Abiraterone Acetate

Drug overview for ABIRATERONE ACETATE (abiraterone acetate):

Generic name: ABIRATERONE ACETATE (A-bir-A-ter-one)
Drug class: Anti-Androgen - Androgen Synthesis Inhibitors
Therapeutic class: Antineoplastics

Abiraterone acetate is a prodrug of abiraterone, a potent, selective, and irreversible inhibitor of cytochrome P-450 (CYP) 17alpha-hydroxylase/C17,20-lyase (also referred to as CYP17); abiraterone is an antineoplastic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

ABIRATERONE ACETATE 250 MG TAB

The following indications for ABIRATERONE ACETATE (abiraterone acetate) have been approved by the FDA:

Indications:
Metastatic castration-resistant prostate cancer
Metastatic castration-sensitive prostate cancer

Professional Synonyms:
Metastatic hormone refractory prostate cancer
Metastatic hormone sensitive prostate cancer

The following dosing information is available for ABIRATERONE ACETATE (abiraterone acetate):

Dosing
Administration
ABIRATERONE ACETATE
ABIRATERONE ACETATE

No enhanced Dosing information available for this drug.

Conventional abiraterone acetate tablets should be administered orally on an empty stomach; no food should be consumed for at least 2 hours before or 1 hour after a dose. Because of normal variations in the content and composition of meals, administration of abiraterone acetate conventional tablets with food is likely to result in highly variable exposure to the drug. The bioavailability of the micronized formulation of abiraterone acetate is less variable compared with the conventional formulation; therefore, the micronized formulation may be administered without regard to food. Conventional and micronized tablets should be swallowed whole with water and should not be chewed or crushed.

Dosing information for ABIRATERONE ACETATE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
ABIRATERONE ACETATE 250 MG TAB	Maintenance	Adults take 4 tablets (1,000 mg) by oral route once daily with water on an empty stomach at least 1 hour before or 2 hours after food
ABIRATERONE ACETATE 500 MG TAB	Maintenance	Adults take 2 tablets (1,000 mg) by oral route once daily with water on an empty stomach at least 1 hour before or 2 hours after food

Generic dosing information for ABIRATERONE ACETATE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
ABIRATERONE ACETATE 250 MG TAB	Maintenance	Adults take 4 tablets (1,000 mg) by oral route once daily with water on an empty stomach at least 1 hour before or 2 hours after food
ABIRATERONE ACETATE 500 MG TAB	Maintenance	Adults take 2 tablets (1,000 mg) by oral route once daily with water on an empty stomach at least 1 hour before or 2 hours after food

The following drug interaction information is available for ABIRATERONE ACETATE (abiraterone acetate):

Contraindicated
Severe
Moderate

There are 1 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
Abiraterone/Radium Ra 223 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: The mechanism of this interaction is not known. CLINICAL EFFECTS: Concurrent use of radium Ra 223 dichloride with abiraterone and prednisolone, prednisone, or methylprednisolone may increase the risk of mortality and fractures.(1-4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The European Medicines Agency (EMA) states that the use of radium Ra 223 with abiraterone and prednisone/prednisolone is contraindicated. Radium Ra 223 is not recommended to be initiated in the first 5 days following the last dose of abiraterone and prednisone/prednisolone.(2,5) The US manufacturers of radium Ra 223 and abiraterone state that radium Ra 223 is not recommended for use in combination with abiraterone and prednisone/prednisolone or methylprednisolone outside of clinical trials.(3,4) Monitor patients for fractures. DISCUSSION: In the ERA 223 trial, a randomized, double-blind, placebo-controlled trial of 806 patients with castration-resistant prostate cancer with bone metastasis, treatment with abiraterone and prednisone/prednisolone plus radium Ra 223 was associated with increased incidences of fractures and deaths (28.6% and 38.5%, respectively), compared to treatment with abiraterone and prednisone/prednisolone plus placebo (11.4% and 35.5%, respectively).(6)	XOFIGO

Drug Interaction

Drug Names

Abiraterone/Radium Ra 223

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: The mechanism of this interaction is not known.

