Nisoldipine (nisoldipine)

Extended-release nisoldipine hydrogel tablets containing 8.5, 17, 25.5, and 34 mg of nisoldipine are bioequivalent to the extended-release formulations containing 10 (no longer commercially available), 20, 30, and 40 mg, respectively.

Nisoldipine is administered orally as extended-release tablets. Nisoldipine is commercially available as a hydrogel extended-release tablet formulation (Sular(R) and generic equivalents) and as extended-release generic tablet preparations; the tablets should be swallowed intact and should not be chewed, broken, divided, or crushed.

Nisoldipine extended-release tablets should be administered on an empty stomach (1 hour before or 2 hours after a meal); because high-fat food increases the peak concentration of nisoldipine, concomitant administration of the drug with such food should be avoided. In addition, because grapefruit juice increases peak concentrations and oral bioavailability of the drug, patients should be instructed to avoid grapefruit-containing foods and beverages before and after administration of a dose of nisoldipine.

Store nisoldipine extended-release tablets (Sular(R)) at 20-25degreesC (excursions permitted to 15-30degreesC) in a tight, light-resistant container; protect from light and moisture. The manufacturer of generic preparations of nisoldipine extended-release tablets recommends that the drug be stored at 20-25degreesC in a tight, light-resistant container, protected from light and moisture.

Nisoldipine is a substrate of cytochrome P-450 (CYP) isoenzyme 3A4.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Felodipine;Nisoldipine/Itraconazol;Ketoconazol;Levoketocon

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Itraconazole(1), ketoconazole(2), and levoketoconazole(3) may inhibit the metabolism of felodipine by CYP3A4. Nisoldipine has a low absolute bioavailability of approximately 5% due to intestinal and hepatic first-pass metabolism by CYP3A4.(4) FDA designates nisoldipine as a CYP3A4 sensitive substrate, i.e. a drug whose plasma area-under-curve (AUC) has been shown to increase 5-fold or more in the presence of a strong inhibitor of CYP3A4.(5) Both itraconazole(1,5-6) and ketoconazole(2,5-6) are strong inhibitors of CYP3A4. In addition, itraconazole has been shown to have negative inotropic effects, which may be additive with those of nisoldipine.(1)

CLINICAL EFFECTS: The concurrent administration of itraconazole or ketoconazole may result in a 6 to 8 fold increase in felodipine AUC(1) or a 10 to 24-fold increase in nisoldipine AUC(1) leading to adverse effects such as severe hypotension or peripheral edema.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of itraconazole(1,7,8), ketoconazole(2,9), or levoketoconazole(3) with felodipine or nisoldipine is contraindicated. The US manufacturer of itraconazole states that concurrent administration with felodipine or nisoldipine is contraindicated during and two weeks after itraconazole treatment.(1) While all dihydropyridine calcium channel blockers are metabolized and could be affected by CYP3A4 inhibitors, nisoldipine and felodipine are particularly sensitive to CYP3A4 inhibition.(6) If ketoconazole or itraconazole therapy is required, it would be prudent to change to a low dose of a different dihydropyridine with careful monitoring for adverse effects.

DISCUSSION: A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole on felodipine. The area-under-curve (AUC) and half-life of felodipine increased by 6-fold and 2-fold, respectively, during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(10) There are two case reports of patients developing edema following the addition of itraconazole to felodipine therapy. In the second report, the patient was rechallenged with concurrent itraconazole and again developed edema.(11) Concurrent use of itraconazole produces clinically significant increases in nisoldipine levels that cannot be managed by dosage adjustment.(1) A randomized cross-over trial in seven subjects examined the effects of ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily). The concurrent use of ketoconazole increased the nisoldipine AUC and Cmax by 24-fold and 11-fold, respectively. Increases in the M9 nisoldipine metabolite were similar.(12) A study in 14 healthy volunteers with concurrent administration of levoketoconazole (400 mg once daily) with felodipine increased the felodipine AUC and Cmax by 1007.3% and 937.1%.(3)

