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  • CLASSES

    Anti-Androgens
    Cytostatic Anti-androgens

    DEA CLASS

    Rx

    DESCRIPTION

    Androgen receptor inhibitor
    Used for the treatment of castration-resistant prostate cancer
    Seizures have been reported

    COMMON BRAND NAMES

    XTANDI

    HOW SUPPLIED

    XTANDI Oral Cap: 40mg

    DOSAGE & INDICATIONS

    For the treatment of prostate cancer.
    For the treatment of metastatic, hormone-sensitive prostate cancer.
    Oral dosage
    Adults

    160 mg PO 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. Radiographic progression-free survival (PFS) by blinded independent central review was significantly improved in patients with metastatic castration-sensitive prostate cancer who were treated with enzalutamide compared with those who received placebo (not reached vs. 19.4 months) in a randomized clinical trial (ARCHES); all patients received a GnRH analog or had a prior bilateral orchiectomy. Results were consistent regardless of volume of disease (high vs. low) and prior docetaxel status (with vs. without). Overall survival data were not mature at the time of the rPFS analysis. In another randomized clinical trial (ENZAMET), treatment with enzalutamide significantly improved overall survival in patients with metastatic hormone-sensitive prostate cancer compared with standard nonsteroidal antiandrogen therapy (i.e., bicalutamide, nilutamide, or flutamide); all patients received continuous testosterone suppression (i.e., LHRH antagonist or surgical castration). Based on subgroup analyses, treatment with enzalutamide may be most beneficial in patients with low-volume disease who are not receiving concomitant treatment with docetaxel.

    For the treatment of castration-resistant prostate cancer.
    Oral dosage
    Adults

    160 mg PO once daily. 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.[51727] Treatment with enzalutamide significantly improved median metastasis-free survival compared with placebo in patients with non-metastatic castration-resistant prostate cancer in a randomized, double-blind, phase 3 clinical trial (PROSPER; 36.6 months vs. 14.6 months).[63325] Enzalutamide also significantly improved the median overall survival compared with placebo in patients with metastatic prostate cancer who were chemotherapy-naive in a placebo-controlled phase 3 trial (PREVAIL; 35.3 months vs. 31.3 months), as well as in patients who had received prior treatment with docetaxel in a separate placebo-controlled phase 3 trial (AFFIRM; 18.4 months vs. 13.6 months).[51733] [57927]

    MAXIMUM DOSAGE

    Adults

    160 mg/day PO.

    Geriatric

    160 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No initial enzalutamide dosage adjustment is necessary in patients with baseline hepatic impairment.

    Renal Impairment

    No initial enzalutamide dosage adjustment is necessary in patients with mild or moderate renal impairment (CrCL, 30 to 89 mL/min). Enzalutamide has not been evaluated in patients with severe renal impairment (CrCL, less than 30 mL/min) or end-stage renal disease.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Enzalutamide should be taken at the same time each day.
    Swallow capsules whole; do not chew, dissolve, or open capsules.
    May take with or without food.

    STORAGE

    XTANDI:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    Brain tumor, driving or operating machinery, head trauma, seizures, stroke

    Use enzalutamide with caution in patients with a history of seizures and in patients with predisposing factors to seizure disorder, such as underlying head trauma (brain injury), transient ischemic attack, cerebral vascular accident (stroke), brain metastases (brain tumor), brain arteriovenous malformation, unexplained loss of consciousness in the last 12 months, or patients receiving concomitant drugs that can lower the seizure threshold. Seizures have been reported with enzalutamide use. Advise patients of the risk of developing a seizure during treatment and the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others, such as driving or operating machinery. Permanently discontinue enzalutamide if a seizure occurs during treatment. Patients with predisposing factors for seizure were generally excluded from clinical trials.

    Encephalopathy

    Posterior reversible encephalopathy syndrome (PRES) has been reported in patients treated with enzalutamide. Patients with headache, lethargy, seizures, confusion, blindness, and other visual or neurologic disturbances should be evaluated for PRES with magnetic resonance imaging (MRI). Mild to severe hypertension may also be present. Discontinue enzalutamide in patients who develop PRES; the safety of reinitiating enzalutamide therapy in these patients is not known.

    Bone fractures

    Monitor and manage patients at risk for bone fractures according to established treatment guidelines and consider the use of bone-targeted agents. Falls and fractures occurred in patients treated with enzalutamide in clinical trials.

    Cardiac disease, diabetes mellitus, hyperlipidemia, hypertension

    Use enzalutamide with caution in patients with a history of cardiac disease and optimize management of patients with cardiovascular risk factors, such as hypertension, diabetes mellitus, and hyperlipidemia. Ischemic heart disease, in some cases leading to death, occurred more often in patients treated with enzalutamide compared with placebo in randomized, clinical trials. Discontinue enzalutamide if grade 3 or 4 ischemic heart disease occurs.

    Angioedema

    Hypersensitivity reactions including angioedema have been observed with enzalutamide treatment in seven randomized clinical trials. Patients should be advised to interrupt therapy with enzalutamide and promptly seek medical care for any symptoms of hypersensitivity. Permanently discontinue enzalutamide for serious hypersensitivity reactions.

    Females, pregnancy

    The safety and efficacy of enzalutamide have not been established in females. Although there are no adequately controlled studies in pregnant women, enzalutamide can cause fetal harm and loss of pregnancy based on animal reproduction studies and its mechanism of action. When administered to pregnant mice during organogenesis, severe adverse developmental effects occurred at doses lower than the maximum recommended human dose. In an embryo-fetal developmental toxicity study, increased post-implantation loss and resorptions, as well as decreased anogenital distance, occurred in mice treated with enzalutamide during organogenesis at exposures approximately 0.4 times the AUC of patients treated with the recommended dose. Maternal toxicity as well as cleft palate and absent palatine bone occurred in mice at 1.1 times the AUC of patients treated with the recommended dose. Developmental toxicities were not observed in rabbits treated with enzalutamide during organogenesis at exposures up to 0.4 times the AUC of patients treated with the recommended dose.

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

    Counsel patients about the reproductive risk and contraception requirements during enzalutamide treatment. Enzalutamide caused teratogenicity and embryofetal death in pregnant mice at doses lower than the maximum recommended human dose. Because of the potential for male-mediated teratogenicity, males with female partners of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 months after treatment with enzalutamide. Males should also use a condom if having sex with a pregnant female. Although there are no data regarding the effect of enzalutamide on human fertility, male infertility has been observed in animal studies. Atrophy of the prostate and seminal vesicals occurred in rats at enzalutamide doses that achieved AUC values similar to those in humans in a 26-week study. Atrophy of the prostate and epididymides and hypospermatogenesis were reported in dogs that received enzalutamide at 0.3 times the human exposure based on AUC in 4-week and 13-week studies.

    Breast-feeding

    Enzalutamide is not indicated for use in women; thus, it is not expected to be used during breast-feeding. There is no information available on the presence of enzalutamide in human milk, the effects of the drug on the breast-fed infant, or the effects of the drug on milk production.

    ADVERSE REACTIONS

    Severe

    asthenia / Delayed / 1.6-9.0
    fatigue / Early / 1.6-9.0
    hypertension / Early / 2.1-7.2
    spinal cord compression / Delayed / 0-6.6
    hyperglycemia / Delayed / 3.2-3.2
    bone fractures / Delayed / 1.0-3.0
    infection / Delayed / 0-2.4
    hematuria / Delayed / 0-1.8
    hyponatremia / Delayed / 1.4-1.4
    diarrhea / Early / 0-1.1
    constipation / Delayed / 0-1.1
    peripheral edema / Delayed / 0-1.0
    seizures / Delayed / 0.5-0.9
    neutropenia / Delayed / 0.9-0.9
    headache / Early / 0.2-0.9
    weight loss / Delayed / 0.2-0.8
    dyspnea / Early / 0-0.6
    angioedema / Rapid / 0.1-0.5
    dizziness / Early / 0.3-0.5
    leukopenia / Delayed / 0.4-0.4
    hypoesthesia / Delayed / 0-0.3
    nausea / Early / 0-0.3
    hot flashes / Early / 0-0.3
    anxiety / Delayed / 0-0.3
    anorexia / Delayed / 0.2-0.3
    insomnia / Early / 0-0.1
    epistaxis / Delayed / 0-0.1
    dysgeusia / Early / 0-0.1
    hypercalcemia / Delayed / 0.1-0.1
    hypermagnesemia / Delayed / 0.1-0.1
    restless legs syndrome (RLS) / Delayed / 0-0.1

