Diltiazem Hydrochloride

INDICATIONS AND USAGE Diltiazem Hydrochloride Extended-Release Capsules (Twice-a-Day Dosage) are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive medications, such as diuretics.

DOSAGE AND ADMINISTRATION Dosages must be adjusted to each patient’s needs, starting with 60 to 120 mg twice daily. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. Although individual patients may respond to lower doses, the usual optimum dosage range in clinical trials was 240 to 360 mg/day. Diltiazem Hydrochloride Extended-Release Capsules have an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of Diltiazem Hydrochloride Extended-Release Capsules or the concomitant antihypertensives may need to be adjusted when adding one to the other. See WARNINGS and PRECAUTIONS regarding use with beta-blockers.

WARNINGS Cardiac Conduction Diltiazem hydrochloride prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (9 of 2,111 patients or 0.43%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal’s angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem (see ADVERSE REACTIONS ). Congestive Heart Failure Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). An acute study of oral diltiazem in patients with impaired ventricular function (ejection fraction 24% ± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt). Experience with the use of diltiazem hydrochloride in combination with beta- blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination. Hypotension Decreases in blood pressure associated with diltiazem hydrochloride therapy may occasionally result in symptomatic hypotension. Acute Hepatic Injury Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to diltiazem hydrochloride is uncertain in some cases, but probable in some (see PRECAUTIONS ).

CONTRAINDICATIONS Diltiazem hydrochloride is contraindicated in (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker, (2) patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by X-ray on admission.

Pregnancy Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human dose or greater. There are no well controlled studies in pregnant women; therefore, use diltiazem hydrochloride in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of diltiazem hydrochloride is deemed essential, an alternative method of infant feeding should be instituted.

ADVERSE REACTIONS Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies. The adverse events described below represent events observed in clinical studies of hypertensive patients receiving either diltiazem hydrochloride tablets or Diltiazem Hydrochloride Extended-Release Capsules, as well as experiences observed in studies of angina and during marketing. The most common events in hypertension studies are shown in a table with rates in placebo patients shown for comparison. Less common events are listed by body system; these include any adverse reactions seen in angina studies that were not observed in hypertension studies. In all hypertensive patients studied (over 900), the most common adverse events were edema (9%), headache (8%), dizziness (6%), asthenia (5%), sinus bradycardia (3%), flushing (3%), and first- degree AV block (3%). Only edema and perhaps bradycardia and dizziness were dose related. The most common events observed in clinical studies (over 2,100 patients) of angina patients and hypertensive patients receiving diltiazem hydrochloride tablets or Diltiazem Hydrochloride Extended-Release Capsules were (i.e., greater than 1%) edema (5.4%), headache (4.5%), dizziness (3.4%), asthenia (2.8%), first-degree AV block (1.8%), flushing (1.7%), nausea (1.6%), bradycardia (1.5%), and rash (1.5%). Double Blind Placebo Controlled Hypertension Trials Adverse Diltiazem N = 315 # pts (%) Placebo N = 211 # pts (%) Headache 38 (12%) 17 (8%) AV block first degree 24 (7.6%) 4 (1.9%) Dizziness 22 (7%) 6 (2.8%) Edema 19 (6%) 2 (0.9%) Bradycardia 19 (6%) 3 (1.4%) ECG abnormality 13 (4.1%) 3 (1.4%) Asthenia 10 (3.2%) 1 (0.5%) Constipation 5 (1.6%) 2 (0.9%) Dyspepsia 4 (1.3%) 1 (0.5%) Nausea 4 (1.3%) 2 (0.9%) Palpitations 4 (1.3%) 2 (0.9%) Polyuria 4 (1.3%) 2 (0.9%) Somnolence 4 (1.3%) — Alk phos increase 3 (1%) 1 (0.5%) Hypotension 3 (1%) 1 (0.5%) Insomnia 3 (1%) 1 (0.5%) Rash 3 (1%) 1 (0.5%) AV block second degree 2 (0.6%) — In addition, the following events were reported infrequently (less than 1%) with Diltiazem Hydrochloride Extended-Release Capsules or diltiazem hydrochloride tablets or have been observed in angina or hypertension trials. Cardiovascular: Angina, arrhythmia, second- or third-degree AV block (see Conduction Warning), bundle branch block, congestive heart failure, syncope, tachycardia, ventricular extrasystoles. Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, nervousness, paresthesia, personality change, tremor. Gastrointestinal: Anorexia, diarrhea, dry mouth, dysgeusia, mild elevations of SGOT, SGPT, and LDH (see Hepatic Warnings), thirst, vomiting, weight increase. Dermatological: Petechiae, photosensitivity, pruritus, urticaria. Other : Amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, sexual difficulties, tinnitus. The following post-marketing events have been reported infrequently in patients receiving diltiazem hydrochloride: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson Syndrome, toxic epidermal necrolysis), extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), purpura, retinopathy, myopathy, and thrombocytopenia. There have been observed cases of a generalized rash, some characterized as leukocytoclastic vasculitis. In addition, events such as myocardial infarction have been observed which are not readily distinguishable from the natural history of the disease in these patients. A definitive cause and e…