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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Kinase inhibitor with activity against BRAF V600E-, BRAF V600K-, and BRAF V600D-mutated melanoma cells
    FDA approved for the treatment of unresectable or metastatic malignant melanoma as monotherapy in patients with a BRAF V600E mutation or in combination with trametinib in patients with BRAF V600E or V600K mutations; mutations must be confirmed using a FDA-approved test
    Cutaneous squamous cell carcinoma, keratoacanthoma, and new primary malignant melanomas have been reported with dabrafenib therapy

    COMMON BRAND NAMES

    Tafinlar

    HOW SUPPLIED

    Tafinlar Oral Cap: 50mg, 75mg

    DOSAGE & INDICATIONS

    For the treatment of malignant melanoma.
    NOTE: Confirm the BRAF V600E or V600K mutation prior to starting therapy. Information on FDA-approved tests for the detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics.
    NOTE: Dabrafenib is not indicated in patients with wild-type BRAF melanoma.
    NOTE: Dabrafenib has been designated as an orphan drug for the treatment of BRAF V600 mutation-positive melanoma by the FDA as a single-agent or in combination with trametinib.
    For the treatment of unresectable or metastatic malignant melanoma in patients with the BRAF V600E mutation, as a single agent.
    Oral dosage
    Adults

    150 mg orally every 12 hours until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Patients with previously untreated BRAF V600-mutated unresectable stage III or metastatic melanoma received oral dabrafenib (n = 187) or dacarbazine 1,000 mg/m2 IV every 3 weeks (n = 63) in a multinational, randomized, phase III study; prior therapy with interleukin-2 was permitted. At a median follow-up time of 5 months, the progression-free survival (PFS) time assessed by investigator review (IR) (primary endpoint) was significantly improved with dabrafenib compared with dacarbazine (5.1 months vs. 2.7 months; hazard ratio = 0.3; 95% CI, 0.18 to 0.51; p < 0.0001); PFS results were confirmed on independent radiologic review (IRR). Dabrafenib was also studied in melanoma patients who had previously untreated brain metastases (cohort A) or progressive brain disease following prior local treatment for metastases (cohort B) in a multinational, phase II study. In cohort A, the overall intracranial response rates (OIRR) assessed by IR (primary endpoint) or IRR, respectively, were 39.2% or 20% in patients with a valine for glutamate substitution at position 600 BRAF mutation (BRAF V600glu; n = 74) and 6.7% or 0% in patients with a valine for lysine substitution at position 600 BRAF mutation (BRAF V600lys; n = 15); duration of responses were 20.1 months (BRAF V600glu) and 12.4 months (BRAF V600lys) by IR review. In cohort B, the OIRR assessed by IR or IRR, respectively, were 30.8% or 19% in patients with a BRAF V600glu mutation (n = 65) and 22.2% or 11% in patients with a BRAF V600lys mutation (n = 18); duration of responses were 28.1 months (BRAF V600glu) and 16.6 months (BRAF V600lys) by IR review. A third party blinded adjudication confirmed the IR assessments in 68% of cases. In patients with the BRAF V600glu mutation, the estimated 6-month overall survival (OS) rates were 61% in both cohort A and B. In patients with the BRAF V600lys mutation, the 6-month OS rates were 27% in cohort A and 41% in cohort B.

    For the treatment of unresectable or metastatic malignant melanoma in patients with the BRAF V600E or V600K mutation, in combination with trametinib.
    Oral dosage
    Adults

    150 mg orally every 12 hours in combination with trametinib 2 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Combination therapy with dabrafenib plus trametinib resulted in a significantly improved median overall survival (OS) time compared with single-agent vemurafenib (median not reached vs. 17.2 months; hazard ratio (HR) = 0.69; 95%CI, 0.53 to 0.89; p = 0.005) in previously untreated patients with unresectable stage IIIC or stage IV melanoma and BRAF V600E or V600K mutations in a planned interim analysis of a randomized, phase III study (n = 704; the COMBI-v study). Based on the significantly improved OS data with combination therapy, the data and safety monitoring committee recommended stopping the study. Cross-over from the vemurafenib to the combination arm was not allowed prior to this interim analysis. The median progression-free survival (PFS) time was also significantly longer in the combination therapy arm compared with the vemurafenib arm (11.4 months vs. 7.3 months; HR = 0.56; 95% CI, 0.46 to 0.69; P < 0.001). Investigator-evaluated median PFS time was significantly improved with dabrafenib plus trametinib compared with dabrafenib plus placebo at a median follow-up of 9 months (9.3 months vs. 8.8 months; HR = 0.75; 95% CI, 0.57 to 0.99; p = 0.03) and following an additional 17 months of follow-up (11 months vs. 8.8 months; HR = 0.67; 95% CI, 0.53 to 0.84; p = 0.0004) in previously untreated patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E or V600K mutations in a randomized, double-blind, phase III study (n = 423; the COMBI-d study). Cross-over from the dabrafenib plus placebo arm to the combination therapy arm was not permitted at the primary analysis. The median OS time (secondary endpoint) was significantly improved with combination therapy compared with dabrafenib plus placebo (25.1 months vs. 18.7 months; HR = 0.71; 95% CI, 0.55 to 0.92; p = 0.0107) at the final analysis.

    For the treatment of asymptomatic brain metastases in patients with BRAF V600E- or V600K-mutation metastatic melanoma and no previous local brain-directed therapy.
    Oral dosage
    Adults

    150 mg orally twice daily in combination with trametinib 2 mg orally once daily until disease progression was evaluated in a cohort of 76 patients in a multicenter, phase II trial. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.

    For the adjuvant treatment of completely resected stage III melanoma in patients with the BRAF V600 mutation, in combination with trametinib†.
    Oral dosage
    Adults

    150 mg orally twice daily in combination with trametinib 2 mg orally once daily for up to 12 months was evaluated in a multinational, randomized, double-blind, placebo-controlled, phase III trial (n = 870; the COMBI-AD trial). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.

    For the treatment of non-small cell lung cancer (NSCLC).
    NOTE: Confirm the BRAF V600E mutation prior to starting therapy. Information on FDA-approved tests for the detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics.
    NOTE: Dabrafenib is not indicated in patients with wild-type BRAF NSCLC.
    NOTE: Dabrafenib has been designated as an orphan drug for the treatment of BRAF mutation-positive NSCLC by the FDA as a single-agent or in combination with trametinib.
    For the treatment of metastatic BRAF V600E mutation-positive NSCLC, in combination with trametinib.
    Oral dosage
    Adults

    150 mg orally every 12 hours in combination with trametinib 2 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. The investigator-assessed overall response rate (ORR) was 63.2% following treatment with dabrafenib and trametinib in a cohort of patients with previously treated stage IV BRAF V600E-mutant NSCLC (n = 57) in a multinational, nonrandomized, 3-cohort, phase II trial. At a median follow-up of 11.6 months, the median duration of response was 9 months and the median progression-free survival time was 8.6 months (evaluated by an independent review committee). Patients in this cohort (median age, 64 years; range, 58 to 71 years) had received up to 3 prior systemic therapies (1 prior therapy, 67%; 2 or 3 prior therapies, 33%) including at least 1 prior platinum-based chemotherapy regimen; patients who received prior BRAF or MEK inhibitor treatment were excluded from this study. The ORR was 61% in a cohort of patients with treatment-naive stage IV BRAF V600E-mutant NSCLC (n = 36) who received dabrafenib and trametinib.

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO

    Geriatric

    300 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 dabrafenib dosage adjustment is necessary in patients with mild hepatic impairment based on a population pharmacokinetic analysis. Dabrafenib has not been studied in patients with moderate to severe hepatic impairment; hepatic and biliary secretion are the primary routes of dabrafenib elimination and exposure may be increased in these patients.

    Renal Impairment

    No dabrafenib dosage adjustment is necessary in patients with mild to moderate renal impairment (glomerular filtration rate (GFR), 30—89 mL/min/1.73 m2) based on a population pharmacokinetic analysis. Dabrafenib has not been studied in patients with severe renal impairment (GFR < 30 mL/min/1.73 m2). Dabrafenib is highly bound to plasma proteins and is unlikely to be removed by hemodialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Dabrafenib should be taken at least 1 hour before or 2 hours after a meal.
    Space doses approximately 12 hours apart. When administered with trametinib, take the once-daily dose of trametinib at the same time each day with either the morning or evening dose of dabrafenib.
    Swallow whole; do not open, crush, or break capsules.
    If a dose is missed, it may be taken up to 6 hours prior to the next dose. If there is less than 6 hours until the next scheduled dose, skip the dose and take the next dose at the scheduled time.

    STORAGE

    Tafinlar:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    In in vitro studies, MAP-kinase signaling activation led to increased BRAF wild-type cell proliferation; therefore, dabrafenib is not indicated for the treatment of BRAF wild-type melanoma. Prior to starting dabrafenib, confirm the BRAF V600E mutation using an FDA-approved test.

