Sular

Generic Name: Nisoldipine
Class: Dihydropyridines
VA Class: CV200
Chemical Name: Methyl 2-methylpropyl ester 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid
Molecular Formula: C20H24N2O6
CAS Number: 63675-72-9

Introduction

Calcium-channel blocking agent; dihydropyridine derivative.1 2 3 4 5 6 8 9 10 11 12 42 45

Uses for Sular

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 11 12 500

Calcium-channel blockers are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

Slideshow: 2014 Update - First Time Brand-to-Generic Switches

Calcium-channel blockers may be preferred in hypertensive patients with certain coexisting conditions (e.g., ischemic heart disease)45 523 and in geriatric patients, including those with isolated systolic hypertension.502 510

Black hypertensive patients generally respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).500 501 504 However, diminished response to these other drug classes is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

Should not be used for acute management of hypertensive crises.46

Sular Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

  • Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

Administration

Oral Administration

Administer orally1 2 3 5 6 7 8 11 12 42 on an empty stomach (1 hour before or 2 hours after a meal);600 avoid concomitant administration with high-fat food.42 600

Extended-release tablets should be swallowed intact and should not be chewed, broken, or crushed.600

Dosage

Reformulated extended-release tablets containing 8.5 or 34 mg of nisoldipine are bioequivalent to original extended-release formulation (no longer commercially available) containing 10 or 40 mg, respectively.84

Adults

Hypertension
Extended-release Tablets
Oral

Manufacturer recommends initial dosage of 17 mg once daily.600

Increase as tolerated in increments of 8.5 mg daily at weekly or less frequent intervals up to 34 mg once daily.600 Monitor BP carefully during initial titration or subsequent upward adjustment in dosage.600

Manufacturer states usual maintenance dosage is 17–34 mg once daily.600

Experts have recommended usual dosage of 10–40 mg once daily as the original extended-release formulation (equivalent to 8.5–34 mg once daily as the reformulated extended-release tablets).84 500

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Prescribing Limits

Adults

Hypertension
Oral

Maximum 34 mg daily.600

Special Populations

Hepatic Impairment

Initially, 8.5 mg daily; monitor BP response closely with each dosage adjustment.600

Reduce initial and maintenance dosages in patients with cirrhosis.1

Renal Impairment

Dosage modification not necessary in patients with mild to moderate renal impairment.1

Geriatric Patients

Initially, 8.5 mg daily; monitor BP response closely with each dosage adjustment.600

Cautions for Sular

Contraindications

  • Known hypersensitivity to nisoldipine or other dihydropyridine-derivative calcium channel blockers.1

Warnings/Precautions

Warnings

Increased Angina and/or Acute MI

Rarely, increased frequency, duration, and/or severity of angina or acute MI, particularly in patients with severe obstructive CAD, upon initiation or dosage increase of calcium-channel blockers.1

Sensitivity Reactions

Tartrazine Sensitivity

Some preparations may contain tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals.600 Incidence of tartrazine sensitivity is low, but it frequently occurs in patients who are sensitive to aspirin.600

General Precautions

Hypotension

Risk of excessive, poorly tolerated hypotension; usually occurs during initial dosage titration or subsequent upward titration.1 Carefully monitor BP, especially during therapy initiation, titration, or dosage increase; closely observe patients currently receiving drugs known to lower BP.1

Heart Failure

Use with caution in patients with heart failure or compromised ventricular function, especially in those receiving concomitant β-adrenergic blocking agents.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether nisoldipine is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Select dosage with caution.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with severe hepatic impairment.1 Dosage reduction required.1 (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Peripheral edema, headache, dizziness, pharyngitis, vasodilation, sinusitis, palpitation, chest pain, nausea, rash.1

Interactions for Sular

Drugs Affecting Hepatic Microsomal Enzymes

Inducers of CYP3A4: Decreased plasma nisoldipine concentrations.1 601 Generally avoid concomitant use.600 601

Inhibitors of CYP3A4: Increased plasma nisoldipine concentrations.600 Generally avoid concomitant use.600