Nifedipine; Nimodipine; Nisoldipine/Slt Strong 3A4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone may induce the CYP3A4 mediated metabolism of nifedipine,(1) and nimodipine,(2,3) and nisoldipine.(4) Nisoldipine is particularly susceptible to changes in CYP3A4 activity.(4,5)

CLINICAL EFFECTS: Concurrent use of barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone may result in decreased levels and effectiveness of nifedipine(1), nimodipine or nisoldipine.(6)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Due to the risk for treatment failure, use an alternative agent if possible. The US manufacturer of nifedipine states that the concurrent use of strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, or primidone is contraindicated because efficacy could be significantly reduced.(1) The UK manufacturer of nimodipine states that the concurrent use of carbamazepine, phenobarbital, phenytoin, or primidone is contraindicated.(2) The US manufacturer of nimodipine states that the concurrent use of strong CYP3A4 inducers should generally be avoided due to decreased nimodipine plasma concentrations and significantly reduced efficacy.(6) The US manufacturer of nisoldipine states it should generally not be coadministered with CYP3A4 inducers. Concurrent administration of phenytoin with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below detectable levels.(7)

DISCUSSION: Coadministration of phenytoin with nifedipine (10 mg capsule and 60 mg extended-release tablet) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of nifedipine by 70%.(1) A study examined nimodipine pharmacokinetics in three groups: normal drug-free controls (n=8), epileptic patients taking enzyme-inducing anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine, n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin, n=1), and epileptic patients taking valproic acid (n=8). In patients taking enzyme-inducing anticonvulsants, nimodipine AUC, Cmax, and half-life (T1/2) were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls. In patients taking valproic acid, nimodipine AUC was 54.5% higher than in control patients.(3) Concurrent administration of phenytoin with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below detectable levels.(7) In a study comparing patients receiving chronic phenytoin therapy to healthy controls, phenytoin decreased the AUC of a single dose of nisoldipine by 89%.(8)

Nisoldipine/Selected Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: CYP3A4 inducers may induce the hepatic metabolism of nisoldipine.(1)

CLINICAL EFFECTS: Concurrent use of an inducer of CYP3A4 may decrease levels and effectiveness of nisoldipine.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of nisoldipine states it should generally not be coadministered with CYP3A4 inducers.(1)

DISCUSSION: Concurrent administration of phenytoin with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below detectable levels.(1) In a study comparing patients receiving chronic phenytoin therapy to healthy controls, phenytoin decreased the AUC of a single dose of nisoldipine by 89%.(2) Selected CYP3A4 inducers linked to this monograph include apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane and St. John's Wort.(3,4)

Selected Cyp3a4 Substrates/Mifepristone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1)

CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2)

PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1)

DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.

Selected Sensitive Cyp3a4 Substrates/Adagrasib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of adagrasib states that coadministration of CYP3A4 substrates should be avoided.(1)

DISCUSSION: In a study, adagrasib (400 mg twice daily) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib (600 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 31-fold and 3.1-fold, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: atazanavir, atorvastatin, brotizolam, darunavir, ebastine, eletriptan, indinavir, nisoldipine, paritaprevir, and tipranavir.(1-3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Calcium Channel Blockers/Dantrolene

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Dantrolene may decrease the release of calcium from the sarcoplasmic reticulum, resulting in additive or synergistic effects with calcium channel blockers.(1)

CLINICAL EFFECTS: Concurrent use of dantrolene and calcium channel blockers may result in cardiogenic shock.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US, UK, and Australian manufacturers of dantrolene state that concurrent use with calcium channel blockers during the management of malignant hyperthermia crisis is not recommended.(2-4) The Australian and UK manufacturers of diltiazem state that concurrent use of dantrolene infusion with calcium channel blockers is contraindicated.(5-6)