    Secondary malignancy

    Secondary malignancy has been reported with dabrafenib monotherapy, specifically cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and new primary malignant melanomas; the incidence of basal cell carcinoma is increased when dabrafenib is used in combination with trametinib. The median time to cuSCC development was 9 weeks (range, 1—53 weeks) across all clinical trials; the median time to basal cell carcinaoma ranged from 4—36 weeks. Combination therapy with trametinib was also associated with 1 case each of KRAS-positive pancreatic adenocarcinoma, recurrent NRAS-positive colorectal cancer, head and neck cancer, and glioblastoma. In vitro, paradoxical MAP-kinase signaling and increased cell proliferation have occurred in BRAF wild-type cells after exposure to BRAF inhibitors; confirm BRAF v600E or V600K mutation status prior to initiation of dabrafenib therapy. Perform a dermatologic evaluation before starting dabrafenib therapy, every 2 months on therapy, and for up to 6 months after therapy discontinuation. No dabrafenib dose modifications are recommended in patients who develop a new primary cutaneous malignancy; however, dabrafenib should be permanently discontinued in patients who develop a RAS-positive non-cutaneous malignancy.

    Dehydration, fever, hypotension, infection, renal failure

    Serious fever and febrile reaction including symptoms of hypotension, rigors/chills, dehydration, and/or renal failure have been reported with dabrafenib therapy; the incidence and severity of fever is higher when dabrafenib is administered in combination with trametinib. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop a fever or a febrile reaction; evaluate these patients for signs and symptoms of infection. If a patient experiences a severe fever or febrile reaction, monitor renal function (e.g., BUN/serum creatinine) during and after the event and give antipyretic agents as secondary prophylaxis when dabrafenib therapy is resumed. In patients who develop a febrile reaction or a second or subsequent fever that does not resolve within 3 days of onset, give corticosteroids (e.g., prednisone 10 mg/day PO) for at least 5 days; ensure there is no evidence of active infection prior to starting corticosteroid therapy. In a clinical trial in patients who received single-agent dabrafenib, the median time to fever onset was 11 days (range, 1 day to 6.6 months) and the median duration of fever was 3 days (range, 1 day to 4.2 months). In pooled results from 2 clinical trials in patients who received dabrafenib in combination with trametinib, the median time to fever onset was 1 month (range, 1 day to 23.5 months) and the median duration of fever was 3 days (range, 1 day to 11.3 months). About one-half of these patients experienced 3 or more episodes of a febrile reaction.

    Diabetes mellitus, hyperglycemia

    Hyperglycemia has been reported with dabrafenib therapy in clinical trials; the incidence and severity of hyperglycemia was higher when dabrafenib was administered with trametinib. Patients with a history of diabetes mellitus may require more intensive hypoglycemic therapy while receiving dabrafenib. In patients with pre-existing diabetes or hyperglycemia, monitor serum glucose levels at baseline and as clinically indicated during therapy; advise patients to report symptoms of severe hyperglycemia (e.g., excessive thirst, increased urinary frequency).

    Iritis

    Uveitis, iritis, and iridocyclitis have been reported with dabrafenib therapy in clinical trials. Steroid and mydriatic ophthalmic drops may provide symptomatic relief for these eye conditions. Monitor patients for visual signs and symptoms of uveitis including vision changes (i.e., blurred vision), photophobia, and eye pain. Continue dabrafenib at the same dose in patients who develop iritis. Hold dabrafenib for mild or moderate uveitis that does not respond to ocular therapy, severe uveitis, or iridocyclitis; initiate treatment as indicated. Permanently discontinue therapy in patients who develop persistent grade 2 or higher uveitis that lasts longer than 6 weeks.

    G6PD deficiency, hemolytic anemia, sulfonamide hypersensitivity

    Dabrafenib contains a sulfonamide moiety so use this agent with caution in patients with a sulfonamide hypersensitivity. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency who receive dabrafenib have an increased risk of developing hemolytic anemia. Therefore, monitor patients with G6PD deficiency for signs of hemolytic anemia.

    Bleeding, GI bleeding, intracranial bleeding

    Bleeding events, including major intracranial bleeding or GI bleeding, can occur when dabrafenib is used in combination with trametinib. Combination therapy should be used with caution in patients with conditions that might increase the risk of hemorrhage. Monitor patients for signs of bleeding and evaluate any unexplained fall in hematocrit, hypotension, or other unexplained symptom.

    Cardiac disease, cardiomyopathy, heart failure, ventricular dysfunction

    Cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and below the institutional lower limit of normal (LLN), has been reported with dabrafenib therapy in clinical trials; the incidence of cardiomyopathy was higher when dabrafenib was administered in combination with trametinib. Use dabrafenib with caution in patients with cardiac disease, especially patients with ventricular dysfunction. Obtain an echocardiogram or multigated acquisition (MUGA) scan prior to starting combination therapy, 1 month after starting dabrafenib, and then every 2 to 3 months during treatment. Hold dabrafenib for symptomatic congestive heart failure or LVEF below the LLN with an absolute decrease of greater than 20% from baseline. Resume dabrafenib at the same dose if LVEF improves to the institutional LLN and an absolute decrease of 10% or less from baseline. In one clinical trial, the median time to cardiomyopathy onset was 8.2 months (range, 28 days to 24.9 months) in patients who received combination therapy and 4.4 months (range, 28 days to 19.1 months) in patients who received dabrafenib alone.

    Skin disease

    Serious skin disease/toxicity including palmar-plantar erythrodysesthesia syndrome (hand and foot syndrome) has been reported with dabrafenib when administered in combination with trametinib; hospitalization was required in some patients due to a secondary infection of the skin. The median time to skin toxicity onset was 37 days (range, 1—225 days) and the median time to resolution was 33 days (range, 3—421 days) in a clinical trial. Monitor patients for signs of skin toxicity and secondary infections. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop severe skin toxicity.

    Pregnancy

    Dabrafenib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and findings from animal studies. Advise females of reproductive potential to avoid pregnancy while taking dabrafenib. Discuss the potential hazard to the fetus if dabrafenib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicity was observed in pregnant rats who received dabrafenib doses that resulted in drug exposures that were about 3 times the recommended human exposure including embryo-lethality, ventricular septal defects, and variation in thymic shape. Additionally, fetal skeletal development delay and reduced fetal body weight occurred with dabrafenib doses that achieved exposure equivalent to the recommended human dose.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during dabrafenib therapy. Female patients of reproductive potential should use highly effective non-hormonal contraceptive methods during and for at least 2 weeks after the last dabrafenib dose; dabrafenib may decrease the concentration of hormonal contraceptive agents resulting in a loss of contraceptive efficacy. Advise women to contact their healthcare provider if pregnancy is suspected or confirmed. Women who become pregnant while receiving dabrafenib should be apprised of the potential hazard to the fetus. Advise males and females of reproductive potential of the potential risk for impaired fertility or infertility with dabrafenib therapy. Testicular degeneration/depletion has been reported in rats and dogs who received dabrafenib at doses equivalent to and 3 times the recommended human exposure. In female rats, reduced fertility occurred at doses that were equivalent to the recommended human dose; a reduced number of ovarian corpora lutea was observed in pregnant rat females at dabrafenib doses that were 3 times the recommended human exposure; additionally, impaired spermatogenesis has been observed in animals.

    Breast-feeding

    According to the manufacturer, women should discontinue breast-feeding during dabrafenib therapy and for 2 weeks after the last dose because of the potential for serious adverse reactions in nursing infants. It is not known if dabrafenib is secreted in human milk or if it affects the breast fed infant or milk production. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 15.0-22.0
    lymphopenia / Delayed / 6.0-22.0
    elevated hepatic enzymes / Delayed / 0-17.0
    neutropenia / Delayed / 2.0-13.0
    hypophosphatemia / Delayed / 0-11.0
    pancreatitis / Delayed / 0-10.0
    interstitial nephritis / Delayed / 0-10.0
    renal failure (unspecified) / Delayed / 7.0-7.0
    anemia / Delayed / 0-7.0
    hyperglycemia / Delayed / 4.7-6.0
    fatigue / Early / 2.0-6.0
    nausea / Early / 2.0-6.0
    hypokalemia / Delayed / 0-6.0
    heart failure / Delayed / 0-6.0
    cardiomyopathy / Delayed / 2.9-6.0
    back pain / Delayed / 2.0-5.0
    fever / Early / 3.7-5.0
    intracranial bleeding / Delayed / 0-5.0
    bleeding / Early / 5.0-5.0
    GI bleeding / Delayed / 0-5.0
    leukopenia / Delayed / 4.0-5.0
    secondary malignancy / Delayed / 4.0-4.0
    vomiting / Early / 2.0-4.0
    hyperbilirubinemia / Delayed / 0-4.0
    thrombocytopenia / Delayed / 0-4.0
    QT prolongation / Rapid / 2.0-4.0
    uveitis / Delayed / 1.0-2.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 2.0-2.0
    headache / Early / 2.0-2.0
    myalgia / Early / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    diarrhea / Early / 0-2.0
    dehydration / Delayed / 0-2.0
    constipation / Delayed / 2.0-2.0
    hypoalbuminemia / Delayed / 0-2.0
    hypomagnesemia / Delayed / 0-2.0
    hypercalcemia / Delayed / 0-2.0
    insomnia / Early / 0-2.0
    hyperkeratosis / Delayed / 1.0-1.0
    arthralgia / Delayed / 0-1.0
    chills / Rapid / 0.5-0.5
    ocular hemorrhage / Delayed / Incidence not known

