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Dabrafenib

Pronunciation

(da BRAF e nib)

Index Terms

  • GSK2118436

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Tafinlar: 50 mg, 75 mg

Brand Names: U.S.

  • Tafinlar

Pharmacologic Category

  • Antineoplastic Agent, BRAF Kinase Inhibitor

Pharmacology

Selectively inhibits some mutated forms of the protein kinase B-raf (BRAF). BRAF V600 mutations result in constitutive activation of the BRAF pathway; through BRAF inhibition, dabrafenib inhibits tumor cell growth. The combination of dabrafenib and trametinib allows for greater inhibition of the MAPK pathway, resulting in BRAF V600 melanoma cell death (Flaherty, 2012).

Absorption

Decreased with a high-fat meal

Distribution

70.3 L

Metabolism

Hepatic via CYP2C8 and CYP3A4 to hydroxy-dabrafenib (active) which is further metabolized via CYP3A4 oxidation to desmethyl-dabrafenib (active)

Excretion

Feces (71%); urine (23%; metabolites only)

Time to Peak

2 hours; delayed with a high-fat meal

Half-Life Elimination

Parent drug: 8 hours; Hydroxy-dabrafenib (active metabolite): 10 hours; Desmethyl-dabrafenib (active metabolite): 21 to 22 hours

Protein Binding

99.7% to plasma proteins

Use: Labeled Indications

Melanoma, metastatic or unresectable:

US labeling: Treatment of unresectable or metastatic melanoma in patients with a BRAF V600E mutation (single agent therapy) or in patients with BRAF V600E or BRAF V600K mutations (in combination with trametinib); confirm BRAF V600E or BRAF V600K mutation status with an approved test prior to treatment.

Canadian labeling: Treatment of unresectable or metastatic melanoma in patients with a BRAF V600 mutation (as detected by a validated test) as single agent therapy or in combination with trametinib.

Limitations of use: Not indicated for treatment of patients with wild-type BRAF melanoma.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to dabrafenib or any component of the formulation.

Dosing: Adult

US labeling:

Melanoma, metastatic or unresectable (with BRAF V600E mutation): Oral: 150 mg twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity (single-agent therapy)

Melanoma, metastatic or unresectable (with BRAF V600E or BRAF V600K mutation): Oral: 150 mg twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity (in combination with trametinib)

Canadian labeling: Melanoma, metastatic or unresectable (with BRAF V600 mutation): Oral: 150 mg twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity (single-agent therapy or in combination with trametinib)

Missed doses: A missed dose may be administered up to 6 hours prior to the next dose; do not administer if <6 hours until the next dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment (GFR ≥30 mL/minute/1.73 m2): No dosage adjustment necessary.

Severe impairment (GFR <30 mL/minute/1.73 m2): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied)

Dosing: Hepatic Impairment

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, metabolism is primarily hepatic and exposure may be increased in patients with moderate to severe impairment.

Dosing: Adjustment for Toxicity

Recommended dabrafenib dose reductions for toxicity:

First dose reduction: 100 mg twice daily

Second dose reduction: 75 mg twice daily

Third dose reduction: 50 mg twice daily

Subsequent modifications (if unable to tolerate 50 mg twice daily): Permanently discontinue.

Note: If using combination therapy, refer to Trametinib monograph for recommended trametinib dose reductions.

Cardiac:

>20% absolute decrease in LVEF from baseline and LVEF is below institutional LLN: Interrupt dabrafenib therapy; if improved, may resume at the same dose.

Symptomatic heart failure: Interrupt dabrafenib therapy; if improved, may resume at the same dose.

Dermatologic:

Intolerable grade 2 skin toxicity or grade 3 or 4 skin toxicity: Interrupt dabrafenib therapy for up to 3 weeks. If toxicity improves within 3 weeks, resume at a lower dose level. If toxicity does not improve within 3 weeks following therapy interruption, permanently discontinue dabrafenib.

New primary cutaneous malignancy: No dabrafenib dosage modification is necessary.

Fever:

Fever of 38.5°C to 40°C (101.3°F to 104°F): Interrupt dabrafenib therapy until temperature normalizes. Resume at the same or lower dose level.

Fever >40°C (104°F) and/or fever complicated by rigors, hypotension, dehydration, or renal failure: Interrupt dabrafenib therapy until temperature normalizes. Resume at a lower dose level or permanently discontinue. May require prophylactic antipyretics (secondary prophylaxis) upon resumption. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of fever, or for fever associated with complications (eg, dehydration, hypotension, severe chills/rigors with no evidence of active infection).

