Sular

INDICATIONS AND USAGE SULAR is indicated for the treatment of hypertension. It may be used alone or in combination with other anti-hypertensive agents.

DOSAGE AND ADMINISTRATION The dosage of SULAR must be adjusted to each patient's needs. Therapy usually should be initiated with 17 mg orally once daily, then increased by 8.5 mg per week or longer intervals, to attain adequate control of blood pressure. Usual maintenance dosage is 17 to 34 mg once daily. Blood pressure response increases over the 8.5 - 34 mg daily dose range but adverse event rates also increase. Doses beyond 34 mg once daily are not recommended. SULAR has been used safely with diuretics, ACE inhibitors, and beta-blocking agents. Patients over age 65, or patients with impaired liver function, are expected to develop higher plasma concentrations of nisoldipine. Their blood pressure should be monitored closely during any dosage adjustment. A starting dose not exceeding 8.5 mg daily is recommended in these patient groups. SULAR tablets should be administered orally once daily. SULAR should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit products should be avoided before and after dosing. SULAR is an extended release dosage form and tablets should be swallowed whole, not bitten, divided or crushed.

CONTRAINDICATIONS SULAR is contraindicated in patients with known hypersensitivity to dihydropyridine calcium channel blockers.

WARNINGS Increased angina and/or myocardial infarction in patients with coronary artery disease: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration and/or severity of angina, or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been established. In controlled studies of SULAR in patients with angina this was seen about 1.5% of the time in patients given nisoldipine, compared with 0.9% in patients given placebo.

Drug Interactions A 30 to 45% increase in AUC and C max of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily. Ranitidine 150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15 - 20%). No pharmacodynamic effects of either histamine H 2 receptor antagonist were observed. CYP3A4 inhibitors and inducers : SULAR is substrate of CYP3A4 and coadministration of SULAR with any known inducer or inhibitor of CYP3A4 should be avoided in general. Coadministration of phenytoin with a dose bioequivalent to 34 mg SULAR tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of SULAR with phenytoin should be avoided and alternative antihypertensive therapy should be considered. Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and not significant. Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine. The blood pressure effect of SULAR tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy. Quinidine at 648 mg bid decreased the bioavailability (AUC) of nisoldipine by 26%, but not the peak concentration. Immediate release nisoldipine increased plasma quinidine concentrations by about 20%. This interaction was not accompanied by ECG changes and its clinical significance is not known. No significant interactions were found between nisoldipine and warfarin or digoxin.