    Moderate

    hyponatremia / Delayed / 6.0-40.0
    peripheral edema / Delayed / 17.0-31.0
    hypocalcemia / Delayed / 9.0-20.0
    erythema / Early / 2.0-15.0
    bullous rash / Early / 0-10.0
    stomatitis / Delayed / 0-10.0
    hypertension / Early / 0-10.0
    photophobia / Early / 0-2.0
    blurred vision / Early / 0-2.0
    iritis / Delayed / 0-2.0
    hypotension / Rapid / Incidence not known
    pneumonitis / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known

    Mild

    rash (unspecified) / Early / 17.0-53.0
    anorexia / Delayed / 19.0-30.0
    cough / Delayed / 11.0-29.0
    night sweats / Early / 6.0-24.0
    alopecia / Delayed / 22.0-22.0
    acneiform rash / Delayed / 4.0-18.0
    dizziness / Early / 9.0-16.0
    muscle cramps / Delayed / 2.0-16.0
    pruritus / Rapid / 11.0-13.0
    xerostomia / Early / 6.0-11.0
    hyperhidrosis / Delayed / 0-10.0
    asthenia / Delayed / 0-10.0
    folliculitis / Delayed / 0-10.0
    pharyngitis / Delayed / 10.0-10.0
    infection / Delayed / 0-10.0
    ocular pain / Early / 0-2.0
    syncope / Early / 0.7-0.7
    epistaxis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Alfentanil: (Major) The concomitant use of dabrafenib and alfentanil may lead to decreased alfentanil concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of alfentanil efficacy. Dabrafenib is a moderate CYP3A4 inducer and alfentanil is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Alogliptin; Pioglitazone: (Major) The concomitant use of dabrafenib and pioglitazone may lead to decreased pioglitazone exposure and loss of efficacy. Use of an alternative agent is recommended. If concomitant use is unavoidable, monitor patients for loss of pioglitazone efficacy. A change in diabetes treatment may be needed based upon clinical response if dabrafenib is started or stopped during treatment with pioglitazone; do not exceed the maximum recommended dose of 45 mg/day. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Pioglitazone is a moderately sensitive CYP2C8 substrate. Administration of Rifampin 600 mg/day for 5 days with a single 30 mg dose of pioglitazone decreased the AUC of pioglitazone by 54% in a drug interaction study (n = 10).
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Telmisartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and clarithromycin, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of clarithromycin efficacy.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The concomitant use of dabrafenib and omeprazole may lead to decreased omeprazole concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of omeprazole efficacy. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Omeprazole is a sensitive CYP2C19 substrate. (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and clarithromycin, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of clarithromycin efficacy.
    Aprepitant, Fosaprepitant: (Major) The concomitant use of dabrafenib and aprepitant, fosaprepitant may lead to decreased aprepitant, fosaprepitant concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of aprepitant, fosaprepitant efficacy. Dabrafenib is a CYP3A4 substrate and a moderate CYP3A4 inducer;aprepitant is a sensitive CYP3A4 substrate and a moderate inhibitor of CYP3A4 when administered as a 30 day oral regimen. Single oral and IV doses have not been shown to alter concentrations of CYP3A4 substrates. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for moderate inducers.
    Aspirin, ASA; Omeprazole: (Major) The concomitant use of dabrafenib and omeprazole may lead to decreased omeprazole concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of omeprazole efficacy. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Omeprazole is a sensitive CYP2C19 substrate.
    Atazanavir: (Major) Coadministration of atazanavir with dabrafenib is not recommended as there is a potential for elevated dabrafenib concentrations and decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Atazanavir is metabolized by CYP3A4; dabrafenib is a moderate CYP3A4 inducer. In addition, darbrafenib is a substrate for CYP2C8; atazanavir is a weak CYP2C8 inhibitor.
    Atazanavir; Cobicistat: (Major) Coadministration of atazanavir with dabrafenib is not recommended as there is a potential for elevated dabrafenib concentrations and decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Atazanavir is metabolized by CYP3A4; dabrafenib is a moderate CYP3A4 inducer. In addition, darbrafenib is a substrate for CYP2C8; atazanavir is a weak CYP2C8 inhibitor. (Major) Coadministration of cobicistat with dabrafenib 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. Cobicstat is metabolized by CYP3A4; dabrafenib is a moderate CYP3A4 inducer.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Use dabrafenib and phenobarbital together with caution; concentrations of either agent may be decreased. Use an alternate agent in place of phenobarbital if possible. If concomitant use cannot be avoided, monitor patients for loss of phenobarbital efficacy. Phenobarbital is a strong CYP3A4 inducer and a substrate of CYP2C9 and CYP2C19; dabrafenib is a CYP3A4 substrate and a CYP2C9 and CYP2C19 inducer.
    Avanafil: (Major) Avoid the concomitant use of dabrafenib and avanafil; decreased avanafil concentrations and loss of efficacy may occur. Use of an alternative agent is recommended. Dabrafenib is a moderate CYP3A4 inducer and avanafil is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Axitinib: (Major) Avoid coadministration of axitinib with dabrafenib if possible, 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 substrate and dabrafenib is a moderate CYP3A4 inducer. Dabrafenib decreased the AUC of another CYP3A4 substrate, midazolam, by 74%. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Azilsartan: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer, and azilsartan, a CYP2C9 substrate, may result in decreased levels of azilsartan; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of azilsartan efficacy.
    Azilsartan; Chlorthalidone: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer, and azilsartan, a CYP2C9 substrate, may result in decreased levels of azilsartan; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of azilsartan efficacy.
    Bedaquiline: (Major) Avoid concurrent use of dabrafenib with bedaquiline. Dabrafenib is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Use dabrafenib and phenobarbital together with caution; concentrations of either agent may be decreased. Use an alternate agent in place of phenobarbital if possible. If concomitant use cannot be avoided, monitor patients for loss of phenobarbital efficacy. Phenobarbital is a strong CYP3A4 inducer and a substrate of CYP2C9 and CYP2C19; dabrafenib is a CYP3A4 substrate and a CYP2C9 and CYP2C19 inducer.
    Boceprevir: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and boceprevir, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of boceprevir efficacy.
    Bosutinib: (Major) The concomitant use of dabrafenib and bosutinib may lead to decreased bosutinib concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of bosutinib efficacy. Dabrafenib is a moderate CYP3A4 inducer and bosutinib is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and dabrafenib 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; dabrafenib is a moderate inducer of CYP3A4.
    Budesonide: (Major) The concomitant use of dabrafenib and budesonide may lead to decreased budesonide concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of budesonide efficacy. Dabrafenib is a moderate CYP3A4 inducer and budesonide is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Budesonide; Formoterol: (Major) The concomitant use of dabrafenib and budesonide may lead to decreased budesonide concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of budesonide efficacy. Dabrafenib is a moderate CYP3A4 inducer and budesonide is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and dabrafenib may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; dabrafenib induces CYP3A4.
    Bupropion: (Major) The concomitant use of dabrafenib and bupropion may lead to decreased bupropion concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of bupropion efficacy. In vitro, dabrafenib is an inducer of CYP2B6 via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Bupropion is a sensitive CYP2B6 substrate.
    Bupropion; Naltrexone: (Major) The concomitant use of dabrafenib and bupropion may lead to decreased bupropion concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of bupropion efficacy. In vitro, dabrafenib is an inducer of CYP2B6 via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Bupropion is a sensitive CYP2B6 substrate.
    Buspirone: (Major) The concomitant use of dabrafenib and buspirone may lead to decreased buspirone concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of buspirone efficacy. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to maintain anxiolytic effect. Dabrafenib is a moderate CYP3A4 inducer and buspirone is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Cabozantinib: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and dabrafenib is necessary. Cabozantinib is primarily metabolized by CYP3A4 and dabrafenib is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Calcium Carbonate: (Moderate) Space the administration of antacids from dabrafenib by at least 2 hours. Antacids elevate the gastric pH and may alter the solubility of dabrafenib. Therefore, the concomitant use of dabrafenib and antacids may reduce the systemic exposure and bioavailability of dabrafenib. No formal trials have been performed to evaluate this interaction and it is not known how this interaction affects the efficacy of dabrafenib.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Space the administration of antacids from dabrafenib by at least 2 hours. Antacids elevate the gastric pH and may alter the solubility of dabrafenib. Therefore, the concomitant use of dabrafenib and antacids may reduce the systemic exposure and bioavailability of dabrafenib. No formal trials have been performed to evaluate this interaction and it is not known how this interaction affects the efficacy of dabrafenib.
    Calcium Carbonate; Risedronate: (Moderate) Space the administration of antacids from dabrafenib by at least 2 hours. Antacids elevate the gastric pH and may alter the solubility of dabrafenib. Therefore, the concomitant use of dabrafenib and antacids may reduce the systemic exposure and bioavailability of dabrafenib. No formal trials have been performed to evaluate this interaction and it is not known how this interaction affects the efficacy of dabrafenib.
    Calcium; Vitamin D: (Moderate) Space the administration of antacids from dabrafenib by at least 2 hours. Antacids elevate the gastric pH and may alter the solubility of dabrafenib. Therefore, the concomitant use of dabrafenib and antacids may reduce the systemic exposure and bioavailability of dabrafenib. No formal trials have been performed to evaluate this interaction and it is not known how this interaction affects the efficacy of dabrafenib.
    Carbamazepine: (Major) Use dabrafenib and carbamazepine together with caution; concentrations of either agent may be decreased resulting in loss of efficacy. Use of an alternate agent in place of carbamazepine is recommended. If concomitant use cannot be avoided, monitor patients for loss of carbamazepine efficacy. Carbamazepine is a CYP3A4 substrate and a strong CYP3A4 inducer; dabrafenib is a CYP3A4 substrate and a moderate CYP3A4 inducer. The AUC values of dabrafenib and its metabolite desmethyl-dabrafenib were decreased by 34% and 30%, respectively, when dabrafenib was coadministered with another strong CYP3A4 inducer for 10 days in a drug interaction study.
    Celecoxib: (Major) The concomitant use of dabrafenib and celecoxib may lead to decreased celecoxib concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of celecoxib efficacy; a celecoxib dose adjustment may be necessary. Dabrafenib is a weak CYP2C9 inducer and celecoxib is a sensitive CYP2C9 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP2C9 substrate decreased the AUC value of the sensitive CYP2C9 substrate by 37%.
