levamlodipine (Rx)

>10%

• Edema (5.4-14.6%)

1-10%

• Fatigue (4.5%)
• Flushing (1.5-4.5%)
• Palpitations (0.7-4.5%)
• Dizziness (1.1-3.4%)
• Palpitations (1.4-3.3%)
• Nausea (2.9%)
• Flushing (0.7-2.6%)
• Abdominal pain (1.6%)
• Somnolence (1.3-1.6%)
• Somnolence (1.4%)

Frequency Not Defined

Cardiovascular: Arrhythmia (eg, ventricular tachycardia, atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis

Central and peripheral nervous system: Hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo

Gastrointestinal: Anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia

General: Allergic reaction, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease

Musculoskeletal system: Arthralgia, arthrosis, muscle cramps, myalgia

Psychiatric: Sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization

Respiratory system: Dyspnea, epistaxis

Skin and appendages: Angioedema, erythema multiforme, pruritus, rash, erythematous rash, maculopapular rash

Special senses: Abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus

Urinary system: Micturition frequency, micturition disorder, nocturia

Autonomic nervous system: Dry mouth, sweating increased

Metabolic and nutritional: Hyperglycemia, thirst

Hemopoietic: Leukopenia, purpura, thrombocytopenia

Postmarketing Reports

Gynecomastia

Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis)

Contraindications

Hypersensitivity

Cautions

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis; owing to the gradual onset of action, acute hypotension is unlikely

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease

Amlodipine is extensively metabolized by the liver; plasma elimination half-life is 56 hr in patients with impaired hepatic function; titrate slowly when administering amlodipine to patients with severe hepatic impairment

Drug interaction overview

• Levoamlodipine is a CYP3A4 substrate

• Effects of other drugs on amlodipine

  • Coadministration with moderate or strong CYP3A inhibitors results in increased systemic exposure to amlodipine and may require dose reduction; monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A inhibitors
  • No information is available on the quantitative effects of CYP3A inducers on amlodipine; closely monitor blood pressure when amlodipine is coadministered with CYP3A inducers
  • Monitor for hypotension when sildenafil is coadministered with amlodipine

• Effects of amlodipine on other drugs

  • Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin; limit simvastatin dose in patients on amlodipine to 20 mg/day
  • Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when coadministered; frequently monitor trough blood levels of cyclosporine and tacrolimus and adjust dose when appropriate

Pregnancy

Limited available data based on postmarketing reports with use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage

There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy

Animal data

• In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated with oral amlodipine during organogenesis at doses ~10 and 20 times the maximum recommended human dose (MRHD)
• In 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

Clinical considerations

• Hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (eg, need for cesarean delivery, postpartum hemorrhage)
• Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death
• Carefully monitor pregnant women with hypertension and managed accordingly

Lactation

Limited available data from a published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%.

No adverse effects of amlodipine on the breastfed infant have been observed

No information available on the effects of amlodipine on milk production

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.

Mechanism of Action

Amlodipine, a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle

A peripheral arterial vasodilator that acts directly on vascular smooth muscle and causes a reduction in peripheral vascular resistance and reduction in blood pressure

Absorption

Peak plasma time: 6-12 hr

Absolute bioavailability: 64-90%

Steady-state: 7-8 days (consecutive day dosing)

Distribution

Protein bound: ~93%

Metabolism

Extensively (about 90%) converted to inactive metabolites via hepatic metabolism

Elimination

Half-life: 30-50 hr

Oral Administration

Take with or without food

Storage

Store bottles at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF); dispense in tight, light-resistant containers