Hemorrhage:

Grade 3 hemorrhage: Interrupt dabrafenib therapy. If hemorrhage improves, resume at a lower dose level. If hemorrhage does not improve following therapy interruption, permanently discontinue dabrafenib.

Grade 4 hemorrhage: Permanently discontinue dabrafenib.

Ocular:

Uveitis including iritis and iridocyclitis: If mild or moderate uveitis does not respond to local ocular therapy (or for severe uveitis), interrupt dabrafenib therapy for up to 6 weeks. If improves to ≤ grade 1 within 6 weeks following therapy interruption, resume at the same dose. If does not improve, or for persistent grade 2 or higher uveitis of >6 week duration, permanently discontinue dabrafenib.

Grade 2 or 3 retinal pigment epithelial detachments (RPED): No dabrafenib dosage modification is necessary.

Retinal vein occlusion: No dabrafenib dosage modification is necessary.

Pulmonary: Interstitial lung disease or pneumonitis: No dabrafenib dosage modification is necessary.

Venous thromboembolism: Uncomplicated DVT or PE: No dabrafenib dosage modification is necessary.

Other toxicity:

Intolerable grade 2 or any grade 3 toxicity: Interrupt dabrafenib therapy until resolution to ≤ grade 1; resume at a lower dose level. If toxicity does not improve following therapy interruption, permanently discontinue dabrafenib.

Grade 4 toxicity (first occurrence): Interrupt dabrafenib therapy until resolution to ≤ grade 1; consider resuming at a lower dose level or permanently discontinue.

Grade 4 toxicity (recurrent after dosage reduction): Permanently discontinue dabrafenib.

New primary noncutaneous malignancy (RAS mutation-positive): Permanently discontinue dabrafenib.

Administration

Administer orally at least 1 hour before or 2 hours after a meal; doses should be ~12 hours apart. Do not open, crush, or break capsules. A missed dose may be administered up to 6 hours prior to the next dose. When administered in combination with trametinib, take the once-daily dose of trametinib at the same time each day with either the morning or evening dose of dabrafenib.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of intact capsules (NIOSH 2014).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Antacids: May decrease the serum concentration of Dabrafenib. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Contraceptives (Estrogens): Dabrafenib may decrease the serum concentration of Contraceptives (Estrogens). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment. Consider therapy modification

Contraceptives (Progestins): Dabrafenib may decrease the serum concentration of Contraceptives (Progestins). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment. Consider therapy modification

CYP2B6 Substrates: Dabrafenib may decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

CYP2C19 Substrates: Dabrafenib may decrease the serum concentration of CYP2C19 Substrates. Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

CYP2C8 Inducers (Strong): May decrease the serum concentration of Dabrafenib. Avoid combination

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Dabrafenib. Avoid combination

CYP2C8 Substrates: Dabrafenib may decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

CYP2C9 Substrates: Dabrafenib may decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

CYP3A4 Inducers (Strong): May decrease the serum concentration of Dabrafenib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Dabrafenib. Avoid combination

CYP3A4 Substrates: Dabrafenib may decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Elbasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir. Avoid combination

Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical). Monitor therapy

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Monitor therapy

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with moderate CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if moderate CYP3A4 inducer therapy is just beginning. Consider therapy modification

H2-Antagonists: May decrease the serum concentration of Dabrafenib. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Management: Although moderate CYP3A inducers are not specifically contraindicated with ibrutinib, prescribing information indicates that they may decrease AUC up to 3-fold. If possible, alternatives with less CYP3A induction should be considered. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

Proton Pump Inhibitors: May decrease the serum concentration of Dabrafenib. Dabrafenib may decrease the serum concentration of Proton Pump Inhibitors. Management: Seek alternatives to the proton pump inhibitor when possible. If concomitant therapy cannot be avoided, monitor for diminished effects of both drugs. Consider therapy modification

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

St John's Wort: May decrease the serum concentration of Dabrafenib. Management: Seek alternatives to St. John's wort when possible. If concomitant therapy cannot be avoided, monitor closely for diminished therapeutic effects of dabrafenib. Consider therapy modification

Trametinib: May enhance the adverse/toxic effect of Dabrafenib. Monitor therapy

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Adverse Reactions

Monotherapy:

>10%:

Cardiovascular: Peripheral edema (17%)

Central nervous system: Fatigue (40%), headache (28% to 32%), chills (17%)

Dermatologic: Dermatological reaction (68%), skin rash (17% to 53%), hyperkeratosis (37%), alopecia (22%), palmar-plantar erythrodysesthesia (20%), pruritus (13%)

