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  • CLASSES

    Anti-Androgens
    Cytostatic Anti-androgens

    DEA CLASS

    Rx

    DESCRIPTION

    Androgen receptor inhibitor
    Used for nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer
    Evaluate for fall and fracture risk; treat with bone-targeted agents if appropriate

    COMMON BRAND NAMES

    ERLEADA

    HOW SUPPLIED

    ERLEADA Oral Tab: 60mg

    DOSAGE & INDICATIONS

    For the treatment of prostate cancer.
    For the treatment of nonmetastatic castration-resistant prostate cancer.
    Oral dosage
    Adult men

    240 mg orally once daily until disease progression or unacceptable toxicity. Patients should concurrently receive treatment with a gonadotropin-releasing hormone (GnRH) analog or have had a bilateral orchiectomy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with apalutamide significantly improved the primary endpoint of metastasis-free survival compared with placebo (40.51 months vs. 16.2 months) in patients with nonmetastatic castration-resistant prostate cancer in a multicenter, randomized, double-blind, phase 3 trial (n = 1,207; SPARTAN trial); results were consistent across subgroups (PSA doubling time, prior use of bone-sparing agent, and locoregional disease). Additionally, apalutamide significantly improved time to metastasis (40.51 months vs. 16.59 months) and progression-free survival (40.51 months vs. 14.72 months). At a median follow-up time of 50.4 months, the median overall survival time was significantly prolonged patients who received apalutamide arm compared with placebo (73.9 months vs. 59.9 months; HR = 0.78; 95% CI, 0.64 to 0.96; p = 0.016). After this study was unblinded; 19% of patients without disease progression in the placebo arm crossed-over to the apalutamide arm.

    For the treatment of metastatic castration-sensitive prostate cancer.
    Oral dosage
    Adult men

    240 mg orally once daily until disease progression or unacceptable toxicity. Patients should concurrently receive treatment with a gonadotropin-releasing hormone (GnRH) analog or have had a bilateral orchiectomy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After a median follow-up of 44 months, treatment with apalutamide plus androgen-deprivation therapy (ADT; n = 525) significantly improved overall survival compared with placebo plus ADT (n = 527) in patients with newly diagnosed metastatic castration-sensitive prostate cancer or relapsed metastatic disease after an initial diagnosis of localized disease (not reached vs. 52.2 months) in a randomized, double-blind, phase 3 trial (the TITAN trial); this improvement remained significant after accounting for 39.5% crossover. Second progression-free survival (not reached vs. 44 months) and time to castrate resistance (not reached vs. 11.4 months) were also significantly delayed in the apalutamide arm. At the interim analysis (median follow-up of 22.7 months), median radiographic progression-free survival could not be estimated in the apalutamide arm and was 22.1 months in the placebo arm.

    MAXIMUM DOSAGE

    Adults

    240 mg by mouth once daily.

    Geriatric

    240 mg by mouth once daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Apalutamide tablets should be swallowed whole; do not crush or dissolve. 
    May be taken with or without food.

    Extemporaneous Compounding-Oral

    The recommended dose of apalutamide may be mixed in applesauce for patients who have difficulty swallowing tablets whole by following the instructions below:
    Mix whole apalutamide tablets in 4 ounces (120 mL) of applesauce by stirring. Do not crush the tablets.
    Wait 15 minutes, and then stir the mixture.
    Wait another 15 minutes, and then stir the mixture again until the tablets are well mixed with no chunks remaining.
    Using a spoon, swallow the mixture right away.
    Rinse the container with 2 ounces (60 mL) of water and immediately drink the contents.
    Repeat the rinse with 2 ounces (60 mL) of water a second time to ensure the whole dose is taken.
    The mixture should be consumed within 1 hour of preparation; do not store apalutamide that is mixed with applesauce.

    STORAGE

    ERLEADA:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Bone fractures

    Evaluate all patients for fall and bone fracture risk. Monitor and manage patients at risk for bone fractures according to established treatment guidelines and consider the use of bone-targeted agents.

    Driving or operating machinery, seizure disorder, seizures

    Use apalutamide with caution in patients with a pre-existing seizure disorder. Seizures were reported with apalutamide therapy in clinical trials; permanently discontinue apalutamide if a seizure occurs. Advise patients of the risk of developing a seizure and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others (e.g., driving or operating machinery) during apalutamide treatment. It is unknown whether anti-epileptic medications will prevent seizures in patients treated with apalutamide. Patients with a history of seizure, predisposing factors for seizure, or receiving drugs known to decrease the seizure threshold or to induce seizures were excluded from clinical trials. There is no clinical experience in readministration of apalutamide to patients who have experienced a seizure.

    Coronary artery disease, diabetes mellitus, hypercholesterolemia, hyperlipidemia, hypertension, stroke

    Cerebrovascular and ischemic cardiovascular events have been reported with apalutamide therapy; some cases were fatal. Patients with a history of heart disease (e.g., coronary artery disease), hypertension, diabetes mellitus, dyslipidemia/hyperlipidemia or hypercholesterolemia, or stroke may be at increased risk for developing cerebrovascular and ischemic cardiovascular events. Therefore, optimize management of cardiovascular risk factors (e.g., hypertension, diabetes mellitus, and hyperlipidemia) prior to starting apalutamide. Monitor for signs and symptoms of cerebrovascular events or ischemic heart disease. Consider discontinuing therapy in patients who experience grade 3 and 4 cerebrovascular or ischemic events.

    Geriatric

    Geriatric patients may be at increased risk for apalutamide-related adverse reactions, including falls. In 1,073 patients who received apalutamide, grade 3 or 4 adverse reactions occurred in 41% of patients aged 65 to 74 years and 49% of patients aged 75 years and older compared with 39% of patients younger than 65 years of age. Falls were reported in 10% and 19% of patients aged 65 to 74 years and 75 years and older, respectively, compared with 8% of patients younger than 65 years of age.

    Pregnancy

    Although there are no adequately controlled studies in pregnant women, apalutamide can cause fetal harm and loss of pregnancy if administered to a pregnant woman based on findings from animal studies and its mechanism of action. The safety and efficacy of apalutamide have not been established in females; it is not indicated for use in women. In a pilot embryofetal development toxicity study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities (e.g., decreased fetal anogenital distance, misshapen pituitary gland, and skeletal variations including unossified phalanges, supernumerary short thoracolumbar ribs, and small, incomplete ossification and/or misshapen hyoid bone) and embryo-fetal lethality (resorptions) at maternal exposures of 2 to 6 times the human clinical exposure (AUC) at the recommended dose.

    Contraception requirements, infertility, male-mediated teratogenicity, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during apalutamide treatment. Apalutamide is not indicated for use in females. Because of the potential for male-mediated teratogenicity, males should use a condom during sex with a pregnant female and males with female partners of reproductive potential should use effective contraception during and for at least 3 months after treatment with apalutamide; sperm donation should also be avoided during treatment and for 3 months after the last dose of apalutamide. Although there are no data regarding the effect of apalutamide on human fertility, male infertility has been observed in animal studies.

    Breast-feeding

    There are no data on the presence of apalutamide or its metabolites in human milk, the effect on a child who is breast-feeding, or the effect on milk production. The safety and efficacy of apalutamide have not been established in females; it is not indicated for use in women.

    ADVERSE REACTIONS

    Severe

    hypertension / Early / 8.0-14.0
    rash / Early / 6.0-6.0
    hypertriglyceridemia / Delayed / 1.6-3.0
    bone fractures / Delayed / 1.5-2.7
    heart failure / Delayed / 0-2.2
    hyperglycemia / Delayed / 0-2.0
    hyperkalemia / Delayed / 0-1.9
    lymphopenia / Delayed / 0-1.8
    asthenia / Delayed / 0-1.4
    fatigue / Early / 0-1.4
    weight loss / Delayed / 0-1.1
    diarrhea / Early / 0-1.1
    arthralgia / Delayed / 0-1.0
    infection / Delayed / 0-0.8
    seizures / Delayed / 0.4-0.4
    myocardial infarction / Delayed / 0-0.4
    leukopenia / Delayed / 0.3-0.4
    anemia / Delayed / 0-0.4
    nephrotoxicity / Delayed / 0-0.4
    pruritus / Rapid / 0-0.2
    GI perforation / Delayed / 0-0.2
    cardiac arrest / Early / 0-0.2
    respiratory arrest / Rapid / 0-0.2
    anorexia / Delayed / 0-0.1
    hypercholesterolemia / Delayed / 0-0.1
    exfoliative dermatitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    penile edema / Early / Incidence not known
    stroke / Early / Incidence not known

    Moderate

    hot flashes / Early / 14.0-23.0
    peripheral edema / Delayed / 11.0-11.0
    hypothyroidism / Delayed / 8.0-8.0
    urinary retention / Early / 0-3.8
    hematuria / Delayed / 1.0
    stomatitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    skin erosion / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    interstitial lung disease / Delayed / Incidence not known

