Procardia Xl

Drug overview for PROCARDIA XL (nifedipine):

Generic name: NIFEDIPINE (nye-FED-i-peen)
Drug class: Calcium Channel Blockers
Therapeutic class: Cardiovascular Therapy Agents

Nifedipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

PROCARDIA XL 30 MG TABLET
PROCARDIA XL 60 MG TABLET
PROCARDIA XL 90 MG TABLET

The following indications for PROCARDIA XL (nifedipine) have been approved by the FDA:

Indications:
Hypertension
Prevention of anginal pain associated with coronary artery disease
Prevention of anginal pain associated with vasospastic angina

Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Prevention of anginal pain associated with angina inversa
Prevention of anginal pain associated with CAD
Prevention of anginal pain associated with Prinzmetal angina
Prevention of anginal pain associated with variant angina
Systemic arterial hypertension

The following dosing information is available for PROCARDIA XL (nifedipine):

Dosing
Administration
PROCARDIA XL
NIFEDIPINE ER

For the management of hypertension in adults, the usual initial dosage of nifedipine as extended-release tablets is 30 or 60 mg once daily. Generally, dosage is increased gradually at 7- to 14-day intervals until optimum control of blood pressure is obtained. If symptoms so warrant and the patient's tolerance and response to therapy are assessed frequently, dosage may be increased more rapidly.

Steady state usually is achieved during the second day of therapy with a given dose as extended-release tablets. The manufacturers state that dosages exceeding 90 mg once daily (Adalat(R) CC) or 120 mg once daily (Procardia XL(R)) as extended-release tablets are not recommended. Some experts recommend a usual dosage range of 30-90 mg once daily.

If nifedipine is used for the management of hypertension in children+, some experts recommend a usual initial dosage of 0.2-0.5 mg/kg daily, administered as extended-release tablets once daily or in 2 divided doses daily.

Dosage may be increased as necessary to a maximum dosage of 3 mg/kg (up to 120 mg), given once daily or in 2 divided doses. Experts state that the drug should be initiated at the low end of the dosage range and the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Because of concerns about potential cardiovascular risks associated with conventional liquid-filled (short-acting) capsules of the drug, short-acting preparations of nifedipine are no longer recommended for use in the management of hypertension.

Nifedipine is administered orally. The drug also has been administered sublingually+ or intrabuccally+ (e.g., for rapid reduction of blood pressure). When nifedipine is administered sublingually or intrabuccally, the conventional liquid-filled capsule must be punctured, chewed, and/or squeezed to express the liquid into the mouth.

However, based on pharmacokinetic considerations (see Pharmacokinetics: Absorption), some clinicians recommend that when a relatively rapid response is desired the drug preferably be administered as conventional liquid-filled capsules that are bitten and then swallowed. Nifedipine extended-release tablets should be swallowed intact and should not be chewed, crushed, or broken. The manufacturer of Adalat(R) CC states that the extended-release nifedipine tablets should be taken on an empty stomach.

Patients should be advised not to become alarmed if they notice a tablet-like substance in their stools; this is normal since the tablet containing the drug is designed to remain intact and slowly release the drug from a nonabsorbable shell during passage through the GI tract. Whenever extended-release tablets of nifedipine are dispensed or administered, care should be taken to ensure that the extended-release dosage form actually was prescribed. The manufacturers recommend that dosage of extended-release nifedipine tablets should be decreased gradually with close clinical supervision when discontinuance of the drug is required.

The manufacturer of Adalat(R) CC states that two 30-mg Adalat(R) CC extended-release tablets may be interchanged with one 60-mg Adalat(R) CC extended-release tablet; however, three 30-mg Adalat(R) CC extended-release tablets should not be considered interchangeable with one 90-mg Adalat(R) CC extended-release tablet (see Pharmacokinetics: Absorption). Concomitant oral administration of 1,4-dihydropyridine-derivative calcium-channel blocking agents (e.g., nifedipine) with grapefruit juice usually should be avoided since potentially clinically important increases in hemodynamic effects may result. (See Grapefruit Juice under Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes.)