    Ceritinib: (Major) Avoid coadministration of ceritinib with dabrafenib due to increased dabrafenib exposure. If coadministration is unavoidable, monitor for dabrafenib-related adverse reactions. Ceritinib is a CYP3A4 inhibitor and dabrafenib is metabolized by CYP3A4.
    Clarithromycin: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and clarithromycin, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of clarithromycin efficacy.
    Clindamycin: (Moderate) Concomitant use of clindamycin and dabrafenib may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; dabrafenib is a moderate inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clopidogrel: (Major) Avoid the concomitant use of dabrafenib and clopidogrel; dabrafenib concentrations may increase resulting in increased toxicity. Use of an alternate agent is recommended. If concomitant use is necessary, monitor patients for dabrafenib toxicity (e.g., skin toxicity, ocular toxicity, and cardiotoxicity). The clopidogrel manufacturer states that a dose adjustment of the CYP2C8 substrate may be necessary. Dabrafenib is a CYP2C8 substrate; the glucuronide metabolite of clopidogrel is a strong CYP2C8 inhibitor. The dabrafenib AUC value increased by 47% when dabrafenib was administered with another strong CYP2C8 inhibitor in a drug interaction study.
    Cobicistat: (Major) Coadministration of cobicistat with dabrafenib 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. Cobicstat is metabolized by CYP3A4; dabrafenib is a moderate CYP3A4 inducer.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with dabrafenib 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. Cobicstat is metabolized by CYP3A4; dabrafenib is a moderate CYP3A4 inducer. (Major) Coadministration of elvitegravir with dabrafenib 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; dabrafenib is a moderate CYP3A4 inducer.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with dabrafenib 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. Cobicstat is metabolized by CYP3A4; dabrafenib is a moderate CYP3A4 inducer. (Major) Coadministration of elvitegravir with dabrafenib 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; dabrafenib is a moderate CYP3A4 inducer.
    Cobimetinib: (Major) Avoid the concomitant use of dabrafenib and cobimetinib; decreased cobimetinib concentrations and loss of efficacy may occur. Use of an alternative agent is recommended. Dabrafenib is a moderate CYP3A4 inducer and cobimetinib is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Conivaptan: (Major) Avoid the concomitant use of dabrafenib and conivaptan; altered levels of either drug may occur. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients closely for dabrafenib adverse reactions (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of conivaptan efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; conivaptan is a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as dabrafenib. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Dapsone: (Moderate) The metabolism of dapsone may be accelerated when administered concurrently with dabrafenib, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Darifenacin: (Major) The concomitant use of dabrafenib and darifenacin may lead to decreased darifenacin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of darifenacin efficacy. Dabrafenib is a moderate CYP3A4 inducer and darifenacin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Darunavir: (Major) The concomitant use of dabrafenib and darunavir may lead to altered concentrations of either drug. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of darunavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; darunavir is a sensitive CYP3A4 substrate and a moderate CYP3A4 inhibitor.
    Darunavir; Cobicistat: (Major) Coadministration of cobicistat with dabrafenib 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. Cobicstat is metabolized by CYP3A4; dabrafenib is a moderate CYP3A4 inducer. (Major) The concomitant use of dabrafenib and darunavir may lead to altered concentrations of either drug. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of darunavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; darunavir is a sensitive CYP3A4 substrate and a moderate CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of dabrafenib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated dabrafenib plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Dabrafenib's product labeling recommends avoidance of coadministration with strong CYP3A4 inhibitors if possible. Dabrafenib is a CYP3A4 substrate, and ritonavir is a potent inhibitor of this enzyme. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Dabrafenib is a CYP3A4 inducer, which could increase the metabolism of the antivirals. If these drugs must be administered together, caution and close monitoring are advised. (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and ritonavir, a strong CYP3A4 inhibitor and a CYP3A4 substrate and inducer, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib or ritonavir adverse effects and/or reduced efficacy.
    Dasatinib: (Major) The concomitant use of dabrafenib and dasatinib may lead to decreased dasatinib concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of dasatinib efficacy. Dabrafenib is a moderate CYP3A4 inducer and dasatinib is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and dabrafenib. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; dabrafenib is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Delavirdine: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and delavirdine, a strong CYP3A4 inhibitor and a CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of delavirdine efficacy.
    Dexamethasone: (Major) Use dabrafenib and dexamethasone together with caution; concentrations of either agent may be decreased. Use an alternate agent in place of dexamethasone if possible. If concomitant use cannot be avoided, monitor patients for loss of dexamethasone efficacy. Dexamethasone and dabrafenib are both CYP3A4 substrates and moderate CYP3A4 inducers.
    Diclofenac: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer, and diclofenac, a CYP2C9 substrate, may result in decreased levels of diclofenac; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of diclofenac efficacy. In addition, an increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Patients should be monitored closely for bleeding.
    Diclofenac; Misoprostol: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer, and diclofenac, a CYP2C9 substrate, may result in decreased levels of diclofenac; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of diclofenac efficacy. In addition, an increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Patients should be monitored closely for bleeding.
    Diphenhydramine; Naproxen: (Moderate) Use dabrafenib and naproxen together with caution; naproxen exposure may be decreased. Use an alternate agent in place of naproxen if possible. If concomitant use with cannot be avoided, monitor patients for loss of naproxen efficacy. Dabrafenib is a weak CYP29 inducer and naproxen is a CYP2C9 substrate. When a single-dose of a sensitive CYP2C9 substrate was administered after 15 days of dabrafenib 150 mg twice daily, the AUC value of the CYP2C9 substrate was decreased by 37%.
    Doxorubicin: (Major) Dabrafenib is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of dabrafenib and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with dabrafenib is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; dabrafenib is a moderate inducer of CYP3A4 and a weak CYP2C9 inducer. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) The concomitant use of dabrafenib and dronedarone may lead to decreased dronedarone concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of dronedarone efficacy. Dabrafenib is a moderate CYP3A4 inducer and dronedarone is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Elbasvir; Grazoprevir: (Major) If possible, avoid concurrent administration of elbasvir with dabrafenib. Dabrafenib is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with dabrafenib. Dabrafenib is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of dabrafenib (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
    Eletriptan: (Major) The concomitant use of dabrafenib and eletriptan may lead to decreased eletriptan concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of eletriptan efficacy. Dabrafenib is a moderate CYP3A4 inducer and eletriptan is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Elvitegravir: (Major) Coadministration of elvitegravir with dabrafenib 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; dabrafenib is a moderate CYP3A4 inducer.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) The concomitant use of dabrafenib and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Dabrafenib is a moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) The concomitant use of dabrafenib and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Dabrafenib is a moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
    Enalapril; Felodipine: (Major) The concomitant use of dabrafenib and felodipine may lead to decreased felodipine concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of felodipine efficacy. Dabrafenib is a moderate CYP3A4 inducer and felodipine is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Eplerenone: (Major) The concomitant use of dabrafenib and eplerenone may lead to decreased eplerenone concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of eplerenone efficacy. Dabrafenib is a moderate CYP3A4 inducer and eplerenone is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with dabrafenib if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Dabrafenib is a CYP3A4 inducer. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Dabrafenib decreased the AUC of another CYP3A4 substrate, midazolam, by 74%. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with dabrafenib may also decrease erlotinib exposure.
    Esomeprazole; Naproxen: (Moderate) Use dabrafenib and naproxen together with caution; naproxen exposure may be decreased. Use an alternate agent in place of naproxen if possible. If concomitant use with cannot be avoided, monitor patients for loss of naproxen efficacy. Dabrafenib is a weak CYP29 inducer and naproxen is a CYP2C9 substrate. When a single-dose of a sensitive CYP2C9 substrate was administered after 15 days of dabrafenib 150 mg twice daily, the AUC value of the CYP2C9 substrate was decreased by 37%.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide if used concomitantly with dabrafenib. Dabrafenib is an inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
    Exemestane: (Moderate) Use caution if coadministration of exemestane with dabrafenib is necessary, and monitor for a possible decrease in the efficacy of exemestane. Exemestane is a CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer. In a pharmacokinetic interaction study (n = 10) with a strong CYP3A4 inducer, rifampicin (600 mg daily for 14 days), the mean Cmax and AUC of exemestane (single dose) decreased by 41% and 54%, respectively. The manufacturer of exemestane recommends a dose increase when concomitant use with a strong CYP3A4 inducer is necessary; recommendations are not available for moderate CYP3A4 inducers.
    Ezetimibe; Simvastatin: (Major) The concomitant use of dabrafenib and simvastatin may lead to decreased simvastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of simvastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and simvastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Felodipine: (Major) The concomitant use of dabrafenib and felodipine may lead to decreased felodipine concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of felodipine efficacy. Dabrafenib is a moderate CYP3A4 inducer and felodipine is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Fosamprenavir: (Severe) The concomitant use of dabrafenib, a CYP3A4 substrate, a moderate CYP3A4 inducer, and CYP2C9 inducer, and fosamprenavir, a strong CYP3A4 inhibitor and a CYP2C9 substrate, may result in altered levels of either agent; avoid concomitant use. Administering fosamprenavir with agents that are highly dependent on CYP3A4 for metabolism and that high plasma levels might cause serious or life-threatening adverse events is contraindicated.