CLINICAL EFFECTS: Concurrent use of radium Ra 223 dichloride with abiraterone and prednisolone, prednisone, or methylprednisolone may increase the risk of mortality and fractures.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The European Medicines Agency (EMA) states that the use of radium Ra 223 with abiraterone and prednisone/prednisolone is contraindicated. Radium Ra 223 is not recommended to be initiated in the first 5 days following the last dose of abiraterone and prednisone/prednisolone.(2,5) The US manufacturers of radium Ra 223 and abiraterone state that radium Ra 223 is not recommended for use in combination with abiraterone and prednisone/prednisolone or methylprednisolone outside of clinical trials.(3,4) Monitor patients for fractures.

DISCUSSION: In the ERA 223 trial, a randomized, double-blind, placebo-controlled trial of 806 patients with castration-resistant prostate cancer with bone metastasis, treatment with abiraterone and prednisone/prednisolone plus radium Ra 223 was associated with increased incidences of fractures and deaths (28.6% and 38.5%, respectively), compared to treatment with abiraterone and prednisone/prednisolone plus placebo (11.4% and 35.5%, respectively).(6)

XOFIGO

There are 7 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
Thioridazine/Abiraterone SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Abiraterone may inhibit the metabolism of thioridazine by CYP2D6.(1) CLINICAL EFFECTS: Concurrent use of abiraterone may result in elevated levels of and toxicity from thioridazine, including potentially life-threatening cardiac arrhythmias such as torsades de pointes.(1) PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers may be affected to a greater extent by CYP2D6 inhibitors. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. 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 torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) 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 torsades 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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) 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 abiraterone states that concurrent use of CYP2D6 substrates with narrow therapeutic indexes such as thioridazine should be avoided. If concurrent use is warranted, consider decreasing the dose of thioridazine.(1) Additionally, 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: Concurrent abiraterone increased the area-under-curve (AUC) and maximum concentration (Cmax) of dextromethorphan (another CYP2D6 substrate) by 2.9-fold and 2.8-fold, respectively.(1)	THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE
Eliglustat/Strong & Moderate CYP2D6 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1) CLINICAL EFFECTS: Concurrent use of an agent that is a strong or moderate inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1) PREDISPOSING FACTORS: If the patient has hepatic impairment, is also taking an inhibitor of CYP3A4 and/or is an extensive or intermediate metabolizer of CYP2D6, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) 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 torsades 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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in both extensive and intermediate CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be continued at 84 mg once daily.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in poor metabolizers of CYP2D6 should be avoided and is contraindicated in extensive and intermediate metabolizers of CYP2D6.(1) If concurrent therapy 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. Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(5) DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(1,3,4) Moderate inhibitors of CYP2D6 include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, escitalopram, levomethadone, mirabegron, moclobemide, and rolapitant.(1,3,4)	CERDELGA
Abiraterone/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of abiraterone.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of abiraterone.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with abiraterone.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. If concurrent administration of abiraterone and a strong CYP3A4 inducers is required, increase the dosing frequency of abiraterone from once daily to twice daily during the co-administration period. If the strong inducer is discontinued, reduce the dose of abiraterone back to the previous dose and frequency.(1) DISCUSSION: In a drug interaction trial, concurrent administration of rifampin, a strong CYP3A4 inducer, decreased abiraterone levels by 55%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3)	ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, TIBSOVO, XTANDI
Tamoxifen/Selected Moderate CYP2D6 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5) CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence. PREDISPOSING FACTORS: Concurrent use of moderate CYP2D6 inhibitors in patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient. Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(15) DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(16) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(17-18) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(19-21) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(22-26) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(15) Moderate inhibitors of CYP2D6 include abiraterone, asunaprevir, berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, mirabegron, moclobemide, rolapitant, and tipranavir/ritonavir.(27-28)	SOLTAMOX, TAMOXIFEN CITRATE