Dosing information for PROCARDIA XL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
PROCARDIA XL 30 MG TABLET	Maintenance	Adults take 1 tablet (30 mg) by oral route once daily
PROCARDIA XL 60 MG TABLET	Maintenance	Adults take 1 tablet (60 mg) by oral route once daily
PROCARDIA XL 90 MG TABLET	Maintenance	Adults take 1 tablet (90 mg) by oral route once daily

Generic dosing information for NIFEDIPINE ER
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
NIFEDIPINE ER 60 MG TABLET	Maintenance	Adults take 1 tablet (60 mg) by oral route once daily
NIFEDIPINE ER 90 MG TABLET	Maintenance	Adults take 1 tablet (90 mg) by oral route once daily
NIFEDIPINE ER 30 MG TABLET	Maintenance	Adults take 1 tablet (30 mg) by oral route once daily

The following drug interaction information is available for PROCARDIA XL (nifedipine):

Contraindicated
Severe
Moderate

There are 2 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
Nifedipine/Selected 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 nifedipine.(1) CLINICAL EFFECTS: Concurrent use of an inducer of CYP3A4 may decrease levels and effectiveness of nifedipine.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inducers with nifedipine is contraindicated.(1) DISCUSSION: In a study in 12 healthy males, pretreatment with rifampin (600 mg daily for 14 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of nifedipine (20 mg) by 95% and 97%, respectively.(1) In a study of 6 healthy subjects, pretreatment with rifampin (600 mg daily for 7 days) increased the clearance of a single oral dose of nifedipine (20 mg) by 9.28-fold and decrease the nifedipine bioavailability by 87%. There were no significant effects on a single intravenous dose of nifedipine.(2) In a study in 6 healthy subjects, pretreatment with a single dose of rifampin (600 mg) 8 hours before a single oral dose of nifedipine decreased nifedipine bioavailability by 64.2%. Nifedipine half-life decreased by 60%. Nifedipine clearance increased by 1.89-fold.(3) There have been case reports of decreased effectiveness of nifedipine during concurrent rifampin therapy.(4-6) Enzalutamide is a strong inducer of CYP3A4.(7) Selected CYP3A4 inducers linked to this monograph include apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin, rifampin, and rifapentine.	BRAFTOVI, ERLEADA, LYSODREN, MITOTANE, ORKAMBI, PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA, TIBSOVO, XTANDI

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

Nifedipine/Selected 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 nifedipine.(1)

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

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

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inducers with nifedipine is contraindicated.(1)

DISCUSSION: In a study in 12 healthy males, pretreatment with rifampin (600 mg daily for 14 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of nifedipine (20 mg) by 95% and 97%, respectively.(1) In a study of 6 healthy subjects, pretreatment with rifampin (600 mg daily for 7 days) increased the clearance of a single oral dose of nifedipine (20 mg) by 9.28-fold and decrease the nifedipine bioavailability by 87%.

There were no significant effects on a single intravenous dose of nifedipine.(2) In a study in 6 healthy subjects, pretreatment with a single dose of rifampin (600 mg) 8 hours before a single oral dose of nifedipine decreased nifedipine bioavailability by 64.2%.

Nifedipine half-life decreased by 60%. Nifedipine clearance increased by 1.89-fold.(3)

There have been case reports of decreased effectiveness of nifedipine during concurrent rifampin therapy.(4-6) Enzalutamide is a strong inducer of CYP3A4.(7) Selected CYP3A4 inducers linked to this monograph include apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin, rifampin, and rifapentine.

BRAFTOVI, ERLEADA, LYSODREN, MITOTANE, ORKAMBI, PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA, TIBSOVO, XTANDI

There are 3 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 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
Cladribine/Selected Inhibitors of CNT or ENT SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of concentrative nucleoside transporters (CNT) or equilibrative nucleoside transporters (ENT) may increase the absorption of cladribine.(1-2) CLINICAL EFFECTS: The concurrent administration of cladribine with an inhibitor of CNT or ENT may result in elevated levels of cladribine and signs of toxicity.(1-2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of cladribine states concurrent use of CNT or ENT inhibitors should be avoided during the 4- to 5-day cladribine treatment.(1-2) Selection of an alternative concurrent medication with no or minimal transporter inhibiting proprieties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of the CNT or ENT inhibitor, separation in timing of administration, and careful patient monitoring is recommended.(1-2) Monitor for signs of hematologic toxicity. Lymphocyte counts should be monitored. DISCUSSION: Cladribine is a substrate of CNT and ENT. Inhibitors of these transporters are expected to increase cladribine levels.(1-2) Nucleoside inhibitors linked to this monograph include: cilostazol, dipyridamole, nifedipine, nimodipine, reserpine, and sulindac.(1-2)	CLADRIBINE, MAVENCLAD