    Mild

    nausea / Early / 0-18.0
    muscle cramps / Delayed / 0-3.2
    dysgeusia / Early / 0-3.2
    vesicular rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with apalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Apalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Abemaciclib: (Major) Avoid coadministration of apalutamide with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.
    Abiraterone: (Major) Avoid coadministration of abiraterone with apalutamide due to decreased abiraterone exposure. If concomitant use is unavoidable, increase the frequency of abiraterone administration to twice daily; reduce the frequency to once daily when apalutamide is discontinued. Abiraterone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and apalutamide due to decreased plasma concentrations of acalabrutinib. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Acalabrutinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with apalutamide can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If apalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Apalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of oxycodone as needed. If apalutamide is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Afatinib: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with apalutamide is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of apalutamide. Afatinib is a P-glycoprotein (P-gp) substrate and apalutamide is a weak P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with apalutamide is necessary. If apalutamide is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like apalutamide with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Aliskiren; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Alpelisib: (Major) Avoid coadministration of alpelisib with apalutamide due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer.
    Alprazolam: (Moderate) Monitor for reduced efficacy of alprazolam and signs of benzodiazepine withdrawal if coadministration with apalutamide is necessary. Alprazolam is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease alprazolam concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Amiodarone: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with apalutamide is necessary. Amiodarone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration may decrease amiodarone plasma concentrations.
    Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Atorvastatin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for decreased efficacy of atorvastatin if coadministration with apalutamide is necessary. Atorvastatin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80% if the doses were separated, but increased the exposure of atorvastatin by 30% with simultaneous administration.
    Amlodipine; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Celecoxib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for decreased efficacy of celecoxib if coadministration with apalutamide is necessary; a celecoxib dosage adjustment may be necessary. Celecoxib is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration may decrease plasma concentrations of celecoxib.
    Amlodipine; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of apalutamide with omeprazole, as omeprazole plasma concentrations may be reduced. Omeprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong inhibitor of both CYP3A4 and CYP2C19. Coadministration with apalutamide decreased the single-dose AUC of omeprazole by 85%. (Major) Consider alternatives to clarithromycin if treatment with apalutamide is necessary. Clarithromycin is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Exposure to apalutamide may also be increased. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Apixaban: (Major) Avoid the concomitant administration of apixaban and drugs that are combined P-gp and strong CYP3A4 inducers, such as apalutamide. Concomitant use of apixaban and apalutamide may result in decreased exposure to apixaban and an increase in the risk of stroke.
    Apremilast: (Major) Avoid coadministration of apremilast with apalutamide due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the single-dose apremilast AUC and Cmax by 72% and 43%, respectively.
    Aprepitant, Fosaprepitant: (Major) Avoid the concurrent use of apalutamide with aprepitant, fosaprepitant due to substantially decreased exposure of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction may be expected. Apalutamide is a strong CYP3A4 inducer and aprepitant is a CYP3A4 substrate. Coadministration with another strong CYP3A inducer decreased the AUC of aprepitant by approximately 11-fold and decreased the mean terminal half-life by 3-fold.
    Aripiprazole: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when a potent CYP3A4 inducer, such as apalutamide, is added to aripiprazole therapy with subsequent adjustments based upon clinical response. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When apalutamide is discontinued, the aripiprazole dose in adults should be reduced to the original dose over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with apalutamide when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with apalutamide, no dosage adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if apalutamide is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.
    Artemether; Lumefantrine: (Contraindicated) Concomitant use of apalutamide and artemether is contraindicated. Apalutamide is a strong inducer of CYP3A4 and artemether is a substrate of this isoenzyme; therefore, coadministration may lead to decreased artemether concentrations and possible reduction in antimalarial activity. Coadministration of another strong CYP3A4 inducer reduced the AUC of artemether and dihydroartemisinin (metabolite of artemether) by 89% and 85%, respectively. (Contraindicated) Concomitant use of apalutamide and lumefantrine is contraindicated due to the risk of decreased lumefantrine concentrations and possible reduction in antimalarial activity. Apalutamide is a strong inducer of CYP3A4 and lumefantrine is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inducer reduced the AUC of lumefantrine by 68%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with apalutamide can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If apalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Apalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol: (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with apalutamide is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate. Apalutamide is a strong CYP2C19 inducer. Coadministration could decrease exposure to carisoprodol and increase exposure to meprobamate. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer. (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with apalutamide is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate. Apalutamide is a strong CYP2C19 inducer. Coadministration could decrease exposure to carisoprodol and increase exposure to meprobamate. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of apalutamide with omeprazole, as omeprazole plasma concentrations may be reduced. Omeprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong inhibitor of both CYP3A4 and CYP2C19. Coadministration with apalutamide decreased the single-dose AUC of omeprazole by 85%.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of oxycodone as needed. If apalutamide is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Contraindicated) Atazanavir is contraindicated for use with apalutamide due to decreased plasma concentrations of atazanavir, which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Apalutamide is a strong CYP3A4 inducer and atazanavir is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer, the Cmax of atazanavir was reduced by 53%, the AUC by 72%, and the Cmin by 98%.
    Atazanavir; Cobicistat: (Contraindicated) Atazanavir is contraindicated for use with apalutamide due to decreased plasma concentrations of atazanavir, which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Apalutamide is a strong CYP3A4 inducer and atazanavir is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer, the Cmax of atazanavir was reduced by 53%, the AUC by 72%, and the Cmin by 98%. (Major) Coadministration of cobicistat with apalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. In addition, there is a potential for increased apalutamide exposure. If these drugs are used together, monitor for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a substrate and strong inducer of CYP3A4. Cobicstat is a substrate and strong inhibitor of CYP3A4. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Atogepant: (Major) Use an atogepant dose of 30 or 60 mg PO once daily if coadministered with apalutamide. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer resulted in a 60% reduction in atogepant exposure and a 30% reduction in atogepant peak concentration.
    Atorvastatin: (Moderate) Monitor for decreased efficacy of atorvastatin if coadministration with apalutamide is necessary. Atorvastatin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80% if the doses were separated, but increased the exposure of atorvastatin by 30% with simultaneous administration.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for decreased efficacy of atorvastatin if coadministration with apalutamide is necessary. Atorvastatin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80% if the doses were separated, but increased the exposure of atorvastatin by 30% with simultaneous administration.
    Avanafil: (Major) Coadministration of avanafil with apalutamide is not recommended by the manufacturer of avanafil due to the potential for decreased efficacy. Avanafil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
    Avapritinib: (Major) Avoid coadministration of avapritinib with apalutamide due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
    Axitinib: (Major) Avoid coadministration of axitinib with apalutamide due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Bedaquiline: (Major) Avoid coadministration of apalutamide with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased bedaquiline exposure by 52%.
    Belumosudil: (Major) Increase the dosage of belumosudil to 200 mg PO twice daily when coadministered with apalutamide. Belumosudil is a CYP3A4 substrate and apalutamide is a strong CYP3A inducer; concomitant use may result in decreased belumosudil exposure and reduced belumosudil efficacy. Coadministration with another strong CYP3A inducer decreased belumosudil exposure by 72% in healthy subjects.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with apalutamide may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of apalutamide may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If apalutamide is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Apalutamide is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Berotralstat: (Major) Avoid coadministration of berotralstat with apalutamide. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and apalutamide is a P-gp inducer.
    Betrixaban: (Major) Avoid the concomitant administration of betrixaban and apalutamide. Concomitant administration of betrixaban and apalutamide results in decreased plasma concentrations of betrixaban that may be insufficient to achieve the intended therapeutic effect. Betrixaban is a P-glycoprotein (P-gp) substrate and apalutamide is a P-gp inducer.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Concomitant use of bictegravir and apalutamide may result in decreased bictegravir plasma concentrations, which may result in the loss of therapeutic efficacy and development of resistance. Bictegravir is a substrate of CYP3A4 and UGT1A1. Apalutamide is a strong CYP3A4 inducer as well as a UGT inducer.
    Bortezomib: (Major) Coadministration of apalutamide with bortezomib is not recommended due to decreases in bortezomib plasma concentrations. Bortezomib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer is expected to decrease the exposure of bortezomib by at least 45%.
    Bosutinib: (Major) Avoid coadministration of bosutinib with apalutamide due to decreased plasma concentrations of bosutinib. Bosutinib is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased bosutinib exposure by 94%.
    Brentuximab vedotin: (Moderate) Monitor for decreased efficacy of brentuximab if coadministration with apalutamide is necessary. Monomethyl auristatin E (MMAE) is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased MMAE exposure by approximately 46%.
    Brexpiprazole: (Major) Double the usual dose of brexpiprazole over 1 to 2 weeks if coadministration with apalutamide is necessary. If apalutamide is discontinued, reduce the brexpiprazole dose to the original level over 1 to 2 weeks. Brexpiprazole is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased brexpiprazole exposure by 73%.
    Brigatinib: (Major) Avoid coadministration of brigatinib with apalutamide due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Brivaracetam: (Major) Increase the dose of brivaracetam by up to 100% in patients taking concomitant apalutamide. Coadministration of brivaracetam with apalutamide may decrease brivaracetam exposure and reduce its efficacy. Brivaracetam is a CYP2C19 substrate and apalutamide is a strong CYP2C19 inducer. Plasma concentrations of brivaracetam were reduced by 45% when administered with another strong CYP2C19 inducer.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and apalutamide are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; apalutamide is a strong inducer of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Bupivacaine; Lidocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with apalutamide is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with apalutamide is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If apalutamide is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with apalutamide is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If apalutamide is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Buspirone: (Moderate) Monitor for decreased efficacy of buspirone if apalutamide is added to a patient on a stable dosage of buspirone; a dose increase of buspirone may be needed to maintain anxiolytic activity. Buspirone is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of buspirone by 89.6%.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Cabotegravir: (Contraindicated) Coadministration of cabotegravir and apalutamide is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; apalutamide is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%.
    Cabotegravir; Rilpivirine: (Contraindicated) Coadministration of cabotegravir and apalutamide is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; apalutamide is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of apalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Apalutamide is a strong inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with apalutamide due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with apalutamide 2 to 3 days after discontinuation of apalutamide. Cabozantinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Canagliflozin: (Moderate) Monitor for decreased efficacy of canagliflozin if coadministration with apalutamide is necessary. In patients taking apalutamide who have an eGFR greater than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. In patients who are tolerating canagliflozin to 200 mg and who require additional glycemic control, the dose may be increased to 300 mg once daily. In patients taking apalutamide who have an eGFR less than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. Consider other antihyperglycemic therapy in patients who require additional glycemic control. Canagliflozin is a UGT1A9 and 2B4 substrate and apalutamide is a UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%.
    Canagliflozin; Metformin: (Moderate) Monitor for decreased efficacy of canagliflozin if coadministration with apalutamide is necessary. In patients taking apalutamide who have an eGFR greater than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. In patients who are tolerating canagliflozin to 200 mg and who require additional glycemic control, the dose may be increased to 300 mg once daily. In patients taking apalutamide who have an eGFR less than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. Consider other antihyperglycemic therapy in patients who require additional glycemic control. Canagliflozin is a UGT1A9 and 2B4 substrate and apalutamide is a UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%.
    Cannabidiol: (Moderate) Consider a dose increase of cannabidiol if coadministered with apalutamide. Consider a dose reduction of apalutamide if apalutamide adverse reactions occur. Coadministration may decrease cannabidiol plasma concentrations resulting in a decrease in efficacy and increase apalutamide exposure increasing the risk of adverse effects. Cannabidiol is metabolized by CYP3A4 and CYP2C19; in vitro data predicts cannabidiol inhibits CYP2C8. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a substrate of CYP2C8.
