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DABRAFENIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dabrafenib is a kinase inhibitor indicated for the treatment of unresectable or metastatic melanoma in adults with BRAF V600E mutation as detected by an FDA-approved method and, as combination therapy with trametinib, to treat unresectable or metastatic melanoma in adults with BRAF V600E or V600K mutations as detected by an FDA-approved method .

Specific Substances

    1) Dabrafenib methanesulfonate
    2) Dabrafenib mesylate
    3) GSK2118436B
    4) CAS 1195768-06-9
    1.2.1) MOLECULAR FORMULA
    1) C23H20F3N5O2S2(Prod Info TAFINLAR(R) oral capsules, 2013)

Available Forms Sources

    A) FORMS
    1) Dabrafenib is available as 50 mg and 75 mg capsules (Prod Info TAFINLAR(R) oral capsules, 2016).
    B) USES
    1) Dabrafenib is used to treat unresectable or metastatic melanoma in adults with BRAF V600E mutation as detected by an FDA-approved method (Prod Info TAFINLAR(R) oral capsules, 2016).
    2) Dabrafenib is also used, as combination therapy with trametinib, to treat unresectable or metastatic melanoma in adults with BRAF V600E or V600K mutations as detected by an FDA-approved method (Prod Info TAFINLAR(R) oral capsules, 2016).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dabrafenib is used to treat unresectable or metastatic melanoma in adults with BRAF V600E mutation. It is also used, as combination therapy with trametinib, to treat unresectable or metastatic melanoma in adults with BRAF V600E or V600K mutations as detected by an FDA-approved method.
    B) PHARMACOLOGY: Dabrafenib is a kinase inhibitor that inhibits in-vivo and in-vitro melanoma cell growth with BRAF V600 mutation. Dabrafenib inhibits BRAF V600E kinases and other kinases, including BRAF V600K, BRAF V600D, and wild-type BRAF and CRAF kinases. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in activated BRAF kinases that may stimulate tumor cell growth; therefore, dabrafenib is not indicated to treat wild-type BRAF melanoma.
    C) EPIDEMIOLOGY: There have been no reports of dabrafenib overdose.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include hyperglycemia, hyperkeratosis, hypophosphatemia, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).
    2) LESS COMMON: Other adverse effects occurring less frequently include hyponatremia, rash, back pain, and myalgia.
    3) RARE: Rare but serious effects that were observed include uveitis and iritis, pancreatitis, and interstitial nephritis.
    E) WITH POISONING/EXPOSURE
    1) Overdose of dabrafenib has not been reported. Extensions of adverse effects seen at therapeutic doses should be expected. In animal studies, dogs chronically administered 5 times the recommended human dose, or greater, developed coronary arterial degeneration/necrosis with hemorrhage and cardiac atrioventricular valve hypertrophy/hemorrhage.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever is a common reaction following dabrafenib therapy.
    0.2.20) REPRODUCTIVE
    A) Although there are no adequate and well-controlled studies of dabrafenib use in pregnant women, maternal exposure to ponatinib may pose a danger to the developing embryo/fetus. Fetal abnormalities observed during animal studies included embryo-lethality, ventricular septal defects, variation in thymic shape, delayed skeletal development, and reduced fetal body weight.
    0.2.21) CARCINOGENICITY
    A) Carcinogenicity studies with dabrafenib have not been conducted. However, an increased risk of cutaneous squamous cell carcinomas was observed in patients treated with dabrafenib during clinical trials. Increased cell proliferation has been observed when BRAF wild-type cells are exposed to BRAF inhibitors.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Monitor serum electrolytes including phosphate, liver enzymes and renal function after significant overdose.
    C) Monitor serum glucose concentration, particularly in patients with pre-existing diabetes or hyperglycemia.
    D) Monitor for signs of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
    E) Serum dabrafenib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    F) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to dabrafenib.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities including hypophosphatemia and hyponatremia.
    C) DECONTAMINATION
    1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be effective due to high protein binding (99.7%) and large volume of distribution of dabrafenib.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestion of one or two extra doses can be monitored at home
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions, any symptomatic patient and those with inadvertent ingestion of more than two extra doses should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be evaluated in a healthcare facility.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted. Patients demonstrating severe fluid and electrolyte imbalance should be admitted.
    4) CONSULT CRITERIA: Consult with a medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) Patients taking these medications may have severe comorbidities and may be receiving other drugs that may produce synergistic effects.
    J) PHARMACOKINETICS
    1) Time to peak concentrations following administration of oral dabrafenib were noted within 2 hours. Protein binding is 99.7%. Volume of distribution is 70.3 L. Dabrafenib is primarily metabolized in the liver by CYP2C8 and CYP3A4. Following radioactive dosing, 71% of dabrafenib was recovered in feces; 23% was recovered in urine as metabolites. The mean terminal half-life is 8 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes infection, SIADH, diuretic overdose.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: 150 mg orally every 12 hours. PEDIATRIC: Safety and efficacy have not been established.