Abiraterone; Cabazitaxel; Vincristine/Rifabutin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Rifabutin is an inducer of CYP3A4 and may increase the metabolism of abiraterone,(1) cabazitaxel,(2,3) and vincristine.(4) CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of abiraterone,(1) cabazitaxel,(3) and vincristine.(4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent use of rifabutin with abiraterone,(1) cabazitaxel,(3) and vincristine.(4) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. If concurrent administration of abiraterone and rifabutin is required, increase the dosing frequency of abiraterone from once daily to twice daily during the co-administration period. If rifabutin is discontinued, reduce the dose of abiraterone back to the previous dose and frequency.(1) DISCUSSION: Abiraterone,(1) cabazitaxel,(2,3) and vincristine (3) are metabolized by CYP3A4. Strong inducers of this isoenzyme are expected to decrease levels of these agents. The US manufacturers of abiraterone(1) and vincristine(4) and the UK manufacturer of cabazitaxel(3) include rifabutin on the list of strong CYP3A4 inducers that should be avoided. In a drug interaction trial, concurrent administration of rifampin, a strong CYP3A4 inducer, decreased abiraterone levels by 55%.(1) In a study in 21 advanced cancer patients, rifampin (600mg) decreased the exposure to cabazitaxel (15mg/m2) by 17%.(2)	RIFABUTIN, TALICIA
Pioglitazone; Repaglinide/Abiraterone SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The mechanism of interaction is not fully understood but may at least partially involve CYP2C8 inhibition by abiraterone, resulting in decreased metabolism of pioglitazone and repaglinide.(1,2) CLINICAL EFFECTS: Concurrent use of pioglitazone or repaglinide with abiraterone may result in elevated levels and clinical effects of the anti-diabetic agents, including severe hypoglycemia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with abiraterone. Consider dosage adjustment of pioglitazone or repaglinide to minimize the risk of hypoglycemia.(1) DISCUSSION: Severe hypoglycemia has been reported in diabetic patients receiving pioglitazone or repaglinide concurrently with abiraterone. A review of the FDA Adverse Events Reporting database found 2 reports of hypoglycemia in patients receiving concurrent abiraterone and repaglinide. One patient was hospitalized with life-threatening outcomes, and the other died, though he also had sepsis and cardiac failure. In a study of 16 healthy volunteers, single-dose abiraterone 1,000 mg increased the maximum concentration (Cmax) and area-under-curve (AUC) of single-dose pioglitazone 15 mg by 23% and 46%.(3)	ACTOPLUS MET, ACTOS, ALOGLIPTIN-PIOGLITAZONE, DUETACT, OSENI, PIOGLITAZONE HCL, PIOGLITAZONE-GLIMEPIRIDE, PIOGLITAZONE-METFORMIN, REPAGLINIDE
Abiraterone/Spironolactone SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: When used in an androgen-deprived environment created by abiraterone, spironolactone binds to the androgen receptor and acts as an androgen agonist. CLINICAL EFFECTS: Spironolactone may increase prostate-specific antigen (PSA) levels in metastatic prostate cancer patients on abiraterone. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of spironolactone and abiraterone is not recommended. DISCUSSION: In a case report, a 67-year-old man with metastatic castration-resistant prostate cancer (mCRPC) on abiraterone for 6 months with good response started spironolactone for heart failure. His PSA rose from 0.004 ng/mL prior to starting spironolactone to 0.93 ng/mL. After spironolactone discontinuation, PSA dropped to 0.38 ng/mL, but subsequently rose again due to disease progression.(3) A 67-year-old man on spironolactone 25 mg daily and a history of prostate cancer experienced bone progression and a rise in PSA. He was started on abiraterone 1,000 mg daily and prednisone 5 mg twice daily, but PSA continued to rise 5 months after starting abiraterone.(3) In a case report, an 86-year-old man on abiraterone for mCRPC started spironolactone and experienced biochemical and radiologic disease progression with PSA rising from 278.7 ng/mL to 792.7 ng/mL. After spironolactone was discontinued, PSA dropped to 334.2 ng/mL.(4) A 57-year-old man with mCRPC on spironolactone failed to respond to abiraterone and prednisone, with PSA rising from 5.97 ng/mL to 8.08 ng/mL. Spironolactone was discontinued and PSA dropped to 2.8 ng/mL after 2 weeks and 0.45 ng/mL after 2 months. After 10 months on abiraterone, the patient experienced disease progression and was switched to enzalutamide. Eight months later, his PSA rose slightly to 0.2 ng/mL. He revealed that he had been taking spironolactone for 3 weeks. Spironolactone was stopped and PSA dropped to 0.14 ng/mL.(5)	ALDACTONE, CAROSPIR, SPIRONOLACTONE, SPIRONOLACTONE-HCTZ