    Moderate

    encephalopathy / Delayed / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    paresthesias / Delayed / 0-6.6
    increased urinary frequency / Early / 0-4.8
    pruritus / Rapid / 0-3.8
    xerosis / Delayed / 0-3.5
    gynecomastia / Delayed / 0-3.4
    vomiting / Early / Incidence not known
    laryngitis / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    rash / Early / Incidence not known
    vertigo / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with enzalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Enzalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Abemaciclib: (Major) Avoid coadministration of enzalutamide 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 enzalutamide 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 enzalutamide 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 enzalutamide is discontinued. Abiraterone is a CYP3A4 substrate and enzalutamide 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 enzalutamide. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure occurred in a drug interaction study. Acalabrutinib is a CYP3A4 substrate; enzalutamide 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 inducer.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Enzalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with enzalutamide is necessary; consider increasing the dose of oxycodone as needed. If enzalutamide is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and enzalutamide 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.
    Acetaminophen; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with enzalutamide is necessary; consider increasing the dose of tramadol as needed. If enzalutamide is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and enzalutamide 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.
    Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with enzalutamide is necessary. If enzalutamide is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like enzalutamide 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 enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer.
    Alprazolam: (Moderate) Monitor for withdrawal symptoms or lack of alprazolam efficacy if coadministration with enzalutamide is necessary. Alprazolam is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Amiodarone: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with enzalutamide is necessary. Consider monitoring amiodarone serum concentrations during concurrent use. Coadministration may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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: (Major) Monitor for decreased efficacy of atorvastatin if coadministration with enzalutamide is necessary. Atorvastatin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80%. (Moderate) Closely monitor blood pressure if coadministration of amlodipine with enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary; a dosage adjustment may be necessary for celecoxib. Celecoxib is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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; Telmisartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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; Lansoprazole: (Major) Avoid coadministration of enzalutamide with lansoprazole due to decreased plasma concentrations of lansoprazole. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Enzalutamide is a moderate CYP2C19 inducer and a strong CYP3A4 inducer. (Major) Coadministration of enzalutamide and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction; consider alternatives to clarithromycin if treatment with enzalutamide is necessary. Clarithromycin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of enzalutamide, a strong CYP3A4 inducer and a moderate CYP2C19 inducer, and omeprazole, a CYP3A4 and CYP2C19 substrate, as omeprazole plasma exposure may be reduced. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC and Cmax of omeprazole was decreased following a single oral dose of omeprazole 20 mg administered after at least 55 days of oral enzalutamide 160 mg/day. (Major) Coadministration of enzalutamide and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction; consider alternatives to clarithromycin if treatment with enzalutamide is necessary. Clarithromycin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible.
    Apremilast: (Major) Coadministration of apremilast with enzalutamide is not recommended due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A4 substrate and enzalutamide 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 coadministration of aprepitant, fosaprepitant with enzalutamide due to decreased plasma concentrations of aprepitant, fosaprepitant. Aprepitant is a CYP3A4 substrate; after administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. Enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of aprepitant by approximately 11-fold and the mean terminal half-life decreased approximately 3-fold.
    Aripiprazole: (Major) Because aripiprazole is partially 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 enzalutamide, is added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is discontinued, the aripiprazole dose should be reduced to the original level over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a strong CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer for more than 14 days, no dose adjustment is necessary for the 662 mg or the 882 mg dose; increase the 441 mg dose to 662 mg. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.
    Artemether; Lumefantrine: (Severe) Coadministration of artemether with enzalutamide is contraindicated due to decreases in artemether plasma concentrations which may result in loss of antimalarial efficacy. Artemether is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposures to artemether and dihydroartemisinin (DHA, metabolite of artemether) by 89% and 85%, respectively. (Severe) Coadministration of lumefantrine with enzalutamide is contraindicated due to decreases in lumefantrine plasma concentrations which may result in loss of antimalarial efficacy. Lumefantrine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to lumefantrine by 68%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Enzalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol: (Minor) Monitor for decreased efficacy of carisoprodol if coadministration with enzalutamide is necessary. Carisoprodol is a CYP2C19 substrate and enzalutamide is a moderate CYP2C19 inducer. The full pharmacological impact of this interaction is unknown.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer. (Minor) Monitor for decreased efficacy of carisoprodol if coadministration with enzalutamide is necessary. Carisoprodol is a CYP2C19 substrate and enzalutamide is a moderate CYP2C19 inducer. The full pharmacological impact of this interaction is unknown.
    Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of enzalutamide, a strong CYP3A4 inducer and a moderate CYP2C19 inducer, and omeprazole, a CYP3A4 and CYP2C19 substrate, as omeprazole plasma exposure may be reduced. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC and Cmax of omeprazole was decreased following a single oral dose of omeprazole 20 mg administered after at least 55 days of oral enzalutamide 160 mg/day.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with enzalutamide is necessary; consider increasing the dose of oxycodone as needed. If enzalutamide is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and enzalutamide 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: (Severe) Coadministration of atazanavir with strong inducers of CYP3A4, such as enzalutamide, is contraindicated. Taking these drugs together could decrease atazanavir concentrations, and may lead to a reduction in antiretroviral activity.
    Atazanavir; Cobicistat: (Severe) Coadministration of atazanavir with strong inducers of CYP3A4, such as enzalutamide, is contraindicated. Taking these drugs together could decrease atazanavir concentrations, and may lead to a reduction in antiretroviral activity. (Major) Coadministration of cobicistat with enzalutamide 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. Cobicistat is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Atorvastatin: (Major) Monitor for decreased efficacy of atorvastatin if coadministration with enzalutamide is necessary. Atorvastatin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80%.
    Atorvastatin; Ezetimibe: (Major) Monitor for decreased efficacy of atorvastatin if coadministration with enzalutamide is necessary. Atorvastatin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80%.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of phenobarbital with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when phenobarbital is discontinued. Enzalutamide is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Avanafil: (Major) Coadministration of avanafil with enzalutamide is not recommended by the manufacturer of avanafil due to the potential for decreased efficacy. Avanafil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations of avanafil may decrease.
    Avapritinib: (Major) Avoid coadministration of avapritinib with enzalutamide due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
    Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with enzalutamide. In patients starting enzalutamide while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as enzalutamide decrease avatrombopag exposure, which may reduce efficacy.
    Axitinib: (Major) Avoid coadministration of axitinib with enzalutamide 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 enzalutamide 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 enzalutamide with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased bedaquiline exposure by 52%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of ergotamine with enzalutamide due to decreased plasma concentrations of ergotamine. Ergotamine is a CYP3A4 substrate with a narrow therapeutic index and enzalutamide is a strong CYP3A4 inducer. (Major) Avoid coadministration of phenobarbital with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when phenobarbital is discontinued. Enzalutamide is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with enzalutamide 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 enzalutamide may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If enzalutamide is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Enzalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Bortezomib: (Major) Coadministration of enzalutamide with bortezomib is not recommended due to decreases in bortezomib plasma concentrations. Bortezomib is a CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of bosutinib. Bosutinib is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Monomethyl auristatin E (MMAE) is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. If enzalutamide is discontinued, reduce the brexpiprazole dose to the original level over 1 to 2 weeks. Brexpiprazole is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased brexpiprazole exposure by 73%.
    Brigatinib: (Major) Avoid coadministration of brigatinib with enzalutamide due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and enzalutamide 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) Co-administration of brivaracetam with enzalutamide may decrease brivaracetam plasma concentrations, likely because of CYP2C19 induction by enzalutamide. When metabolized, brivaracetam undergoes hydroxylation that is mediated by CYP2C19. During drug interaction studies, co-administration of brivaracetam with rifampin, another CYP2C19 inducer, decreased brivaracetam plasma concentrations by 45%. The dose of brivaracetam should be increased by up to 100% in patients in patients taking concomitant rifampin, and similar consideration may be warranted when brivaracetam is used with enzalutamide.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and enzalutamide 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; enzalutamide is a strong inducer of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Bupivacaine; Lidocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with enzalutamide is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If enzalutamide is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If enzalutamide is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Buspirone: (Moderate) Monitor for decreased efficacy of buspirone if enzalutamide 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 CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of buspirone by 89.6%.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with enzalutamide 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 enzalutamide 2 to 3 days after discontinuation of enzalutamide. Cabozantinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Caffeine; Ergotamine: (Major) Avoid coadministration of ergotamine with enzalutamide due to decreased plasma concentrations of ergotamine. Ergotamine is a CYP3A4 substrate with a narrow therapeutic index and enzalutamide is a strong CYP3A4 inducer.