Specific Drugs and Foods

Drug or Food

Interaction

Comments

β-Adrenergic blocking agents

Increased risk of hypotension and exacerbation of heart failure1

Digoxin

Pharmacokinetic interaction unlikely1

Grapefruit juice

Increased nisoldipine bioavailability1

Avoid grapefruit-containing foods and beverages for at least 1 hour before and after administration of a dose1 44 46

Histamine H2-receptor antagonists

Possible increased nisoldipine concentrations with cimetidine; no significant interaction with ranitidine1

Phenytoin

Decreased plasma concentrations of nisoldipine to undetectable levels1

Avoid concomitant use1

Quinidine

Possible decreased AUC of nisoldipine1

Clinical significance unknown1

Warfarin

Pharmacokinetic interaction unlikely1

Sular Pharmacokinetics

Absorption

Bioavailability

Relatively well absorbed from the GI tract following oral administration,600 601 with peak plasma concentrations attained in about 9.2 hours.600

Absolute bioavailability is low (about 5%), due to presystemic metabolism in the intestine; presystemic metabolism decreases from proximal to distal parts of intestine.1 600 601 602 Bioavailability of extended-release preparation is increased since nisoldipine is released in the colon where presystemic metabolism is reduced.1 601 602

Food

A high-fat meal increases peak plasma concentrations by up to 245%, but decreases AUC by 25%.600

Special Populations

In geriatric patients, plasma concentrations increased about 2- to 3-fold.1

In patients with hepatic cirrhosis, plasma concentrations increased by 4–5 times.1

Distribution

Extent

Not known whether nisoldipine is distributed into milk.1

Plasma Protein Binding

>99%.1 601

Elimination

Metabolism

Extensively metabolized; major pathway appears to involve hydroxylation.600 Thought to be metabolized principally by CYP isoenzymes.1 Precise enzymes responsible for metabolism are unknown, but other dihydropyridine-derivative calcium-channel blocking agents are metabolized by CYP3A4.1

Elimination Route

Excreted principally in urine (60–80%) as metabolites.1

Half-life

Approximately 13.7 hours.600

Stability

Storage

Oral

Extended-Release Tablets

Tight, light-resistant containers at 20–25°C.1 Protect from light and moisture.1

Actions

  • Inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells.1

  • Peripheral arterial vasodilator; acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance (afterload) and BP.1

Advice to Patients

  • Importance of swallowing extended-release tablets whole; do not chew, crush, or break.1

  • Importance of avoiding administration with a high-fat meal; administer 1 hour before or 2 hours after a meal.600

  • Importance of avoiding grapefruit-containing foods and beverages for at least 1 hour before and after administration of a dose.1 44 46

  • Importance of informing patients that some preparations may contain tartrazine.600

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nisoldipine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release, film-coated

8.5 mg*

Nisoldipine Extended-release Tablets

Sular

Shionogi

17 mg*

Nisoldipine Extended-release Tablets

Sular

Shionogi

25.5 mg*

Nisoldipine Extended-release Tablets

34 mg*

Nisoldipine Extended-release Tablets

Sular

Shionogi

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 01/2015. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nisoldipine 17MG 24-hr Tablets (MYLAN): 30/$189.98 or 90/$539.96

Nisoldipine 20MG 24-hr Tablets (MYLAN): 30/$200.00 or 90/$575.95

Nisoldipine 25.5MG 24-hr Tablets (MYLAN): 30/$218.00 or 90/$623.99

Nisoldipine 30MG 24-hr Tablets (MYLAN): 30/$219.00 or 90/$614.97

Nisoldipine 40MG 24-hr Tablets (MYLAN): 30/$220.48 or 90/$616.47

Nisoldipine 8.5MG 24-hr Tablets (MYLAN): 30/$156.98 or 90/$438.95

Sular 17MG 24-hr Tablets (SHIONOGI PHARMA): 100/$1,000.01 or 300/$2,995.08

Sular 25.5MG 24-hr Tablets (SHIONOGI PHARMA): 100/$939.54 or 300/$2,807.02

Sular 34MG 24-hr Tablets (SHIONOGI PHARMA): 100/$905.00 or 300/$2,702.64

Sular 8.5MG 24-hr Tablets (SHIONOGI PHARMA): 100/$658.92 or 300/$1,959.49

AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions January 6, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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