DISCUSSION: Cardiogenic shock in patients treated simultaneously with verapamil and dantrolene is rare but has been reported.(2-4,7) Concurrent use of dantrolene and verapamil in swine has been reported to result in cardiogenic shock and hyperkalemia.(8) In dogs, the combination has been reported to cause hyperkalemia.(9) The combination of diltiazem and dantrolene has been reported to cause adverse cardiovascular effects in swine.(10) A study in swine showed no adverse effects from the combination of dantrolene and nifedipine(10) and one patient who experience cardiogenic shock with dantrolene and verapamil had no adverse effects with the combination of dantrolene and nifedipine;(7) however, the US manufacturer cannot endorse the safety of the combination.(2)

Selected Calcium Channel Blockers/Rifamycins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Multiple mechanisms appear to be involved. Rifampin may increase the hepatic metabolism of the calcium channel blockers, increase first-pass hepatic metabolism of oral calcium channel blockers, and decrease the protein binding of calcium channel blockers.(1-8)

CLINICAL EFFECTS: Concurrent use of rifampin may decrease levels and effectiveness of the calcium channel blocker.(1-8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Observe the patient for a decrease in the therapeutic effects of the calcium channel blocker if rifampin is initiated. The dose of the calcium channel blocker may need to be adjusted if rifampin is initiated or discontinued.(1-7) The US manufacturer of diltiazem states that concurrent use should be avoided.(2) The manufacturer of lercanidipine states that concurrent use is not recommended.(10)

DISCUSSION: In healthy subjects, pretreatment with rifampin (600 mg daily) reduced the concentration of a single dose of isradipine (5 mg) below a detectable level. The study concluded that the concentrations and effects of isradipine may be either reduced or absent as a result of increased isradipine metabolism.(1) Concurrent administration of rifampin has been shown to lower diltiazem levels below detectable limits.(2) In a study in 5 healthy subjects, pretreatment with rifampin (6 days) decreased the area-under-curve (AUC) of a single oral dose of nilvadipine (4 mg) by 96.5%. Pretreatment with rifampin abolished nilvadipine-induced hypotensive effects and tachycardia.(3) A study in six subjects examined the effects of pretreatment with rifampin (600 mg daily for 15 days) on single doses of verapamil (10 mg intravenously or 120 mg orally). Rifampin significantly decreased the maximum concentration (Cmax) and AUC of oral verapamil and resulted in no changes in the P-R interval. There were small decreases in the AUC of intravenous verapamil.(4) In a study in 8 male subjects, pretreatment with rifampin (600 mg daily for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and the apparent oral-clearance of S-verapamil by 32-fold. The bioavailability of S-verapamil decreased 25-fold. The effect of oral verapamil on AV conduction was almost abolished. No significant changes were noted for intravenous administration of verapamil.(5) In a study in 16 hypertensive chronic kidney disease patients, amlodipine levels decreased an average of 82% after initiation of rifampin. In eight of the 16 patients, the levels were undetectable.(9) There have been case reports of decreased effectiveness of barnidipine,(6) manidipine,(6) nisoldipine,(6) and verapamil(7,8) during concurrent rifampin therapy.

Selected Calcium Channel Blockers/Selected Macrolides

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Some macrolides may inhibit metabolism of calcium channel blockers.(1) In some patients, calcium channel blockers may inhibit the metabolism of the macrolide. Some macrolides have been associated with cardiac arrhythmias, including torsades de pointes.(2)

CLINICAL EFFECTS: In some patients, concurrent use may result in elevated levels of and effects from the calcium channel blockers, including hypotension,(2,3) shock,(2) and acute kidney failure.(3) In others, elevated levels of the macrolide may occur, which may increase the risk of sudden death from cardiac causes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid the concurrent use of calcium channel blockers with macrolides that inhibit CYP.(1,2) Depending on the infection, azithromycin may be an alternative in patients maintained on calcium channel blockers.(1) If concurrent use is required, monitor patients for and instruct them to report signs of hypotension, cardiac arrhythmias, or renal failure.