    Cannabidiol: (Moderate) Consider a dose increase of cannabidiol if coadministered with enzalutamide. Coadministration may decrease cannabidiol plasma concentrations resulting in a decrease in efficacy. Cannabidiol is metabolized by CYP3A4; enzalutamide is a strong inducer of CYP3A4.
    Carbamazepine: (Major) Avoid coadministration of carbamazepine with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy; carbamazepine plasma concentrations may also decrease. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when carbamazepine is discontinued. An increased dose of carbamazepine may also be necessary; monitor carbamazepine concentrations. Both enzalutamide and carbamazepine are substrates and strong inducers of CYP3A4. The composite AUC of enzalutamide plus N-desmethyl enzalutamide decreased by 37% in the presence of a strong CYP3A4 inducer. CYP3A4 inducers can decrease serum concentrations of carbamazepine and decrease its effectiveness.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Cariprazine: (Major) Coadministration of cariprazine with enzalutamide is not recommended as the net effect of CYP3A4 induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with cariprazine with CYP3A4 inducers has not been evaluated.
    Carisoprodol: (Minor) Monitor for decreased efficacy of carisoprodol if coadministration with enzalutamide is necessary. Carisoprodol is a CYP2C19 substrate and enzalutamide is a moderate CYP2C19 inducer. The full pharmacological impact of this interaction is unknown.
    Celecoxib: (Moderate) Monitor for decreased efficacy of celecoxib if coadministration with enzalutamide is necessary; a dosage adjustment may be necessary for celecoxib. Celecoxib is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Ceritinib: (Major) Avoid coadministration of ceritinib with enzalutamide due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Enzalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Enzalutamide 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 enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Citalopram: (Moderate) Monitor for decreased efficacy of citalopram if coadministration with enzalutamide is necessary. Citalopram is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 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) Coadministration of enzalutamide and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction; consider alternatives to clarithromycin if treatment with enzalutamide is necessary. Clarithromycin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible.
    Clindamycin: (Moderate) Monitor for decreased efficacy of clindamycin if coadministration with enzalutamide is necessary. Clindamycin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration may reduce plasma concentrations of clindamycin.
    Clonazepam: (Moderate) Monitor patients for decreased efficacy and a change in clonazepam dosage requirements when giving concurrently with enzalutamide. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam is used with strong CYP3A4 inducers. Clonazepam is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Clopidogrel: (Major) Avoid coadministration of clopidogrel with enzalutamide if possible due to increased enzalutamide exposure. If concomitant use is unavoidable, reduce the dose of enzalutamide to 80 mg once daily; the original dose of enzalutamide may be resumed when clopidogrel is discontinued. Enzalutamide is a CYP2C8 substrate and the acyl-beta-glucuronide metabolite of clopidogrel is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold.
    Clozapine: (Major) Coadministration of clozapine with enzalutamide 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 enzalutamide is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Cobicistat: (Major) Coadministration of cobicistat with enzalutamide 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. Cobicistat is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with enzalutamide due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; enzalutamide is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
    Codeine: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with enzalutamide 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 enzalutamide 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. Enzalutamide is a strong CYP3A4 inducer.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and enzalutamide; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Cyclosporine: (Major) Closely monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with enzalutamide is necessary. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; enzalutamide is a strong CYP3A4 inducer.
    Daclatasvir: (Severe) Coadministration of daclatasvir and enzalutamide is contraindicated due to decreased daclatasvir exposure resulting in potential loss of virologic control. Daclatasvir is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer reduced the daclatasvir AUC by 79%.
    Dapagliflozin; Saxagliptin: (Moderate) Monitor for increased blood sugars if coadministration of saxagliptin with enzalutamide is necessary. Saxagliptin is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A4 metabolite and enzalutamide 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 enzalutamide is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Enzalutamide is a strong CYP3A4 inducer and darifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Darunavir: (Major) Coadministration of darunavir with enzalutamide is not recommended as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Darunavir; Cobicistat: (Major) Coadministration of cobicistat with enzalutamide 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. Cobicistat is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer. (Major) Coadministration of darunavir with enzalutamide is not recommended as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of cobicistat with enzalutamide 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. Cobicistat is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer. (Major) Coadministration of darunavir with enzalutamide is not recommended as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of paritaprevir with enzalutamide is contraindicated due to the potential for decreased paritaprevir concentrations and the potential development of viral resistance. Paritaprevir is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased paritaprevir exposure by 70%. (Severe) Coadministration of ritonavir with enzalutamide is contraindicated as there is a potential for decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Dasatinib: (Major) Avoid coadministration of dasatinib and enzalutamide due to the potential for decreased dasatinib exposure and reduced efficacy. Consider an alternative to enzalutamide with less potential for enzyme induction. If coadministration cannot be avoided, consider an increased dose of dasatinib and monitor for toxicity. Dasatinib is a CYP3A4 substrate; enzalutamide 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.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and enzalutamide. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate and enzalutamide 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 enzalutamide is not recommended as there is a potential for decreased delavirdine concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Delavirdine is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer.
    Dexamethasone: (Moderate) Monitor for decreased efficacy of dexamethasone if coadministration with enzalutamide is necessary; consider increasing the dose of dexamethasone if clinically appropriate. Dexamethasone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Dexlansoprazole: (Major) Avoid coadministration of dexlansoprazole with enzalutamide due to decreased plasma concentrations of dexlansoprazole. Dexlansoprazole is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Dextromethorphan; Quinidine: (Moderate) Closely monitor quinidine concentrations if enzalutamide is added to existing quinidine therapy. No special precautions appear necessary if enzalutamide is started several weeks before quinidine, but quinidine doses may require adjustment if enzalutamide is added or discontinued during quinidine therapy. Quinidine is a CYP3A4 substrate and enzalutamide 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 withdrawal symptoms or lack of efficacy if coadministration of diazepam with enzalutamide is necessary. Diazepam is a CYP3A4, CYP2C9, and CYP2C19 substrate; enzalutamide is a strong CYP3A4 inducer, as well as a moderate CYP2C9 and CYP2C19 inducer.
    Diclofenac: (Moderate) Monitor for decreased efficacy of diclofenac if coadministration with enzalutamide is necessary; a dosage adjustment of diclofenac may be necessary. Diclofenac is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Diclofenac; Misoprostol: (Moderate) Monitor for decreased efficacy of diclofenac if coadministration with enzalutamide is necessary; a dosage adjustment of diclofenac may be necessary. Diclofenac is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Dienogest; Estradiol valerate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Enzalutamide is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Major) Avoid coadministration of dihydroergotamine with enzalutamide due to decreased plasma concentrations of dihydroergotamine. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index and enzalutamide is a strong CYP3A4 inducer.
    Diltiazem: (Major) Avoid coadministration of diltiazem and enzalutamide due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and enzalutamide 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 enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Disopyramide: (Moderate) Monitor disopyramide serum concentrations and for loss of efficacy when coadministration with enzalutamide is necessary. Disopyramide exposure may be decreased during concurrent use. Enzalutamide is a strong CYP3A4 inducer; disopyramide is a CYP3A4 substrate.
    Docetaxel: (Major) Avoid coadministration of docetaxel with enzalutamide due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A4 substrate and enzalutamide 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 enzalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Enzalutamide 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 enzalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Enzalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Rilpivirine: (Severe) Concurrent use of enzalutamide 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. Enzalutamide is a potent 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 enzalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Enzalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Donepezil: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with enzalutamide is necessary. Donepezil is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Donepezil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Doravirine: (Severe) Concurrent administration of doravirine and enzalutamide 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; enzalutamide is a strong CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Severe) Concurrent administration of doravirine and enzalutamide 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; enzalutamide is a strong CYP3A4 inducer.
    Doxorubicin: (Major) Avoid coadministration of doxorubicin with enzalutamide due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Dronabinol is a CYP2C9 and CYP3A4 substrate. Enzalutamide is a strong CYP3A4 inducer and a moderate inducer of CYP2C9.
    Dronedarone: (Major) Avoid coadministration of dronedarone with enzalutamide due to decreased dronedarone exposure. Dronedarone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased dronedarone exposure by 80%.
    Drospirenone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Drospirenone; Estradiol: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Drospirenone; Ethinyl Estradiol: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Duvelisib: (Major) Avoid coadministration of duvelisib with enzalutamide. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. Duvelisib is a CYP3A substrate; enzalutamide 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.
    Efavirenz: (Major) Use caution if enzalutamide 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 >= 50 kg). Enzalutamide 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 enzalutamide 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 >= 50 kg). Enzalutamide 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 enzalutamide 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 >= 50 kg). Enzalutamide 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 enzalutamide may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; enzalutamide is a strong inducer of CYP3A.
    Elbasvir; Grazoprevir: (Severe) Concurrent administration of enzalutamide 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. Enzalutamide is a strong CYP3A inducer, while elbasvir is a substrate of CYP3A. (Severe) Concurrent administration of enzalutamide 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. Enzalutamide is a strong CYP3A inducer, while grazoprevir is a substrate of CYP3A.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of elexacaftor; tezacaftor; ivacaftor with enzalutamide 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). Enzalutamide 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 enzalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a CYP3A4 substrate and enzalutamide 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 enzalutamide 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 enzalutamide, 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%.
