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Nisoldipine

Class: Dihydropyridines
- Calcium-Channel Blocking Agents, Dihydropyridine
- Calcium Antagonists
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
Brands: Sular

Medically reviewed by Drugs.com on Mar 9, 2021. Written by ASHP.

Introduction

Calcium-channel blocking agent; dihydropyridine derivative.

Uses for Nisoldipine

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).

Calcium-channel blockers are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics. While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.

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).

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Other hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg. Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.

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

Calcium-channel blockers may be particularly useful in black patients with hypertension; such 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). However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.

Should not be used for acute management of hypertensive crises.

Nisoldipine Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.

  • If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.

  • If adequate BP response not achieved with a single antihypertensive agent, either maximize dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, thiazide diuretic). Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved with 2 antihypertensive agents, add a third drug.

Administration

Oral Administration

Administer orally on an empty stomach (1 hour before or 2 hours after a meal); avoid concomitant administration with high-fat food.

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

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.

Adults

Hypertension
Extended-release Tablets
Oral

Manufacturer recommends initial dosage of 17 mg once daily.

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

Usual maintenance dosage:17–34 mg once daily.

Prescribing Limits

Adults

Hypertension
Oral

Maximum 34 mg daily.

Special Populations

Hepatic Impairment

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

Reduce initial and maintenance dosages in patients with cirrhosis.

Renal Impairment

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

Geriatric Patients

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

Cautions for Nisoldipine

Contraindications

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

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.

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. Incidence of tartrazine sensitivity is low, but it frequently occurs in patients who are sensitive to aspirin.

General Precautions

Hypotension

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

Heart Failure

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

Specific Populations

Pregnancy

Category C.

Lactation

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

Pediatric Use

Safety and efficacy not established.

Geriatric Use

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

Hepatic Impairment

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

Common Adverse Effects

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

Interactions for Nisoldipine

Drugs Affecting Hepatic Microsomal Enzymes

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

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

Specific Drugs and Foods

Drug or Food

Interaction

Comments

β-Adrenergic blocking agents

Increased risk of hypotension and exacerbation of heart failure

Digoxin

Pharmacokinetic interaction unlikely

Grapefruit juice

Increased nisoldipine bioavailability

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

Histamine H2-receptor antagonists

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

Phenytoin

Decreased plasma concentrations of nisoldipine to undetectable levels

Avoid concomitant use

Quinidine

Possible decreased AUC of nisoldipine

Clinical significance unknown

Warfarin

Pharmacokinetic interaction unlikely

Nisoldipine Pharmacokinetics

Absorption

Bioavailability

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

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

Food

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

Special Populations

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

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

Distribution

Extent

Not known whether nisoldipine is distributed into milk.

Plasma Protein Binding

>99%.

Elimination

Metabolism

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

Elimination Route

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

Half-life

Approximately 13.7 hours.

Stability

Storage

Oral

Extended-Release Tablets

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

Actions

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

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

Advice to Patients

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

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

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

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

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

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

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* 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

AHFS DI Essentials™. © Copyright 2021, Selected Revisions March 19, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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