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DRUG IMAGES
NISOLDIPINE ER 20 MG TABLET
NISOLDIPINE ER 40 MG TABLET
NISOLDIPINE ER 30 MG TABLET
NISOLDIPINE ER 17 MG TABLET
NISOLDIPINE ER 8.5 MG TABLET
NISOLDIPINE ER 25.5 MG TABLET
NISOLDIPINE ER 34 MG TABLET
The following indications for NISOLDIPINE (nisoldipine) have been approved by the FDA:
Indications:
Hypertension
Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Systemic arterial hypertension
Indications:
Hypertension
Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Systemic arterial hypertension
The following dosing information is available for NISOLDIPINE (nisoldipine):
Although the hypotensive effect of nisoldipine usually is modest and well tolerated, excessive and poorly tolerated hypotension occasionally occurs. Because such exaggerated responses usually have been observed during initial titration or subsequent upward adjustment in dosage of the drug, careful monitoring of blood pressure during these periods is recommended. Close observation is particularly important in patients already receiving drugs known to lower blood pressure.
The reformulated extended-release tablets of nisoldipine containing 8.5 or 34 mg of the drug are bioequivalent to the original extended-release formulation (no longer commercially available) containing 10 or 40 mg, respectively, of the drug.
For the management of hypertension in adults, the manufacturer states that the usual initial dosage of nisoldipine extended-release tablets is 17 mg once daily. In geriatric patients older than 65 years of age, the initial dosage should not exceed 8.5 mg daily, and blood pressure response should be monitored closely with each dosage adjustment.
If blood pressure response is inadequate with the initial dosage, nisoldipine dosage may be increased in increments of 8.5 mg daily at weekly or less frequent intervals up to a maximum of 34 mg once daily. The usual maintenance dosage of the drug is 17-34 mg once daily.
Because patients with hepatic impairment may have substantially reduced nisoldipine clearance, the manufacturer recommends that the initial dosage not exceed 8.5 mg daily in such adult patients, and blood pressure response should be monitored closely with each dosage adjustment. Patients with cirrhosis generally require and tolerate lower than usual initial and maintenance dosages of the drug.
Nisoldipine should be administered cautiously in patients with severe hepatic dysfunction.
Since pharmacokinetics and bioavailability of nisoldipine are not altered substantially in patients with mild-to-moderate renal impairment, the manufacturer states that modification of nisoldipine dosage is not necessary in such patients.
The reformulated extended-release tablets of nisoldipine containing 8.5 or 34 mg of the drug are bioequivalent to the original extended-release formulation (no longer commercially available) containing 10 or 40 mg, respectively, of the drug.
For the management of hypertension in adults, the manufacturer states that the usual initial dosage of nisoldipine extended-release tablets is 17 mg once daily. In geriatric patients older than 65 years of age, the initial dosage should not exceed 8.5 mg daily, and blood pressure response should be monitored closely with each dosage adjustment.
If blood pressure response is inadequate with the initial dosage, nisoldipine dosage may be increased in increments of 8.5 mg daily at weekly or less frequent intervals up to a maximum of 34 mg once daily. The usual maintenance dosage of the drug is 17-34 mg once daily.
Because patients with hepatic impairment may have substantially reduced nisoldipine clearance, the manufacturer recommends that the initial dosage not exceed 8.5 mg daily in such adult patients, and blood pressure response should be monitored closely with each dosage adjustment. Patients with cirrhosis generally require and tolerate lower than usual initial and maintenance dosages of the drug.
Nisoldipine should be administered cautiously in patients with severe hepatic dysfunction.
Since pharmacokinetics and bioavailability of nisoldipine are not altered substantially in patients with mild-to-moderate renal impairment, the manufacturer states that modification of nisoldipine dosage is not necessary in such patients.
Nisoldipine is administered orally. The extended-release tablets should be swallowed intact; they should not be chewed, broken, 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 for at least 1 hour before and after administration of a dose of nisoldipine. (See Drugs and Foods Affecting Hepatic Microsomal Enzymes: Grapefruit Juice, in Drug Interactions, in Cyclosporine 92:44.) The manufacturer also states that concomitant use of nisoldipine and any known inducer (e.g., phenytoin) or inhibitor of the cytochrome P-450 (CYP) 3A4 isoenzyme should be avoided and alternative antihypertensive therapy should be considered for patients receiving such agents. Concomitant use of nisoldipine and phenytoin reportedly has resulted in a reduction of plasma nisoldipine concentrations to undetectable levels.