    Capmatinib: (Major) Avoid coadministration of capmatinib and apalutamide due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Carbamazepine: (Moderate) Closely monitor carbamazepine levels if coadministration with apalutamide is necessary. Carbamazepine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 can increase the rate of carbamazepine metabolism and decrease carbamazepine levels.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Cariprazine: (Major) Coadministration of cariprazine with apalutamide is not recommended as the net effect of CYP3A4 induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with cariprazine with CYP3A4 inducers has not been evaluated.
    Carisoprodol: (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with apalutamide is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate. Apalutamide is a strong CYP2C19 inducer. Coadministration could decrease exposure to carisoprodol and increase exposure to meprobamate. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Carvedilol: (Moderate) Monitor for decreased efficacy of carvedilol if coadministration with apalutamide is necessary. Carvedilol is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration with a multi-enzyme inducer decreased plasma concentrations of carvedilol by about 70%.
    Celecoxib: (Moderate) Monitor for decreased efficacy of celecoxib if coadministration with apalutamide is necessary; a celecoxib dosage adjustment may be necessary. Celecoxib is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration may decrease plasma concentrations of celecoxib.
    Ceritinib: (Major) Avoid concomitant use of ceritinib with apalutamide as ceritinib exposure may be decreased, which may reduce its efficacy; apalutamide exposure may also increase. Ceritinib is a CYP3A substrate and a strong CYP3A4 inhibitor. Apalutamide is a CYP3A4 substrate and a strong CYP3A inducer. Coadministration with a strong CYP3A inducer decreased ceritinib exposure by 70%. Coadministration with a strong CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) by 28%.
    Chloramphenicol: (Moderate) Monitor for an increase in apalutamide-related adverse reactions if coadministration with chloramphenicol is necessary. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with apalutamide can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If apalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Apalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with apalutamide can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If apalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Apalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Cisapride: (Moderate) Monitor for decreased efficacy of cisapride if coadministration with apalutamide is necessary. Apalutamide is a strong CYP3A4 inducer and cisapride is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of cisapride.
    Citalopram: (Moderate) Monitor for decreased efficacy of citalopram if coadministration with apalutamide is necessary. Citalopram is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer. Coadministration with another strong CYP3A4 inducer did not affect citalopram plasma concentrations, but increased clearance of citalopram with strong CYP3A4 inducers is possible.
    Clarithromycin: (Major) Consider alternatives to clarithromycin if treatment with apalutamide is necessary. Clarithromycin is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Exposure to apalutamide may also be increased. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Clindamycin: (Moderate) Monitor for loss of clindamycin efficacy with coadministration of apalutamide as concurrent use may decrease clindamycin exposure. Clindamycin is a CYP3A4 substrate; apalutamide is a strong inducer of CYP3A4.
    Clonazepam: (Moderate) Monitor patients for decreased efficacy and a change in clonazepam dosage requirements when giving concurrently with apalutamide. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam is used with strong CYP3A4 inducers. Clonazepam is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Clopidogrel: (Major) Avoid concomitant use of clopidogrel and apalutamide due to the risk of bleeding. If use together is necessary, monitor for bleeding and apalutamide-related toxicity; consider dose reduction based on tolerability in patients experiencing grade 3 or higher adverse reactions or toxicities. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19 and is also a strong CYP2C8 inhibitor; apalutamide is a strong CYP2C19 inducer and a substrate of CYP2C8.
    Clorazepate: (Moderate) Monitor for decreased efficacy of clorazepate if coadministration with apalutamide is necessary. Clorazepate is a prodrug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by CYP2C19 and CYP3A4. Apalutamide is a strong CYP3A4 and CYP2C19 inducer. Concomitant use may decrease N-desmethyldiazepam plasma concentrations.
    Clozapine: (Major) Coadministration of clozapine with apalutamide is not recommended due to decreased plasma concentrations of clozapine. If concomitant use is unavoidable, the patient should be monitored for loss of efficacy; consider increasing the clozapine dose if necessary. When apalutamide is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Cobicistat: (Major) Coadministration of cobicistat with apalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. In addition, there is a potential for increased apalutamide exposure. If these drugs are used together, monitor for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a substrate and strong inducer of CYP3A4. Cobicstat is a substrate and strong inhibitor of CYP3A4. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with apalutamide due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
    Codeine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with apalutamide can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If apalutamide is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Apalutamide is a strong CYP3A4 inducer.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and apalutamide; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A4 inducer decreased exposure after a single dose of copanlisib by 60%.
    Crizotinib: (Major) Avoid coadministration of crizotinib with apalutamide due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and apalutamide is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Cyclosporine: (Moderate) Closely monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with apalutamide is necessary. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; apalutamide is a strong CYP3A4 inducer.
    Dabigatran: (Major) Coadministration of dabigatran with apalutamide should generally be avoided due to the risk of deceased dabigatran exposure which may reduce efficacy. Dabigatran is a P-glycoprotein (P-gp) substrate and apalutamide is a weak P-gp inducer.
    Daclatasvir: (Contraindicated) Concomitant use of daclatasvir with apalutamide is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Apalutamide is a potent inducer of the hepatic isoenzyme CYP3A4 and daclatasvir is a substrate of this isoenzyme.
    Dapagliflozin; Saxagliptin: (Moderate) Monitor for increased blood sugars if coadministration of saxagliptin with apalutamide is necessary. Saxagliptin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased saxagliptin exposure by 76%.
    Dapsone: (Moderate) Monitor for an increase in hemolysis if coadministration of dapsone with apalutamide is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A4 metabolite and apalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers may increase the formation of dapsone hydroxylamine, a metabolite associated with hemolysis. Coadministration with another strong CYP3A4 inducer decreased dapsone levels by 7-fold to 10-fold; in leprosy, this reduction has not required a change in dosage.
    Darifenacin: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with apalutamide is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Apalutamide is a strong CYP3A4 inducer and darifenacin is a CYP3A4 substrate.
    Darolutamide: (Major) Avoid coadministration of darolutamide with apalutamide due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Apalutamide is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
    Darunavir: (Major) Coadministration of darunavir with apalutamide is not recommended as there is a potential for decreased darunavir concentrations; exposure to apalutamide may also increase. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Darunavir; Cobicistat: (Major) Coadministration of cobicistat with apalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. In addition, there is a potential for increased apalutamide exposure. If these drugs are used together, monitor for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a substrate and strong inducer of CYP3A4. Cobicstat is a substrate and strong inhibitor of CYP3A4. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%. (Major) Coadministration of darunavir with apalutamide is not recommended as there is a potential for decreased darunavir concentrations; exposure to apalutamide may also increase. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of cobicistat with apalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. In addition, there is a potential for increased apalutamide exposure. If these drugs are used together, monitor for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a substrate and strong inducer of CYP3A4. Cobicstat is a substrate and strong inhibitor of CYP3A4. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%. (Major) Coadministration of darunavir with apalutamide is not recommended as there is a potential for decreased darunavir concentrations; exposure to apalutamide may also increase. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Coadministration of paritaprevir with apalutamide is contraindicated due to the potential for decreased paritaprevir concentrations and the potential development of viral resistance. Paritaprevir is metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased paritaprevir exposure by 70%. (Contraindicated) Coadministration of ritonavir with apalutamide is contraindicated as there is a potential for decreased ritonavir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; exposure to apalutamide may also increase. Ritonavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Dasatinib: (Major) Avoid coadministration of dasatinib and apalutamide due to the potential for decreased dasatinib exposure and reduced efficacy. If concomitant use is unavoidable, consider an increased dose of dasatinib and monitor for toxicity. Dasatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concurrent use of another strong CYP3A4 inducer decreased the mean Cmax and AUC of dasatinib by 81% and 82%, respectively.
    Deferasirox: (Moderate) Monitor serum ferritin levels and clinical response to deferasirox if coadministration with apalutamide is necessary. Deferasirox is a substrate of UGT1A1 and 1A3. Apalutamide may be a UGT inducer.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and apalutamide due to the risk of significantly decreased concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate and apalutamide is a strong inducer of CYP3A4. Administration with multiple doses of another strong CYP3A4 inducer decreased deflazacort exposure by 95%.
    Delavirdine: (Major) Coadministration of delavirdine with apalutamide is not recommended as there is a potential for decreased delavirdine concentrations; exposure to apalutamide may also increase. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Delavirdine is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Desogestrel; Ethinyl Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Dexamethasone: (Moderate) Monitor for decreased efficacy of dexamethasone if coadministration with apalutamide is necessary; consider increasing the dose of dexamethasone if clinically appropriate. Dexamethasone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Dexlansoprazole: (Major) Avoid coadministration of dexlansoprazole with apalutamide due to decreased plasma concentrations of dexlansoprazole. Dexlansoprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer.
    Dextromethorphan; Quinidine: (Moderate) Closely monitor quinidine concentrations if apalutamide is added to existing quinidine therapy. No special precautions appear necessary if apalutamide is started several weeks before quinidine, but quinidine doses may require adjustment if apalutamide is added or discontinued during quinidine therapy. Quinidine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the half-life and corresponding AUC of quinidine by 50% to 60%.
    Diazepam: (Moderate) Monitor for diazepam withdrawal symptoms or lack of efficacy if coadministration of diazepam with apalutamide is necessary. Diazepam is a CYP3A4, CYP2C9, and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer, as well as a weak CYP2C9 inducer.
    Diclofenac: (Moderate) Monitor for decreased efficacy of diclofenac if coadministration with apalutamide is necessary; a dosage adjustment of diclofenac may be necessary. Diclofenac is a CYP2C9 substrate and apalutamide is a CYP2C9 inducer.
    Diclofenac; Misoprostol: (Moderate) Monitor for decreased efficacy of diclofenac if coadministration with apalutamide is necessary; a dosage adjustment of diclofenac may be necessary. Diclofenac is a CYP2C9 substrate and apalutamide is a CYP2C9 inducer.
    Dienogest; Estradiol valerate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations when starting, adjusting, or discontinuing apalutamide. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index and apalutamide is a weak P-gp inducer. Drugs that induce P-gp have the potential to alter digoxin pharmacokinetics.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with apalutamide can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If apalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Apalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Diltiazem: (Major) Avoid coadministration of diltiazem and apalutamide due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable levels.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Disopyramide: (Moderate) Monitor disopyramide serum concentrations and for loss of efficacy when coadministration with apalutamide is necessary. Disopyramide exposure may be decreased during concurrent use. Apalutamide is a strong CYP3A4 inducer and disopyramide is a CYP3A4 substrate.
    Docetaxel: (Major) Avoid coadministration of docetaxel with apalutamide due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with other strong CYP3A4 inducers increased docetaxel metabolism by 2.6-fold to 32-fold.
    Dolutegravir: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with apalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Apalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with apalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Apalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use of apalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Apalutamide is a strong inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with apalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Apalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Donepezil: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with apalutamide is necessary. Donepezil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Donepezil; Memantine: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with apalutamide is necessary. Donepezil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Doravirine: (Contraindicated) Concurrent administration of doravirine and apalutamide is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent administration of doravirine and apalutamide is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer.
    Doxorubicin: (Major) Avoid coadministration of doxorubicin with apalutamide due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Dronabinol: (Moderate) Monitor for a decrease in dronabinol efficacy if coadministration with apalutamide is necessary. Dronabinol is a CYP2C9 and CYP3A4 substrate. Apalutamide is a strong CYP3A4 inducer and a weak inducer of CYP2C9.
    Dronedarone: (Major) Avoid coadministration of dronedarone with apalutamide due to decreased dronedarone exposure. Dronedarone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased dronedarone exposure by 80%.
    Drospirenone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Drospirenone; Estetrol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Drospirenone; Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Drospirenone; Ethinyl Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Duvelisib: (Major) Avoid coadministration of duvelisib with apalutamide. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. Duvelisib is a CYP3A substrate; apalutamide is a strong CYP3A inducer. In drug interaction studies, coadministration of duvelisib with another strong CYP3A inducer for 7 days decreased duvelisib Cmax and AUC by 66% and 82%, respectively
    Edoxaban: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with apalutamide is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-glycoprotein (P-gp) substrate and apalutamide is a weak P-gp inducer.
