trial included patients with hypertension plus type 2 diabetes and renal impairment who were at high risk of cardiovascular and renal events
• Coadministration of aliskiren with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with diabetes or kidney (renal) impairment; their use is contraindicated in patients with diabetes
• Avoid coadministration of aliskiren with ARBs or ACEIs in moderate to severe renal impairment (ie, GFR <60 mL/min)
• Hyperkalemia: Increases in serum potassium >5.5 mEq/L were infrequent with aliskiren (0.9% compared to 0.6% with placebo); however, when used in combination with an ACE inhibitor in a diabetic population, increases in serum potassium were more frequent (5.5%)

 

Pregnancy and lactation

Pregnancy category: C (1st trimester); D (2nd & 3rd trimesters), see Boxed Warning

Lactation: excretion in milk unknown; breastfeeding not recommended while taking aliskiren/amlodipine

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Tekamlo (aliskiren/amlodipine)

Mechanism of action

Aliskiren: Renin inhibitor; blocks effect of increased renin levels, thereby decreasing feedback loop and reducing plasma renin activity, angiotensin I, and angiotensin II

Amlodipine: Calcium channel blocker; inhibits extracellular Ca ions across the membranes of myocardial cells and vascular smooth muscle cells, resulting in inhibition of cardiac and vascular smooth muscle contraction; this action causes dilation of the main coronary and systemic arteries

 

Pharmacokinetics

Aliskiren

• Onset: Within 2 weeks
• Bioavailability: 3%
• Peak Plasma Time: 1-3 hr
• Metabolism: Metabolized by CYP3A4
• Half-Life: 24 hr
• Excretion: Urine (25% as parent compound in urine)  

Amlodipine

• Duration: 24 hr (antihypertensive effects)
• Vd: 21 L/kg
• Bioavailability: 64-90%
• Half-life: 30-50 hr
• Metabolism: Liver (>90%)
• Protein binding: 93-98%
• Peak plasma time: 6-12 hr
• Excretion: Urine (70%)