Sular () (nisoldipine) is an extended release tablet dosage form of the dihydropyridine calcium channel blocker nisoldipine. Nisoldipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, methyl 2-methylpropyl ester, CHNO, and has the structural formula:
Nisoldipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 388.4. Sular () tablets comprise three layers: a top barrier layer, a middle layer containing nisoldipine, and a bottom barrier layer. The erodible barrier layers and the hydrogel middle layer provide for the controlled release of the drug. Sular () tablets contain either 8.5, 17, 25.5 or 34 mg of nisoldipine for once-a-day oral administration.
Inactive ingredients in the formulation include: Hypromellose,hypromellose phthalate, lactose,glyceryl behenate, povidone, magnesium stearate, silicon dioxide,methacrylic acid copolymer, and sodium lauryl sulfate. Inactive ingredients in the film coating include: polydextrose, titanium dioxide, hypromellose, polyethylene glycol, iron oxide, and carnauba wax. Additionally, the 17 mg formulation contains FD&C Yellow #5.
Nisoldipine is a member of the dihydropyridine class of calcium channel antagonists (calcium ion antagonists or slow channel blockers) that inhibit the transmembrane influx of calcium into vascular smooth muscle and cardiac muscle. It reversibly competes with other dihydropyridines for binding to the calcium channel. Because the contractile process of vascular smooth muscle is dependent upon the movement of extracellular calcium into the muscle through specific ion channels, inhibition of the calcium channel results in dilation of the arterioles. studies show that the effects of nisoldipine on contractile processes are selective, with greater potency on vascular smooth muscle than on cardiac muscle. Although, like other dihydropyridine calcium channel blockers, nisoldipine has negative inotropic effects , studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those that affect cardiac contractility.
The effect of nisoldipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance. While nisoldipine, like other dihydropyridines, exhibits a mild diuretic effect, most of the antihypertensive activity is attributed to its effect on peripheral vascular resistance.
Nisoldipine pharmacokinetics are independent of the dose across the clicinal dosage range of 17 to 51 mg, with plasma concentrations proportional to dose. Nisoldipine accumulation, during multiple dosing, is predictable from a single dose. Nisoldipine is relatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces. The absolute bioavailability of nisoldipine is about 5%. Nisoldipine's low bioavailability is due, in part, to pre-systemic metabolism in the gut wall, and this metabolism decreases from the proximal to the distal parts of the intestine. A pronounced food-effect is observed when Sular () is administered with a high-fat meal resulting in an increased peak concentration (C) of up to 245%. Total exposure (AUC) is decreased by 25%. As a result, Sular () should be taken on an empty stomach (1 hour before or 2 hours after a meal).
Maximal plasma concentrations of nisoldipine are reached at 9.2 ± 5.1 hours. The terminal elimination half-life (reflecting post absorption clearance of nisoldipine) ranges from 13.7 ± 4.3 hours. After oral administration, the concentration of (+)-nisoldipine, the active enantiomer, is about 6 times higher than the inactive (-) -nisoldipine enantiomer. The plasma protein binding of nisoldipine is very high, with less than 1% unbound over the plasma concentration range of 100 ng/mL to 10 mcg/mL.
Nisoldipine is highly metabolized; 5 major urinary metabolites have been identified. Although 60 - 80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine. The major biotransformation pathway appears to be the hydroxylation of the isobutyl ester. A hydroxylated derivative of the side chain, present in plasma at concentrations approximately equal to the parent compound, appears to be the only active metabolite, and has about 10% of the activity of the parent compound. Cytochrome P450 enzymes are believed to play a major role in the metabolism of nisoldipine. The particular isoenzyme system responsible for its metabolism has not been identified, but other dihydropyridines are metabolized by cytochrome P450 IIIA4. Nisoldipine should not be administered with grapefruit juice, as this has been shown, in a study of 12 subjects, to interfere with nisoldipine metabolism, resulting in a mean increase in Cmax of about 3-fold (ranging up to about 7-fold) and AUC of almost 2-fold (ranging up to about 5-fold). A similar phenomenon has been seen with several other dihydropyridine calcium channel blockers.
The antihypertensive efficacy of Sular () was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with Sular () as monotherapy and about 300 with placebo; 4 of the five studies compared 2 or 3 fixed doses while the fifth allowed titration from doses bioequivalent to 8.5 - 34 mg. Once daily administration of Sular () produced sustained reductions in systolic and diastolic blood pressures over the 24 hour dosing interval in both supine and standing positions. The mean placebo-subtracted reductions in supine systolic and diastolic blood pressure at trough, 24 hours post-dose, in these studies, are shown below. Changes in standing blood pressure were similar:
In patients receiving atenolol, supine blood pressure reductions with Sular () doses bioequivalent to 17 and 34 mg once daily were 12/6 and 19/8 mm Hg, respectively. The sustained antihypertensive effect of Sular () was demonstrated by 24 hour blood pressure monitoring and examination of peak and trough effects. The trough/peak ratios ranged from 70 to 100% for diastolic and systolic blood pressure. The mean change in heart rate in these studies was less than one beat per minute. In 4 of the 5 studies, patients received intial doses bioequivalent to 17-25.5 mg Sular () without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of Sular () .
Patient race and gender did not influence the blood pressure lowering effect of Sular () . Despite the higher plasma concentration of nisoldipine in the elderly, there was no consistent difference in their blood pressure response except that the lowest clinical dose was somewhat more effective than in non-elderly patients. No postural effect on blood pressure was apparent and there was no evidence of tolerance to the antihypertensive effect of Sular () in patients treated for up to one year.
Sular () is an extended release tablet and should be swallowed whole. Tablets should not be chewed, divided or crushed. Sular () should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit juice, which has been shown to increase significantly the bioavailability of nisoldipine and other dihydropyridine type calcium channel blockers, should not be taken with Sular () .
This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose {MRHD} on a mg/m basis, respectively and female mice for up to 21 months (mean doses of up to 217 mg/kg/day, 20 times the MRHD on a mg/m basis) revealed no evidence of tumorigenic effect of nisoldipine. In male mice receiving a mean dose of 163 mg nisoldipine/kg/day (16 times the MRHD of 60 mg/day on a mg/m basis), an increased frequency of stomach papilloma, but still within the historical range, was observed. No evidence of stomach neoplasia was observed at lower doses (up to 58 mg/kg/day). Nisoldipine was negative when tested in a battery of genotoxicity assays including the Ames test and the CHO/HGRPT assay for mutagenicity and the mouse micronucleus test and CHO cell test for clastogenicity.
When administered to male and female rats at doses of up to 30 mg/kg/day (about 5 times the MRHD on a mg/m basis) nisoldipine had no effect on fertility.
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.
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.