    Efavirenz: (Major) Use caution if apalutamide and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients weighing at least 50 kg). Apalutamide is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Use caution if apalutamide and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients weighing at least 50 kg). Apalutamide is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Use caution if apalutamide and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients weighing at least 50 kg). Apalutamide is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Elagolix: (Moderate) Concomitant use of elagolix and apalutamide may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; apalutamide is a strong inducer of CYP3A.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Moderate) Concomitant use of elagolix and apalutamide may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; apalutamide is a strong inducer of CYP3A.
    Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of apalutamide with elbasvir is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. Apalutamide is a strong CYP3A inducer and elbasvir is a substrate of CYP3A. (Contraindicated) Concurrent administration of apalutamide with grazoprevir is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Apalutamide is a strong CYP3A inducer and grazoprevir is a substrate of CYP3A.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of elexacaftor; tezacaftor; ivacaftor with apalutamide is not recommended as concurrent use may decrease exposure of elexacaftor; tezacaftor; ivacaftor. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive CYP3A4 substrate). Apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer significantly decreased ivacaftor exposure by 89%; elexacaftor and tezacaftor exposures are expected to also decrease during coadministration of strong CYP3A4 inducers. (Major) Coadministration of ivacaftor with apalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and apalutamide together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of apalutamide, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%. Tezacaftor exposures can also be expected to decrease significantly during coadministration with strong CYP3A inducers.
    Elvitegravir: (Major) Coadministration of elvitegravir with apalutamide is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with apalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. In addition, there is a potential for increased apalutamide exposure. If these drugs are used together, monitor for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a substrate and strong inducer of CYP3A4. Cobicstat is a substrate and strong inhibitor of CYP3A4. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%. (Major) Coadministration of elvitegravir with apalutamide is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with apalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. In addition, there is a potential for increased apalutamide exposure. If these drugs are used together, monitor for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a substrate and strong inducer of CYP3A4. Cobicstat is a substrate and strong inhibitor of CYP3A4. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%. (Major) Coadministration of elvitegravir with apalutamide is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concurrent use of apalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Apalutamide is a strong inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent use of apalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Apalutamide is a strong inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Enalapril; Felodipine: (Major) Avoid coadministration of felodipine with apalutamide if possible due to decreased plasma concentrations of felodipine. Felodipine is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased felodipine exposure by 94% in a pharmacokinetic study.
    Encorafenib: (Major) Avoid coadministration of encorafenib and apalutamide due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Entrectinib: (Major) Avoid coadministration of entrectinib with apalutamide due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Eravacycline: (Major) Increase the dose of eravacycline to 1.5 mg/kg IV every 12 hours when coadministered with a strong CYP3A4 inducer, such as apalutamide. Concomitant use of strong CYP3A4 inducers decreases the exposure of eravacycline, which may reduce its efficacy. When eravacycline was administered with a strong CYP3A4/3A5 inducer, the eravacycline AUC was decreased by 35% and its clearance was increased by 54%.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and apalutamide due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Erlotinib: (Major) Avoid coadministration of erlotinib with apalutamide if possible due to decreased plasma concentrations of erlotinib. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Esomeprazole: (Major) Avoid coadministration of esomeprazole with apalutamide due to decreased esomeprazole plasma concentrations. Esomeprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer. Coadministration with another strong inducer of CYP3A4 inducer decreased omeprazole exposure by 37.9% in CYP2C19 poor metabolizers and by 43.9% in extensive metabolizers; esomeprazole is an enantiomer of omeprazole.
    Estazolam: (Moderate) Monitor for withdrawal symptoms or lack of estazolam efficacy if coadministration with apalutamide is necessary. Estazolam is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. While no in vivo drug-drug interaction studies were conducted between estazolam and inducers of CYP3A, compounds that are potent CYP3A inducers would be expected to decrease estazolam concentrations.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estradiol; Levonorgestrel: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estradiol; Norethindrone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estradiol; Norgestimate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estradiol; Progesterone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and apalutamide should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed apalutamide. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on apalutamide, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Eszopiclone: (Moderate) Monitor for decreased efficacy of eszopiclone if coadministration with apalutamide is necessary. Eszopiclone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased racemic zopiclone exposure by 80%; a similar effect would be expected with eszopiclone.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Ethinyl Estradiol; Norelgestromin: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Ethinyl Estradiol; Norgestrel: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Etonogestrel: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Etonogestrel; Ethinyl Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Etravirine: (Major) The concomitant use of apalutamide with etravirine is not recommended due to significant decreases in etravirine plasma concentrations and, thus, possible loss of therapeutic effect. Etravirine is a CYP3A4, CYP2C19, and CYP2C9 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer, as well as a weak CYP2C9 inducer.
    Everolimus: (Major) Avoid coadministration of everolimus with apalutamide due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of apalutamide and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Exemestane: (Major) If coadministration of exemestane with apalutamide is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
    Fedratinib: (Major) Avoid coadministration of fedratinib with apalutamide as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Felodipine: (Major) Avoid coadministration of felodipine with apalutamide if possible due to decreased plasma concentrations of felodipine. Felodipine is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased felodipine exposure by 94% in a pharmacokinetic study.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with apalutamide is necessary. If apalutamide is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like apalutamide with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Finerenone: (Major) Avoid concurrent use of finerenone and apalutamide due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased overall exposure to finerenone by 90%.
    Flibanserin: (Major) Coadministration of flibanserin with apalutamide is not recommended due to decreased plasma concentrations of flibanserin. Flibanserin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased flibanserin exposure by 95%.
    Flurazepam: (Moderate) Monitor for withdrawal symptoms or lack of flurazepam efficacy if coadministration with apalutamide is necessary. Flurazepam is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Fosamprenavir: (Major) Coadministration of fosamprenavir with apalutamide is not recommended as there is a potential for decreased fosamprenavir concentrations, which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Additionally, exposure to apalutamide may also be increased. Fosamprenavir is a CYP3A4 substrate and strong CYP3A4 inhibitor; apalutamide is a strong CYP3A4 inducer and CYP3A4 substrate.
    Fostamatinib: (Major) Avoid the concomitant use of fostamatinib with apalutamide. Concomitant use of fostamatinib with a strong CYP3A4 inducer decreases exposure to the major active metabolite, R406. R406 is extensively metabolized by CYP3A4; apalutamide is a strong CYP3A4 inducer. Concomitant use of fostamatinib with another strong CYP3A4 inducer decreased R406 AUC by 75% and Cmax by 59%.
    Fostemsavir: (Contraindicated) Concomitant use of fostemsavir and apalutamide is contraindicated. Use of these drugs together may significantly decrease the plasma concentrations of temsavir, the active moiety of fostemsavir, thereby increasing the risk for HIV treatment failure or development of viral resistance. Temsavir is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Gefitinib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with apalutamide is necessary. If apalutamide is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Gemfibrozil: (Moderate) Monitor for an increase in apalutamide-related adverse reactions if coadministration with gemfibrozil is necessary. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with gemfibrozil decreased the Cmax of single-dose apalutamide by 21% but increased the AUC by 68%; strong CYP2C8 inhibition is expected to increase the steady-state apalutamide Cmax by 32% and AUC by 44%. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 23%.
    Gilteritinib: (Major) Avoid coadministration of gilteritinib and apalutamide due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; apalutamide is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Glasdegib: (Major) Avoid coadministration of glasdegib and apalutamide due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with apalutamide is not recommended as apalutamide may significantly decrease plasma concentrations of glecaprevir resulting in loss of efficacy. Glecaprevir is a CYP3A4 and P-glycoprotein (P-gp) substrate. Apalutamide is a strong CYP3A4 inducer and a weak inducer of P-gp. Coadministration with another strong CYP3A4 and P-gp inducer decreased glecaprevir exposure by 66%. (Moderate) Monitor for decreased efficacy of pibrentasvir if coadministration with apalutamide is necessary. Pibrentasvir is a P-glycoprotein (P-gp) and BCRP substrate. Apalutamide is a weak P-gp and BCRPP inducer. Concomitant use may decrease pibrentasvir plasma concentrations.
    Glimepiride: (Moderate) Monitor for decreased efficacy of glimepiride if coadministration with apalutamide is necessary. Glimepiride is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration with other CYP2C inducers decreased plasma concentrations of glimepiride, leading to worsened glycemic control.
    Glimepiride; Rosiglitazone: (Moderate) Monitor for decreased efficacy of glimepiride if coadministration with apalutamide is necessary. Glimepiride is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration with other CYP2C inducers decreased plasma concentrations of glimepiride, leading to worsened glycemic control.
    Glyburide: (Moderate) Monitor blood sugars if coadministration of glyburide with apalutamide is necessary. Glyburide is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration may decrease glyburide plasma concentrations, resulting in increased blood sugars.
    Glyburide; Metformin: (Moderate) Monitor blood sugars if coadministration of glyburide with apalutamide is necessary. Glyburide is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration may decrease glyburide plasma concentrations, resulting in increased blood sugars.
    Granisetron: (Moderate) Monitor for decreased efficacy of granisetron if coadministration with apalutamide is necessary. Granisetron is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. In a human pharmacokinetic study, coadministration with another strong CYP3A4 inducer increased the total plasma clearance of granisetron by 25%. The clinical significance of this change is not known.
    Grapefruit juice: (Moderate) The exposure to apalutamide may be significantly increased in patients who regularly consume grapefruit or grapefruit juice, a strong CYP3A4 inhibitor.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Guanfacine: (Major) A dose increase of extended-release (ER) guanfacine should be considered if coadministration with apalutamide is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking apalutamide; increase the dose of guanfacine over 1 to 2 weeks if apalutamide therapy is added to a patient already taking guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased guanfacine exposure by 70%.
    Haloperidol: (Moderate) Monitor for decreased efficacy of haloperidol if coadministration with apalutamide is necessary. Haloperidol is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased haloperidol plasma concentrations by a mean of 70% and increased mean scores on the Brief Psychiatric Rating Scale from baseline.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with apalutamide. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and apalutamide is a strong CYP3A inducer.
    Ibrutinib: (Major) Avoid coadministration of ibrutinib with apalutamide due to decreased plasma concentrations of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of oxycodone as needed. If apalutamide is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Idelalisib: (Major) Avoid coadministration of idelalisib with apalutamide due to decreased plasma concentrations of idelalisib; exposure to apalutamide may also increase. Idelalisib is a CYP3A4 substrate and strong CYP3A4 inhibitor. Apalutamide is a CYP3A4 substrate and strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased idelalisib exposure by 75%. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with apalutamide is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; apalutamide is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Imatinib: (Major) Avoid coadministration of imatinib with apalutamide if possible due to decreased plasma concentrations of imatinib. If concomitant use is unavoidable, increase the dose of imatinib by at least 50%, carefully monitoring clinical response; imatinib doses up to 1,200 mg per day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers. Imatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer increased imatinib clearance by 3.8-fold, which significantly decreased the mean Cmax and AUC of imatinib.
    Imipramine: (Moderate) Monitor for decrease in the efficacy of imipramine if coadministration with apalutamide is necessary; adjust the dose of imipramine if clinically appropriate. Imipramine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. The plasma concentration of imipramine may decrease when given concomitantly with CYP3A4 inducers.
    Indacaterol: (Moderate) Monitor for decreased efficacy of indacaterol if coadministration with apalutamide is necessary. Indacaterol is a substrate of CYP3A4, UGT, and P-glycoprotein (P-gp). Apalutamide is a strong CYP3A4 inducer, as well as an inducer of UGT and a weak P-gp inducer.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor for decreased efficacy of indacaterol if coadministration with apalutamide is necessary. Indacaterol is a substrate of CYP3A4, UGT, and P-glycoprotein (P-gp). Apalutamide is a strong CYP3A4 inducer, as well as an inducer of UGT and a weak P-gp inducer.
    Indinavir: (Major) Coadministration of indinavir with apalutamide is not recommended as there is a potential for decreased indinavir concentrations, which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; exposure to apalutamide may also increase. Indinavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Infigratinib: (Major) Avoid concurrent use of infigratinib and apalutamide. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of infigratinib by 56%.
    Irinotecan Liposomal: (Major) Avoid coadministration of irinotecan with apalutamide unless there are no therapeutic alternatives, due to decreased plasma concentrations of irinotecan; consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Apalutamide is a strong CYP3A4 inducer as well as a UGT inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or its active metabolite SN-38 in both adult and pediatric patients.
    Irinotecan: (Major) Avoid coadministration of irinotecan with apalutamide unless there are no therapeutic alternatives, due to decreased plasma concentrations of irinotecan; consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Apalutamide is a strong CYP3A4 inducer as well as a UGT inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or its active metabolite SN-38 in both adult and pediatric patients.
    Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with apalutamide is contraindicated due to the potential for decreased isavuconazole serum concentrations and treatment failure. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; apalutamide is a strong inducer of this enzyme. Coadministration with another strong CYP3A4 inducer decreased isavuconazole serum concentrations by 97%.
    Isradipine: (Major) Monitor for decreased efficacy of isradipine if coadministration with apalutamide is necessary. Isradipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased isradipine levels to below detectable limits.
    Istradefylline: (Major) Avoid coadministration of istradefylline with apalutamide as istradefylline exposure and efficacy may be reduced. Apalutamide is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
    Itraconazole: (Major) The use of apalutamide within 2 weeks of itraconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of itraconazole and increase the dose of itraconazole as necessary. Exposure to apalutamide may also increase; monitor for apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Itraconazole is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Coadministration with itraconazole decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar.
    Ivabradine: (Major) Avoid coadministration of ivabradine and apalutamide due to decreased plasma concentrations of ivabradine. Ivabradine is a CYP3A4 substrate and apalutamide is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ivabradine exposure by approximately half.
    Ivacaftor: (Major) Coadministration of ivacaftor with apalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with apalutamide due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
    Ixabepilone: (Major) Avoid coadministration of ixabepilone with apalutamide due to decreased plasma concentrations of ixabepilone; consider an alternative to apalutamide with no or minimal CYP3A4 induction potential. If concomitant use is unavoidable, the dose of ixabepilone may be gradually increased as tolerated from 40 mg/m2 to 60 mg/m2 IV over 4 hours; monitor carefully for ixabepilone-related toxicities. Ixabepilone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ixabepilone exposure by 43%.
    Ixazomib: (Major) Avoid the concomitant use of ixazomib and apalutamide; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the ixazomib Cmax and AUC by 54% and 74%, respectively.
    Ketoconazole: (Major) The use of apalutamide within 2 weeks of systemic ketoconazole therapy is not recommended due to the potential for decreased exposure to ketoconazole; apalutamide exposure may also increase. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole and an increase in apalutamide-related adverse reactions. Increase the dose of ketoconazole as necessary; consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Ketoconazole is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Lamotrigine: (Moderate) Adjustments in lamotrigine escalation and maintenance dose regimens may be necessary with concomitant apalutamide use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and apalutamide induces glucuronidation.
    Lansoprazole: (Major) Avoid coadministration of lansoprazole with apalutamide due to decreased lansoprazole exposure. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of lansoprazole with apalutamide due to decreased lansoprazole exposure. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer. (Major) Consider alternatives to clarithromycin if treatment with apalutamide is necessary. Clarithromycin is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Exposure to apalutamide may also be increased. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Lansoprazole; Naproxen: (Major) Avoid coadministration of lansoprazole with apalutamide due to decreased lansoprazole exposure. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer.
    Lapatinib: (Major) Avoid coadministration of lapatinib with apalutamide due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If apalutamide is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with apalutamide due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If apalutamide is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of apalutamide. Larotrectinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp) and BCRP, such as apalutamide. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Coadministration of ledipasvir with apalutamide is not recommended. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Ledipasvir is a P-glycoprotein (P-gp) substrate and apalutamide is a weak P-gp inducer.
    Lefamulin: (Major) Avoid coadministration of lefamulin with apalutamide unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; apalutamide is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
    Lemborexant: (Major) Avoid coadministration of lemborexant and apalutamide as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer.
    Letermovir: (Major) Concurrent administration of letermovir and apalutamide is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Apalutamide may induce UGT and is a weak inducer of P-gp. Also, plasma concentrations of apalutamide could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Apalutamide is metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions of intolerable toxicities.
    Leuprolide; Norethindrone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Levamlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Levonorgestrel: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Levonorgestrel; Ethinyl Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Lidocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with apalutamide is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Lidocaine; Prilocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with apalutamide is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and apalutamide is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. The exposure of apalutamide may also be increased, increasing the risk for apalutamide-related adverse reactions. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; apalutamide is a CYP3A4 substrate and strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
    Lopinavir; Ritonavir: (Contraindicated) Coadministration of lopinavir with apalutamide is contraindicated. Taking these drugs together could decrease lopinavir concentrations, and may lead to a reduction in antiretroviral activity. Lopinavir is a CYP3A4 substrate. Apalutamide is a strong CYP3A4 inducer. (Contraindicated) Coadministration of ritonavir with apalutamide is contraindicated as there is a potential for decreased ritonavir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; exposure to apalutamide may also increase. Ritonavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Lorlatinib: (Contraindicated) Coadministration of lorlatinib with apalutamide is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue apalutamide for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Lumacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with apalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Lumateperone: (Major) Avoid coadministration of lumateperone and apalutamide as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of lumateperone with another strong CYP3A4 inducer significantly decreased lumateperone exposure.
    Lurasidone: (Contraindicated) Coadministration of lurasidone with apalutamide is contraindicated due to decreased plasma concentrations of lurasidone. Lurasidone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased lurasidone exposure by 83%.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and apalutamide due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and apalutamide is a strong CYP3A inducer.
    Macimorelin: (Major) Discontinue apalutamide and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can significantly decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer.
    Macitentan: (Major) Avoid coadministration of macitentan with apalutamide due to decreased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced systemic availability of the pharmacologically active moieties of macitentan by approximately 50% or more, which may lead to reduced efficacy.
    Maraviroc: (Major) Increase the adult maraviroc dose to 600 mg PO twice daily if coadministration with apalutamide is necessary without a concomitant strong CYP3A4 inhibitor, as maraviroc concentrations may be expected to decrease. Coadministration of maraviroc and apalutamide is contraindicated in patients with CrCL less than 30 mL/min. For pediatric patients, concomitant use of maraviroc with apalutamide without a strong CYP3A inhibitor is not recommended. If the patient's medication regimen also contains a strong CYP3A inhibitor, the CYP3A inhibitor's actions are expected to exceed that of the inducer; overall, increased maraviroc concentrations are expected. Maraviroc is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Medroxyprogesterone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Mefloquine: (Moderate) Monitor for decreased efficacy of mefloquine if coadministration with apalutamide is necessary. Mefloquine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased mefloquine exposure by 68%.
    Mestranol; Norethindrone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Metformin; Repaglinide: (Moderate) An increased dose of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with apalutamide is necessary. Repaglinide is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased repaglinide exposure by 32% to 80%.
    Metformin; Saxagliptin: (Moderate) Monitor for increased blood sugars if coadministration of saxagliptin with apalutamide is necessary. Saxagliptin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased saxagliptin exposure by 76%.
    Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with apalutamide is necessary; these effects may be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. Consider increasing the dose of methadone as needed. If apalutamide is discontinued, consider a dose reduction of methadone and frequently monitor for signs or respiratory depression and sedation. Methadone is a substrate of CYP2C9, CYP2C19, and CYP3A4. Apalutamide is a strong CYP3A4 and CYP2C19 inducer, as well as a weak CYP2C9 inducer. Concomitant use with CYP3A4 inducers can decrease methadone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Midazolam: (Major) Monitor for withdrawal symptoms or lack of midazolam efficacy if coadministration with apalutamide is necessary. Midazolam is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with apalutamide decreased single-dose midazolam exposure by 92%.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and apalutamide as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Mifepristone: (Major) Avoid coadministration of mifepristone (Korlym) with apalutamide due to possible decreases in the plasma concentrations of mifepristone; exposure to apalutamide may also increase. The impact of apalutamide on the efficacy of short-term mifepristone for termination of pregnancy is unknown; refer to the follow-up assessment to verify that treatment has been successful. Mifepristone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. The concomitant use of CYP3A4 inducers with mifepristone has not been studied.
    Mirtazapine: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with apalutamide is necessary; a dosage adjustment of mirtazapine may be necessary. Mirtazapine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and apalutamide. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Use of a strong CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 92%.
    Modafinil: (Moderate) Monitor for decreased efficacy of modafinil if coadministration with apalutamide is necessary. Modafinil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. The probability of effect of apalutamide on modafinil exposure is low due to the existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil; however, plasma concentrations of modafinil may be impacted by strong CYP3A4 inducers.
    Naldemedine: (Major) Avoid coadministration of naldemedine with apalutamide due to a significant decrease in naldemedine plasma concentrations which may reduce efficacy. Naldemedine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naldemedine exposure by 83%.
    Naloxegol: (Major) Coadministration of naloxegol with apalutamide is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with apalutamide is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Naproxen; Esomeprazole: (Major) Avoid coadministration of esomeprazole with apalutamide due to decreased esomeprazole plasma concentrations. Esomeprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer. Coadministration with another strong inducer of CYP3A4 inducer decreased omeprazole exposure by 37.9% in CYP2C19 poor metabolizers and by 43.9% in extensive metabolizers; esomeprazole is an enantiomer of omeprazole.
    Nateglinide: (Moderate) Monitor for decreased efficacy of nateglinide if coadministration with apalutamide is necessary. Nateglinide is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration may decrease nateglinide plasma concentrations resulting in hyperglycemia.
    Nefazodone: (Moderate) Monitor for decreased efficacy of nefazodone and an increase in apalutamide-related adverse reactions if coadministration is necessary. Nefazodone is a substrate and strong inhibitor of CYP3A4. Apalutamide is a substrate and strong inducer of CYP3A4. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%. Use of apalutamide with a strong CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide). No initial dose adjustment of apalutamide is required, although the dose of apalutamide may need to be reduced based upon tolerability.
    Nelfinavir: (Contraindicated) Coadministration of nelfinavir and apalutamide is contraindicated due to the potential for subtherapeutic antiretroviral activity and the subsequent possibility for the development of resistant HIV mutations; exposure to apalutamide may also increase. Nelfinavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. When administered with another strong CYP3A inducer, the plasma AUC, Cmax, and Cmin of nelfinavir decreased by 83%, 76%, and 92%, respectively. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Neratinib: (Major) Avoid concomitant use of apalutamide with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%.
    Nevirapine: (Moderate) Concomitant use of apalutamide with nevirapine should be undertaken with caution due to potential decreased nevirapine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nevirapine is primarily a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nevirapine exposure by greater than 50%.
    Nifedipine: (Major) Avoid coadministration of nifedipine with apalutamide and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and apalutamide; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and apalutamide is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Nimodipine: (Major) Avoid coadministration of nimodipine with apalutamide due to decreased plasma concentrations of nimodipine. Nimodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers.
    Nintedanib: (Major) Avoid coadministration of nintedanib with apalutamide due to decreased plasma concentrations of nintedanib. Nintedanib is a substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4. Apalutamide is a strong CYP3A4 inducer as well as a weak P-gp inducer. Coadministration with oral doses of another P-gp and CYP3A4 inducer decreased exposure to nintedanib by 50%.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with apalutamide due to decreased plasma concentrations of nisoldipine. Nisoldipine is a CYP3A4 substrate and enzalutamide is a apalutamide CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norethindrone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norethindrone; Ethinyl Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norgestimate; Ethinyl Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norgestrel: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Olanzapine; Samidorphan: (Major) Avoid the concurrent use of samidorphan and apalutamide; decreased samidorphan exposure and loss of efficacy may occur. Samidorphan is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer reduced samidorphan exposure by 73%.
    Olaparib: (Major) Avoid coadministration of olaparib with apalutamide due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and apalutamide is a strong CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with another strong CYP3A inducer decreased the olaparib Cmax by 71% and the AUC by 87%.