    Eliglustat: (Major) Coadministration of eliglustat and enzalutamide significantly decreases eliglustat exposure and is not recommended in extensive, intermediate, or poor metabolizers of CYP2D6. Enzalutamide is a strong CYP3A inducer, and eliglustat is a CYP3A substrate.
    Elvitegravir: (Major) Coadministration of elvitegravir with enzalutamide 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; enzalutamide is a strong CYP3A4 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with enzalutamide 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. Cobicistat is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer. (Major) Coadministration of elvitegravir with enzalutamide 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; enzalutamide is a strong CYP3A4 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with enzalutamide 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. Cobicistat is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer. (Major) Coadministration of elvitegravir with enzalutamide 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; enzalutamide is a strong CYP3A4 inducer.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Severe) Concurrent use of enzalutamide 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. Enzalutamide is a potent 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: (Severe) Concurrent use of enzalutamide 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. Enzalutamide is a potent 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 enzalutamide if possible due to decreased plasma concentrations of felodipine. Felodipine is a sensitive CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; enzalutamide 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 enzalutamide due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; enzalutamide 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 enzalutamide. 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 enzalutamide due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A4 and CYP2C9 substrate; enzalutamide is a strong CYP3A4 inducer as well as a CYP2C9 inducer.
    Ergotamine: (Major) Avoid coadministration of ergotamine with enzalutamide due to decreased plasma concentrations of ergotamine. Ergotamine is a CYP3A4 substrate with a narrow therapeutic index and enzalutamide is a strong CYP3A4 inducer.
    Erlotinib: (Major) Avoid coadministration of erlotinib with enzalutamide 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). Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Esomeprazole: (Major) Avoid coadministration of esomeprazole with enzalutamide due to decreased esomeprazole plasma concentrations. Esomeprazole is a CYP3A4 and CYP2C19 substrate. Enzalutamide is a strong CYP3A4 inducer and a moderate 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.
    Esomeprazole; Naproxen: (Major) Avoid coadministration of esomeprazole with enzalutamide due to decreased esomeprazole plasma concentrations. Esomeprazole is a CYP3A4 and CYP2C19 substrate. Enzalutamide is a strong CYP3A4 inducer and a moderate 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 enzalutamide is necessary. Estazolam is a CYP3A4 substrate and enzalutamide 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) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Estradiol; Levonorgestrel: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Estradiol; Norethindrone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Estradiol; Norgestimate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Estradiol; Progesterone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Eszopiclone: (Moderate) Monitor for decreased efficacy of eszopiclone if coadministration with enzalutamide is necessary. Eszopiclone is a CYP3A4 substrate and enzalutamide 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: (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Desogestrel: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Etonogestrel: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Levonorgestrel: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Norelgestromin: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Norethindrone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Norgestimate: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ethinyl Estradiol; Norgestrel: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Etonogestrel: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Etravirine: (Major) The concomitant use of enzalutamide with etravirine is not recommended due to significant decreases in etravirine plasma concentrations and, thus, possible loss of therapeutic effect. Enzalutamide is a strong CYP3A4 inducer and etravirine is a CYP3A4 substrate.
    Everolimus: (Major) Depending on the indication, coadministration of enzalutamide with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of enzalutamide with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Exemestane: (Major) If coadministration of exemestane with enzalutamide is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
    Fedratinib: (Major) Avoid coadministration of fedratinib with enzalutamide as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; enzalutamide 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 enzalutamide if possible due to decreased plasma concentrations of felodipine. Felodipine is a sensitive CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. If enzalutamide is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like enzalutamide 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.
    Flibanserin: (Major) Coadministration of flibanserin with enzalutamide is not recommended due to decreased plasma concentrations of flibanserin. Flibanserin is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Flurazepam is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Fosamprenavir: (Major) Coadministration of fosamprenavir with enzalutamide is not recommended as there is a potential for decreased fosamprenavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Fosamprenavir is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer.
    Fosphenytoin: (Major) Avoid coadministration of fosphenytoin with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy; phenytoin (the active metabolite of fosphenytoin) plasma concentrations may also be reduced. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when fosphenytoin is discontinued. Monitor phenytoin serum concentrations and adjust fosphenytoin doses as needed. Enzalutamide is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Enzalutamide is also a moderate CYP2C9 and CYP2C19 inducer and fosphenytoin is a CYP2C9 and CYP2C19 substrate. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Fostamatinib: (Major) Concomitant use of fostamatinib with enzalutamide is not recommended due to the risk of decreased efficacy of fostamatinib. The active metabolite of fostamatinib, R406, is extensively metabolized by CYP3A4. Enzalutamide is a strong CYP3A4 inducer. Concomitant use of fostamatinib with another strong CYP3A4 inducer decreased R406 AUC by 75% and Cmax by 59%.
    Gefitinib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with enzalutamide is necessary. If enzalutamide is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Gemfibrozil: (Major) Avoid coadministration of gemfibrozil with enzalutamide if possible due to increased enzalutamide exposure. If concomitant use is unavoidable, reduce the dose of enzalutamide to 80 mg once daily; the original dose of enzalutamide may be resumed when gemfibrozil is discontinued. Enzalutamide is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with gemfibrozil increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold.
    Glasdegib: (Major) Avoid coadministration of glasdegib and enzalutamide due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; enzalutamide 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 enzalutamide is not recommended as enzalutamide may significantly decrease plasma concentrations of glecaprevir resulting in loss of efficacy. Glecaprevir is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Glimepiride: (Moderate) Monitor for decreased efficacy of glimepiride if coadministration with enzalutamide is necessary. Glimepiride is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer. Coadministration with other CYP2C9 inducers decreased plasma concentrations of glimepiride, leading to worsened glycemic control.
    Glimepiride; Pioglitazone: (Moderate) Monitor for decreased efficacy of glimepiride if coadministration with enzalutamide is necessary. Glimepiride is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer. Coadministration with other CYP2C9 inducers decreased plasma concentrations of glimepiride, leading to worsened glycemic control.
    Glimepiride; Rosiglitazone: (Moderate) Monitor for decreased efficacy of glimepiride if coadministration with enzalutamide is necessary. Glimepiride is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer. Coadministration with other CYP2C9 inducers decreased plasma concentrations of glimepiride, leading to worsened glycemic control.
    Glyburide: (Moderate) Monitor blood sugars if coadministration of glyburide with enzalutamide is necessary due to decreased plasma concentrations of glyburide. Glyburide is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Glyburide; Metformin: (Moderate) Monitor blood sugars if coadministration of glyburide with enzalutamide is necessary due to decreased plasma concentrations of glyburide. Glyburide is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Granisetron: (Moderate) Monitor for decreased efficacy of granisetron if coadministration with enzalutamide is necessary. Granisetron is a CYP3A4 substrate and enzalutamide 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.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Guanfacine: (Major) A dose increase of extended-release (ER) guanfacine should be considered if coadministration with enzalutamide is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking enzalutamide; increase the dose of guanfacine over 1 to 2 weeks if enzalutamide 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 enzalutamide 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 enzalutamide is necessary. Haloperidol is a CYP3A4 substrate and enzalutamide 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 enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Monitor for decreased efficacy of propranolol if coadministration with enzalutamide is necessary. Propranolol is a CYP2C19 substrate and enzalutamide is a CYP2C19 inducer.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with enzalutamide 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 enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Hydroxyprogesterone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Ibrutinib: (Major) Avoid coadministration of ibrutinib with enzalutamide due to decreased plasma concentrations of ibrutinib. Ibrutinib is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary; consider increasing the dose of oxycodone as needed. If enzalutamide is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of idelalisib. Idelalisib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased idelalisib exposure by 75%.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with enzalutamide is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; enzalutamide 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 enzalutamide 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 enzalutamide 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 enzalutamide is necessary; adjust the dose of imipramine if clinically appropriate. Imipramine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. The plasma concentration of imipramine may decrease when given concomitantly with CYP3A4 inducers.
    Indinavir: (Major) Coadministration of indinavir with enzalutamide is not recommended as there is a potential for decreased indinavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Indinavir is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer.
