Sdamlo Drug Information

• Adult recommended starting dose: 5 mg orally once daily with maximum dose 10 mg orally once daily. ( 2.1 ) Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg orally once daily. ( 2.1 ) Pediatric starting dose: 2.5 mg to 5 mg orally once daily. ( 2.2 ) Important Limitation: Doses in excess of 5 mg daily have not been studied in pediatric patients. ( 2.2 ) 2.1 Recommended Dosage in Adults Hypertension The usual initial antihypertensive oral dose of Sdamlo is 5 mg orally once daily, and the maximum dose is 10 mg orally once daily. Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg orally once daily and this dose may be used when adding Sdamlo 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. Angina The recommended dose for chronic stable or vasospastic angina is 5 mg to 10 mg orally once daily, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg orally once daily for adequate effect. Coronary Artery Disease The recommended dose range for patients with coronary artery disease is 5 mg to 10 mg once daily. In clinical studies, the majority of patients required 10 mg orally once daily [see Clinical Studies (14.4) ] . 2.2 Recommended Dosage in Pediatric Patients for Hypertension The recommended antihypertensive dose in pediatric patients ages 6 to 17 years is 2.5 mg to 5 mg orally once daily. Doses in excess of 5 mg orally once daily have not been studied in pediatric patients [see Clinical Pharmacology (12.4), Clinical Studies (14.1) ] . 2.3 Preparation and Administration of Sdamlo for Oral Solution
• Remove the cap and peel off the seal.
• Use one tablespoon to measure 15 mL of room temperature water. Add the 15 ml water to the container.
• Wait for 60 seconds to allow the content to fully dissolve. Shaking the container is not required.
• Consume the entire content of the container immediately or within 60 minutes.
• Rinse the container with similar amount of water 1 to 2 times and consume the rinses.

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 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 (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine 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 N=275 5 mg N=296 10 mg 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 (%) (N=1730) Placebo (%) (N=1250) Fatigue 4.5

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

adverse reactions, there was a greater incidence in women than men associated with amlodipine treatment as show in the following table: Amlodipine Placebo Male=% (N=1218) Female=% (N=512) Male=% (N=914) Female=% (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 safety of amlodipine at doses of 2.5 mg and 5 mg

once daily was evaluated in a randomized placebo-controlled trial in 268 pediatric patients aged 6 to 17 years with hypertension. Adverse reactions were similar to those in adults.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of amlodipine. 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. General: gynecomastia Hepatic: jaundice and hepatic enzyme elevations, some require hospitalization.

Neurologic: extrapyramidal disorder.

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 maleate 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 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) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day 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.

Pediatric Use The safety and effectiveness of amlodipine for the treatment of hypertension have been established in pediatric patients aged 6 to 17 years. Use of amlodipine in this age group is supported by evidence from a randomized, placebo-controlled trial in pediatric patients 6 to 17 years of age with hypertension. . The safety and effectiveness of amlodipine have not been established in pediatric patients less than 6 years of age.

Sdamlo 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 is limited. Single oral doses of amlodipine maleate 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.