Clinical Effects

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Dabrafenib may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Prod Info TAFINLAR(R) oral capsules, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) HYPERKERATOSIS
    1) WITH THERAPEUTIC USE
    a) Hyperkeratosis occurred in 37% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 0% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).
    B) PAPILLOMA
    1) WITH THERAPEUTIC USE
    a) Papilloma, including skin papilloma, occurred in 27% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 2% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).
    C) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia occurred in 22% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 2% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).
    D) ACRAL ERYTHEMA DUE TO CYTOTOXIC THERAPY
    1) WITH THERAPEUTIC USE
    a) Palmar-plantar erythrodysesthesia (PPES) syndrome occurred in 20% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 2% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).
    E) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash occurred in 17% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 0% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).

Summary Of Exposure

    A) USES: Dabrafenib is used to treat unresectable or metastatic melanoma in adults with BRAF V600E mutation. It is also used, as combination therapy with trametinib, to treat unresectable or metastatic melanoma in adults with BRAF V600E or V600K mutations as detected by an FDA-approved method.
    B) PHARMACOLOGY: Dabrafenib is a kinase inhibitor that inhibits in-vivo and in-vitro melanoma cell growth with BRAF V600 mutation. Dabrafenib inhibits BRAF V600E kinases and other kinases, including BRAF V600K, BRAF V600D, and wild-type BRAF and CRAF kinases. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in activated BRAF kinases that may stimulate tumor cell growth; therefore, dabrafenib is not indicated to treat wild-type BRAF melanoma.
    C) EPIDEMIOLOGY: There have been no reports of dabrafenib overdose.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include hyperglycemia, hyperkeratosis, hypophosphatemia, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).
    2) LESS COMMON: Other adverse effects occurring less frequently include hyponatremia, rash, back pain, and myalgia.
    3) RARE: Rare but serious effects that were observed include uveitis and iritis, pancreatitis, and interstitial nephritis.
    E) WITH POISONING/EXPOSURE
    1) Overdose of dabrafenib has not been reported. Extensions of adverse effects seen at therapeutic doses should be expected. In animal studies, dogs chronically administered 5 times the recommended human dose, or greater, developed coronary arterial degeneration/necrosis with hemorrhage and cardiac atrioventricular valve hypertrophy/hemorrhage.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever is a common reaction following dabrafenib therapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Pyrexia occurred in 28% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 10% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial. In the same study, serious febrile drug reactions (serious cases of fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause) were reported in 7 out of 187 patients (3.7%) treated with dabrafenib compared with 0 patients in the dacarbazine group (Prod Info TAFINLAR(R) oral capsules, 2013).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) UVEITIS AND IRITIS: Across all clinical trials, 6 out of 586 (1%) patients treated with dabrafenib developed uveitis or iritis requiring treatment with steroid and mydriatic ophthalmic eye drops (Prod Info TAFINLAR(R) oral capsules, 2013).