    Irinotecan Liposomal: (Major) Avoid administration of enzalutamide during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Irinotecan: (Major) Avoid administration of enzalutamide during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Isavuconazonium: (Severe) Concomitant use of isavuconazonium with enzalutamide 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; enzalutamide is a strong inducer of this enzyme. There was a 97% decrease in isavuconazole serum concentrations when coadministered with another strong CYP3A4 inducer.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of enzalutamide with rifampin if possible due to the risk of decreased enzalutamide plasma concentrations. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg PO once daily. If rifampin is discontinued, resume the dose of enzalutamide used prior to initiation of rifampin. Enzalutamide is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of enzalutamide with rifampin if possible due to the risk of decreased enzalutamide plasma concentrations. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg PO once daily. If rifampin is discontinued, resume the dose of enzalutamide used prior to initiation of rifampin. Enzalutamide is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Isradipine: (Major) Monitor for decreased efficacy of isradipine if coadministration with enzalutamide is necessary. Isradipine is a CYP3A4 substrate and enzalutamide 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 enzalutamide as istradefylline exposure and efficacy may be reduced. Enzalutamide 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 enzalutamide within 2 weeks of itraconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of itraconazole; increase the dose of itraconazole as necessary. Itraconazole is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Ivabradine: (Major) Avoid coadministration of ivabradine and enzalutamide due to decreased plasma concentrations of ivabradine. Ivabradine is a CYP3A4 substrate and enzalutamide is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ivabradine exposure by approximately half.
    Ivacaftor: (Major) Coadministration of ivacaftor with enzalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of ixabepilone; consider an alternative to enzalutamide 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 enzalutamide 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 enzalutamide; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
    Ketoconazole: (Major) The use of enzalutamide within 2 weeks of systemic ketoconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; increase the dose of ketoconazole as necessary. Ketoconazole is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Lansoprazole: (Major) Avoid coadministration of enzalutamide with lansoprazole due to decreased plasma concentrations of lansoprazole. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Enzalutamide is a moderate CYP2C19 inducer and a strong CYP3A4 inducer.
    Lansoprazole; Naproxen: (Major) Avoid coadministration of enzalutamide with lansoprazole due to decreased plasma concentrations of lansoprazole. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Enzalutamide is a moderate CYP2C19 inducer and a strong CYP3A4 inducer.
    Lapatinib: (Major) Avoid coadministration of lapatinib with enzalutamide 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 enzalutamide is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with enzalutamide due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If enzalutamide is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of enzalutamide. Larotrectinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Lefamulin: (Major) Avoid coadministration of lefamulin with enzalutamide unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
    Lesinurad: (Moderate) Monitor for decreased efficacy of lesinurad if coadministration with enzalutamide is necessary. Lesinurad is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer. Coadministration with another CYP2C9 inducer deceased lesinurad exposure by 38%.
    Lesinurad; Allopurinol: (Moderate) Monitor for decreased efficacy of lesinurad if coadministration with enzalutamide is necessary. Lesinurad is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer. Coadministration with another CYP2C9 inducer deceased lesinurad exposure by 38%.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Levonorgestrel: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Lidocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with enzalutamide is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Lopinavir; Ritonavir: (Severe) Coadministration of lopinavir with strong inducers of CYP3A4, such as enzalutamide, is contraindicated. Taking these drugs together could decrease lopinavir concentrations, and may lead to a reduction in antiretroviral activity. (Severe) Coadministration of ritonavir with enzalutamide is contraindicated as there is a potential for decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Lorlatinib: (Severe) Coadministration of lorlatinib with enzalutamide is contraindicated due to the potential for serious hepatotoxicity; the efficacy of lorlatinib may also be decreased. Discontinue enzalutamide for 3 plasma half-lives prior to initiating lorlatinib. Lorlatinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Severe hepatotoxicity indicated by increased AST/ALT (grade 2, 8%; grade 3 or 4, 83%) occurred in healthy subjects receiving a single 100-mg dose of lorlatinib with multiple daily doses of another strong CYP3A4 inducer (n = 12); ALT and AST returned to normal limits after a median of 15 days. Additionally, the mean AUC and Cmax of lorlatinib were decreased by 85% and 76%, respectively.
    Lumacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with enzalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Lumacaftor; Ivacaftor: (Major) Coadministration of lumacaftor; ivacaftor with enzalutamide is not recommended due to decreased plasma concentrations of both enzalutamide and ivacaftor, which may compromise efficacy. Enzalutamide is a CYP3A4 substrate and strong inducer; ivacaftor is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. Coadministration with a strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Lumateperone: (Major) Avoid coadministration of lumateperone and enzalutamide as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of lumateperone with another strong CYP3A4 inducer significantly decreased lumateperone exposure.
    Lurasidone: (Severe) Concurrent use of lurasidone with strong CYP3A4 inducers, such as enzalutamide, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Decreased blood concentrations of lurasidone are expected when the drug is co-administered with strong inducers of CYP3A4. Coadministration with another strong CYP3A4 inducer decreased lurasidone exposure by 83%.
    Macimorelin: (Major) Discontinue enzalutamide 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 enzalutamide is a strong CYP3A4 inducer.
    Macitentan: (Major) Avoid coadministration of macitentan with enzalutamide due to decreased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and enzalutamide 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) Coadministration of maraviroc, a CYP3A substrate, and enzalutamide, a strong CYP3A inducer, without a concomitant strong CYP3A inhibitor may decrease maraviroc concentrations, therefore, the adult maraviroc dose should be increased to 600 mg PO twice daily when coadministered with enzalutamide without a concomitant strong CYP3A inhibitor. Coadministration of maraviroc and enzalutamide is contraindicated in patients with CrCl less than 30 mL/min. For pediatric patients, concomitant use of maraviroc with a strong CYP3A inducer, 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.
    Medroxyprogesterone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Mefloquine: (Moderate) Monitor for decreased efficacy of mefloquine if coadministration with enzalutamide is necessary. Mefloquine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased mefloquine exposure by 68%.
    Mephobarbital: (Major) Avoid coadministration of mephobarbital with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when mephobarbital is discontinued. Enzalutamide is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Mestranol; Norethindrone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Metformin; Repaglinide: (Moderate) An increased dose of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with enzalutamide is necessary. Repaglinide is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Saxagliptin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased saxagliptin exposure by 76%.
    Methadone: (Major) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with enzalutamide 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 enzalutamide 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; enzalutamide is a strong CYP3A4 inducer, as well as a moderate inducer of both CYP2C9 and CYP2C19. Concomitant use with inducers of CYP enzymes 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) Avoid the concomitant use of enzalutamide, a strong CYP3A4 inducer, and midazolam, a CYP3A4 substrate, as midazolam plasma exposure may be reduced. Coadministration with enzalutamide decreased midazolam exposure by 86%.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and enzalutamide as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; enzalutamide 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) When mifepristone is administered for the treatment of Cushing's syndrome, avoid coadministration of enzalutamide. When mifepristone is administered for pregnancy termination, follow-up assessment to verify that treatment has been successful is recommended in patients receiving enzalutamide. Coadministration may decrease mifepristone exposure reducing efficacy. Mifepristone is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. The impact of CYP3A4 inducers on mifepristone efficacy is unknown.
    Mirtazapine: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with enzalutamide is necessary; a dosage adjustment of mirtazapine may be necessary. Mirtazapine is a CYP3A4 substrate and enzalutamide 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%.
    Mitotane: (Major) Avoid coadministration of mitotane with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when mitotane is discontinued. Enzalutamide is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Modafinil: (Moderate) Monitor for decreased efficacy of modafinil if coadministration with enzalutamide is necessary. Modafinil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. The probability of effect of enzalutamide 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.
    Montelukast: (Minor) Enzalutamide may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Enzalutamide is a strong CYP3A inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Naldemedine: (Major) Avoid coadministration of naldemedine with enzalutamide due to a significant decrease in naldemedine plasma concentrations which may reduce efficacy. Naldemedine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naldemedine exposure by 83%.
    Naloxegol: (Major) Coadministration of naloxegol with enzalutamide is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
    Nateglinide: (Moderate) Monitor for hyperglycemia if coadministration of nateglinide with enzalutamide is necessary; an increased dose of nateglinide and more frequent blood glucose monitoring may be necessary. Nateglinide is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Nefazodone: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with enzalutamide is necessary. Nefazodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Nelfinavir: (Severe) Coadministration of nelfinavir and enzalutamide is contraindicated due to the potential for subtherapeutic antiretroviral activity and the subsequent possibility for the development of resistant HIV mutations. Enzalutamide is a strong CYP3A4 inducer and nelfinavir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of nelfinavir. When administered with another strong CYP3A inducer, the plasma AUC, Cmax, and Cmin of nelfinavir decreased by 83%, 76%, and 92%, respectively.
    Neratinib: (Major) Avoid concomitant use of enzalutamide with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and enzalutamide 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%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of netupitant with enzalutamide due to decreased plasma concentrations of netupitant. Netupitant is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased netupitant exposure by 82%.