    Fosphenytoin: (Major) Use dabrafenib and fosphenytoin together with caution; concentrations of either agent may be decreased. Use an alternate agent in place of fosphenytoin if possible. If concomitant use cannot be avoided, monitor patients for loss of fosphenytoin efficacy. Fosphenytoin is a strong CYP3A4 inducer and a substrate of CYP2C9 and CYP2C19; dabrafenib is a CYP3A4 substrate and a CYP2C9 and CYP2C19 inducer.
    Gefitinib: (Major) Monitor for clinical response of gefitinib if used concomitantly with dabrafenib. Gefitinib is metabolized significantly by CYP3A4 and dabrafenib is a CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Gemfibrozil: (Major) Avoid the concomitant use of dabrafenib and gemfibrozil; dabrafenib exposure increased by 47% when these drugs were administered together in a drug interaction study. Use of an alternate agent in place of gemfibrozil is recommended. If concomitant use cannot be avoided, monitor patients for dabrafenib toxicity (e.g., skin toxicity, ocular toxicity, and cardiotoxicity). Dabrafenib is a CYP2C8 substrate; gemfibrozil is a strong CYP2C8 inhibitor. The dabrafenib AUC value increased by 47% when dabrafenib 75 mg PO twice daily was administered with gemfibrozil 600 mg twice daily for 4 days in a drug interaction study; there were no change in the AUC values of the metabolites, hydroxy-dabrafenib and desmethyl-dabrafenib.
    Glimepiride: (Major) The concomitant use of dabrafenib and glimepiride may lead to decreased glimepiride concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of glimepiride efficacy. Dabrafenib is a weak CYP2C9 inducer and glimepiride is a moderately sensitive CYP2C9 substrate.
    Glimepiride; Pioglitazone: (Major) The concomitant use of dabrafenib and glimepiride may lead to decreased glimepiride concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of glimepiride efficacy. Dabrafenib is a weak CYP2C9 inducer and glimepiride is a moderately sensitive CYP2C9 substrate. (Major) The concomitant use of dabrafenib and pioglitazone may lead to decreased pioglitazone exposure and loss of efficacy. Use of an alternative agent is recommended. If concomitant use is unavoidable, monitor patients for loss of pioglitazone efficacy. A change in diabetes treatment may be needed based upon clinical response if dabrafenib is started or stopped during treatment with pioglitazone; do not exceed the maximum recommended dose of 45 mg/day. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Pioglitazone is a moderately sensitive CYP2C8 substrate. Administration of Rifampin 600 mg/day for 5 days with a single 30 mg dose of pioglitazone decreased the AUC of pioglitazone by 54% in a drug interaction study (n = 10).
    Glimepiride; Rosiglitazone: (Major) The concomitant use of dabrafenib and glimepiride may lead to decreased glimepiride concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of glimepiride efficacy. Dabrafenib is a weak CYP2C9 inducer and glimepiride is a moderately sensitive CYP2C9 substrate. (Major) The concomitant use of dabrafenib and rosiglitazone may lead to decreased rosiglitazone exposure and loss of efficacy. Use of an alternative agent is recommended. If concomitant use is unavoidable, monitor patients for loss of rosiglitazone efficacy. A change in diabetes treatment may be needed based upon clinical response if dabrafenib is started or stopped during treatment with rosiglitazone. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Rosiglitazone is a moderately sensitive CYP2C8 substrate. Administration of rifampin 600 mg/day for 6 days with a single 8 mg dose of rosiglitazone decreased the AUC of rosiglitazone by 66% in a drug interaction study.
    Grapefruit juice: (Major) Avoid the concomitant use of dabrafenib, a CYP3A4 substrate, and grapefruit juice, a CYP3A4 inhibitor, as dabrafenib levels may increase.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer and losartan, a CYP2C9 substrate, may result in decreased levels of losartan; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of losartan efficacy.
    Ibrutinib: (Major) The concomitant use of dabrafenib and ibrutinib may lead to decreased ibrutinib concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of ibrutinib efficacy. Dabrafenib is a moderate CYP3A4 inducer and ibrutinib is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%. Additionally, simulations using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inducers may decrease ibrutinib exposure up to 3-fold.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with dabrafenib, a CYP3A substrate, as dabrafenib toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Indinavir: (Major) Avoid the concomitant use of dabrafenib and indinavir; altered levels of either drug may occur. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients closely for dabrafenib adverse reactions (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of indinavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; indinavir is a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate.
    Irinotecan: (Major) Dabrafenib is a moderate CYP3A4 inducer; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Isavuconazonium: (Major) The concomitant use of dabrafenib and isavuconazonium may lead to decreased isavuconazonium concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of isavuconazonium efficacy. Dabrafenib is a CYP3A4 substrate and a moderate CYP3A4 inducer; isavuconazonium is a sensitive CYP3A4 substrate and a moderate inhibitor of CYP3A4. The use of isavuconazonium is contraindicated with strong CYP3A4 inducers; however, the manufacturer does not provide guidance for moderate inducers. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Isoniazid, INH: (Major) Avoid the concomitant use of dabrafenib, a CYP3A4 substrate, and isoniazid, INH a strong CYP3A4 inhibitor, as dabrafenib levels may increase. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of dabrafenib, a CYP3A4 substrate, and isoniazid, INH a strong CYP3A4 inhibitor, as dabrafenib levels may increase. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of dabrafenib, a CYP3A4 substrate, and isoniazid, INH a strong CYP3A4 inhibitor, as dabrafenib levels may increase. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity.
    Itraconazole: (Major) Avoid dabrafenib use during and for 2 weeks after discontinuation of itraconazole treatment. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of itraconazole efficacy. The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and itraconazole, a strong CYP3A4 inhibitor and a CYP3A4 substrate, may result in altered levels of either agent.
    Ivabradine: (Major) Avoid coadministration of ivabradine and dabrafenib. Ivabradine is primarily metabolized by CYP3A4; dabrafenib is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ivacaftor: (Major) The concomitant use of dabrafenib and ivacaftor may lead to decreased ivacaftor concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of ivacaftor efficacy. Dabrafenib is a moderate CYP3A4 inducer and ivacaftor is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Ketoconazole: (Major) Avoid the concomitant use of dabrafenib and ketoconazole; dabrafenib exposure increased by 71% when these drugs were administered together in a drug interaction study. Additionally, the concentrations of ketoconazole may be decreased resulting in loss of efficacy. Use of an alternate agent in place of ketoconazole is recommended. If concomitant use cannot be avoided, monitor patients for dabrafenib toxicity (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of ketoconazole efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; ketoconazole is a strong CYP3A4 inhibitor and a CYP3A4 substrate. The AUC values of dabrafenib and its active metabolites, hydroxy-dabrafenib and desmethyl-dabrafenib, were increased by 71%, 82%, and 68%, respectively, when dabrafenib 75 mg PO twice daily was administered with ketoconazole 400 mg PO once daily for 4 days in a drug interaction study.
    Lansoprazole; Naproxen: (Moderate) Use dabrafenib and naproxen together with caution; naproxen exposure may be decreased. Use an alternate agent in place of naproxen if possible. If concomitant use with cannot be avoided, monitor patients for loss of naproxen efficacy. Dabrafenib is a weak CYP29 inducer and naproxen is a CYP2C9 substrate. When a single-dose of a sensitive CYP2C9 substrate was administered after 15 days of dabrafenib 150 mg twice daily, the AUC value of the CYP2C9 substrate was decreased by 37%.
    Lesinurad: (Moderate) Dabrafenib may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Dabrafenib is a mild CYP2C9 inducer, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Dabrafenib may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Dabrafenib is a mild CYP2C9 inducer, and lesinurad is a CYP2C9 substrate.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and dabrafenib may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; dabrafenib induces CYP3A4.
    Lomitapide: (Major) The concomitant use of dabrafenib and lomitapide may lead to decreased lomitapide concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of lomitapide efficacy. Dabrafenib is a moderate CYP3A4 inducer and lomitapide is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with dabrafenib. Loperamide is metabolized by the hepatic enzyme CYP3A4; dabrafenib is an inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with dabrafenib. Loperamide is metabolized by the hepatic enzyme CYP3A4; dabrafenib is an inducer of this enzyme.
    Lopinavir; Ritonavir: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and lopinavir; ritonavir may result in altered levels of either agent; avoid concomitant use if possible. Ritonavir is a strong CYP3A4 inhibitor and a CYP3A4 substrate and inducer, while lopinavir is a CYP3A4 substrate. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib or ritonavir adverse effects and/or reduced efficacy. (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and ritonavir, a strong CYP3A4 inhibitor and a CYP3A4 substrate and inducer, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib or ritonavir adverse effects and/or reduced efficacy.
    Losartan: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer and losartan, a CYP2C9 substrate, may result in decreased levels of losartan; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of losartan efficacy.
    Lovastatin: (Major) The concomitant use of dabrafenib and lovastatin may lead to decreased lovastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of lovastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and lovastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Lovastatin; Niacin: (Major) The concomitant use of dabrafenib and lovastatin may lead to decreased lovastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of lovastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and lovastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant administration of dabrafenib and lumacaftor; ivacaftor. If concomitant use is unavoidable, monitor patients closely for loss of dabrafenib efficacy. Dabrafenib is primarily metabolized by CYP3A4 and CYP2C8. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce and/or inhibit CYP2C8.
    Lumacaftor; Ivacaftor: (Major) The concomitant use of dabrafenib and ivacaftor may lead to decreased ivacaftor concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of ivacaftor efficacy. Dabrafenib is a moderate CYP3A4 inducer and ivacaftor is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Lurasidone: (Major) The concomitant use of dabrafenib and lurasidone may lead to decreased lurasidone concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of lurasidone efficacy.It may be necessary to increase the lurasidone dose after chronic treatment (7 days or more) with dabrafenib. Dabrafenib is a moderate CYP3A4 inducer and lurasidone is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Maraviroc: (Major) The concomitant use of dabrafenib and maraviroc may lead to decreased maraviroc concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of maraviroc efficacy. Dabrafenib is a moderate CYP3A4 inducer and maraviroc is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Meloxicam: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer, and meloxicam, a CYP2C9 substrate, may result in decreased levels of meloxicam; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of meloxicam efficacy. In addition, an increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Patients should be monitored closely for bleeding.