    Oliceridine: (Moderate) Monitor for reduced efficacy of oliceridine and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of oliceridine as needed. If apalutamide is discontinued, consider a dose reduction of oliceridine and frequently monitor for signs of respiratory depression and sedation. Oliceridine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease the plasma concentrations of oliceridine; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Coadministration of paritaprevir with apalutamide is contraindicated due to the potential for decreased paritaprevir concentrations and the potential development of viral resistance. Paritaprevir is metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased paritaprevir exposure by 70%. (Contraindicated) Coadministration of ritonavir with apalutamide is contraindicated as there is a potential for decreased ritonavir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; exposure to apalutamide may also increase. Ritonavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Omeprazole: (Major) Avoid concomitant use of apalutamide with omeprazole, as omeprazole plasma concentrations may be reduced. Omeprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong inhibitor of both CYP3A4 and CYP2C19. Coadministration with apalutamide decreased the single-dose AUC of omeprazole by 85%.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of apalutamide with omeprazole, as omeprazole plasma concentrations may be reduced. Omeprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong inhibitor of both CYP3A4 and CYP2C19. Coadministration with apalutamide decreased the single-dose AUC of omeprazole by 85%. (Moderate) Monitor for decreased efficacy of rifabutin and potential issues of resistance if coadministration with apalutamide is necessary. Rifabutin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid concomitant use of apalutamide with omeprazole, as omeprazole plasma concentrations may be reduced. Omeprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong inhibitor of both CYP3A4 and CYP2C19. Coadministration with apalutamide decreased the single-dose AUC of omeprazole by 85%.
    Osilodrostat: (Major) Monitor cortisol concentration and patient's signs and symptoms during coadministration of osilodrostat and apalutamide. Concurrent use may decrease osilodrostat exposure and reduce its efficacy; an increase in osilodrostat dose may be necessary. After discontinuation of apalutamide, monitor cortisol concentration and patient's signs and symptoms; a reduction in osilodrostat dose may be needed. Osilodrostat is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Osimertinib: (Major) Avoid coadministration of apalutamide with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If apalutamide is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Ospemifene: (Moderate) Monitor for decreased efficacy of ospemifene if coadministration with apalutamide is necessary. Ospemifene is a CYP2C9, CYP2C19, and CYP3A4 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer as well as a weak inducer of CYP2C9. Coadministration with a strong CYP3A4/moderate CYP2C9 and CYP2C19 inducer decreased ospemifene exposure by 58%.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of oxycodone as needed. If apalutamide is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with apalutamide is necessary. Paclitaxel is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Palbociclib: (Major) Avoid coadministration of apalutamide with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
    Paliperidone: (Major) Avoid using apalutamide if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of apalutamide is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Oral paliperidone may be used; however, a dosage increase may be necessary. Paliperidone is a P-glycoprotein (P-gp) substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. Apalutamide is a strong CYP3A4 inducer and a weak P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased steady-state exposure of paliperidone by 37%.
    Panobinostat: (Major) Avoid the concomitant use of panobinostat and apalutamide due to the possibility of significantly decreased plasma concentrations of panobinostat. Apalutamide is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
    Pazopanib: (Major) Avoid coadministration of pazopanib with apalutamide due to the potential for decreased plasma concentrations of pazopanib. Pazopanib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and apalutamide due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pemigatinib exposure by 85%.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to apalutamide therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If apalutamide is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased perampanel exposure by 50% to 67%.
    Perindopril; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with apalutamide as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. Pexidartinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased pexidartinib exposure by 65%.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as apalutamide. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Pioglitazone; Glimepiride: (Moderate) Monitor for decreased efficacy of glimepiride if coadministration with apalutamide is necessary. Glimepiride is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration with other CYP2C inducers decreased plasma concentrations of glimepiride, leading to worsened glycemic control.
    Pitolisant: (Major) Monitor for loss of pitolisant efficacy after initiation of apalutamide. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if apalutamide is discontinued. Pitolisant is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
    Polatuzumab Vedotin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of apalutamide due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; apalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
    Ponatinib: (Major) Avoid coadministration of ponatinib with apalutamide if possible due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Ponesimod: (Major) Avoid concurrent use of ponesimod and apalutamide and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and apalutamide is a strong CYP3A inducer that may decrease ponesimod exposure.
    Posaconazole: (Major) Coadministration of apalutamide with posaconazole should generally be avoided due to the possibility of decreased posaconazole plasma concentrations, unless the benefit outweighs the risk. If concomitant use is unavoidable, closely monitor for breakthrough fungal infections and for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Posaconazole is a P-glycoprotein (P-gp) substrate and strong CYP3A4 inhibitor. Apalutamide is a weak P-gp inducer and a CYP3A4 substrate. Inducers of P-gp may affect posaconazole plasma concentrations. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Pralsetinib: (Major) Avoid coadministration of apalutamide with pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is unavoidable, double the current dose of pralsetinib starting on day 7 of coadministration. After apalutamide has been discontinued for at least 14 days, resume the pralsetinib dose taken prior to initiating apalutamide. Pralsetinib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the pralsetinib AUC by 68%.
    Praziquantel: (Contraindicated) The concomitant use of apalutamide with praziquantel is contraindicated due to the potential for decreased exposure and efficacy of praziquantel. If treatment with praziquantel is necessary, treatment with apalutamide should be discontinued 4 weeks before administration of praziquantel. Treatment with apalutamide can then be restarted 1 day after completion of praziquantel treatment. Apalutamide is a strong CYP3A4 inducer and praziquantel is a CYP3A4 substrate. In a crossover study with a 2-week washout period, administration of praziquantel followed by another strong CYP3A inducer resulted in undetectable plasma concentrations of praziquantel in 7 out of 10 subjects. When praziquantel was administered two weeks after discontinuation of the strong inducer, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone.
    Progesterone: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Progestins: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Propranolol: (Moderate) Monitor for decreased efficacy of propranolol if coadministration with apalutamide is necessary. Propranolol is a CYP2C19 substrate and apalutamide is a strong CYP2C19 inducer.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased efficacy of propranolol if coadministration with apalutamide is necessary. Propranolol is a CYP2C19 substrate and apalutamide is a strong CYP2C19 inducer.
    Quazepam: (Moderate) Monitor for withdrawal symptoms or lack of quazepam efficacy if coadministration with apalutamide is necessary. Quazepam is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Quetiapine: (Major) Increase the dose of quetiapine by up to 5-fold if coadministration with apalutamide is necessary. If apalutamide is discontinued, reduce the quetiapine dose to the original level in 7 to 14 days. Quetiapine is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold.
    Quinidine: (Moderate) Closely monitor quinidine concentrations if apalutamide is added to existing quinidine therapy. No special precautions appear necessary if apalutamide is started several weeks before quinidine, but quinidine doses may require adjustment if apalutamide is added or discontinued during quinidine therapy. Quinidine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the half-life and corresponding AUC of quinidine by 50% to 60%.
    Quinine: (Major) Monitor for lack of quinine efficacy if coadministration with apalutamide is necessary. Quinine is a CYP3A4, CYP2C19, CYP2C9, and P-glycoprotein (P-gp) substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer, as well as a weak inducer of CYP2C9 and P-gp. Coadministration with another strong CYP3A4 inducer that also induces multiple other enzymes decreased the quinine AUC by 75% to 85%.
    Ranolazine: (Contraindicated) The concomitant use of apalutamide with ranolazine is contraindicated due to decreased plasma concentrations of ranolazine resulting in decreased efficacy. Apalutamide is a strong CYP3A4 inducer and ranolazine is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
    Regorafenib: (Major) Avoid coadministration of regorafenib with apalutamide due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the active metabolite M-5, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased regorafenib exposure by 50% and increased M-5 exposure by 264%.
    Relugolix: (Major) Avoid concurrent use of relugolix and apalutamide. Concurrent use may decrease relugolix exposure and compromise the efficacy of relugolix therapy. If concurrent use is unavoidable, increase the relugolix maintenance dose to 240 mg once daily. If apalutamide is discontinued resume the recommended relugolix treatment dose of 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) and CYP3A substrate and apalutamide is a P-gp and strong CYP3A inducer. Concurrent use of another P-gp and strong CYP3A inducer decreased relugolix overall exposure by 55%.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concurrent use of relugolix and apalutamide. Concurrent use may decrease relugolix exposure and compromise the efficacy of relugolix therapy. If concurrent use is unavoidable, increase the relugolix maintenance dose to 240 mg once daily. If apalutamide is discontinued resume the recommended relugolix treatment dose of 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) and CYP3A substrate and apalutamide is a P-gp and strong CYP3A inducer. Concurrent use of another P-gp and strong CYP3A inducer decreased relugolix overall exposure by 55%. (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Repaglinide: (Moderate) An increased dose of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with apalutamide is necessary. Repaglinide is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased repaglinide exposure by 32% to 80%.
    Ribociclib: (Major) Avoid coadministration of ribociclib with apalutamide, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy; consider an alternative treatment with less potential to induce CYP3A. Exposure to apalutamide may also be increased. Ribociclib is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure by 89%. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with apalutamide, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy; consider an alternative treatment with less potential to induce CYP3A. Exposure to apalutamide may also be increased. Ribociclib is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure by 89%. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Rifabutin: (Moderate) Monitor for decreased efficacy of rifabutin and potential issues of resistance if coadministration with apalutamide is necessary. Rifabutin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Rilpivirine: (Contraindicated) Concurrent use of apalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Apalutamide is a strong inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Rimegepant: (Major) Avoid coadministration of rimegepant with apalutamide; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration of rimegepant with another strong CYP3A4 inducer decreased rimegepant exposure by 80%.
    Riociguat: (Moderate) Dosage recommendations for riociguat are not available if coadministration with apalutamide is necessary. Riociguat is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers may significantly reduce riociguat exposure, but data are not available.
    Ripretinib: (Major) Avoid coadministration of ripretinib with apalutamide. Coadministration may decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
    Risperidone: (Major) The manufacturer of oral risperidone recommends a slow upward titration of the risperidone dose as needed up to double the patient's usual dose during use of a strong 3A4 inducer like apalutamide. When using Risperdal Consta, the patient will require close monitoring for 4 to 8 weeks when starting apalutamide. A lower dose of Risperdal Consta may be prescribed between 2 to 4 weeks before the planned discontinuation of apalutamide to adjust for the expected increase in plasma concentrations of risperidone and its active metabolite. For patients treated with the recommended dose of Risperdal Consta 25 mg and discontinuing apalutamide, it is recommended to continue the 25 mg dose unless a reduction to 12.5 mg or discontinuation of treatment is indicated. The efficacy of the 12.5 mg dose has not been studied in clinical trials. When initiating apalutamide in patients receiving the long-acting subcutaneous risperidone injection (Perseris), close monitoring for 4 to 8 weeks is recommended. In patients receiving 90 mg of Perseris, consider increasing the dose to 120 mg. In patients receiving 120 mg of Perseris, additional oral risperidone may need to be considered. Upon discontinuation of apalutamide in patients receiving 120 mg of Perseris, the dose of Perseris and additional use of oral risperidone should be re-evaluated and adjusted if necessary. For patients receiving 90 mg of Perseris, the current dose of Perseris may be maintained unless clinical circumstances require interruption of Perseris treatment.
    Ritonavir: (Contraindicated) Coadministration of ritonavir with apalutamide is contraindicated as there is a potential for decreased ritonavir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; exposure to apalutamide may also increase. Ritonavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Rivaroxaban: (Major) Avoid coadministration of apalutamide with rivaroxaban due to decreased exposure to rivaroxaban which may reduce efficacy. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) substrate. Apalutamide is a strong CYP3A4 inducer and a weak P-gp inducer. Coadministration with another combined P-gp and strong CYP3A4 inducer decreased rivaroxaban exposure by up to 50%.
    Roflumilast: (Major) Coadministration of roflumilast with apalutamide is not recommended due to decreased plasma concentrations of roflumilast. Roflumilast is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased roflumilast exposure by 80%; exposure to roflumilast N-oxide was decreased by 56%.
    Rolapitant: (Major) Avoid coadministration of rolapitant with apalutamide due to decreased plasma concentrations of rolapitant. Rolapitant is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased rolapitant exposure by 85%; the mean half-life of rolapitant decreased from 176 hours to 41 hours.
    Romidepsin: (Major) Avoid coadministration of romidepsin with apalutamide if possible due to decreased plasma concentrations of romidepsin. Romidepsin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. The effect of strong CYP3A4 inducers on the exposure of romidepsin is unknown.
    Ruxolitinib: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with apalutamide; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Saquinavir: (Major) Coadministration of saquinavir with apalutamide is not recommended as there is a potential for decreased saquinavir concentrations, which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; apalutamide exposure may also increase. Saquinavir is a sensitive CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Saxagliptin: (Moderate) Monitor for increased blood sugars if coadministration of saxagliptin with apalutamide is necessary. Saxagliptin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased saxagliptin exposure by 76%.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Selegiline: (Moderate) Use caution if selegiline and apalutamide are used concomitantly. Although apalutamide is a strong CYP3A4 inducer and selegiline is a CYP3A4 substrate, adequate studies have not been conducted to evaluate its effect, if any, on the effectiveness of selegiline.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and apalutamide due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selpercatinib exposure by 87%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and apalutamide due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
    Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with apalutamide is necessary. Sildenafil is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant administration of strong CYP3A inducers is expected to substantially decrease plasma concentrations of sildenafil. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A inducers.
    Simeprevir: (Major) Coadministration of simeprevir with apalutamide is not recommended as there is a potential for decreased simeprevir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Simeprevir is a CYP3A4 and OATP1B1 substrate. Apalutamide is a strong CYP3A4 inducer as well as a weak OATP1B1 inducer.
    Siponimod: (Moderate) Concomitant use of siponimod and apalutamide is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with apalutamide is not recommended in any patient if they are also receiving a moderate CYP2C9 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
    Sirolimus: (Major) Avoid coadministration of sirolimus with apalutamide due to decreased plasma concentrations of sirolimus. Sirolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate. Apalutamide is a strong CYP3A4 inducer and a weak P-gp inducer. Coadministration with another P-gp and strong CYP3A4 inducer decreased sirolimus exposure by 82%.
    Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp) and BCRP, such as apalutamide. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp) and BCRP, such as apalutamide. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Coadministration of velpatasvir with apalutamide is not recommended due to the potential for loss of antiviral efficacy. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp) and BCRP, such as apalutamide. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Coadministration of velpatasvir with apalutamide is not recommended due to the potential for loss of antiviral efficacy. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. (Major) Coadministration of voxilaprevir with apalutamide is not recommended due to decreased plasma concentrations of voxilaprevir, potentially resulting in loss of antiviral efficacy. Voxilaprevir is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Solifenacin: (Minor) Monitor for decreased efficacy of solifenacin if coadministration with apalutamide is necessary. Solifenacin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Studies have not been conducted to evaluate the effect of CYP3A4 inducers on solifenacin, but inducers of CYP3A4 may decrease solifenacin plasma concentrations.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and apalutamide; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
    Sorafenib: (Major) Avoid coadministration of sorafenib with apalutamide due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Sotorasib: (Major) Avoid concurrent use of sotorasib and apalutamide. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if apalutamide must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of sufentanil injection as needed. If apalutamide is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Sunitinib: (Major) Avoid coadministration of apalutamide with sunitinib if possible due to decreased exposure to sunitinib which could decrease efficacy. If concomitant use is unavoidable, consider increasing the daily dose of sunitinib to a maximum of 87.5 mg for patients with GIST or RCC, and to a maximum of 62.5 mg for patients with pNET; monitor carefully for toxicity. Sunitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to sunitinib and its primary active metabolite by 46%.
    Suvorexant: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with apalutamide is necessary. Suvorexant is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased suvorexant exposure by 77% to 88%.
    Tacrolimus: (Moderate) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with apalutamide is necessary. Tacrolimus is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly increased tacrolimus clearance.
    Tamoxifen: (Major) Avoid coadministration of apalutamide with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Tasimelteon: (Major) Avoid coadministration of tasimelteon with apalutamide due to the potential for a large decrease in tasimelteon exposure resulting in reduced efficacy. Tasimelteon is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tasimelteon exposure by about 90%.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with apalutamide as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Telithromycin: (Major) Avoid coadministration of telithromycin with apalutamide due to decreased plasma concentrations of telithromycin, which may result in decreased efficacy; exposure to apalutamide may also increase. Telithromycin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. In the presence of a strong inducer, the Cmax of telithromycin was decreased by 79% and the AUC was decreased by 86%.
    Telmisartan; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
    Temsirolimus: (Major) Avoid coadministration of temsirolimus with apalutamide due to the risk of decreased plasma concentrations of temsirolimus. If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If apalutamide is discontinued, decrease the dose of temsirolimus to the dose used before initiation of apalutamide. Temsirolimus is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Teniposide: (Moderate) Monitor patients for reduced efficacy of teniposide if coadministration with apalutamide is necessary. Teniposide is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers reduced plasma concentrations of teniposide.
    Tepotinib: (Major) Avoid concomitant use of tepotinib and apalutamide due to decreased plasma concentrations of tepotinib, which may reduce its efficacy. Tepotinib is a CYP3A substrate and apalutamide is a strong CYP3A inducer.
    Tezacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with apalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and apalutamide together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of apalutamide, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%. Tezacaftor exposures can also be expected to decrease significantly during coadministration with strong CYP3A inducers.
    Thiotepa: (Major) Avoid the concomitant use of thiotepa and apalutamide if possible; increased metabolism to the active thiotepa metabolite may result in increased thiotepa toxicity (e.g., infection, bleeding, skin toxicity). Consider an alternative agent with no or minimal potential to induce CYP3A4. If coadministration is necessary, monitor patients for signs and symptoms of thiotepa toxicity. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; apalutamide is a strong CYP3A4 inducer,
    Tiagabine: (Moderate) Monitor for decreased efficacy of tiagabine if coadministration with apalutamide is necessary. Tiagabine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking another strong CYP3A4 inducer.
    Ticagrelor: (Major) Avoid coadministration of ticagrelor with apalutamide due to decreased plasma concentrations of ticagrelor. Ticagrelor is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ticagrelor exposure by 86%.
    Tinidazole: (Moderate) Monitor for decreased efficacy of tinidazole if coadministration with apalutamide is necessary. Tinidazole is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use may accelerate the elimination of tinidazole, decreasing plasma concentrations.
    Tipranavir: (Contraindicated) Tipranavir is contraindicated for use with apalutamide. Apalutamide is a CYP3A4 substrate and strong inducer. Tipranavir is a CYP3A4 substrate and strong inhibitor; coadministration significantly reduces plasma concentrations of tipranavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Exposure to apalutamide may also increase.
    Tivozanib: (Major) Avoid concomitant use of tivozanib with apalutamide due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
    Tofacitinib: (Major) Coadministration of tofacitinib and apalutamide is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC and Cmax of tofacitinib by 84% and 74%, respectively.
    Tolvaptan: (Major) Avoid concurrent use of tolvaptan and apalutamide due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Toremifene: (Major) Avoid coadministration of apalutamide with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Torsemide: (Moderate) Monitor diuretic effect and blood pressure if coadministration of torsemide with apalutamide is necessary. Torsemide is a CYP2C9 substrate and apalutamide is a CYP2C9 inducer. Concomitant use of CYP2C9 inducers increases torsemide clearance and decreases torsemide plasma concentrations.
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with apalutamide due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
    Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of tramadol as needed. If apalutamide is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of tramadol as needed. If apalutamide is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with apalutamide is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Trazodone: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with apalutamide. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Triazolam: (Moderate) Monitor for withdrawal symptoms or lack of triazolam efficacy if coadministration with apalutamide is necessary. Triazolam is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Tucatinib: (Major) Avoid coadministration of tucatinib and apalutamide due to the risk of decreased tucatinib exposure which may reduce its efficacy. Additionally, apalutamide-related adverse reactions may increase. Tucatinib is a CYP3A4 and CYP2C8 substrate and a strong CYP3A4 inhibitor; apalutamide is a CYP3A4 substrate and strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
    Ubrogepant: (Major) Avoid the coadministration of ubrogepant and apalutamide as concurrent use may decrease ubrogepant exposure and reduce the efficacy. Ubrogepant is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer resulted in an 80% reduction in ubrogepant exposure.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and apalutamide is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Upadacitinib: (Major) Coadministration of upadacitinib with apalutamide is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
    Valbenazine: (Major) Coadministration of valbenazine with apalutamide is not recommended as plasma concentrations of valbenazine and its active metabolite may be decreased. Reduced exposure of valbenazine and its active metabolite may reduce efficacy. Valbenazine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to valbenazine and NBI-98782 by 70% and 80%, respectively.
    Valproic Acid, Divalproex Sodium: (Moderate) Monitor valproic acid concentrations and watch for decreased efficacy if coadministration with apalutamide is necessary. Valproic acid is a CYP2C9 substrate as well as a substrate of UGT1A4 and 2B7. Apalutamide is a weak CYP2C9 inducer and may also be a UGT inducer.
    Vandetanib: (Major) Avoid coadministration of vandetanib with apalutamide due to decreased plasma concentrations of vandetanib and increased concentrations of the active metabolite. Vandetanib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased the geometric mean AUC of vandetanib by 40%; the geometric mean AUC and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively.
    Vemurafenib: (Major) Avoid coadministration of vemurafenib with apalutamide due to decreased plasma concentrations of vemurafenib. If unavoidable, increase to dose of vemurafenib by 240 mg as tolerated. The original dose of vemurafenib may be resumed 2 weeks after apalutamide is discontinued. Vemurafenib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to vemurafenib by 40%.
    Venetoclax: (Major) Avoid coadministration of venetoclax with apalutamide due to decreased plasma concentrations of venetoclax. Venetoclax is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with apalutamide is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Vilazodone: (Moderate) Consider increasing the dose of vilazodone up to 2-fold over 1 to 2 weeks (maximum, 80 mg per day) based on clinical response if coadministration with apalutamide is necessary for more than 14 days. After discontinuation of apalutamide, resume the previous vilazodone dose over 1 to 2 weeks. Vilazodone is primarily metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer. Decreased plasma concentrations of vilazodone are expected if vilazodone is used concomitantly with strong CYP3A4 inducers.
    Vincristine Liposomal: (Major) Avoid coadministration of vincristine with apalutamide due to decreased plasma concentrations of vincristine. Vincristine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Vincristine: (Major) Avoid coadministration of vincristine with apalutamide due to decreased plasma concentrations of vincristine. Vincristine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Voclosporin: (Major) Avoid coadministration of voclosporin with apalutamide. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased voclosporin exposure by 87%.
    Vorapaxar: (Major) Avoid coadministration of vorapaxar and apalutamide due to decreased serum concentrations of vorapaxar. Vorapaxar is a CYP3A4 substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A4 inducer decreased vorapaxar exposure by 55%; the impact on efficacy for a change in exposure of this magnitude is not known.
    Voriconazole: (Contraindicated) Coadministration of voriconazole with apalutamide is contraindicated due to decreased plasma concentrations of voriconazole; exposure to apalutamide may also increase. Voriconazole is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Voriconazole plasma concentrations may be reduced by roughly 95%; doubling the dose of voriconazole did not restore adequate exposure to voriconazole during concomitant use with another strong CYP3A4 inducer.
    Vortioxetine: (Major) Consider increasing the dose of vortioxetine (maximum, 3 times the original dose) if coadministration with apalutamide for longer than 14 days is necessary. Vortioxetine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Voxelotor: (Major) Avoid coadministration of voxelotor and apalutamide as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily. Voxelotor is a substrate of CYP3A4; apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease voxelotor exposure by up to 77%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with apalutamide is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Apalutamide is a weak CYP2C9 and strong CYP3A4 inducer and the enantiomers of warfarin are CYP2C9/CYP3A4 substrates.
    Zaleplon: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with apalutamide is necessary. Zaleplon is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with apalutamide could lead to ineffectiveness of zaleplon.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and apalutamide. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. The AUC of zanubrutinib was decreased by 93% when coadministered with another strong CYP3A4 inducer.
    Ziprasidone: (Moderate) Monitor for decreased efficacy of ziprasidone if coadministration with apalutamide is necessary. Ziprasidone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ziprasidone exposure by 35%.
    Zolpidem: (Major) Coadministration of zolpidem with apalutamide is not recommended due to decreased plasma concentrations of zolpidem. Zolpidem is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased zolpidem exposure by 73% and significantly reduced the pharmacodynamic effects of zolpidem.
    Zonisamide: (Moderate) Monitor for decreased efficacy of zonisamide if coadministration with apalutamide is necessary; adjust the dose of zonisamide as clinically appropriate. Zonisamide is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the zonisamide half-life by 8 to 19 hours. These effects are unlikely to be of clinical significance when zonisamide is added to apalutamide therapy; however, changes in zonisamide concentrations may occur if apalutamide is added, dose adjusted, or withdrawn from zonisamide therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequately controlled studies in pregnant women, apalutamide can cause fetal harm and loss of pregnancy if administered to a pregnant woman based on findings from animal studies and its mechanism of action. The safety and efficacy of apalutamide have not been established in females; it is not indicated for use in women. In a pilot embryofetal development toxicity study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities (e.g., decreased fetal anogenital distance, misshapen pituitary gland, and skeletal variations including unossified phalanges, supernumerary short thoracolumbar ribs, and small, incomplete ossification and/or misshapen hyoid bone) and embryo-fetal lethality (resorptions) at maternal exposures of 2 to 6 times the human clinical exposure (AUC) at the recommended dose.