    Nevirapine: (Moderate) Concomitant use of enzalutamide 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 a CYP3A4 substrate and enzalutamide 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 enzalutamide, 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 enzalutamide 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 enzalutamide; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of nimodipine. Nimodipine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with enzalutamide due to decreased plasma concentrations of nisoldipine. Nisoldipine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Norethindrone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Norgestrel: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Olaparib: (Major) Avoid coadministration of olaparib with enzalutamide due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and enzalutamide 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%.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of paritaprevir with enzalutamide is contraindicated due to the potential for decreased paritaprevir concentrations and the potential development of viral resistance. Paritaprevir is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased paritaprevir exposure by 70%. (Severe) Coadministration of ritonavir with enzalutamide is contraindicated as there is a potential for decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Omeprazole: (Major) Avoid concomitant use of enzalutamide, a strong CYP3A4 inducer and a moderate CYP2C19 inducer, and omeprazole, a CYP3A4 and CYP2C19 substrate, as omeprazole plasma exposure may be reduced. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC and Cmax of omeprazole was decreased following a single oral dose of omeprazole 20 mg administered after at least 55 days of oral enzalutamide 160 mg/day.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of enzalutamide, a strong CYP3A4 inducer and a moderate CYP2C19 inducer, and omeprazole, a CYP3A4 and CYP2C19 substrate, as omeprazole plasma exposure may be reduced. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC and Cmax of omeprazole was decreased following a single oral dose of omeprazole 20 mg administered after at least 55 days of oral enzalutamide 160 mg/day. (Moderate) Monitor for decreased efficacy of rifabutin and potential issues of resistance if coadministration with enzalutamide is necessary. Rifabutin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid concomitant use of enzalutamide, a strong CYP3A4 inducer and a moderate CYP2C19 inducer, and omeprazole, a CYP3A4 and CYP2C19 substrate, as omeprazole plasma exposure may be reduced. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC and Cmax of omeprazole was decreased following a single oral dose of omeprazole 20 mg administered after at least 55 days of oral enzalutamide 160 mg/day.
    Osimertinib: (Major) Avoid coadministration of osimertinib with enzalutamide due to the risk of decreased osimertinib exposure, resulting in decreased efficacy. If concomitant use is unavoidable, increase the daily dose of osimertinib to 160 mg. Resume normal dosing of osimertinib (80 mg once daily) 3 weeks after discontinuation of enzalutamide. Osimertinib is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Ospemifene is a CYP2C9, CYP2C19, and CYP3A4 substrate. Enzalutamide is a strong CYP3A4 inducer as well as a moderate inducer of CYP2C9 and CYP2C19. Coadministration with another strong CYP3A4/moderate CYP2C9 and CYP2C19 inducer decreased ospemifene exposure by 58%.
    Oxcarbazepine: (Moderate) Monitor MHD, the active metabolite of oxcarbazepine, concentrations during oxcarbazepine dosage titration if enzalutamide and oxcarbazepine are used concurrently. A dose adjustment of oxcarbazepine may be required after initiation, dosage modification, or discontinuation of enzalutamide. Enzalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased plasma concentrations of MHD by 25% to 40%.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with enzalutamide is necessary; consider increasing the dose of oxycodone as needed. If enzalutamide is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Paclitaxel is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Palbociclib: (Major) Avoid coadministration of enzalutamide with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and enzalutamide 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 a strong inducer of CYP3A4 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 a strong CYP3A4 inducer such as enzalutamide is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug.
    Panobinostat: (Major) Avoid the concomitant use of panobinostat and enzalutamide; panobinostat levels may be significantly decreased and its efficacy reduced. Enzalutamide 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 coadministered with panobinostat.
    Pazopanib: (Major) Avoid coadministration of pazopanib with enzalutamide due to the potential for decreased plasma concentrations of pazopanib. Pazopanib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to enzalutamide therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If enzalutamide is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide 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 enzalutamide as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. Pexidartinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased pexidartinib exposure by 65%.
    Phenobarbital: (Major) Avoid coadministration of phenobarbital with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when phenobarbital is discontinued. Enzalutamide is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Phenytoin: (Major) Avoid coadministration of phenytoin with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy; phenytoin plasma concentrations may also be reduced. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when phenytoin is discontinued. Monitor phenytoin serum concentrations and adjust phenytoin doses as needed. Enzalutamide is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Enzalutamide is also a moderate CYP2C9 and CYP2C19 inducer and phenytoin is a CYP2C9 and CYP2C19 substrate. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    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 enzalutamide. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Pitolisant: (Major) Monitor for loss of pitolisant efficacy after initiation of enzalutamide. 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 enzalutamide is discontinued. Pitolisant is a CYP3A4 substrate; enzalutamide 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 enzalutamide due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; enzalutamide 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 enzalutamide if possible due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Praziquantel: (Severe) The concomitant use of enzalutamide with praziquantel is contraindicated due to the potential for decreased exposure and efficacy of praziquantel. If treatment with praziquantel is necessary, treatment with enzalutamide should be discontinued 4 weeks before administration of praziquantel. Treatment with enzalutamide can then be restarted 1 day after completion of praziquantel treatment. Enzalutamide 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.
    Primidone: (Major) Avoid coadministration of primidone with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when primidone is discontinued. Enzalutamide is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Progesterone: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Progestins: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Propranolol: (Moderate) Monitor for decreased efficacy of propranolol if coadministration with enzalutamide is necessary. Propranolol is a CYP2C19 substrate and enzalutamide is a CYP2C19 inducer.
    Quazepam: (Moderate) Monitor for withdrawal symptoms or lack of quazepam efficacy if coadministration with enzalutamide is necessary. Quazepam is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Quetiapine: (Major) Increase the dose of quetiapine by up to 5-fold if coadministration with enzalutamide is necessary. If enzalutamide is discontinued, reduce the quetiapine dose to the original level in 7 to 14 days. Quetiapine is a sensitive CYP3A4 substrate and enzalutamide 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 enzalutamide is added to existing quinidine therapy. No special precautions appear necessary if enzalutamide is started several weeks before quinidine, but quinidine doses may require adjustment if enzalutamide is added or discontinued during quinidine therapy. Quinidine is a CYP3A4 substrate and enzalutamide 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: (Moderate) Monitor for lack of quinine efficacy if coadministration with enzalutamide is necessary. Quinine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased quinine exposure by 75% to 85%.
    Ramelteon: (Moderate) Monitor for a decrease in the efficacy of ramelteon if coadministration with enzalutamide is necessary. Ramelteon is a CYP3A4 and CYP2C9 substrate. Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 inducer. Coadministration with another strong CYP3A4 and moderate CYP2C9 inducer decreased total exposure to ramelteon and metabolite M-II by approximately 80%.
    Ranolazine: (Severe) The concomitant use of enzalutamide with ranolazine is contraindicated due to decreased plasma concentrations of ranolazine resulting in decreased efficacy. Enzalutamide 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 enzalutamide 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 enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased regorafenib exposure by 50% and increased M-5 exposure by 264%.
    Repaglinide: (Moderate) An increased dose of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with enzalutamide is necessary. Repaglinide is a CYP3A4 substrate and enzalutamide 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 enzalutamide, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy; consider an alternative treatment with less potential to induce CYP3A. Ribociclib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 substrate decreased ribociclib exposure by 89%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with enzalutamide, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy; consider an alternative treatment with less potential to induce CYP3A. Ribociclib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 substrate decreased ribociclib exposure by 89%.
    Rifabutin: (Moderate) Monitor for decreased efficacy of rifabutin and potential issues of resistance if coadministration with enzalutamide is necessary. Rifabutin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Rifampin: (Major) Avoid coadministration of enzalutamide with rifampin if possible due to the risk of decreased enzalutamide plasma concentrations. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg PO once daily. If rifampin is discontinued, resume the dose of enzalutamide used prior to initiation of rifampin. Enzalutamide is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Rilpivirine: (Severe) Concurrent use of enzalutamide 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. Enzalutamide is a potent 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.
    Riociguat: (Major) Dosage recommendations for riociguat are not available if coadministration with enzalutamide is necessary. Riociguat is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers may significantly reduce riociguat exposure, but data are not available.
    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 3A4 inducer like enzalutamide. When using Risperdal Consta, the patient will require close monitoring for 4 to 8 weeks when starting enzalutamide. A lower dose of Risperdal Consta may be prescribed between 2 to 4 weeks before the planned discontinuation of enzalutamide 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 enzalutamide, 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. Potent inducers of CYP3A4, such as enzalutamide, may decrease plasma concentrations of risperidone and its active metabolite. In an open, randomized two-phase crossover study, another strong CYP3A4 inducer caused significant decreases in risperidone plasma concentrations in healthy volunteers.
    Ritonavir: (Severe) Coadministration of ritonavir with enzalutamide is contraindicated as there is a potential for decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Roflumilast: (Major) Coadministration of roflumilast with enzalutamide is not recommended due to decreased plasma concentrations of roflumilast. Roflumilast is a CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of rolapitant. Rolapitant is a CYP3A4 substrate and enzalutamide 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 enzalutamide if possible due to decreased plasma concentrations of romidepsin. Romidepsin is a CYP3A4 substrate and enzalutamide 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 enzalutamide; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; enzalutamide 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 enzalutamide is not recommended as there is a potential for decreased saquinavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Saquinavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Saxagliptin: (Moderate) Monitor for increased blood sugars if coadministration of saxagliptin with enzalutamide is necessary. Saxagliptin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased saxagliptin exposure by 76%.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with estrogens, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If 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 enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Selegiline: (Moderate) Monitor for decreased efficacy of selegiline if coadministration with enzalutamide is necessary. Selegiline is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Adequate studies have not been done to assess the effect of CYP3A4 inducers on selegiline.
    Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with enzalutamide is necessary. Sildenafil is a CYP3A4 (major) and CYP2C9 (minor) substrate. Enzalutamide is a strong CYP3A4 inducer and a moderate inducer of CYP2C9. 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: (Moderate) Coadministration of simeprevir with enzalutamide is not recommended as there is a potential for decreased simeprevir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Simeprevir is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer.
