ion (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 ).

foliative dermatitis have also been infrequently reported. should a dermatologic reaction persist, the drug should be discontinued.

t- 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 effect relationship between these events and diltiazem hydrochloride therapy cannot yet be established. exfoliative dermatitis (proven by rechallenge) has also been reported. to report suspected adverse reactions, contact northstar rx llc at 1-800-206-7821 or fda at 1-800- fda-1088 or www.fda.gov/medwatch

revents spontaneous and ergonovine-provoked coronary artery spasm. it causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end diastolic pressure have not been affected. increased heart failure has, however, been reported in occasional patients with preexisting impairment of ventricular function. there are as yet few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. resting heart rate is usually slightly reduced by diltiazem. diltiazem hydrochloride extended-release capsules produces antihypertensive effects both in the supine and standing positions. postural hypotension is infrequently noted upon suddenly assuming an upright position. no reflex tachycardia is associated with the chronic antihypertensive effects. diltiazem hydrochloride extended-release capsules decrease vascular resistance, increase cardiac output (by increasing stroke volume), and produce a slight decrease or no change in heart rate. during dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievable systolic pressure is usually reduced. heart rate at maximum exercise does not change or is slightly reduced. chronic therapy with diltiazem hydrochloride produces no change or an increase in plasma catecholamines. no increased activity of the renin- angiotensin-aldosterone axis has been observed. diltiazem hydrochloride extended-release capsules antagonize the renal and peripheral effects of angiotensin ii. hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio. intravenous diltiazem hydrochloride in doses of 20 mg prolongs ah conduction time and av node functional and effective refractory periods by approximately 20%. in a study involving single oral doses of 300 mg of diltiazem hydrochloride in six normal volunteers, the average maximum pr prolongation was 14% with no instances of greater than first-degree av block. diltiazem-associated prolongation of the ah interval is not more pronounced in patients with first-degree heart block. in patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases). chronic oral administration of diltiazem hydrochloride in doses of up to 360 mg/day has resulted in small increases in pr interval, and on occasion produces abnormal prolongation (see warnings ). pharmacokinetics and metabolism diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%. diltiazem hydrochloride undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine. in vitro binding studies show diltiazem hydrochloride is 70% to 80% bound to plasma proteins. competitive in vitro ligand binding studies have also shown diltiazem hydrochloride binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. the plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. desacetyl diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent a coronary vasodilator as diltiazem. minimum therapeutic plasma levels of diltiazem hydrochloride appear to be in the range of 50 to 200 ng/ml. there is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose. a study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. a single study in nine patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function. diltiazem hydrochloride extended-release capsules (twice-a-day dosage) a single 120 mg dose of the capsule results in detectable plasma levels within 2 to 3 hours and peak plasma levels at 6 to 11 hours. the apparent elimination half-life after single or multiple dosing is 5 to 7 hours. a departure from linearity similar to that observed with the diltiazem hydrochloride tablet is observed. as the dose of diltiazem hydrochloride extended-release capsules is increased from a daily dose of 120 mg (60 mg b.i.d.) to 240 mg (120 mg b.i.d.) daily, there is an increase in area-under-the-curve of 2.6 times. when the dose is increased from 240 mg to 360 mg daily, there is an increase in area-under-the-curve of 1.8 times. the average plasma levels of the capsule dosed twice daily at steady-state are equivalent to the tablet dosed four times daily when the same total daily dose is administered.

�€ on the cap and “562” on the body with black ink, filled with white to off-white pellets. store at 20°c to 25°c (68°f to 77 ° f); excursions permitted to 15 ° c to 30 ° c (59°f to 86 ° f) [see usp controlled room temperature]. avoid excessive humidity. dispense in a tight, light-resistant container as defined in the usp using a child-resistant closure. manufactured for: northstar rx llc memphis, tn 38141 manufactured by: glenmark pharmaceuticals limited pithampur, madhya pradesh 454775, india revision no. 1 revised: june 2022