There are 5 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
Tramadol/Selected Moderate to Strong CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Abiraterone, asunaprevir, berotralstat, bupropion, cinacalcet, dacomitinib, dronedarone, duloxetine, eliglustat, escitalopram, fluoxetine, hydroquinidine, levomethadone, lorcaserin, mirabegron, paroxetine, quinidine, rolapitant, oral terbinafine, and tipranavir are moderate or strong inhibitors of CYP2D6 and may decrease conversion of tramadol to its more active O-demethylated metabolite (M1).(1-6) M1 is up to 6 times more potent than tramadol in producing analgesia.(1) CLINICAL EFFECTS: Tramadol analgesic efficacy may be decreased due to lower mu-opioid receptor mediated analgesia.(1,9,10) Higher concentrations of tramadol may be associated with increased inhibition of norepinephrine and serotonin reuptake, increasing risk for seizures and serotonin syndrome.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(7) PREDISPOSING FACTORS: Risk for seizure may be increased with tramadol doses above the recommended range, in patients with metabolic disorders, alcohol or drug withdrawal, infection of the central nervous system, or with a history of seizures or head trauma.(1) Treatment with multiple medications which increase serotonin levels, or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(1,7) Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer.(14) Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.(14) PATIENT MANAGEMENT: If a CYP2D6 inhibitor is started in a patient stabilized on long term tramadol therapy, monitor for loss of analgesic efficacy. When initiating tramadol in a patient stabilized on a moderate or strong CYP2D6 inhibitor, anticipate lower analgesic efficacy. Hospitalized patients may need added doses of rescue analgesics to achieve adequate pain control.(9,10) To decrease risk for serotonin syndrome, consider change to an alternative analgesic for patients taking other serotonin increasing drugs in addition to concomitant tramadol and a CYP2D6 inhibitor. If a CYP2D6 inhibitor is discontinued, consider lowering the dose of tramadol until patient achieves stable drug effects. The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(12) DISCUSSION: Tramadol and its M1 metabolite both contribute to analgesic efficacy. Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal opioid receptor binding. The M1 metabolite has 200 times greater binding affinity for the mu-opioid receptor than tramadol and is 6 times more potent in producing analgesia.(1) CYP2D6 converts tramadol to M1.(1,8) A prospective study evaluated the impact of 2D6 genotype on tramadol analgesia after abdominal surgery. Rescue doses of opioids were required in 47% of poor metabolizers (PM) versus 22% of extensive metabolizers (EM) of 2D6.(9) A follow-up study included 2D6 EM patients who received concomitant treatment with 2D6 inhibitors. Levels of the M1 metabolite were decreased by 80-90% compared with EM patients not taking 2D6 inhibitors. The authors noted some EM patients were converted to the PM phenotype.(10) In both studies, higher M1 levels were associated with greater analgesic efficacy and decreased need for rescue opioid treatment.(9,10) A study in 12 healthy volunteers found that a single dose of tramadol (50 mg) given to patients on terbinafine (a strong CYP2D6 inhibitor) resulted in tramadol AUC and Cmax that were 2.1-fold and 1.5-fold higher, respectively, than tramadol given alone. The AUC and Cmax of M1 were decreased by 64 % and 78 %, respectively.(13) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(12)	CONZIP, QDOLO, TRAMADOL HCL, TRAMADOL HCL ER, TRAMADOL HCL-ACETAMINOPHEN