Endocrine & metabolic: Hyperglycemia (49% to 50%; grades 3/4: 2% to 6%), hypophosphatemia (37% to 40%), increased gamma-glutamyl transferase (38%), hyponatremia (8% to 36%), hypoalbuminemia (23%), hypokalemia (23%), hyperkalemia (15%)

Gastrointestinal: Diarrhea (28%), abdominal pain (21%), nausea (21%), decreased appetite (19%), vomiting (15%), constipation (11%)

Hematologic & oncologic: Lymphocytopenia (40%; grades 3/4: 6%), anemia (28%), papilloma (27%), leukopenia (21%), malignant neoplasm of skin (keratoacanthoma and squamous cell carcinoma; 7% to 19%; grades 3/4: 4%)

Hepatic: Increased serum alkaline phosphatase (19% to 26%), increased serum AST (15%), increased serum ALT (11%)

Neuromuscular & skeletal: Arthralgia (27% to 34%), myalgia (11% to 23%), limb pain (19%), back pain (11% to 12%)

Respiratory: Cough (12% to 21%)

Miscellaneous: Fever (26% to 28%; grades 3/4: ≤4%)

1% to 10%:

Cardiovascular: Prolonged Q-T interval on ECG (>60 msec from baseline: 2%; >500 msec: 2%)

Central nervous system: Dizziness (9%), insomnia (8%)

Dermatologic: Actinic keratosis (9%), night sweats (6%), xeroderma (6%), acneiform eruption (4%), erythema (2%)

Endocrine & metabolic: Hypocalcemia (9%), hypomagnesemia (6%), hypercalcemia (4%), dehydration (2%)

Gastrointestinal: Pancreatitis (<10%), xerostomia (6%)

Genitourinary: Urinary tract infection (9%)

Hematologic & oncologic: Neutropenia (9%; grades 3/4: 2%), thrombocytopenia (8%), basal cell carcinoma (2%), hemorrhage (2%), malignant melanoma (2%)

Hypersensitivity: Hypersensitivity (bullous rash, <10%)

Neuromuscular & skeletal: Muscle spasm (4%)

Ophthalmic: Uveitis (including iritis, 1%)

Renal: Interstitial nephritis (<10%), increased serum creatinine (9%)

Respiratory: Nasopharyngitis (10%)

Miscellaneous: Febrile reaction (2%)

Combination therapy with trametanib:

>10%:

Cardiovascular: Peripheral edema (28% to 31%), prolonged Q-T interval on ECG (>60 msec from baseline: 13%; >500 msec: 4%)

Central nervous system: Chills (50% to 58%), fatigue (53% to 57%), headache (29% to 37%), insomnia (11% to 18%), dizziness (13% to 16%)

Dermatologic: Dermatological reaction (65%; 3% required hospitalization), skin rash (43% to 45%), night sweats (15% to 24%), xeroderma (9% to 18%), acneiform eruption (11% to 16%), actinic keratosis (7% to 15%), erythema (6% to 15%), pruritus (11%)

Endocrine & metabolic: Hyperglycemia (58% to 67%; grades 3/4: 5% to 6%), increased gamma-glutamyl transferase (54% to 56%), hyponatremia (48% to 55%), hypoalbuminemia (43% to 53%), hypophosphatemia (41% to 47%), hypokalemia (15% to 29%), hyperkalemia (18% to 22%), hypocalcemia (13% to 20%), hypercalcemia (15% to 19%), hypomagnesemia (2% to 18%), dehydration (6% to 11%)

Gastrointestinal: Nausea (44% to 46%), vomiting (40% to 43%), diarrhea (26% to 36%), abdominal pain (24% to 33%), decreased appetite (22% to 30%), constipation (17% to 22%), xerostomia (11%)

Genitourinary: Urinary tract infection (6% to 13%)

Hematologic & oncologic: Leukopenia (46% to 62%; grades 3/4: 4% to 5%), lymphocytopenia (55% to 59%; grades 3/4: 19% to 22%), anemia (46% to 55%; grades 3/4: 4% to 7%), neutropenia (37% to 55%; grades 3/4: 2% to 13%), thrombocytopenia (31%; grades 3/4: 2% to 4%), hemorrhage (11% to 16%; major hemorrhage [intracranial or gastric]: 5%)

Hepatic: Increased serum alkaline phosphatase (60% to 67%), increased serum AST (54% to 60%), increased serum ALT (35% to 42%), hyperbilirubinemia (7% to 15%)

Neuromuscular & skeletal: Arthralgia (27% to 44%), myalgia (22% to 24%), back pain (11% to 18%), limb pain (11% to 16%), muscle spasm (2% to 16%)