There are 13 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 Beta-blockers/Selected Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Synergistic pharmacologic activity. CLINICAL EFFECTS: May see an increase in the therapeutic and toxic effects of both drugs. Concurrent use in patients with low heart rates may unmask sick sinus syndrome. PREDISPOSING FACTORS: Preexisting left ventricular dysfunction and high doses of the beta-blocking agent may predispose patients to adverse responses to this drug combination. Other possible factors include parenteral administration and concurrent administration of other cardio-depressant drugs such as antiarrhythmics. PATIENT MANAGEMENT: Monitor the patient for signs of increased cardio-depressant effects and hypotension. Adjust the dose accordingly. DISCUSSION: Coadministration of these classes of drugs may be effective in the treatment of angina pectoris and hypertension. Patients should be screened in order to determine who should receive this combination of agents. The concurrent use of mibefradil and beta-blockers in patients with low heart rates may unmask underlying sick sinus syndrome. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	ACEBUTOLOL HCL, ATENOLOL, ATENOLOL-CHLORTHALIDONE, BETAPACE, BETAPACE AF, BETIMOL, BISOPROLOL FUMARATE, BISOPROLOL-HYDROCHLOROTHIAZIDE, BRIMONIDINE TARTRATE-TIMOLOL, BYSTOLIC, CARVEDILOL, CARVEDILOL ER, COMBIGAN, COREG, COREG CR, CORGARD, COSOPT, COSOPT PF, DORZOLAMIDE-TIMOLOL, HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, ISTALOL, KAPSPARGO SPRINKLE, LOPRESSOR, METOPROLOL SUCCINATE, METOPROLOL TARTRATE, METOPROLOL-HYDROCHLOROTHIAZIDE, NADOLOL, NEBIVOLOL HCL, PINDOLOL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID, SOTALOL, SOTALOL AF, SOTALOL HCL, SOTYLIZE, TENORETIC 100, TENORETIC 50, TENORMIN, TIMOLOL, TIMOLOL MALEATE, TIMOLOL-BIMATOPROST, TIMOLOL-BRIMONI-DORZOL-BIMATOP, TIMOLOL-BRIMONIDIN-DORZOLAMIDE, TIMOLOL-DORZOLAMIDE-BIMATOPRST, TIMOPTIC OCUDOSE, TOPROL XL
Digoxin/Selected Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Calcium channel blockers may inhibit the renal clearance of digoxin through an unknown mechanism. CLINICAL EFFECTS: Plasma digoxin concentrations may be elevated. In addition, the negative chronotropic effects of digoxin and bepridil are additive, resulting in a cumulative decrease in heart rate. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias. PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity. PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor serum digoxin levels and observe the patient for symptoms of digoxin toxicity. Upon adding a calcium channel blocker, digoxin should first be decreased in anticipation of interaction, then adjust the dosage accordingly. The dosage of digoxin may need to be decreased by 15-50% or the frequency of administration may be reduced. DISCUSSION: The effect of bepridil on steady-state serum digoxin levels was studied in a randomized, double-blind investigation. Concurrent administration of bepridil and digoxin produced a 34% increase in serum digoxin levels compared to administration of digoxin alone. Concomitant administration of both drugs was associated with additive negative chronotropic effects. Information on the effects of diltiazem on digoxin concentrations are conflicting. Several studies have reported that concurrent use of digoxin and diltiazem led to an increased steady state digoxin level as well as an increased digoxin area-under-curve (AUC) and decreased renal clearance, and reduced volume of distribution. However, one of these studies reported no significant change in digoxin half-life, peak concentration (Cmax), time to Cmax (Tmax), or volume of distribution, and seven other studies reported no effect of diltiazem on serum digoxin concentrations or renal digoxin clearance. Concomitant isradipine administration significantly decreased (by 9%) the the digoxin volume of distribution and increased (by 25%) digoxin Cmax; however, the digoxin steady state serum concentration, AUC, and renal clearance were not affected. In patients with congestive heart failure on digoxin therapy, the addition of felodipine resulted in a significant increase in digoxin Cmax attained following oral administration. This increase was most notable in patients with high felodipine serum concentrations. Digoxin trough levels and six hour post-dose levels were unaffected; as were digoxin AUC measurements. There is one case report of an interaction between nifedipine and digoxin; however, a study in 28 patients found no effect of nifedipine on digoxin. A study in ten subjects showed that nisoldipine increased digoxin levels by 15%. Information on the effects of nicardipine on digoxin kinetics is conflicting. One study in twenty patients showed no effect of nicardipine on digoxin. One study in ten subjects showed a significant increase in digoxin levels: however, this was seen in only one subject. Concurrent nitrendipine has been shown to increase digoxin serum levels by 57% and digoxin AUC by 15%. Concurrent diltiazem has been shown to increase digoxin serum concentration by 20%. Concurrent nifedipine has been shown to increase digoxin serum concentration by 45%.	DIGITEK, DIGOXIN, DIGOXIN MICRONIZED, LANOXIN, LANOXIN PEDIATRIC