    There are no data on the presence of apalutamide or its metabolites in human milk, the effect on a child who is breast-feeding, or the effect on milk production. The safety and efficacy of apalutamide have not been established in females; it is not indicated for use in women.

    MECHANISM OF ACTION

    Apalutamide is an androgen receptor inhibitor that binds directly to the ligand-binding domain of the androgen receptor. It inhibits androgen receptor nuclear translocation and DNA binding, as well as impeding androgen receptor-mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of the androgen receptor, with one-third the activity of apalutamide in an in vitro transcriptional reporter assay. Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.

    PHARMACOKINETICS

    Apalutamide is administered orally. It is 96% bound to plasma proteins, while the active metabolite, N-desmethyl apalutamide, is 95% protein bound; protein binding is not concentration dependent. The mean apparent volume of distribution (Vd) at steady-state is approximately 276 L. Metabolism is the main route of elimination. Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form its active metabolite, N-desmethyl apalutamide. After a single dose, CYP2C8 plays a larger role in metabolism (58%) than CYP3A4 (13%); however, at steady-state, the contributions of CYP2C8 and CYP3A4 are 40% and 37%, respectively. The parent drug represents 45% and the active metabolite, N-desmethyl apalutamide, represents 44% of the total AUC after a single radiolabeled dose. Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributes to the clinical activity of apalutamide. Apalutamide clearance (CL/F) was 1.3 L/hour after single dosing, and increased to 2 L/hour at steady-state after once-daily dosing, likely due to CYP3A4 auto-induction. Auto-induction likely reaches its maximum at the recommended dosage as exposure of apalutamide is dose proportional over a range of 30 to 480 mg. The mean effective half-life is approximately 3 days at steady-state. Up to 70 days after a single oral radiolabeled dose, 65% was recovered in urine (unchanged apalutamide, 1.2%; N-desmethyl apalutamide, 2.7%) and 24% was recovered in feces (unchanged apalutamide, 1.5%; N-desmethyl apalutamide, 2%).
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT, P-glycoprotein (P-gp), BCRP, and OATP1B1
    Apalutamide is a substrate of CYP2C8 and CYP3A4. Apalutamide and N-desmethyl apalutamide are also P-gp substrates; however, because apalutamide is completely absorbed after oral administration, P-gp does not limit absorption, and induction or inhibition of P-gp is not expected to affect the bioavailability of apalutamide. In vitro, apalutamide and N-desmethyl apalutamide are moderate-to-strong CYP3A4 and CYP2B6 inducers, moderate CYP2B6 and CYP2C8 inhibitors, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide is also a weak P-gp, BCRP, and OATP1B1 inducer. Apalutamide may induce UGT. In vitro, apalutamide and N-desmethyl apalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs), and do not inhibit organic anion transporter 1. Clinically significant interactions are expected with drugs that are strong CYP3A4 or strong CYP2C8 inhibitors and inducers and also those drugs that are primarily metabolized by CYP3A4, CYP2C19, CYP2C9, P-gp, BRCP, OATP1B1, and UGT.

    Oral Route

    The mean absolute oral bioavailability (F) of apalutamide was approximately 100%. The AUC and Cmax of apalutamide increased proportionally following repeated once-daily dosing of 30 mg to 480 mg. After administration of the recommended dosage (240 mg once daily), the mean accumulation ratio was approximately 5-fold. The Cmax of apalutamide at steady-state was 6 mcg/mL (standard deviation (SD), 1.7 mcg/mL) and the AUC was 100 mcg x h/mL (SD, 32 mcg x hour/mL). The median time to reach peak plasma concentration (Tmax) was 2 hours (range, 1 to 5 hours). Daily fluctuations in plasma concentrations were low (mean peak-to-trough ratio, 1.63).
     
    The Cmax of active metabolite, N-desmethyl apalutamide, was 5.9 mcg/mL (SD, 1 mcg/mL) and AUC was 124 mcg x hour/mL (SD, 23 mcg x hour/mL) at steady state after the recommended dosage. N-desmethyl apalutamide had a flat concentration-time profile at steady-state (mean peak-to-trough ratio, 1.27). The mean AUC metabolite/parent drug ratio following repeat dose administration was 1.3.
     
    Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (55% to 60% fat; 25% to 28% carbohydrates; 15% to 17% protein) did not result in clinically relevant changes in Cmax and AUC. The Tmax was delayed by approximately 2 hours with food. Apalutamide is not ionizable under relevant physiological pH condition, therefore acid-lowering agents are not expected to affect the solubility or bioavailability of apalutamide.
     
    Oral administration of four 60-mg apalutamide tablets dispersed in applesauce resulted in no clinically relevant changes in Cmax and AUC when compared to administration of four intact 60-mg tablets under fasting conditions.