DISCUSSION: A retrospective review examined sudden cardiac death in Tennessee Medicaid patients. Erythromycin use increased the risk of sudden cardiac death by 1.79-fold. Concurrent use of erythromycin with a potent inhibitor of CYP3A4 (diltiazem, fluconazole, itraconazole, ketoconazole, troleandomycin, or verapamil) increased the risk of sudden cardiac death by 5.35-fold when compared to patients receiving no antibiotic therapy.(2) In a retrospective review of residents of Ontario, Canada aged 66 or older who were receiving calcium channel blockers, use of clarithromycin and erythromycin were associated with an increased risk of hospitalization for hypotension (odds ratio 3.7 and 5.8, respectively). There was no association between use of azithromycin and hospitalization for hypotension.(2) In a retrospective review of residents of Ontario, Canada aged 65 or older who were receiving calcium channel blockers, use of clarithromycin was associated with an increased risk of hospitalization with acute kidney injury when compared to use of azithromycin (0.44% of patients versus 0.22% - odds ratio 1.98). Risk was highest with the use of nifedipine (odds ratio 5.33). Use of clarithromycin was also associated with a higher risk of hospitalization with hypotension (0.12% of patients versus 0.07%, odds ratio 1.60) and all-cause mortality (1.02% of patients versus 0.59%, odds ratio 1.74).(3) In a cross-over study in 12 healthy male subjects, the administration of a single dose of felodipine (10 mg extended-release) after four doses of erythromycin (250 mg) resulted in an increase in felodipine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 149%, 127%, and 61%, respectively. Concurrent administration increased dehydrofelodipine AUC, Cmax, and half-life by 92%, 56%, and 93%, respectively, when compared to felodipine administration alone. Concurrent administration of felodipine and erythromycin decreased felodipine M3 metabolite AUC and Cmax concentrations by 41% and 36%, respectively. The extent of the interaction was extremely variable between subjects.(4) In a case report, a 43 year-old female developed palpitations, flushing, ankle edema, and hypotension 2-4 days after the addition of erythromycin to felodipine therapy. Felodipine levels were found to be elevated.(5) In a case report, a 77 year-old male developed shock, heart block, and multi-organ failure two days after the addition of clarithromycin to nifedipine therapy.(6) In a case report, a 76 year-old female developed hypotension, bradycardia, shortness of breath, and weakness two days after the addition of telithromycin to verapamil therapy.(7)

Selected Cyp3a4 Substrates/Ceritinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ceritinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of ceritinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents. Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: cyclosporine, felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.(1,2)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing ceritinib.(1) Patients maintained on ceritinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects.

DISCUSSION: In a study, ceritinib (750 mg daily for 3 weeks) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to midazolam alone.(1) Thus, ceritinib is expected to increase levels of cyclosporine, felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.

Selected Cyp3a4 Substrates/Crizotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Crizotinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of crizotinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents.(1) Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, simvastatin, and sirolimus.(1-2)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition.

PATIENT MANAGEMENT: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing crizotinib.(1) Patients maintained on crizotinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects. Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(3)

DISCUSSION: Crizotinib (250 mg twice daily for 28 days) increased the area-under-curve (AUC) of oral midazolam by 3.7-fold.(1) Thus, crizotinib is expected to increase levels of abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, and simvastatin.

Selected Cyp3a4 Substrates/Lonafarnib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lonafarnib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus.

CLINICAL EFFECTS: Concurrent use of lonafarnib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lonafarnib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, monitor for adverse effects and consider dose reduction of the CYP3A4 substrate according to its prescribing information.(1) The manufacturer of lonafarnib states that the dose of P-gp substrates may need to be reduced with coadministration with lonafarnib.(1)

DISCUSSION: In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%, respectively.(1) In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24% and 21%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: bromocriptine, cabergoline, cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine, mefloquine, nisoldipine, oliceridine, regorafenib, sirolimus, and zanubrutinib.(1-3)

Selected Cyp3a4 Substrates/Pexidartinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Pexidartinib is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of pexidartinib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pexidartinib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: everolimus, felodipine, fentanyl, hydroquinidine, midazolam, nisoldipine, quinidine, sirolimus, tacrolimus, ticagrelor, and triazolam.(1-3)