The possibility that nisoldipine may share the drug interaction potential of nifedipine, another 1,4-dihydropyridine derivative, also should be considered and the usual precautions observed. (See Drug Interactions in Nifedipine 24:28.08.) Patients should be advised that some commercially available preparations may contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in individuals who are sensitive to aspirin. The manufacturer states that safety and efficacy of nisoldipine in children have not been established.
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 for at least 1 hour before and after administration of a dose of nisoldipine. (See Drugs and Foods Affecting Hepatic Microsomal Enzymes: Grapefruit Juice, in Drug Interactions, in Cyclosporine 92:44.) The manufacturer also states that concomitant use of nisoldipine and any known inducer (e.g., phenytoin) or inhibitor of the cytochrome P-450 (CYP) 3A4 isoenzyme should be avoided and alternative antihypertensive therapy should be considered for patients receiving such agents. Concomitant use of nisoldipine and phenytoin reportedly has resulted in a reduction of plasma nisoldipine concentrations to undetectable levels.
The possibility that nisoldipine may share the drug interaction potential of nifedipine, another 1,4-dihydropyridine derivative, also should be considered and the usual precautions observed. (See Drug Interactions in Nifedipine 24:28.08.) Patients should be advised that some commercially available preparations may contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in individuals who are sensitive to aspirin. The manufacturer states that safety and efficacy of nisoldipine in children have not been established.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| NISOLDIPINE ER 8.5 MG TABLET | Maintenance | Adults take 1 tablet (8.5 mg) by oral route once daily |
| NISOLDIPINE ER 17 MG TABLET | Maintenance | Adults take 1 tablet (17 mg) by oral route once daily |
| NISOLDIPINE ER 25.5 MG TABLET | Maintenance | Adults take 1 tablet (25.5 mg) by oral route once daily |
| NISOLDIPINE ER 34 MG TABLET | Maintenance | Adults take 1 tablet (34 mg) by oral route once daily |
| NISOLDIPINE ER 20 MG TABLET | Maintenance | Adults take 1 tablet (20 mg) by oral route once daily |
| NISOLDIPINE ER 30 MG TABLET | Maintenance | Adults take 1 tablet (30 mg) by oral route once daily |
| NISOLDIPINE ER 40 MG TABLET | Maintenance | Adults take 1 tablet (40 mg) by oral route once daily |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| NISOLDIPINE ER 8.5 MG TABLET | Maintenance | Adults take 1 tablet (8.5 mg) by oral route once daily |
| NISOLDIPINE ER 17 MG TABLET | Maintenance | Adults take 1 tablet (17 mg) by oral route once daily |
| NISOLDIPINE ER 25.5 MG TABLET | Maintenance | Adults take 1 tablet (25.5 mg) by oral route once daily |
| NISOLDIPINE ER 34 MG TABLET | Maintenance | Adults take 1 tablet (34 mg) by oral route once daily |
| NISOLDIPINE ER 20 MG TABLET | Maintenance | Adults take 1 tablet (20 mg) by oral route once daily |
| NISOLDIPINE ER 30 MG TABLET | Maintenance | Adults take 1 tablet (30 mg) by oral route once daily |
| NISOLDIPINE ER 40 MG TABLET | Maintenance | Adults take 1 tablet (40 mg) by oral route once daily |
The following drug interaction information is available for NISOLDIPINE (nisoldipine):
There are 4 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Nifedipine; Nimodipine; 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: 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) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIMIDONE, SEZABY, TEGRETOL, TEGRETOL XR, TENCON |
| Felodipine; Nisoldipine/Itraconazole; Ketoconazole; Levoketoconazole 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) |
ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, RECORLEV, SPORANOX, TOLSURA |
| 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. |
KORLYM, MIFEPREX, MIFEPRISTONE |
| 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) |
BRAFTOVI, ERLEADA, LYSODREN, MITOTANE, ORKAMBI, TIBSOVO, XTANDI |
There are 11 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| 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. |
PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA |
| Selected Macrolides/Selected Calcium Channel Blockers 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) |
CLARITHROMYCIN, CLARITHROMYCIN ER, E.E.S. 200, E.E.S. 400, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, LANSOPRAZOL-AMOXICIL-CLARITHRO, OMECLAMOX-PAK, VOQUEZNA TRIPLE PAK |
| Dantrolene/Calcium Channel Blockers 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) |
DANTRIUM, DANTROLENE SODIUM, REVONTO, RYANODEX |
| 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. |
ZYKADIA |
| 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.(1,4) 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.(5) 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) 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.(3) 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, alfentanil, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, sirolimus, ticagrelor, triazolam, and ulipristal.(1,4,6) |