Brexpiprazole/Moderate CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of brexpiprazole.(1) CLINICAL EFFECTS: Concurrent administration of a moderate CYP2D6 inhibitor may result in elevated levels of and toxicity from brexpiprazole.(1) PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are receiving concomitant treatment with a strong or moderate CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor. Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to increase brexpiprazole levels 5.1-fold in extensive metabolizers of CYP2D6.(1) PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a moderate CYP2D6 inhibitor: - in patients with schizophrenia or major depressive disorder who are taking a moderate CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual dose. - no empiric dosage adjustment is recommended for patients receiving moderate CYP2D6 inhibitors without a strong or moderate inhibitor of CYP3A4. The dose of brexpiprazole should be adjusted to its original level if the CYP2D6 inhibitor is discontinued.(1) Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(2) DISCUSSION: Coadministration of quinidine, a strong inhibitor of CYP2D6, increased the area-under-curve (AUC) of brexpiprazole approximately 2-fold.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(2) Moderate CYP2D6 inhibitors linked to this monograph include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, mirabegron, moclobemide, and rolapitant.	REXULTI
Metoprolol/Selected CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of metoprolol.(1,2) CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from metoprolol.(1,2) PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6,(1,2) elderly,(3) and on higher doses of beta-blockers.(3) PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2) The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(4) DISCUSSION: In a case report, a patient maintained on metoprolol developed bradycardia following the addition of bupropion.(5) In a study in 20 healthy females, diphenhydramine increased the AUC of metoprolol by 21%. Heart rate reduction increased 29%.(6) In a randomized study in 16 healthy subjects, diphenhydramine decreased metoprolol oral and nonrenal clearance by 2-fold in extensive 2D6 metabolizers. In extensive 2D6 metabolizers, metoprolol-induced effects on heart rate, systolic blood pressure, and aortic blood flow peak velocity were all increased. There were no effects of diphenhydramine in poor metabolizers.(7) Fluoxetine has been shown to inhibit metoprolol metabolism in vitro.(8) There is a case report of severe bradycardia following the addition of fluoxetine to metoprolol.(9) In a 3-way, randomized, cross-over study in healthy subjects, paroxetine (20 mg daily) increased the area-under-curve (AUC) of both S- and R-metoprolol by 3-fold, and 4-fold, respectively, regardless of whether the formulation of metoprolol was immediate release or extended release. Concurrent paroxetine also significantly decreased heart rate and blood pressure when compared to metoprolol alone.(10) In an open-label, randomized, cross-over study in 10 healthy subjects, paroxetine increased the AUC of S-metoprolol and R-metoprolol from an immediate release formulation (50 mg)by 4-fold and 5-fold, respectively. Paroxetine increased the AUC of S-metoprolol and R-metoprolol from an extended release formulation (100 mg) by 3-fold and 4-fold, respectively.(11) In a study in patients with acute myocardial infarction and depression, paroxetine (20 mg daily) increased the AUC of metoprolol 3-fold. Mean heart rate was significantly lower following the addition of paroxetine to metoprolol. Two patients experienced bradycardia and severe orthostatic hypotension.(12) In an open trial in 8 healthy males, paroxetine (20 mg daily) increased the AUC of S-metoprolol and R-metoprolol by 4-fold and 7-fold, respectively.(13) There are case reports of complete atrioventricular block(14) and bradycardia(15) with concurrent metoprolol and paroxetine. A systematic review and meta-analysis of CYP2D6 interactions between metoprolol and either paroxetine or fluoxetine reviewed 9 articles including 4 primary and 2 observational studies as well as 3 case reports. Experimental studies noted paroxetine increased the AUC of metoprolol 3-fold to 5-fold and significantly decreased blood pressure and heart rate. Paroxetine and fluoxetine have shown equipotent inhibitor capacity on CYP2D6. The metabolite, norfluoxetine, is also an inhibitor of CYP2D6.(16) A retrospective cohort study evaluated morbidity in patients on a beta-blocker primarily metabolized by CYP2D6 (e.g., nebivolol, metoprolol, carvedilol, propranolol, labetalol) and started on a strong or moderate CYP2D6-inhibiting antidepressant (e.g., fluoxetine, paroxetine, bupropion, duloxetine). Use of such an antidepressant with a beta-blocker was associated with an increased risk of hospitalization or ED visit due to an adverse hemodynamic event (HR 1.53, 95% CI 1.03-2.81, p=0.04).(3) CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet, citalopram, dacomitinib, dimenhydrinate, diphenhydramine, duloxetine, escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib, lorcaserin, osilodrostat, paroxetine, ranitidine, ranolazine, rolapitant, and sertraline. 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.	KAPSPARGO SPRINKLE, LOPRESSOR, METOPROLOL SUCCINATE, METOPROLOL TARTRATE, METOPROLOL-HYDROCHLOROTHIAZIDE, TOPROL XL