    Metformin; Pioglitazone: (Major) The concomitant use of dabrafenib and pioglitazone may lead to decreased pioglitazone exposure and loss of efficacy. Use of an alternative agent is recommended. If concomitant use is unavoidable, monitor patients for loss of pioglitazone efficacy. A change in diabetes treatment may be needed based upon clinical response if dabrafenib is started or stopped during treatment with pioglitazone; do not exceed the maximum recommended dose of 45 mg/day. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Pioglitazone is a moderately sensitive CYP2C8 substrate. Administration of Rifampin 600 mg/day for 5 days with a single 30 mg dose of pioglitazone decreased the AUC of pioglitazone by 54% in a drug interaction study (n = 10).
    Metformin; Repaglinide: (Major) The concomitant use of dabrafenib and repaglinide may lead to decreased repaglinide concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of repaglinide efficacy. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Repaglinide is a sensitive CYP2C8 substrate.
    Metformin; Rosiglitazone: (Major) The concomitant use of dabrafenib and rosiglitazone may lead to decreased rosiglitazone exposure and loss of efficacy. Use of an alternative agent is recommended. If concomitant use is unavoidable, monitor patients for loss of rosiglitazone efficacy. A change in diabetes treatment may be needed based upon clinical response if dabrafenib is started or stopped during treatment with rosiglitazone. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Rosiglitazone is a moderately sensitive CYP2C8 substrate. Administration of rifampin 600 mg/day for 6 days with a single 8 mg dose of rosiglitazone decreased the AUC of rosiglitazone by 66% in a drug interaction study.
    Midazolam: (Major) The concomitant use of dabrafenib and midazolam led to significantly decreased midazolam concentrations in a drug interaction study. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of midazolam efficacy. Dabrafenib is a moderate CYP3A4 inducer and midazolam is a sensitive CYP3A4 substrate. Administration of dabrafenib 150 mg twice daily for 15 days with a single 3 mg dose of midazolam decreased the AUC of midazolam by 74% in a drug interaction study.
    Naloxegol: (Major) The concomitant use of dabrafenib and naloxegol may lead to decreased naloxegol concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of naloxegol efficacy. Dabrafenib is a moderate CYP3A4 inducer and naloxegol is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Naproxen: (Moderate) Use dabrafenib and naproxen together with caution; naproxen exposure may be decreased. Use an alternate agent in place of naproxen if possible. If concomitant use with cannot be avoided, monitor patients for loss of naproxen efficacy. Dabrafenib is a weak CYP29 inducer and naproxen is a CYP2C9 substrate. When a single-dose of a sensitive CYP2C9 substrate was administered after 15 days of dabrafenib 150 mg twice daily, the AUC value of the CYP2C9 substrate was decreased by 37%.
    Naproxen; Pseudoephedrine: (Moderate) Use dabrafenib and naproxen together with caution; naproxen exposure may be decreased. Use an alternate agent in place of naproxen if possible. If concomitant use with cannot be avoided, monitor patients for loss of naproxen efficacy. Dabrafenib is a weak CYP29 inducer and naproxen is a CYP2C9 substrate. When a single-dose of a sensitive CYP2C9 substrate was administered after 15 days of dabrafenib 150 mg twice daily, the AUC value of the CYP2C9 substrate was decreased by 37%.
    Naproxen; Sumatriptan: (Moderate) Use dabrafenib and naproxen together with caution; naproxen exposure may be decreased. Use an alternate agent in place of naproxen if possible. If concomitant use with cannot be avoided, monitor patients for loss of naproxen efficacy. Dabrafenib is a weak CYP29 inducer and naproxen is a CYP2C9 substrate. When a single-dose of a sensitive CYP2C9 substrate was administered after 15 days of dabrafenib 150 mg twice daily, the AUC value of the CYP2C9 substrate was decreased by 37%.
    Nateglinide: (Moderate) The concomitant use of dabrafenib, a CYP2C9 inducer, and nateglinide, a CYP2C9 substrate, may result in decreased levels of nateglinide; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of nateglinide efficacy.
    Nefazodone: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and nefazodone, a strong CYP3A4 inhibitor and a CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of nefazodone efficacy.
    Neratinib: (Major) Avoid concomitant use of dabrafenib with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. The effect of moderate CYP3A4 induction on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inducer decreased neratinib exposure by 87% and decreased exposure to active metabolites M6 and M7 by 37% to 49%. Because of the significant impact on neratinib exposure from strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers should be considered as they may also significantly decrease neratinib exposure.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and the plasma concentrations of medications that are primarily metabolized through CYP3A4, such as dabrafenib, can increase with coadministration. The inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer should be avoided since a strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. Dabrafenib is a CYP3A4 inducer. If coadministration is necessary, no dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
    Niacin; Simvastatin: (Major) The concomitant use of dabrafenib and simvastatin may lead to decreased simvastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of simvastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and simvastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Nintedanib: (Major) Dabrafenib is a CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as dabrafenib should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Nisoldipine: (Major) Avoid the concomitant use of dabrafenib and nisoldipine; decreased nisoldipine concentrations and loss of efficacy may occur. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of nisoldipine efficacy. Dabrafenib is a moderate CYP3A4 inducer and nisoldipine is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Non-oral combination contraceptives: (Major) Avoid concomitant use of dabrafenib and hormonal contraceptives; decreased hormonal contraceptive concentrations and loss of efficacy may occur. Use of an alternative non-hormonal contraceptive method of birth control is recommended during treatment for 2 weeks after the last dose of dabrafenib. Dabrafenib is a moderate CYP3A4 inducer and many hormonal contraceptive are CYP3A4 substrates.
    Olaparib: (Major) Avoid the coadministration of olaparib with dabrafenib due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of dabrafenib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated dabrafenib plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Dabrafenib's product labeling recommends avoidance of coadministration with strong CYP3A4 inhibitors if possible. Dabrafenib is a CYP3A4 substrate, and ritonavir is a potent inhibitor of this enzyme. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Dabrafenib is a CYP3A4 inducer, which could increase the metabolism of the antivirals. If these drugs must be administered together, caution and close monitoring are advised. (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and ritonavir, a strong CYP3A4 inhibitor and a CYP3A4 substrate and inducer, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib or ritonavir adverse effects and/or reduced efficacy.
    Omeprazole: (Major) The concomitant use of dabrafenib and omeprazole may lead to decreased omeprazole concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of omeprazole efficacy. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Omeprazole is a sensitive CYP2C19 substrate.
    Omeprazole; Sodium Bicarbonate: (Major) The concomitant use of dabrafenib and omeprazole may lead to decreased omeprazole concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of omeprazole efficacy. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Omeprazole is a sensitive CYP2C19 substrate. (Moderate) Space the administration of antacids from dabrafenib by at least 2 hours. Antacids elevate the gastric pH and may alter the solubility of dabrafenib. Therefore, the concomitant use of dabrafenib and antacids may reduce the systemic exposure and bioavailability of dabrafenib. No formal trials have been performed to evaluate this interaction and it is not known how this interaction affects the efficacy of dabrafenib.
    Oral Contraceptives: (Major) Avoid concomitant use of dabrafenib and hormonal contraceptives; decreased hormonal contraceptive concentrations and loss of efficacy may occur. Use of an alternative non-hormonal contraceptive method of birth control is recommended during treatment for 2 weeks after the last dose of dabrafenib. Dabrafenib is a moderate CYP3A4 inducer and many hormonal contraceptive are CYP3A4 substrates.
    Ospemifene: (Moderate) The concomitant use of dabrafenib, a CYP2C9 inducer, and ospemifene, a CYP2C9 substrate, may result in decreased levels of ospemiphene, which may decrease the clinical effect. Monitor patients for reduced ospemiphene efficacy.
    Palbociclib: (Major) Use caution and monitor patients for decreased palbociclib efficacy if dabrafenib is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and dabrafenib is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Perampanel: (Major) Consider alternative therapy or start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with dabrafenib due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of dabrafenib occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Dabrafenib is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Phenobarbital: (Major) Use dabrafenib and phenobarbital together with caution; concentrations of either agent may be decreased. Use an alternate agent in place of phenobarbital if possible. If concomitant use cannot be avoided, monitor patients for loss of phenobarbital efficacy. Phenobarbital is a strong CYP3A4 inducer and a substrate of CYP2C9 and CYP2C19; dabrafenib is a CYP3A4 substrate and a CYP2C9 and CYP2C19 inducer.
    Phenytoin: (Major) Use dabrafenib and phenytoin together with caution; concentrations of either agent may be decreased. Use an alternate agent in place of phenytoin if possible. If concomitant use cannot be avoided, monitor patients for loss of phenytoin efficacy. Phenytoin is a strong CYP3A4 inducer and a substrate of CYP2C9 and CYP2C19; dabrafenib is a CYP3A4 substrate and a CYP2C9 and CYP2C19 inducer.
    Pioglitazone: (Major) The concomitant use of dabrafenib and pioglitazone may lead to decreased pioglitazone exposure and loss of efficacy. Use of an alternative agent is recommended. If concomitant use is unavoidable, monitor patients for loss of pioglitazone efficacy. A change in diabetes treatment may be needed based upon clinical response if dabrafenib is started or stopped during treatment with pioglitazone; do not exceed the maximum recommended dose of 45 mg/day. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Pioglitazone is a moderately sensitive CYP2C8 substrate. Administration of Rifampin 600 mg/day for 5 days with a single 30 mg dose of pioglitazone decreased the AUC of pioglitazone by 54% in a drug interaction study (n = 10).