XENLETA |
| 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) 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.(4) 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, simvastatin, and sirolimus. |
XALKORI |
| 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) |
TUKYSA |
| 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: alfentanil, everolimus, felodipine, fentanyl, hydroquinidine, midazolam, nisoldipine, quinidine, sirolimus, tacrolimus, ticagrelor, and triazolam.(1-3) |
TURALIO |
| 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, pomalidomide, regorafenib, sirolimus, and zanubrutinib.(1-3) |
ZOKINVY |
| 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: alfentanil, felodipine, fentanyl, hydroquinidine, parenteral lefamulin, midazolam, nisoldipine, quinidine, tacrolimus, ticagrelor, and triazolam.(2,3) |
LUMAKRAS |
| Selected Sensitive CYP3A4 Substrates/Adagrasib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) |
KRAZATI |
There are 6 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| 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. |
CIMETIDINE |
| 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) |
DIFLUCAN, FLUCONAZOLE, FLUCONAZOLE-NACL, NOXAFIL, POSACONAZOLE, VFEND, VFEND IV, VORICONAZOLE |
| Selected MAOIs/Selected Antihypertensive Agents 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 and sparsentan. |
NARDIL, PARNATE, PHENELZINE SULFATE, TRANYLCYPROMINE SULFATE |
| Tizanidine/Selected Antihypertensives 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) |
TIZANIDINE HCL, ZANAFLEX |
| Lacosamide/Beta-Blockers; Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (beta-blockers, calcium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including beta-blockers and calcium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1) DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) Two postmarketing reports of third-degree AV block in patients with significant cardiac history and also receiving metoprolol and amlodipine during infusion of lacosamide injection at doses higher than recommended have been reported.(1) A case report of an 88 year old female taking bisoprolol documented complete AV block after initiation of lacosamide. The patient required pacemaker implementation.(2) |
LACOSAMIDE, MOTPOLY XR, VIMPAT |
| Apomorphine/Selected Antihypertensives and Vasodilators 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) |
APOKYN, APOMORPHINE HCL, ONAPGO |
The following contraindication information is available for NISOLDIPINE (nisoldipine):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 1 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Severe hypotension |
There are 2 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Hypotension |
| Severe coronary artery disease |
There are 2 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Chronic heart failure |
| Severe hepatic disease |
The following adverse reaction information is available for NISOLDIPINE (nisoldipine):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 37 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Peripheral edema |
Chest pain Hypotension Progressive angina pectoris Skin rash |
| Rare/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 |
There are 81 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Headache disorder |
Dizziness Nausea Palpitations Pharyngitis Sinusitis Vasodilation of blood vessels |
| Rare/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 |
The following precautions are available for NISOLDIPINE (nisoldipine):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
No enhanced Pregnancy information available for this drug.
No enhanced Lactation information available for this drug.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for NISOLDIPINE (nisoldipine):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for NISOLDIPINE (nisoldipine)'s list of indications:
| Hypertension | |
| I10 | Essential (primary) hypertension |
| I11 | Hypertensive heart disease |
| I11.0 | Hypertensive heart disease with heart failure |
| I11.9 | Hypertensive heart disease without heart failure |
| I12 | Hypertensive chronic kidney disease |
| I12.0 | Hypertensive chronic kidney disease with stage 5 chronic kidney disease or end stage renal disease |
| I12.9 | Hypertensive chronic kidney disease with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13 | Hypertensive heart and chronic kidney disease |
| I13.0 | Hypertensive heart and chronic kidney disease with heart failure and stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.1 | Hypertensive heart and chronic kidney disease without heart failure |
| I13.10 | Hypertensive heart and chronic kidney disease without heart failure, with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.11 | Hypertensive heart and chronic kidney disease without heart failure, with stage 5 chronic kidney disease, or end stage renal disease |
| I13.2 | Hypertensive heart and chronic kidney disease with heart failure and with stage 5 chronic kidney disease, or end stage renal disease |
| I15.1 | Hypertension secondary to other renal disorders |
Formulary Reference Tool