ACH-AMLODIPINE

1 Dosing Considerations Dosage should be individualized depending on patient's tolerance and responsiveness. 2 Recommended Dose and Dosage Adjustment • For both hypertension and angina, the recommended initial dose of ACH-Amlodipine is 5 mg once daily.

If necessary, dose can be increased after 1-2 weeks to a maximum dose of 10 mg once daily. • Use in the Elderly or in Patients with Impaired Renal Function: The recommended initial dose in patients over 65 years of age or patients with impaired renal function is 5 mg once daily.

4 Geriatrics). • Use in Patients with Impaired Hepatic Function: Dosage requirements have not been established in patients with impaired hepatic function. When ACH-Amlodipine is used in these patients, the dosage should be carefully and gradually adjusted depending on patients tolerance and response.

5 mg once daily should be considered (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic). 5 mg to 5 mg once daily. 2 Pharmacodynamics). 4 Administration ACH-Amlodipine can be administered once daily, at any time of the day, with or without food.

5 Missed Dose The patient should be advised that if they miss a dose, it should be taken immediately unless it has been more than 12 hours since the missed dose. In such an event, the patient should wait for the next scheduled dose and continue on the regular schedule.

A double dose should not be taken to make up for a missed dose. ACH-Amlodipine (amlodipine besylate) Page 7 of 37

1 Adverse Reaction Overview The most serious adverse reaction associated with the amlodipine besylate is hypotension especially under gross overdose (see 5 OVERDOSAGE). 2 Clinical Trial Adverse Reactions). 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions.

The adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real- world use.

ACH-Amlodipine (amlodipine besylate) Page 11 of 37 Amlodipine besylate has been administered to 1,714 patients (805 hypertensive and 909 angina patients) in controlled clinical trials (vs placebo alone and with active comparative agents).

Most adverse reactions reported during therapy were of mild to moderate severity. 9% of patients. 3%). 7%). 5%). 5%). 5%). 5%). 5%). 4%). 7%). 6% of patients. 8%). 9%). 6%). 9%). 9%). 0%). 0%). 7%). 1%). 8%). 6%). 3 Less Common Clinical Trial Adverse Reactions Amlodipine besylate has been evaluated for safety in about 11,000 patients with hypertension and angina.

1% of patients in comparative clinical trials (double-blind comparative vs placebo or active agents; n = 2,615) or under conditions of open trials or marketing experience where a causal relationship is uncertain. Autonomic Nervous System: dry mouth, hyperhidrosis.

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, myocardial infarction, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis, chest pain.

Central and Peripheral Nervous System: hypoaesthesia/paraesthesia, neuropathy peripheral, tremor, vertigo. Gastrointestinal: anorexia, constipation, dysphagia, vomiting, gingival hyperplasia, change in bowel habits, dyspepsia General: allergic reaction, asthenia+, back pain, pain, hot flushes, malaise, rigors, and weight increased/weight decreased.

, Hepatic/Biliary/Pancreatic). 5 mg to 5 mg once daily. 2 Pharmacodynamics). 4 Administration ACH-Amlodipine can be administered once daily, at any time of the day, with or without food. 5 Missed Dose The patient should be advised that if they miss a dose, it should be taken immediately unless it has been more than 12 hours since the missed dose.

In such an event, the patient should wait for the next scheduled dose and continue on the regular schedule. A double dose should not be taken to make up for a missed dose.

ACH-Amlodipine (amlodipine besylate) Page 7 of 37 5 OVERDOSAGE Symptoms:

Overdosage can cause excessive peripheral vasodilation with marked and probably prolonged hypotension and possibly a reflex tachycardia. In humans, experience with overdosage of ACH-Amlodipine is limited. In healthy volunteers, the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

A patient who took 70 mg of amlodipine with benzodiazepine developed shock which was refractory to treatment and died. In a 19 month old child who ingested 30 mg of amlodipine (about 2 mg/kg) there was no evidence of hypotension but tachycardia (180 bpm) was observed.

5 hrs after ingestion and on subsequent observation (overnight) no sequelae were noted.

Treatment:

Clinically significant hypotension due to overdosage requires active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output.

A vasoconstrictor (such as norepinephrine) may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. As amlodipine besylate is highly protein bound, hemodialysis is not likely to be of benefit.

ACH-Amlodipine is contraindicated in patients: • who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

• who are hypersensitive to other dihydropyridines. Amlodipine besylate is a dihydropyridine ACH-Amlodipine (amlodipine besylate) Page 6 of 37 calcium channel blocker. 2 Breast-feeding). • with severe hypotension (less than 90 mmHg systolic).

• with shock including cardiogenic shock. g. high grade aortic stenosis). • with haemodynamically unstable heart failure after acute myocardial infarction.