Levamlodipine Drug Information

• Adult recommended starting dose: 2.5 mg once daily with maximum dose 5 mg once daily. ( 2.1 ) ○ Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 1.25 mg once daily. ( 2.1 )
• Pediatric starting dose: 1.25 mg to 2.5 mg once daily. ( 2.2 ) Important Limitation : Doses in excess of 2.5 mg daily have not been studied in pediatric patients. ( 2.2 ) 2.1 Adults The usual initial antihypertensive oral dose of levamlodipine is 2.5 mg once daily, and the maximum dose is 5 mg once daily. Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 1.25 mg once daily and this dose may be used when adding levamlodipine to other antihypertensive therapy. Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titrate more rapidly, however, if clinically warranted, provided the patient is assessed frequently. 2.2 Children The effective antihypertensive oral dose in pediatric patients ages 6–17 years is 1.25 mg to 2.5 mg once daily. Doses in excess of 2.5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology ( 12.4 ), Clinical Studies ( 14.1 )] .

Clinical Trials Experience

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 the clinical trials of another drug and may not reflect the rates observed in practice. Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine besylate was well-tolerated at doses up to 10 mg daily.

Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besylate (N = 1730) at doses up to 10 mg to placebo (N = 1250), discontinuation of amlodipine besylate because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows: Amlodipine Placebo 2.5 mg 5 mg 10 mg N=275 N=296 N=268 N=520 Edema 1.8 3.0 10.8

Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0.0 Palpitation 0.7

1.4 4.5

Other adverse reactions that were not clearly dose related but were reported

with an incidence greater than 1.0% in placebo-controlled clinical trials include the following: Amlodipine (%) Placebo (%) (N=1,730) (N=1,250) Fatigue 4.5

Nausea 2.9 1.9 Abdominal Pain 1.6 0.3 Somnolence 1.4 0.6 For several

adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table: Amlodipine Placebo Male=% Female=% Male=% Female=% (N=1,218) (N=512) (N=914) (N=336) Edema 5.6 14.6 1.4

Flushing 1.5 4.5 0.3 0.9 Palpitations 1.4 3.3 0.9 0.9 Somnolence 1.3

1.6 0.8

The following events occurred in <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; they are listed to alert the physician to a possible relationship: Cardiovascular : arrhythmia (including ventricular tachycardia and 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,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease. Musculoskeletal System : arthralgia, arthrosis, muscle cramps,1 myalgia. Psychiatric : sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System : dyspnea,1 epistaxis. Skin and Appendages : angioedema, erythema multiforme, pruritus,1 rash,1 rash erythematous, rash maculopapular. 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. 1 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. Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

In the CAMELOT and PREVENT studies of amlodipine in coronary artery disease, the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine. Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Impact of Other Drugs on Amlodipine

CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

Sildenafil Monitor for hypotension when sildenafil is co-administered with amlodipine .

Impact of Amlodipine on Other Drugs 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 . Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate .

Pregnancy Risk Summary The limited available data based on post-marketing reports with amlodipine 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 . In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine during organogenesis at doses approximately 10 and 20-times the maximum recommended human dose (MRHD), respectively. 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 . 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 birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Clinical Considerations 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. Data Animal Data No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine 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) in rats receiving amlodipine at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation.

Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

Pediatric Use Levamlodipine (1.25 to 2.5 mg daily) is effective in lowering blood pressure in patients 6 to 17 years . Effect of levamlodipine on blood pressure in patients less than 6 years of age is not known.

Levamlodipine is contraindicated in patients with known sensitivity to amlodipine. Known sensitivity to amlodipine.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine limited. Single oral doses of amlodipine equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths.

Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension. If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential.

Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.