    Siponimod: (Major) Concomitant use of siponimod and enzalutamide is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; enzalutamide is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
    Sirolimus: (Major) Avoid coadministration of sirolimus with enzalutamide due to decreased plasma concentrations of sirolimus. Sirolimus is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Sofosbuvir; Velpatasvir: (Major) Coadministration of velpatasvir with enzalutamide 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 enzalutamide is a strong CYP3A4 inducer.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Coadministration of velpatasvir with enzalutamide 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 enzalutamide is a strong CYP3A4 inducer. (Major) Coadministration of voxilaprevir with enzalutamide is not recommended due to decreased plasma concentrations of voxilaprevir, potentially resulting in loss of antiviral efficacy. Voxilaprevir is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Solifenacin: (Minor) Monitor for decreased efficacy of solifenacin if coadministration with enzalutamide is necessary. Solifenacin is a CYP3A4 substrate and enzalutamide 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 enzalutamide; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of St. John's Wort with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when St. John's Wort is discontinued. Enzalutamide is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if enzalutamide must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with enzalutamide is necessary; consider increasing the dose of sufentanil injection as needed. If enzalutamide 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 enzalutamide 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 sunitinib with enzalutamide if possible due to decreased plasma concentrations of sunitinib. If concomitant use is unavoidable, consider increasing the dose of sunitinib to a maximum of 87.5 mg for GIST and RCC patients, or a maximum of 62.5 mg for patients with pNET; carefully monitor these patients for sunitinib-related toxicities. Sunitinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the combined exposure of sunitinib and its primary active metabolite by 46%.
    Suvorexant: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with enzalutamide is necessary. Suvorexant is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased suvorexant exposure by 77% to 88%.
    Tacrolimus: (Major) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with enzalutamide is necessary. Tacrolimus is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly increased tacrolimus clearance.
    Tadalafil: (Major) Avoid coadministration of tadalafil with enzalutamide in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of enzalutamide due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Tamoxifen: (Major) Avoid coadministration of enzalutamide with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and enzalutamide 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) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as enzalutamide, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with enzalutamide as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Telithromycin: (Major) Avoid coadministration of telithromycin with enzalutamide due to decreased plasma concentrations of telithromycin, which may result in decreased efficacy. Telithromycin is a CYP3A4 substrate and enzalutamide 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%.
    Temsirolimus: (Major) Avoid coadministration of temsirolimus with enzalutamide 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 enzalutamide is discontinued, decrease the dose of temsirolimus to the dose used before initiation of enzalutamide. Temsirolimus is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Teniposide is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers reduced plasma concentrations of teniposide.
    Terbinafine: (Moderate) Monitor patients for breakthrough fungal infections if coadministration of terbinafine with enzalutamide is necessary. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may decrease the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9, and CYP3A4. Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 inducer.
    Tezacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with enzalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a CYP3A4 substrate and enzalutamide 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 enzalutamide 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 enzalutamide, 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%.
    Thiotepa: (Major) Avoid the concomitant use of thiotepa and enzalutamide 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; enzalutamide is a strong CYP3A4 inducer,
    Tiagabine: (Moderate) Monitor for decreased efficacy of tiagabine if coadministration with enzalutamide is necessary. Tiagabine is a CYP3A4 substrate and enzalutamide 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 enzalutamide due to decreased plasma concentrations of ticagrelor. Ticagrelor is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Tinidazole is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Concomitant use may accelerate the elimination of tinidazole, decreasing plasma concentrations.
    Tipranavir: (Severe) Tipranavir is contraindicated for use with enzalutamide. Enzalutamide is a strong CYP3A4 inducer and tipranavir is a CYP3A4 substrate; coadministration significantly reduces plasma concentrations of tipranavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Tofacitinib: (Major) Coadministration of tofacitinib and enzalutamide is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Tolvaptan: (Major) Avoid coadministration of tolvaptan with enzalutamide due to decreased plasma concentrations of tolvaptan. If concomitant use of enzalutamide is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    Toremifene: (Major) Avoid coadministration of enzalutamide with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Torsemide is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer. Concomitant use of CYP2C9 inducers increases torsemide clearance and decreases torsemide plasma concentrations.
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with enzalutamide due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% 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 enzalutamide is necessary; consider increasing the dose of tramadol as needed. If enzalutamide is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Trazodone: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with enzalutamide. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; enzalutamide 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 enzalutamide is necessary. Triazolam is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Ubrogepant: (Major) Avoid the coadministration of ubrogepant and enzalutamide as concurrent use may decrease ubrogepant exposure and reduce the efficacy. Ubrogepant is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer resulted in an 80% reduction in ubrogepant exposure.
    Ulipristal: (Major) Avoid coadministration of ulipristal with enzalutamide due to decreased plasma concentrations of ulipristal. Ulipristal is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ulipristal exposure by 93%, while exposure to monodemethyl-ulipristal acetate decreased by 90%.
    Upadacitinib: (Major) Coadministration of upadacitinib with enzalutamide is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
    Valbenazine: (Major) Coadministration of valbenazine with enzalutamide 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 enzalutamide 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 enzalutamide is necessary. Valproic acid is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Vandetanib: (Major) Avoid coadministration of vandetanib with enzalutamide due to decreased plasma concentrations of vandetanib and increased concentrations of the active metabolite. Vandetanib is a CYP3A4 substrate and enzalutamide 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 enzalutamide 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 enzalutamide is discontinued. Vemurafenib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to vemurafenib by 40%.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and enzalutamide; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the coadministration of multiple doses of a strong CYP3A4 inducer.
    Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with enzalutamide is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and enzalutamide 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 enzalutamide is necessary for more than 14 days. After discontinuation of enzalutamide, resume the previous vilazodone dose over 1 to 2 weeks. Vilazodone is primarily metabolized by CYP3A4 and enzalutamide 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 enzalutamide due to decreased plasma concentrations of vincristine. Vincristine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Vincristine: (Major) Avoid coadministration of vincristine with enzalutamide due to decreased plasma concentrations of vincristine. Vincristine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Vorapaxar: (Major) Avoid coadministration of vorapaxar and enzalutamide due to decreased serum concentrations of vorapaxar. Vorapaxar is a CYP3A4 substrate and enzalutamide 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: (Severe) Coadministration of voriconazole with enzalutamide is contraindicated due to decreased plasma concentrations of voriconazole. Voriconazole is a CYP2C9, CYP2C19, and CYP3A4 substrate. Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 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 enzalutamide for longer than 14 days is necessary. Vortioxetine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Voxelotor: (Major) Avoid coadministration of voxelotor and enzalutamide 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; enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease voxelotor exposure by up to 77%.
    Warfarin: (Major) Avoid coadministration of warfarin with enzalutamide if possible due to decreased plasma concentrations of warfarin. If concomitant use is unavoidable, conduct additional INR monitoring and adjust the dose of warfarin as clinically appropriate. The S-enantiomer of warfarin is a CYP2C9 and CYP2C19 substrate, while the R-enantiomer is a substrate of CYP2C19 and CYP3A4; the S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance. Enzalutamide is a moderate CYP2C9 and CYP2C19 inducer and a strong CYP3A4 inducer.
    Zaleplon: (Major) Consider an alternative to enzalutamide if treatment with zaleplon is necessary due to decreased plasma concentrations of zaleplon. Zaleplon is a CYP3A4 substrate and enzalutamide 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%.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and enzalutamide. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. The AUC of zanubrutinib was decreased by 93% when coadministered with another strong CYP3A4 inducer.
    Zolpidem: (Major) Coadministration of zolpidem with enzalutamide is not recommended due to decreased plasma concentrations of zolpidem. Zolpidem is a CYP3A4 substrate and enzalutamide 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) Closely monitor for decreased efficacy of zonisamide if enzalutamide is added to existing zonisamide therapy or if the dose of enzalutamide is increased or decreased; the dose of zonisamide may need to be adjusted. This interaction is unlikely to be of clinical significance when zonisamide is added to existing enzalutamide therapy. Zonisamide is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. The half-life of zonisamide decreased from 46 hours to 27 to 38 hours when administered with a weak CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    The safety and efficacy of enzalutamide have not been established in females. Although there are no adequately controlled studies in pregnant women, enzalutamide can cause fetal harm and loss of pregnancy based on animal reproduction studies and its mechanism of action. When administered to pregnant mice during organogenesis, severe adverse developmental effects occurred at doses lower than the maximum recommended human dose. In an embryo-fetal developmental toxicity study, increased post-implantation loss and resorptions, as well as decreased anogenital distance, occurred in mice treated with enzalutamide during organogenesis at exposures approximately 0.4 times the AUC of patients treated with the recommended dose. Maternal toxicity as well as cleft palate and absent palatine bone occurred in mice at 1.1 times the AUC of patients treated with the recommended dose. Developmental toxicities were not observed in rabbits treated with enzalutamide during organogenesis at exposures up to 0.4 times the AUC of patients treated with the recommended dose.