Selected Cyp3a4 Substrates/Sotorasib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sotorasib is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of sotorasib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of sotorasib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: Coadministration of sotorasib with midazolam, a sensitive CYP3A4 substrate, decreased midazolam area-under-curve (AUC) by 53% and maximum concentration (Cmax) by 48%.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: felodipine, fentanyl, hydroquinidine, parenteral lefamulin, midazolam, nisoldipine, quinidine, tacrolimus, ticagrelor, and triazolam.(2,3)

Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)

CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)

DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)

Selected Sensitive Cyp3a4 Substrates/Tucatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tucatinib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Tucatinib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus.

CLINICAL EFFECTS: Concurrent use of tucatinib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tucatinib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, consider dose reduction of the CYP3A4 substrate.(1) The manufacturer of tucatinib states that the dose of P-gp substrates may need to be reduced with coadministration with tucatinib.(1)

DISCUSSION: In a study, tucatinib increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (2 mg) by 5.7-fold and 3-fold, respectively.(1) In a study, tucatinib increased the AUC and Cmax of digoxin (0.5 mg single dose) by 1.5-fold and 2.4-fold, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: cyclosporine, midazolam, nisoldipine, and sirolimus.(1-3)

Selected Sensitive Cyp3a4 Substrates/Voxelotor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Voxelotor is an inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of voxelotor may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: A greater risk for serious adverse events would be expected from drugs having a narrow therapeutic window.

PATIENT MANAGEMENT: The manufacturer of voxelotor states that co-administration of sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. If concomitant use is unavoidable, consider dose reduction of the sensitive substrate.(1)

DISCUSSION: In a study, voxelotor increased the AUC of a single dose of midazolam by 1.6-fold. After multiple doses of midazolam, a 2.5-fold increase in AUC is predicted.(1) Sensitive CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: avanafil, conivaptan, cyclosporine, dihydroergotamine, eplerenone, ergotamine, everolimus, felodipine, fentanyl, lomitapide, lovastatin, methylergonovine, midazolam, nisoldipine, sildenafil, simvastatin, ticagrelor, tolvaptan, triazolam, and vardenafil.(2,3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Calcium Channel Blockers/Selected Hepatitis C Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Boceprevir(1), ombitasvir-paritaprevir-ritonavir,(2) or telaprevir(3) may inhibit the metabolism of calcium channel blockers by CYP3A4.

CLINICAL EFFECTS: Concurrent use of boceprevir, ombitasvir-paritaprevir-ritonavir, or telaprevir may result in elevated levels of and toxicity from calcium channel blockers.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with either boceprevir, ombitasvir-paritaprevir-ritonavir, or telaprevir and amlodipine for increased calcium channel blocker effects. The dosage of the calcium channel blocker may need to be adjusted(1,3) or an alternative agent considered.(1,3) The US manufacturer of ombitasvir-paritaprevir-ritonavir states that when administered concomitantly with amlodipine the dose of amlodipine should be decreased by at least 50%. Monitor patients for edema and/or signs and symptoms of hypotension. If these events occur, consider further dose reduction of amlodipine or switching to an alternative calcium channel blocker.

DISCUSSION: In a study in 19 healthy subjects, telaprevir (750 mg every 8 hours for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of amlodipine (5mg) by 1.27-fold and 2.79-fold, respectively.(3,4) In an interaction study, 26 healthy subjects were given ombitasvir-paritaprevir-ritonavir and dasabuvir for 24 days. A single dose of amlodipine 5 mg was given on day 1 and 14 of therapy. Amlodipine AUC increased 2.1-fold and the half-life increased from 42 (+ or - 6.7) hours to 104 (+ or - 18) hours.(5)

Felodipine; Nisoldipine/Selected Azole Antifungals

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Azole antifungal agents may inhibit the first-pass and elimination metabolism of calcium channel blockers by CYP3A4.