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
Slt Calcium Channel Blockers/Atazanavir;Darunavir;Fosamprenavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Atazanavir, darunavir, and fosamprenavir may inhibit the CYP3A4-mediated metabolism of calcium channel blockers.(1-5) CLINICAL EFFECTS: Concurrent use of atazanavir, darunavir, or fosamprenavir may result in increased levels of calcium channel blockers. The combination of atazanavir with non-dihydropyridines may result in an additive effect on the PR interval.(1-2,6-7) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US Department of Health and Human Services HIV guidelines recommend that concurrent use of calcium channel blockers with protease inhibitors be monitored closely. The dose of the calcium channel blocker should be titrated to clinical response and adverse events.(5) Additional recommendations apply to patients on atazanavir. EKG monitoring is recommended for patients on concurrent therapy with calcium channel blockers. A dose reduction of diltiazem by 50% should be considered for patients starting atazanavir.(1,2,5) DISCUSSION: In a study in 28 subjects, concurrent atazanavir (400 mg daily) with diltiazem (180 mg daily) increased the diltiazem area-under-curve (AUC) and maximum concentration (Cmax) by 225% and 98%, respectively.(1,2) Diltiazem minimum concentration (Cmin) increased by 242%. The Cmax, AUC, and Cmin of desacetyl-diltiazem increased by 272%, 265%, and 221%, respectively. There were no significant effects on atazanavir levels.(1)	ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, PREZCOBIX, PREZISTA, REYATAZ, SYMTUZA
Tacrolimus/Selected Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Some calcium channel blockers may inhibit the metabolism of tacrolimus by CYP3A4.(1-13) CLINICAL EFFECTS: Concurrent use of calcium channel blockers may result in elevated levels of and side effects from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1-13) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction). PATIENT MANAGEMENT: Patients maintained on tacrolimus should be closely monitored if calcium channel blockers such as amlodipine, diltiazem, felodipine, nifedipine, or verapamil are initiated or discontinued. The dosage of tacrolimus may need to be adjusted or the calcium channel blocker may need to be discontinued. When concurrent therapy of selected calcium channel blockers and tacrolimus is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: A study of 9 healthy volunteers who are CYP3A5 expressers found that concomitant tacrolimus and amlodipine resulted in increased tacrolimus AUC by 2.44-fold and 4.1-fold in a single-dose and a 7-day multi-dose study, respectively, compared to tacrolimus alone. No interaction was observed in CYP3A5 non-expressers.(2) However, a case report of a 4-year-old renal transplant patient who is a CYP3A5 non-expresser on tacrolimus and started on amlodipine described increased tacrolimus trough level and AUC from 3.7 to 12.2 ng/mL and 211 to 638 h/ng/mL, respectively.(3) A non-randomized study in 2 liver and 2 renal transplant recipients examined the effects of diltiazem on tacrolimus. In the 2 kidney recipients, concurrent diltiazem at a dosage of 20 mg daily increased tacrolimus AUC by 26% and by 67%. Diltiazem at a dosage of 180 mg increased tacrolimus AUC by 48% and by 177%. In the 2 liver recipients, no tacrolimus increases were seen until diltiazem dosage reached 60 mg daily. One subject received 120 mg of diltiazem daily and tacrolimus AUC was increased by 18%. The other subject received 180 mg diltiazem daily and tacrolimus AUC increased 22%.(4) There is one case report of elevated tacrolimus levels and toxicity in a liver transplant patient 3 days after the addition of diltiazem to his regimen.(5) There is one case report of elevated tacrolimus levels in a renal transplant patient.(6) In contrast, a retrospective review of renal transplant patients found no difference in tacrolimus-related side effects or tacrolimus exposure in patients treated with diltiazem versus those not treated with diltiazem.(7) There is one report of increased tacrolimus levels with concurrent felodipine in a renal transplant patient.(8) A retrospective review examined the effects of nifedipine on tacrolimus dosing requirements in renal transplant patients. In patients who received concurrent nifedipine (n=22), tacrolimus daily dosing requirements were 26%, 29%, and 38% lower at 3, 6, and 12 months post-transplant when compared to patients not taking nifedipine (n=28).(9) In a study of liver transplant patients, nifedipine improved kidney function as indicated by lowering of serum creatinine levels at 6 and 12 months.(10) In vitro studies in human tissue found that tacrolimus metabolism was inhibited by nifedipine and verapamil.(12,13)	ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL
Selected Calcium Channel Blockers/Selected Strong CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the first-pass and elimination metabolism of calcium channel blockers by CYP3A4. CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers metabolized by CYP3A4 may result in elevated levels of the calcium channel blocker and risk of adverse effects, including hypotension and bradycardia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors 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 adjusted or an alternative agent considered. Monitor patients for increased calcium channel blocker effects. If the strong CYP3A4 inhibitor 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.(10,11) 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.(7) PKPB modeling of nifedipine and ritonavir noted a decreased systolic blood pressure > 40 mmHg.(8) There are several case reports of patients developing increased levels of calcium channel blockers and adverse effects with concurrent strong CYP3A4 inhibitors.(9-16) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, cobicistat, grapefruit, idelalisib, indinavir, itraconazole, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, ribociclib, saquinavir, tipranavir, troleandomycin, tucatinib, and voriconazole.(17,18)	APTIVUS, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VORICONAZOLE, ZYDELIG, ZYKADIA
Dronedarone/Diltiazem; Nifedipine; Verapamil SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Dronedarone my inhibit the metabolism of diltiazem, nifedipine, and verapamil by CYP3A4. Diltiazem and verapamil may inhibit the metabolism of dronedarone by CYP3A4. Calcium channel blockers may potentiate dronedarone conduction effects by depressing the sinus and AV nodes.(1) CLINICAL EFFECTS: Concurrent use may result in elevated levels and effects of both dronedarone and the calcium channel blocker. Calcium channel blockers may also potentiate dronedarone's conduction effects. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Give low initial doses of the calcium channel blockers. The dosage of the calcium channel blocker should only be increased after ECG verification of good tolerability.(1) DISCUSSION: Concurrent use of diltiazem and verapamil with dronedarone (exact dosages not stated) increased dronedarone exposure by 1.7-fold and 1.4-fold, respectively.(1) Concurrent use of dronedarone with diltiazem, nifedipine, or verapamil (exact dosages not stated) increased exposure of the calcium channel blocker by 1.4-fold to 1.5-fold.(1)	MULTAQ
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
Selected Calcium Channel Blockers/Nirmatrelvir-Ritonavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Nirmatrelvir-ritonavir may inhibit the metabolism of calcium channel blockers by CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use of nirmatrelvir-ritonavir may result in elevated levels of and toxicity from calcium channel blockers. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of nirmatrelvir-ritonavir and selected calcium channel blockers should be approached with caution. Monitor patients receiving concurrent therapy with nirmatrelvir-ritonavir and either amlodipine, diltiazem, felodipine, nicardipine, nifedipine, or verapamil for increased calcium channel blocker effects. The dosage of the calcium channel blocker may need to be adjusted.(1,2) The Journal of American College of Cardiology recommends a 50% reduction in the dose amlodipine for 8 days with the initiation of nirmatrelvir-ritonavir. Close monitoring of blood pressure and dose reduction or temporary discontinuation of calcium channel blockers may be needed. Resume calcium channel blockers 3 days after the last dose of nirmatrelvir-ritonavir.(3) DISCUSSION: Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor and may increase the levels of calcium channel blockers that are CYP3A4 substrates.(1,2) In a case report of a 80-year old female on verapamil, on day 2 of concurrent nirmatrelvir-ritonavir the patient presented to the hospital with symptomatic bradycardia (heart rate of 28 beats per minute and blood pressure of 58/35 mmHg) requiring hospitalization, medical management, and a temporary transvenous pacer.(4)	PAXLOVID
Labetalol/Selected Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both labetalol and calcium channel blockers have negative inotropic and chronotropic effects. CLINICAL EFFECTS: Concurrent use of labetalol with calcium channel blockers may result in additive cardiovascular effects. PREDISPOSING FACTORS: Preexisting left ventricular dysfunction and high doses of the beta-blocking agent may predispose patients to adverse responses to this drug combination. Other possible factors include parenteral administration and concurrent administration of other cardio-depressant drugs such as antiarrhythmics. PATIENT MANAGEMENT: The concurrent use of labetalol and calcium channel blockers should be monitored closely for signs of increased cardio-depressant effects and hypotension. Adjust the dose of one or both medicines accordingly. DISCUSSION: Concurrent use of labetalol with calcium channel blockers may result in additive cardiovascular effects. Coadministration of these classes of drugs may be effective in the treatment of angina pectoris and hypertension. Patients should be screened in order to determine who should receive this combination of agents.	LABETALOL HCL, LABETALOL HCL-WATER