    Posaconazole: (Major) Avoid the concomitant use of dabrafenib, a CYP3A4 substrate, and posaconazole, a strong CYP3A4 inhibitor, as dabrafenib levels may increase. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with dabrafenib, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Quetiapine: (Major) The concomitant use of dabrafenib and quetiapine may lead to decreased quetiapine concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of quetiapine efficacy. Dabrafenib is a moderate CYP3A4 inducer and quetiapine is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Repaglinide: (Major) The concomitant use of dabrafenib and repaglinide may lead to decreased repaglinide concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of repaglinide efficacy. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Repaglinide is a sensitive CYP2C8 substrate.
    Ribociclib: (Major) Coadministration of ribociclib and dabrafenib may decrease exposure to ribociclib. If another agent cannot be substituted and coadministration of these agents is unavoidable, closely monitor for a decreased response to ribociclib. The systemic exposure of dabrafenib may also increase resulting in an increase of treatment-related adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; dabrafenib is a CYP3A4 inducer and a substrate of CYP3A4 and CYP2C8, while metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates.
    Ribociclib; Letrozole: (Major) Coadministration of ribociclib and dabrafenib may decrease exposure to ribociclib. If another agent cannot be substituted and coadministration of these agents is unavoidable, closely monitor for a decreased response to ribociclib. The systemic exposure of dabrafenib may also increase resulting in an increase of treatment-related adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; dabrafenib is a CYP3A4 inducer and a substrate of CYP3A4 and CYP2C8, while metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates.
    Rilpivirine: (Major) The concomitant use of dabrafenib and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Dabrafenib is a moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
    Ritonavir: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and ritonavir, a strong CYP3A4 inhibitor and a CYP3A4 substrate and inducer, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib or ritonavir adverse effects and/or reduced efficacy.
    Rosiglitazone: (Major) The concomitant use of dabrafenib and rosiglitazone may lead to decreased rosiglitazone exposure and loss of efficacy. Use of an alternative agent is recommended. If concomitant use is unavoidable, monitor patients for loss of rosiglitazone efficacy. A change in diabetes treatment may be needed based upon clinical response if dabrafenib is started or stopped during treatment with rosiglitazone. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Rosiglitazone is a moderately sensitive CYP2C8 substrate. Administration of rifampin 600 mg/day for 6 days with a single 8 mg dose of rosiglitazone decreased the AUC of rosiglitazone by 66% in a drug interaction study.
    Saquinavir: (Major) Avoid the concomitant use of dabrafenib and saquinavir; altered levels of either drug may occur. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients closely for dabrafenib adverse reactions (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of saquinavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; saquinavir is a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate.
    Sildenafil: (Major) The concomitant use of dabrafenib and sildenafil may lead to decreased sildenafil concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of sildenafil efficacy. Dabrafenib is a moderate CYP3A4 inducer and sildenafil is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Simvastatin: (Major) The concomitant use of dabrafenib and simvastatin may lead to decreased simvastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of simvastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and simvastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Simvastatin; Sitagliptin: (Major) The concomitant use of dabrafenib and simvastatin may lead to decreased simvastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of simvastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and simvastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Sirolimus: (Major) The concomitant use of dabrafenib and sirolimus may lead to decreased sirolimus concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor sirolimus levels and for loss of sirolimus efficacy; adjust the sirolimus dose as necessary. Dabrafenib is a moderate CYP3A4 inducer and sirolimus is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Sodium Bicarbonate: (Moderate) Space the administration of antacids from dabrafenib by at least 2 hours. Antacids elevate the gastric pH and may alter the solubility of dabrafenib. Therefore, the concomitant use of dabrafenib and antacids may reduce the systemic exposure and bioavailability of dabrafenib. No formal trials have been performed to evaluate this interaction and it is not known how this interaction affects the efficacy of dabrafenib.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with dabrafenib. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; dabrafenib is an inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with dabrafenib. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; dabrafenib is an inducer of CYP3A4. (Major) Avoid coadministration of voxilaprevir (a CYP3A4 substrate) with moderate to strong inducers of CYP3A4, such as dabrafenib. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and dabrafenib; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer in vitro. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
    Streptogramins: (Major) Avoid the concomitant use of dabrafenib, a CYP3A4 substrate, and dalfopristin; quinupristin, a strong CYP3A4 inhibitor, as dabrafenib levels may increase. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity.
    Tacrolimus: (Major) The concomitant use of dabrafenib and tacrolimus may lead to decreased tacrolimus concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor tacrolimus levels and for loss of tacrolimus efficacy. Dabrafenib is a moderate CYP3A4 inducer and tacrolimus is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Tamoxifen: (Major) Dabrafenib is a CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Dabrafenib may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known. If coadministration is necessary, monitor for tamoxifen efficacy.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and dabrafenib. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as dabrafenib, may reduce the efficacy of tasimelteon.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and dabrafenib is necessary, as the systemic exposure of dabrafenib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of dabrafenib. Dabrafenib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with dabrafenib is necessary, due to the risk of decreased efficacy of temsirolimus. Temsirolimus is a CYP3A4 substrate and dabrafenib is a moderate inducer of CYP3A4. The manufacturer of temsirolimus recommends a dose increase if coadministered with a strong CYP3A4 inducer, but recommendations are not available for concomitant use of moderate CYP3A4 inducers. Coadministration of temsirolimus with rifampin, a strong CYP3A4/5 inducer, had no significant effect on the AUC or Cmax of temsirolimus, but decreased the sirolimus AUC and Cmax by 56% and 65%, respectively.
    Ticagrelor: (Major) The concomitant use of dabrafenib and ticagrelor may lead to decreased ticagrelor concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of ticagrelor efficacy. Dabrafenib is a moderate CYP3A4 inducer and ticagrelor is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Tipranavir: (Major) Avoid the concomitant use of dabrafenib and tipranavir; altered levels of either drug may occur. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients closely for dabrafenib adverse reactions (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of tipranavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; tipranavir is a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate.
    Tolvaptan: (Major) The concomitant use of dabrafenib and tolvaptan may lead to decreased tolvaptan concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of tolvaptan efficacy. Dabrafenib is a moderate CYP3A4 inducer and tolvaptan is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and dabrafenib is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a 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. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducer.
    Triazolam: (Major) The concomitant use of dabrafenib and triazolam may lead to decreased triazolam concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of triazolam efficacy. Dabrafenib is a moderate CYP3A4 inducer and triazolam is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Vandetanib: (Major) Avoid the concomitant use of vandetanib with known strong CYP3A4 inducers such as dabrafenib, as there is an unpredictable effect on vandetanib efficacy and toxicity. Dabrafenib is an inducer of CYP3A4. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively. Coadministration of dabrafenib 150 mg twice daily for 15 days and a single dose of midazolam 3 mg (a CYP3A4 substrate) decreased midazolam AUC by 74%.
    Vardenafil: (Major) The concomitant use of dabrafenib and vardenafil may lead to decreased vardenafil concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of vardenafil efficacy. Dabrafenib is a moderate CYP3A4 inducer and vardenafil is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and dabrafenib; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including dabrafenib. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including dabrafenib. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vinorelbine: (Moderate) Caution is warranted when dabrafenib is administered with vinorelbine, as there is a potential for the metabolism of vinorelbine to be affected, decreasing drug efficacy. Monitor patients receiving these drugs concurrently for clinical effects. Vinorelbine is a substrate for cytochrome P450 (CYP) 3A4, and dabrafenib is a CYP3A4 inducer.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and dabrafenib. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with dabrafenib, a CYP3A inducer.
    Voriconazole: (Major) The concomitant use of dabrafenib and voriconazole may result in altered levels of either agent. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for dabrafenib toxicity (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and loss of voriconazole efficacy. Dabrafenib is a CYP3A4 substrate, a moderate CYP3A4 inducer, and an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Voriconazole is a strong CYP3A4 inhibitor and a substrate of CYP3A4, CYP2C9, and CYP2C19.
    Warfarin: (Major) The concomitant use of dabrafenib and warfarin led to decreased S- and R-warfarin exposure in a drug interaction study. Monitor INR levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib therapy; adjust the warfarin dose as necessary. Dabrafenib is a moderate CYP3A4 inducer and a weak CYP2C9 inducer; warfarin is a substrate of CYP3A4 and CYP2C9. In a drug interaction study, administration of dabrafenib 150 mg twice daily for 15 days with a single 15 mg-dose of warfarin decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and decreased the AUC of R-warfarin (a CYP3A4/CYP1A2 substrate) by 33%.
    Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as dabrafenib. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    Dabrafenib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and findings from animal studies. Advise females of reproductive potential to avoid pregnancy while taking dabrafenib. Discuss the potential hazard to the fetus if dabrafenib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicity was observed in pregnant rats who received dabrafenib doses that resulted in drug exposures that were about 3 times the recommended human exposure including embryo-lethality, ventricular septal defects, and variation in thymic shape. Additionally, fetal skeletal development delay and reduced fetal body weight occurred with dabrafenib doses that achieved exposure equivalent to the recommended human dose.