    MECHANISM OF ACTION

    Enzalutamide is an androgen receptor (AR) antagonist that works by competitively inhibiting androgen binding to ARs and by inhibiting AR nuclear translocation and co-activator recruitment of the ligand-receptor complex. Enzalutamide caused decreased proliferation and prostate cancer cell death in vitro and decreased tumor volume in a mouse xenograft model. The androgen-AR signaling pathway is important in castration-resistant prostate cancer (CRPC). Enzalutamide differs from other agents that are indicated for the treatment of metastatic prostate cancer that also target the androgen-AR pathway. Enzalutamide is a pure AR antagonist, whereas bicalutamide is an AR antagonist that exhibits some degree of AR agonist activity. Enzalutamide inhibits the androgen-AR pathway at the receptor and post-receptor ligand binding level, whereas abiraterone is a CYP17 inhibitor that works at the pre-receptor ligand binding level via extragonadal androgen synthesis inhibition. Unlike CYP17 inhibitors, enzalutamide does not require the concomitant use of corticosteroids.

    PHARMACOKINETICS

    Enzalutamide is administered orally. It is 97% to 98% protein bound, primarily to albumin; N-desmethyl enzalutamide (major active metabolite) is 95% protein bound. In vitro, there was no protein binding displacement between enzalutamide and other highly protein-bound drugs (e.g., warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations. The mean apparent volume of distribution (V/F) of enzalutamide after a single dose in patients with metastatic castration-resistant prostate cancer (CRPC) was 110 L (CV, 29%) and the mean apparent clearance (CL/F) was 0.56 L/hour (range, 0.33 to 1.02 L/hour). The mean terminal half-life for enzalutamide in patients is 5.8 days (range, 2.8 days to 10.2 days); the mean terminal half-life for N-desmethyl enzalutamide in healthy volunteers is approximately 7.8 to 8.6 days. Enzalutamide is primarily eliminated by hepatic metabolism. After a single oral dose of radiolabeled enzalutamide, 85% of radioactivity was recovered by 77 days post-dose: 71% in urine (including trace amounts of enzalutamide and N-desmethyl enzalutamide) and 14% in feces (0.4 as unchanged drug and 1% as N-desmethyl enzalutamide).[51727]
     
    Affected cytochrome P450 isoenzymes and drug transporter: CYP2C8, CYP2C9, CYP2C19, CYP3A4
    In vitro, CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. After administration of a single radiolabeled dose, enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 30%, 49%, and 10% of the total recovered radioactivity. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). In vitro data suggest that carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite. While enzalutamide interacts with CYP2C8 inhibitors and CYP3A4 inducers, coadministration with itraconazole (strong CYP3A4 inhibitor) increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on Cmax; enzalutamide may be administered with CYP3A4 inhibitors. In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite inhibit CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5; in vitro, enzalutamide causes time-dependent inhibition of CYP1A2 while the parent drug and N-desmethyl enzalutamide also inhibit P-glycoprotein (P-gp) and BCRP at clinically relevant concentrations. Enzalutamide is also a moderate CYP2C9 and CYP2C19 inducer as well as a strong CYP3A4 inducer; in vitro it also induced CYP2B6.[51727]

    Oral Route

    The plasma enzalutamide pharmacokinetics are adequately described by a linear 2-compartment model with first-order absorption. Following oral administration, the median time to reach maximum plasma concentrations of enzalutamide (Tmax) is 1 hour (range, 0.5 to 3 hours). At steady-state, the plasma mean Cmax for enzalutamide is 16.6 mcg/mL (CV, 23%) and the mean Cmax for N-desmethyl enzalutamide is 12.7 mcg/mL (CV, 30%). Mean predose plasma trough values are 11.4 mcg/mL (CV, 26%) and 13 mcg/mL (CV, 30%), respectively. When administered daily, steady-state is achieved by day 28, with an accumulation of approximately 8.3-fold relative to a single dose. Daily fluctuation in enzalutamide plasma concentrations is low (mean peak-to-trough ratio, 1.25). At steady-state, enzalutamide showed approximately dose-proportional pharmacokinetics over the daily dose range of 30 mg to 360 mg. Administration with a high-fat meal did not alter the AUC of enzalutamide or N-desmethyl enzalutamide.[51727]