CLINICAL EFFECTS: The concurrent administration of azole antifungals with calcium channel blockers metabolized by CYP3A4 may result in elevated levels of the calcium channel blocker and adverse effects, including hypotension and edema.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of azole antifungals with calcium channel blockers should be approached with caution. When these agents are used concurrently, the dose of the calcium channel blocker may need to be decreased and patients should be observed for increased effects. If the azole antifungal is discontinued, the dose of the calcium channel blocker may need to be increased and patients should be observed for decreased effects.

DISCUSSION: A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole on felodipine. The half-life of felodipine increased by 71% during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(1,2) There are two case reports of patients developing edema following the addition of itraconazole to felodipine therapy. In the second report, the patient was rechallenged with concurrent itraconazole and again developed edema.(3) In a case report, following the withdrawal of fluconazole from concurrent nifedipine therapy, a loss in blood-pressure control occurred.(4) In another report, a patient developed edema following the addition of itraconazole to nifedipine therapy.(5) A randomized cross-over trial in seven subjects examined the effects of ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily). The concurrent use of ketoconazole increased the nisoldipine area-under-curve (AUC) and Cmax by 24-fold and 11-fold, respectively. Increases in the M9 nisoldipine metabolite were similar.(6) Posaconazole has been shown to inhibit CYP3A4.(7,8) Voriconazole has been shown to inhibit the metabolism of felodipine in vitro.(9)

Selected Antihypertensive Agents/Selected Maois

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2)

CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension.

DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine, moxonidine, and sparsentan.

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives/Tizanidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

Selected Calcium Channel Blockers/Cimetidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cimetidine may decrease the metabolism of diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and nitrendipine.

CLINICAL EFFECTS: The pharmacological effects of the calcium channel blocker may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Observe the patient for changes in clinical response to the calcium channel blocker when starting or stopping cimetidine. The dosage of the calcium channel blocker may need to be adjusted. Ideally, suggest an alternative H-2 antagonist such as famotidine, nizatidine, or ranitidine.

DISCUSSION: Significant effects have been observed during concurrent administration of nifedipine or felodipine with cimetidine. During combined administration of nifedipine and cimetidine in six healthy volunteers, the area-under-curve (AUC) of nifedipine was increased by 80% compared to nifedipine alone. Increased heart rate and a drop in mean arterial pressure 14 mmHg were also reported. Ranitidine showed only a nonsignificant 25% rise in peak plasma levels of nifedipine and no effects on blood pressure. Similar results were reported in another study where concurrent administration of felodipine and cimetidine resulted in an increase in felodipine AUC and maximum concentration (Cmax) by 50%. Concurrent administration of cimetidine has also been shown to increase the AUC and Cmax of diltiazem by 53% and 58%, respectively. The manufacturers of isradipine and nicardipine recommend carefully monitoring patients receiving concurrent therapy with cimetidine. The manufacturer of isradipine states that concurrent therapy with cimetidine has been shown to increase the AUC of isradipine by 50%. The manufacturer of nifedipine states that careful titration is necessary in patients receiving concurrent therapy. The manufacturers of felodipine and diltiazem state that dosage adjustments may be necessary in patients receiving concurrent therapy. Ranitidine has much less affinity for CYP metabolism than cimetidine and would therefore be expected to have less of an effect on calcium channel blocker metabolism. Studies have shown that nizatidine and famotidine do not inhibit CYP3A4 metabolism.

Selected Sensitive Cyp3a4 Substrates/Schisandra

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

*Known hypersensitivity to nisoldipine, any ingredient in the formulation, or other dihydropyridine-derivative calcium-channel blockers.

• Severe hypotension

• Hypotension
• Severe coronary artery disease

• Chronic heart failure
• Severe hepatic disease

The most common adverse effects of nisoldipine in clinical studies were peripheral edema, headache, dizziness, pharyngitis, vasodilation, sinusitis, palpitation, chest pain, nausea, and rash.