The following contraindication information is available for PROCARDIA XL (nifedipine):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

No enhanced Contraindications information available for this drug.

There are 1 contraindications. Absolute contraindication.

Contraindication List
Kock pouch

There are 7 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Chronic idiopathic constipation
Gastrointestinal obstruction
Hypotension
Intestinal stenosis
Myasthenia gravis
Porphyria
Severe aortic valve stenosis

There are 4 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Gastrointestinal hypomotility
Hepatic cirrhosis
Kidney disease with reduction in glomerular filtration rate (GFr)
Peripheral edema

The following adverse reaction information is available for PROCARDIA XL (nifedipine):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 17 severe adverse reactions.

More Frequent	Less Frequent
None.	Pulmonary edema

Rare/Very Rare
Acute eruptions of skin Allergic dermatitis Arthralgia Bullous dermatitis Chronic heart failure Erythema multiforme Gastrointestinal concretion Gastrointestinal obstruction Gastrointestinal ulcer Gingival hyperplasia Progressive angina pectoris Purpura Skin rash Stevens-johnson syndrome Tachycardia Toxic epidermal necrolysis

There are 20 less severe adverse reactions.

More Frequent	Less Frequent
Headache disorder Peripheral edema	Constipation Cramps in legs Dizziness Epistaxis Erectile dysfunction Fatigue Flushing General weakness Increased urinary frequency Nausea Paresthesia Rhinitis

Rare/Very Rare
Anticholinergic toxicity Hypotension Insomnia Palpitations Phototoxicity Visual changes

The following precautions are available for PROCARDIA XL (nifedipine):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Nifedipine has been shown to be teratogenic in rats and rabbits. Digital anomalies similar to those reported with phenytoin also have been reported in the offspring of animals receiving nifedipine or other dihydropyridines; these anomalies may occur secondary to compromised uterine blood flow. Nifedipine administration in rats, mice, rabbits, and monkeys also has been associated with a variety of other embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, and rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species).