ADVERSE EXPERIENCES More than 6000 patients world-wide have received nisoldipine in clinical trials for the treatment of hypertension, either as the immediate release or the SULAR extended release formulation. Of about 1,500 patients who received SULAR in hypertension studies, about 55% were exposed for at least 2 months and about one third were exposed for over 6 months, the great majority at doses equivalent to 17 mg and above. SULAR is generally well-tolerated. In the U.S. clinical trials of SULAR in hypertension, 10.9% of the 921 SULAR patients discontinued treatment due to adverse events compared with 2.9% of 280 placebo patients. The frequency of discontinuations due to adverse experiences was related to dose, with a 5.4% and 10.9% discontinuation rate at the lowest and highest daily dose, respectively. The most frequently occurring adverse experiences with SULAR are those related to its vasodilator properties; these are generally mild and only occasionally lead to patient withdrawal from treatment. The table below, from U.S. placebo-controlled parallel dose response trials of SULAR using doses across the clinical dosage range in patients with hypertension, lists all of the adverse events, regardless of the causal relationship to SULAR, for which the overall incidence on SULAR was both >1% and greater with SULAR than with placebo. Adverse Event Nisoldipine (%) (n=663) Placebo (%) (n=280) Peripheral Edema 22 10 Headache 22 15 Dizziness 5 4 Pharyngitis 5 4 Vasodilation 4 2 Sinusitis 3 2 Palpitation 3 1 Chest Pain 2 1 Nausea 2 1 Rash 2 1 Only peripheral edema and possibly dizziness appear to be dose related. Adverse Event SULAR, dose bioequivalent to: Placebo 8.5 mg 17 mg 25.5 mg 34 mg (Rates in %) N=280 N=30 N=170 N=105 N=139 Peripheral Edema 10 7 15 20 27 Dizziness 4 7 3 3 4 The common adverse events occurred at about the same rate in men as in women, and at a similar rate in patients over age 65 as in those under that age, except that headache was much less common in older patients. Except for peripheral edema and vasodilation, which were more common in whites, adverse event rates were similar in blacks and whites. The following adverse events occurred in ≤1% of all patients treated for hypertension in U.S. and foreign clinical trials, or with unspecified incidence in other studies. Although a causal relationship of SULAR to these events cannot be established, they are listed to alert the physician to a possible relationship with SULAR treatment. Body As A Whole : cellulitis, chills, facial edema, fever, flu syndrome, malaise Cardiovascular : atrial fibrillation, cerebrovascular accident, congestive heart failure, first degree AV block, hypertension, hypotension, jugular venous distension, migraine, myocardial infarction, postural hypotension, ventricular extrasystoles, supraventricular tachycardia, syncope, systolic ejection murmur, T wave abnormalities on ECG (flattening, inversion, nonspecific changes), venous insufficiency Digestive : abnormal liver function tests, anorexia, colitis, diarrhea, dry mouth, dyspepsia, dysphagia, flatulence, gastritis, gastrointestinal hemorrhage, gingival hyperplasia, glossitis, hepatomegaly, increased appetite, melena, mouth ulceration Endocrine : diabetes mellitus, thyroiditis Hemic and Lymphatic : anemia, ecchymoses, leukopenia, petechiae Metabolic and Nutritional : gout, hypokalemia, increased serum creatine kinase, increased nonprotein nitrogen, weight gain, weight loss Musculoskeletal : arthralgia, arthritis, leg cramps, myalgia, myasthenia, myositis, tenosynovitis Nervous : abnormal dreams, abnormal thinking and confusion, amnesia, anxiety, ataxia, cerebral ischemia, decreased libido, depression, hypesthesia, hypertonia, insomnia, nervousness, paresthesia, somnolence, tremor, vertigo Respiratory : asthma, dyspnea, end inspiratory wheeze and fine rales, epistaxis, increased cough, laryngitis, pharyngitis, pleural effusion, rhinitis, sinusitis Skin and Appendages : acne, alopecia, dry skin, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, maculopapular rash, pruritus, pustular rash, skin discoloration, skin ulcer, sweating, urticaria Special Senses : abnormal vision, amblyopia, blepharitis, conjunctivitis, ear pain, glaucoma, itchy eyes, keratoconjunctivitis, otitis media, retinal detachment, tinnitus, watery eyes, taste disturbance, temporary unilateral loss of vision, vitreous floater Urogenital : dysuria, hematuria, impotence, nocturia, urinary frequency, increased BUN and serum creatinine, vaginal hemorrhage, vaginitis The following postmarketing event has been reported very rarely in patients receiving SULAR: systemic hypersensitivity reaction which may include one or more of the following; angioedema, shortness of breath, tachycardia, chest tightness, hypotension, and rash. A definite causal relationship with SULAR has not been established. An unusual event observed with immediate release nisoldipine but not observed with SULAR was one case of photosensitivity. Gynecomastia has been associated with the use of calcium channel blockers.

Pregnancy Nisoldipine was neither teratogenic nor fetotoxic at doses that were not maternally toxic. Nisoldipine was fetotoxic but not teratogenic in rats and rabbits at doses resulting in maternal toxicity (reduced maternal body weight gain). In pregnant rats, increased fetal resorption (postimplantation loss) was observed at 100 mg/kg/day and decreased fetal weight was observed at both 30 and 100 mg/kg/day. These doses are, respectively, about 5 and 16 times the MRHD when compared on a mg/m 2 basis. In pregnant rabbits, decreased fetal and placental weights were observed at a dose of 30 mg/kg/day, about 10 times the MRHD when compared on a mg/m 2 basis. In a study in which pregnant monkeys (both treated and control) had high rates of abortion and mortality, the only surviving fetus from a group exposed to a maternal dose of 100 mg nisoldipine/kg/day (about 30 times the MRHD when compared on a mg/m 2 basis) presented with forelimb and vertebral abnormalities not previously seen in control monkeys of the same strain. There are no adequate and well controlled studies in pregnant women. SULAR should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.