    According to the manufacturer, women should discontinue breast-feeding during dabrafenib therapy and for 2 weeks after the last dose because of the potential for serious adverse reactions in nursing infants. It is not known if dabrafenib is secreted in human milk or if it affects the breast fed infant or milk production. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Dabrafenib is a kinase inhibitor that has demonstrated activity against some mutated forms of BRAF kinases including BRAF V600E, BRAF V600K, and BRAF V600D in melanoma cells in vitro and in vivo. Dabrafenib inhibits wild-type BRAF and CRAF kinases in vitro. Approximately 40—50% of melanomas have BRAF mutations. Some BRAF mutations (e.g., BRAF V600 mutations) signal mitogen activated protein kinase (MAPK) pathways resulting in the hyperactivation of MEK and extracellular receptor kinase (ERK) leading to melanoma cell proliferation in the absence of growth factors that would normally be required for cell proliferation.
     
    Potential mechanisms of resistance to dabrafenib include upregulation of MAPK signaling, phosphatase tensin homologue (PTEN) loss, hepatocyte growth factor (HGF)/MET signaling, amplified cyclin D1 (CCND1), and amplified receptor tyrosine kinase (RTK) signaling through PI3K and mTOR.

    PHARMACOKINETICS

    Dabrafenib is administered orally. It is highly bound to plasma proteins (99.7%) and has an apparent volume of distribution of 70.3 L. Dabrafenib is metabolized by CYP3A4 and CYP2C8 isoenzymes to hydroxy-dabrafenib which is further oxidized to carboxy-dabrafenib and excreted in the bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib which may be reabsorbed from the gut. Both the hydroxy- and desmethyl-dabrafenib metabolites are likely to contribute to the clinical activity of dabrafenib. Desmethyl-dabrafenib is metabolized by CYP3A4 to oxidative metabolites. The mean terminal half-life is 8 hours for dabrafenib, 10 hours for hydroxy-dabrafenib, and 21 to 22 hours for carboxy-dabrafenib and desmethyl-dabrafenib. The apparent clearance is 17 L/hour after a single dabrafenib dose and 34.4 L/hour after twice-daily dosing for 2 weeks. The fecal route is the main route of dabrafenib excretion. Following a radioactive dabrafenib dose, 71% of the dose was recovered in the feces and 23% of the total reactivity was recovered as metabolites only in the urine.
     
    Affected cytochrome P450 isoenzymes and transporters: CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2B6, P-gp, BCRP, OATP1B1, OAT1B3, OAT1, OAT3
    Dabrafenib is primarily metabolized by CYP3A4 and CYP2C8 isoenzymes. Also, hydroxy-dabrafenib and desmethyl-dabrafenib are substrates of CYP3A4. Avoid the concomitant use of dabrafenib with strong CYP3A4 and CYP2C8 inhibitors if possible; monitor closely for dabrafenib adverse reactions if concomitant use is unavoidable. Additionally, concomitant use of dabrafenib with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. No clinically significant drug interactions are expected when dabrafenib is administered with strong CYP3A4 inducers or acid reducing agents based on data from drug interactions studies. The AUC values of dabrafenib and its metabolite desmethyl-dabrafenib were decreased by 34% and 30%, respectively, when dabrafenib 150 mg PO twice daily was administered with rifampin 600 mg PO once daily (a strong CYP3A4 inducer and moderate CYP2C8 inducer) for 10 days in a drug interaction study; there was no change in the AUC value of hydroxy-dabrafenib. The AUC values of dabrafenib and its metabolite hydroxy-dabrafenib were increased by 3% and 5%, respectively, when dabrafenib 150 mg PO twice daily was administered with rabeprazole 40 mg PO once daily for 4 days in a drug interaction study; he AUC value of desmethyl –dabrafenib was decreased by 15%. In vitro, dabrafenib is a substrate for P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP); additionally, it may also induce isoenzymes CYP2B6, CYP2C8, and CYP2C19; UDP glucuronosyltransferases (UGT); and transporters. In vitro data demonstrate that dabrafenib induces CYP3A4 and CYP2B6 by pregnane X receptor (PXR) and constitutive androstane receptor (CAR) nuclear receptor activation; induction of CYP2C enzymes may also occur via this mechanism. In vitro, dabrafenib and its active metabolites inhibited the human organic anion transport (OAT) polypeptides OATP1B1 and OAT1B3 and OAT1 and OAT3; dabrafenib and desmethyl-dabrafenib were moderate inhibitors of BCRP.

    Oral Route

    The mean absolute oral bioavailability of dabrafenib is 95%. Following oral administration, the median time to peak plasma concentration (Tmax) is 2 hours. Dabrafenib exhibits dose proportional exposure over a dosage range of 12 mg to 300 mg following a single dose. The mean accumulation ratio was 0.73 (coefficient of variance, 38%) following 150 mg twice daily dosing; the mean metabolite-to-parent AUC ratios were 0.9 for hydroxy-dabrafenib, 11 for carboxy-dabrafenib, and 0.7 for desmethyl-dabrafenib.
     
    Effects of Food: Administering dabrafenib with a high-fat meal decreases the Cmax by 51%, decreases the AUC by 31%, and delays the median Tmax by 3.6 hours when compared to the fasted state. Take the dabrafenib dose either at least 1 hour before or at least 2 hours after a meal.