More Frequent

• Peripheral edema

Less Frequent

• Chest pain
• Hypotension
• Progressive angina pectoris
• Skin rash

Rare or Very Rare

• Acute myocardial infarction
• Anemia
• Angioedema
• Atrial fibrillation
• Cellulitis
• Cerebral ischemia
• Cerebrovascular accident
• Chest tightness
• Chronic heart failure
• Colitis
• Diabetes mellitus
• Dyspnea
• Exfoliative dermatitis
• First degree atrioventricular heart block
• Gastrointestinal hemorrhage
• Gingival hyperplasia
• Glaucoma
• Hepatomegaly
• Hypersensitivity drug reaction
• Hypokalemia
• Keratoconjunctivitis
• Leukopenia
• Maculopapular rash
• Myositis
• Orthostatic hypotension
• Peripheral venous insufficiency
• Pleural effusions
• Retinal detachment
• Supraventricular tachycardia
• Tachycardia
• Thyroiditis
• Ventricular premature beats

More Frequent

• Headache disorder

Less Frequent

• Dizziness
• Nausea
• Palpitations
• Pharyngitis
• Sinusitis
• Vasodilation of blood vessels

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal vaginal bleeding
• Acne vulgaris
• Acute bacterial otitis media
• Acute cognitive impairment
• Alopecia
• Anorexia
• Aphthous stomatitis
• Arthralgia
• Arthritis
• Asthma
• Ataxia
• Black tarry stools
• Blepharitis
• Chills
• Conjunctivitis
• Cough
• Cramps in legs
• Depression
• Diarrhea
• Dream disorder
• Drowsy
• Dry skin
• Dyschromia
• Dysgeusia
• Dyspepsia
• Dysphagia
• Dysuria
• Earache
• Ecchymosis
• Epistaxis
• Erectile dysfunction
• Eye tearing
• Facial edema
• Fever
• Flatulence
• Flu-like symptoms
• Gastritis
• Glossitis
• Gout
• Hematuria
• Hyperhidrosis
• Hypoesthesia
• Hypotonia
• Increased appetite
• Increased urinary frequency
• Insomnia
• Laryngitis
• Libido changes
• Malaise
• Memory impairment
• Myalgia
• Nervousness
• Nocturia
• Ocular itching
• Paresthesia
• Petechiae
• Pruritus of skin
• Rhinitis
• Skin inflammation
• Skin ulcer
• Syncope
• Tenosynovitis
• Tinnitus
• Toxic amblyopia
• Tremor
• Urticaria
• Vaginitis
• Vertigo
• Visual changes
• Vitreous floater
• Weight gain
• Weight loss
• Xerostomia

No enhanced messaging available.

Safety and efficacy of nisoldipine have not been established in pediatric patients younger than 18 years of age.

In animal studies, nisoldipine was not teratogenic, but demonstrated fetotoxicity at maternally toxic doses (reduced maternal body weight gain). Increased fetal resorption (postimplantation loss), decreased fetal and placental weights, and high rates of abortion and mortality, with limb and vertebral abnormalities found in the only surviving fetus, were observed in rats, rabbits, and monkeys, respectively, treated with nisoldipine at doses 5-30 times the maximum recommended human dose (MRHD) on a mg/m2 basis.

There are no adequate and well controlled studies of nisoldipine in pregnant women. Nisoldipine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

It is not known whether nisoldipine is distributed into human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

In geriatric patients older than 65 years of age, the initial dosage should not exceed 8.5 mg daily if using the hydrogel extended-release tablets or 10 mg daily if using generic extended-release tablets, and blood pressure response should be monitored closely with each dosage adjustment.

When nisoldipine is administered to elderly patients, peak plasma concentrations and AUC are 2- to 3-fold higher compared to younger subjects. Clinical studies of nisoldipine did not include sufficient numbers of patients older than 65 years of age to determine whether they respond differently than younger patients. While other clinical experience generally has not revealed age-related differences in response, in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The manufacturer states nisoldipine should be administered cautiously in elderly patients; a lower initial dosage is recommended and blood pressure response should be monitored closely with each dosage adjustment.