The dosages (on a mg/kg basis) of nifedipine associated with teratogenic, embryotoxic, or fetotoxic effects in animals were higher (3.5-42 times) than the maximum recommended human dosage (120 mg daily); however, such dosages were within one order of magnitude of the maximum recommended human dosage. The dosages of nifedipine associated with placentotoxic effects in monkeys were equivalent to or lower than the maximum recommended human dosage on a mg/m2 basis. There are no adequate and well-controlled studies using nifedipine in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Nifedipine is distributed into milk. In one lactating woman who received 10, 20, and 30 mg of the drug every 8 hours as conventional capsules, peak milk concentrations of nifedipine occurred within 1 hour after a dose and ranged from about 13-53 ng/mL; the drug generally was not detectable during the hour prior to a dose. Because of the potential for serious adverse reactions to nifedipine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

No enhanced Geriatric Use information available for this drug.

The following icd codes are available for PROCARDIA XL (nifedipine)'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
Prevention of anginal pain from vasospastic angina
I20.1	Angina pectoris with documented spasm
I25.111	Atherosclerotic heart disease of native coronary artery with angina pectoris with documented spasm
I25.701	Atherosclerosis of coronary artery bypass graft(s), unspecified, with angina pectoris with documented spasm
I25.711	Atherosclerosis of autologous vein coronary artery bypass graft(s) with angina pectoris with documented spasm
I25.721	Atherosclerosis of autologous artery coronary artery bypass graft(s) with angina pectoris with documented spasm
I25.731	Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with angina pectoris with documented spasm
I25.751	Atherosclerosis of native coronary artery of transplanted heart with angina pectoris with documented spasm
I25.761	Atherosclerosis of bypass graft of coronary artery of transplanted heart with angina pectoris with documented spasm
I25.791	Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris with documented spasm
Prevention of anginal pain in coronary artery disease
I20.2	Refractory angina pectoris
I20.81	Angina pectoris with coronary microvascular dysfunction
I20.89	Other forms of angina pectoris
I20.9	Angina pectoris, unspecified
I25.112	Atherosclerotic heart disease of native coronary artery with refractory angina pectoris
I25.118	Atherosclerotic heart disease of native coronary artery with other forms of angina pectoris
I25.119	Atherosclerotic heart disease of native coronary artery with unspecified angina pectoris
I25.702	Atherosclerosis of coronary artery bypass graft(s), unspecified, with refractory angina pectoris
I25.708	Atherosclerosis of coronary artery bypass graft(s), unspecified, with other forms of angina pectoris
I25.709	Atherosclerosis of coronary artery bypass graft(s), unspecified, with unspecified angina pectoris
I25.712	Atherosclerosis of autologous vein coronary artery bypass graft(s) with refractory angina pectoris
I25.718	Atherosclerosis of autologous vein coronary artery bypass graft(s) with other forms of angina pectoris
I25.719	Atherosclerosis of autologous vein coronary artery bypass graft(s) with unspecified angina pectoris
I25.722	Atherosclerosis of autologous artery coronary artery bypass graft(s) with refractory angina pectoris
I25.728	Atherosclerosis of autologous artery coronary artery bypass graft(s) with other forms of angina pectoris
I25.729	Atherosclerosis of autologous artery coronary artery bypass graft(s) with unspecified angina pectoris
I25.732	Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with refractory angina pectoris
I25.738	Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with other forms of angina pectoris
I25.739	Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with unspecified angina pectoris
I25.752	Atherosclerosis of native coronary artery of transplanted heart with refractory angina pectoris
I25.758	Atherosclerosis of native coronary artery of transplanted heart with other forms of angina pectoris
I25.759	Atherosclerosis of native coronary artery of transplanted heart with unspecified angina pectoris
I25.762	Atherosclerosis of bypass graft of coronary artery of transplanted heart with refractory angina pectoris
I25.768	Atherosclerosis of bypass graft of coronary artery of transplanted heart with other forms of angina pectoris
I25.769	Atherosclerosis of bypass graft of coronary artery of transplanted heart with unspecified angina pectoris
I25.792	Atherosclerosis of other coronary artery bypass graft(s) with refractory angina pectoris
I25.798	Atherosclerosis of other coronary artery bypass graft(s) with other forms of angina pectoris
I25.799	Atherosclerosis of other coronary artery bypass graft(s) with unspecified angina pectoris