Cardiovascular

    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) In animal studies, dogs administered 50 mg/kg/day (5 times the recommended human dose based on AUC), or greater, for up to 4 weeks developed coronary arterial degeneration/necrosis with hemorrhage and cardiac atrioventricular valve hypertrophy/hemorrhage (Prod Info TAFINLAR(R) oral capsules, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough occurred in 12% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 5% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in 32% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 8% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis occurred in less than 10% of patients (n=586) treated with dabrafenib across all clinical trials (Prod Info TAFINLAR(R) oral capsules, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Increased alkaline phosphatase levels occurred in 19% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 14% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) INTERSTITIAL NEPHRITIS
    1) WITH THERAPEUTIC USE
    a) Interstitial nephritis occurred in less than 10% of patients (n=586) treated with dabrafenib across all clinical trials (Prod Info TAFINLAR(R) oral capsules, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia occurred in 27% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 2% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia occurred in 11% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 0% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia occurred in 50% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) compared with 43% of patients treated with dacarbazine 1000 mg/m(2) IV every 3 weeks (n=59) in a multicenter, randomized, open-label controlled trial (Prod Info TAFINLAR(R) oral capsules, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions resulting in bullous rash were observed in less than 10% of patients (n=586) treated with dabrafenib across all clinical trials (Prod Info TAFINLAR(R) oral capsules, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Although there are no adequate and well-controlled studies of dabrafenib use in pregnant women, maternal exposure to ponatinib may pose a danger to the developing embryo/fetus. Fetal abnormalities observed during animal studies included embryo-lethality, ventricular septal defects, variation in thymic shape, delayed skeletal development, and reduced fetal body weight.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) During animal studies, administration of dabrafenib at doses approximately 3 times the recommended human exposure based on the AUC resulted in developmental toxicities, including embryo-lethality, ventricular septal defects, and variation in thymic shape . Delays in skeletal development and reduced fetal body weight were observed with doses equivalent to the recommended human exposure based on the AUC (Prod Info TAFINLAR(R) oral capsules, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Do not give this drug to a pregnant woman. If pregnancy occurs, apprise the patient of the potential for fetal harm (Prod Info TAFINLAR(R) oral capsules, 2015).
    B) CONTRACEPTION
    1) Use of adequate contraception is required in females of reproductive potential during therapy and for at least 2 weeks after discontinuation. Advise patient to use non-hormonal methods of contraception as dabrafenib can decrease the effectiveness of hormonal methods (Prod Info TAFINLAR(R) oral capsules, 2015).
    C) ANIMAL STUDIES
    1) During animal studies, administration of dabrafenib at doses approximately 3 times the recommended human exposure based on the AUC resulted in developmental toxicities, including embryo-lethality, ventricular septal defects, and variation in thymic shape . Delays in skeletal development and reduced fetal body weight were observed with doses equivalent to the recommended human exposure based on the AUC (Prod Info TAFINLAR(R) oral capsules, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Lactation studies have not been conducted and the effects on a nursing infant or milk production are unknown (Prod Info TAFINLAR(R) oral capsules, 2015).
    B) BREAST MILK