Oliceridine/Moderate CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Oliceridine is metabolized equally by CYP2D6 and CYP3A4. Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or CYP3A4.(1) CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from oliceridine including profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater increase in the levels of and toxcity of oliceridine.(1) PATIENT MANAGEMENT: Caution should be used when administering oliceridine to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4. Dosage adjustments should be made if warranted. Closely monitor these patients for respiratory depression and sedation at frequent intervals and evaluate subsequent doses based on response. If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is necessary, less frequent dosing of oliceridine may be required. If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued, increase of the oliceridine dosage may be necessary. Monitor for signs of opioid withdrawal. Patients receiving concurrent therapy with both a strong or moderate CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse effects. Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and a strong CYP3A4 inhibitor may require less frequent dosing of oliceridine.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with agents that may increase opioid drug levels.(2) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: In a study of four healthy subjects who are CYP2D6 poor metabolizers, itraconazole (200 mg daily for 5 days) increased the area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1) In a study of subjects who were not CYP2D6 poor metabolizers, ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the pharmacokinetics of oliceridine.(1) Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, lorcaserin, mirabegron, moclobemide, and rolapitant.(4)	OLINVYK
Propranolol/Selected CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of propranolol.(1) CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from propranolol, including hypotension and bradycardia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with propranolol and CYP2D6 inhibitors. The dosage of propranolol may need to be adjusted.(1) DISCUSSION: In a pharmacokinetic study in 16 healthy volunteers, concurrent use of quinidine 200 mg (a CYP2D6 inhibitor) increased the area-under-curve (AUC) of propranolol by 2.29-fold.(2) In a pharmacokinetic study in 6 healthy subjects, concurrent use of quinidine increased propranolol AUC 2-fold.(3) A retrospective review of concurrent use of propranolol and antidepressants evaluated the risk of hospitalization or emergency room visit within 30 days of concurrent prescription. In patients receiving antidepressants with moderate to strong CYP2D6 inhibitory effects, patient were an increased risk compared to patients receiving no antidepressants (Hazard Ratio (HR) = 1.53; 95% CI 1.03-2.81 vs. HR = 1.24; 95% CI 0.82-1.88).(4) Case reports of bradycardia and cardiac adverse effects have been reported with concurrent use of propranolol and the antidepressants fluoxetine and paroxetine (strong CYP2D6 inhibitors).(5) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, mavorixafor, and paroxetine. Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir, berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, lorcaserin, mirabegron, moclobemide, quinine, ranolazine, and rolapitant. Weak CYP2D6 inhibitors include: celecoxib, desvenlafaxine, diphenhydramine, dimenhydrinate, dronabinol, fedratinib, hydroxychloroquine, imatinib, osilodrostat, ranitidine, and sertraline.(6)	HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID

The following contraindication information is available for ABIRATERONE ACETATE (abiraterone acetate):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*None.

There are 1 contraindications. Absolute contraindication.

Contraindication List
Child-pugh class C hepatic impairment

There are 6 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Child-pugh class B hepatic impairment
Chronic heart failure
Disease of liver
Hypertension
Hypokalemia
Pregnancy

There are 3 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
30 day risk period post-myocardial infarction
Edema
Hypoglycemic disorder

The following adverse reaction information is available for ABIRATERONE ACETATE (abiraterone acetate):

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse effects reported in 10% or more of patients receiving abiraterone acetate (conventional) in combination with prednisone (twice daily) for the treatment of metastatic castration-resistant prostate cancer and at an incidence that is at least 2% higher than that reported with placebo and prednisone in the COU-AA-301 or COU-AA-302 studies include fatigue, joint swelling or discomfort, edema, muscle discomfort, constipation, diarrhea, hot flush, hypertension, cough, insomnia, contusion, upper respiratory tract infection, urinary tract infection, dyspnea, dyspepsia, nasopharyngitis, and hematuria. Laboratory abnormalities reported in 20% or more of patients receiving abiraterone acetate (conventional) in combination with prednisone (twice daily) and at an incidence that is at least 2% higher than that reported with placebo include hypertriglyceridemia, hyperglycemia, elevated concentrations of aminotransferases (i.e., ALT, AST), lymphopenia, hypernatremia, hypokalemia, and hypophosphatemia. In the STAAR study, adverse effects reported in men with metastatic castration-resistant prostate cancer who received micronized abiraterone acetate were generally similar to adverse effects reported in those who received conventional abiraterone acetate.

One or more adverse effects were reported in 75% of patients who received micronized abiraterone acetate and in 83% of those who received conventional abiraterone acetate. Adverse effects reported in 10% or more of patients receiving abiraterone acetate (conventional) in combination with prednisone (once daily) for the treatment of high-risk metastatic castration-sensitive prostate cancer and at an incidence that is at least 2% higher than that reported with placebo in the LATITUDE study include hypertension, hypokalemia, lymphopenia, elevated concentrations of aminotransferases (i.e., ALT, AST), and hot flush.

There are 24 severe adverse reactions.

More Frequent	Less Frequent
Abnormal hepatic function tests Accidental fall Anemia Cardiac arrhythmia Fracture Hypertension Hypokalemia Lymphopenia	Atrial fibrillation Hyperbilirubinemia Increased alanine transaminase Increased aspartate transaminase

Rare/Very Rare
Acute hepatic failure Acute myocardial infarction Adrenocortical insufficiency Anaphylaxis Cardiomegaly Cardiomyopathy Heart failure Hepatitis Hypoglycemic disorder Interstitial pneumonitis Myocardial ischemia Rhabdomyolysis

There are 28 less severe adverse reactions.

More Frequent	Less Frequent
Arthralgia Body fluid retention Bruising Cough Diarrhea Dyspepsia Dyspnea Edema Fatigue Fever Flushing Headache disorder Hematuria Hypercholesterolemia Hyperglycemia Hypertriglyceridemia Increased urinary frequency Insomnia Myalgia Nausea Nocturia Pharyngitis Skin rash Upper respiratory infection Urinary tract infection Vomiting	Chest pain

Rare/Very Rare
Myopathy

The following precautions are available for ABIRATERONE ACETATE (abiraterone acetate):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy have not been established in pediatric patients.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Based on its mechanism of action and animal findings, abiraterone can cause fetal harm and potential loss of pregnancy if administered to pregnant women.

Safety and efficacy of abiraterone have not been established in females. It is not known whether abiraterone is distributed into milk in humans. The effects of the drug on the breast-fed infant or milk production also are not known.

In clinical trials evaluating abiraterone acetate (conventional), 70% of patients were 65 years of age or older and 27% were 75 years of age or older. No overall differences in safety and efficacy were observed between geriatric patients and younger adults. However, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.

Metastatic castration-resistant prostate cancer
C61	Malignant neoplasm of prostate
Z19.2	Hormone resistant malignancy status
Metastatic castration-sensitive prostate cancer
C61	Malignant neoplasm of prostate
Z19.1	Hormone sensitive malignancy status