    1) Because of the potential for serious adverse effects in the breastfed infant, breastfeeding is not recommended during therapy and for 2 weeks after discontinuation (Prod Info TAFINLAR(R) oral capsules, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) A reduction in fertility was reported in female animals administered dabrafenib at doses equivalent to the recommended human exposure based on the AUC and a reduction in the number of ovarian corpora lutea was reported with doses approximately 3 times the recommended human exposure based on the AUC. In male animals, testicular degeneration/depletion was reported with dabrafenib doses up to 3 times the recommended human exposure based on the AUC (Prod Info TAFINLAR(R) oral capsules, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Carcinogenicity studies with dabrafenib have not been conducted. However, an increased risk of cutaneous squamous cell carcinomas was observed in patients treated with dabrafenib during clinical trials. Increased cell proliferation has been observed when BRAF wild-type cells are exposed to BRAF inhibitors.
    3.21.3) HUMAN STUDIES
    A) NEW PRIMARY CUTANEOUS MALIGNANCIES
    1) BASAL CELL CARCINOMA
    a) In a multicenter, randomized, open-label dose-ranging trial, 9% of patients treated with dabrafenib mesylate in combination with trametinib for BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (n=55) developed basal cell carcinoma (BCC) compared with 2% of the patients treated with dabrafenib only (n=53). The range of time to the diagnosis of BCC was 28 to 249 days for combination therapy and 197 days for monotherapy (Prod Info TAFINLAR oral capsules, 2014).
    2) CUTANEOUS SQUAMOUS CELL CARCINOMA OR KERATOACANTHOMA
    a) In a multicenter, randomized, open-label dose-ranging trial, 7% of patients treated with dabrafenib mesylate in combination with trametinib for BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (n=55) developed cutaneous squamous cell carcinoma (SCC) compared with 19% of the patients treated with dabrafenib only (n=53). The range of time to the diagnosis of SCC was 136 to 197 days for combination therapy and 9 to 197 days for monotherapy (Prod Info TAFINLAR oral capsules, 2014).
    b) In a multicenter, randomized, open-label controlled trial, 7% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) developed cutaneous squamous cell carcinomas or keratoacanthomas (cuSCC) compared with none of the patients treated with dacarbazine (n=59). An incidence of 11% was observed for cuSCC development in dabrafenib-treated patients across all clinical trials (n=586). The median time to the first occurrence of cuSCC was 9 weeks (range: 1 to 53 weeks). The relationship between dabrafenib use and the development of cuSCC is not clear (Prod Info TAFINLAR oral capsules, 2014).
    3) MALIGNANT MELANOMA
    a) MALIGNANT MELANOMA: In a multicenter, randomized, open-label controlled trial, 2% of patients treated with dabrafenib mesylate 150 mg oral twice daily for unresectable or metastatic BRAF V600E mutation-positive melanoma (n=187) developed new primary malignant melanomas compared with none of the patients treated with dacarbazine (n=59). However, the relationship between dabrafenib use and the development of malignant melanoma is not clear (Prod Info TAFINLAR oral capsules, 2014).
    4) NON-CUTANEOUS MALIGNANCY
    a) In a multicenter, randomized, open-label dose-ranging trial, 4 patients treated with dabrafenib mesylate in combination with trametinib for BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (n=55) developed non-cutaneous malignancies including KRAS mutation-positive pancreatic adenocarcinoma, glioblastoma, head and neck carcinoma, and recurrent NRAS mutation-positive colorectal carcinoma (Prod Info TAFINLAR oral capsules, 2014).
    5) PRIMARY MELANOMA
    a) In a multicenter, randomized, open-label dose-ranging trial, 0% of patients treated with dabrafenib mesylate in combination with trametinib for BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (n=55) developed new primary melanoma compared with 2% of the patients treated with dabrafenib only (n=53) (Prod Info TAFINLAR oral capsules, 2014).
    B) TUMOR PROMOTION IN BRAF WILD-TYPE MELANOMA
    1) Evidence of paradoxical activation of MAP-kinase signaling and increased cell proliferation were observed during in vitro experiments when BRAF wild-type cells were exposed to BRAF inhibitors (Prod Info TAFINLAR oral capsules, 2014).

Genotoxicity

    A) There was no evidence of mutagenicity in the following tests: bacterial reverse mutation assay (Ames test), mouse lymphoma assay. There was no evidence of clastogenicity during in vivo rat bone marrow micronucleus testing (Prod Info TAFINLAR oral capsules, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Monitor serum electrolytes including phosphate, liver enzymes and renal function after significant overdose.
    C) Monitor serum glucose concentration, particularly in patients with pre-existing diabetes or hyperglycemia.
    D) Monitor for signs of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
    E) Serum dabrafenib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    F) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to dabrafenib.
    4.1.2) SERUM/BLOOD
    A) SUMMARY
    1) Monitor serum electrolytes including phosphate, liver enzymes and renal function after significant overdose.
    2) Monitor serum glucose concentration, particularly in patients with pre-existing diabetes or hyperglycemia.
    3) Monitor for signs of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
    4) Serum dabrafenib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    B) PREGNANCY
    1) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to dabrafenib (Prod Info TAFINLAR(R) oral capsules, 2013).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted. Patients demonstrating severe fluid and electrolyte imbalance should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestion of one or two extra doses can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult with a medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions, any symptomatic patient and those with inadvertent ingestion of more than two extra doses should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be evaluated in a healthcare facility.

Monitoring

    A) Monitor vital signs.
    B) Monitor serum electrolytes including phosphate, liver enzymes and renal function after significant overdose.
    C) Monitor serum glucose concentration, particularly in patients with pre-existing diabetes or hyperglycemia.
    D) Monitor for signs of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
    E) Serum dabrafenib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    F) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to dabrafenib.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities including hypophosphatemia and hyponatremia.
    B) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) Monitor serum electrolytes including phosphate, liver enzymes and renal functions after significant overdose.
    3) Monitor serum glucose concentrations, particularly in patients with pre-existing diabetes or hyperglycemia.
    4) Monitor for signs of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
    5) Serum dabrafenib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    6) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to dabrafenib.
    C) HYPERSENSITIVITY REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) LACK OF EFFECT
    1) Hemodialysis is UNLIKELY to be effective due to high protein binding (99.7%) and large volume of distribution of dabrafenib.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: 150 mg orally every 12 hours. PEDIATRIC: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose of dabrafenib is 150 mg orally every 12 hours as a single agent or in combination with trametinib. A missed dose may be taken 6 or more hours prior to the next dose (Prod Info TAFINLAR oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of dabrafenib have not been established in pediatric patients (Prod Info TAFINLAR oral capsules, 2014).

Minimum Lethal Exposure

    A) A specific toxic dose has not been established (Prod Info TAFINLAR(R) oral capsules, 2013).
    B) In animal studies, dogs administered 50 mg/kg/day (5 times the recommended human dose based on AUC), or greater, for up to 4 weeks developed coronary arterial degeneration/necrosis with hemorrhage and cardiac atrioventricular valve hypertrophy/hemorrhage (Prod Info TAFINLAR(R) oral capsules, 2013).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Dabrafenib is a kinase inhibitor that inhibits in vivo and in vitro melanoma cell growth with BRAF V600 mutation. Dabrafenib inhibits BRAF V600E kinases with an in-vitro IC50 value of 0.65 nanomole (nM), BRAF V600K kinases with an IC50 value of 0.5 nM, and BRAF V600D kinases with an IC 50 value of 1.84 nM. Dabrafenib also inhibits wild-type BRAF kinases with an IC50 value of 3.2 nM and CRAF kinases with an IC50 value of 5 nM, and other kinases (eg, SIK1, NEK11, LIMK1) at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in activated BRAF kinases that may stimulate tumor cell growth; therefore, dabrafenib is not indicated to treat wild-type BRAF melanoma (Prod Info TAFINLAR(R) oral capsules, 2016).

Physicochemical

Physical Characteristics

    A) Dabrafenib mesylate is available as a white to slightly colored solid. Above pH 4 in aqueous media, dabrafenib is practically insoluble and is very slightly soluble at pH 1 (Prod Info TAFINLAR(R) oral capsules, 2013).

Molecular Weight

    A) 615.68 (Prod Info TAFINLAR(R) oral capsules, 2013)

References

General Bibliography

    1) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    2) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    5) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    6) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    7) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    8) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    9) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    10) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    11) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    12) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    13) Product Information: TAFINLAR oral capsules, dabrafenib oral capsules. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2014.
    14) Product Information: TAFINLAR(R) oral capsules, dabrafenib oral capsules. GlaxoSmithKline (per FDA), Reseach Triangle Park, NC, 2015.
    15) Product Information: TAFINLAR(R) oral capsules, dabrafenib oral capsules. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2013.
    16) Product Information: TAFINLAR(R) oral capsules, dabrafenib oral capsules. Novartis Pharmaceuticals Corporation (per FDA), East Hanover, NJ, 2016.
    17) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    18) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    19) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.