Renal: Increased serum creatinine (20% to 24%)

Respiratory: Cough (11% to 29%), oropharyngeal pain (7% to 13%)

Miscellaneous: Fever (57% to 71%; grades 3/4: 5% to 9%), febrile reaction (25%)

1% to 10%:

Cardiovascular: Hypertension (<10%), cardiomyopathy (≤9%), venous thromboembolism (deep vein thrombosis or pulmonary embolism; 7%)

Dermatologic: Cellulitis (<10%), folliculitis (<10%), hyperhidrosis (<10%), hyperkeratosis (<10%), palmar-plantar erythrodysesthesia (<10%), paronychia (<10%), pustular rash (<10%), secondary skin infection (3%)

Endocrine & metabolic: Hyperglycemia (grade 3: 5% to 6%)

Gastrointestinal: Pancreatitis (<10%), stomatitis (<10%)

Hematologic & oncologic: Cutaneous papilloma (<10%), basal cell carcinoma (9%), malignant neoplasm of skin (keratoacanthoma and squamous cell carcinoma; 7%)

Neuromuscular & skeletal: Weakness (<10%)

Ophthalmic: Blindness (transient; <10%), blurred vision (<10%), retinal detachment (pigment epithelium; 1%), uveitis (1%)

Renal: Renal failure (2% to 7%)

<1% (Limited to important or life-threatening): Glioblastoma, Kaposi sarcoma, malignant neoplasm of colon and rectum (recurrent NRAS mutation-positive), malignant neoplasm of head and neck, pancreatic adenocarcinoma (KRAS mutation-positive)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiomyopathy: Cardiomyopathy may occur when used as a single agent or in combination with trametinib. The median time to onset of cardiomyopathy was ~8 months (range: 28 days to ~25 months) when used in combination with trametinib, and ~4 months (range: 28 days to ~19 months) for single agent therapy. Assess LVEF (by echocardiogram or MUGA scan) prior to combination therapy initiation, at 1 month, and then at 2- to 3-month intervals while on therapy. Cardiac dysfunction may require dabrafenib treatment interruption (see trametinib monograph for dosage modifications). Cardiomyopathy resolved following dose adjustments and/or interruption.

• Dermatologic toxicity: Serious dermatologic toxicity (eg, rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, erythema) may occur when used in combination with trametinib (known complication of single-agent trametinib therapy); some patients required hospitalization for severe toxicity or for secondary skin infections. The median time to onset and resolution of skin toxicity for combination therapy was 2 months (range: 1 day to 22 months) and 1.2 months (range: 1 day to ~24 months), respectively. Monitor for dermatologic toxicity and signs/symptoms of secondary infections. Treatment interruption, dose reduction, and/or therapy discontinuation may be necessary.

• Febrile reactions: Serious febrile reactions and fever (any severity) complicated by hypotension, rigors or chills, dehydration, or renal failure were observed during dabrafenib single-agent therapy and when used in combination with trametinib. The incidence and severity were higher with combination therapy than with single-agent dabrafenib. The median time to initial fever (single-agent therapy) was 11 days (range: 1 day to 6.6 months); median duration was 3 days (range: 1 day to 4.2 months). In patients treated with combination therapy, the median time to onset of fever was 1 month (range: 1 day to 23.5 months) and the median duration was 3 days (range: 1 day to 11.3 months). Interrupt dabrafenib therapy for fever ≥38.5°C (101.3°F) or for any other serious febrile reaction complicated by hypotension, rigors/chills, dehydration, or renal failure; evaluate promptly for signs/symptoms of infection. Dosage reduction (or discontinuation) may be required; when resuming therapy after a febrile reaction, may require administration of antipyretics as secondary prophylaxis. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 5 days for second or subsequent episodes of pyrexia if temperature does not return to baseline within 3 days of fever onset, or for pyrexia associated with complications (eg, dehydration, hypotension, severe chills/rigors with no evidence of active infection).

• Hemorrhage: Hemorrhage, including symptomatic bleeding in a critical area/organ, may occur with dabrafenib either as a single agent or in combination with trametinib. Major bleeding events (some fatal) included intracranial or gastrointestinal hemorrhage. May require treatment interruption and dosage reduction; permanently discontinue dabrafenib (and trametinib) for all grade 4 hemorrhagic events and any grade 3 event that does not improve with therapy interruption.

• Hyperglycemia: Hyperglycemia may occur while on therapy (either as a single agent or in combination with trametinib); may require initiation of insulin or oral hypoglycemic agent therapy (or an increased dose if already taking). Monitor serum glucose at baseline and as clinically necessary in patients with preexisting diabetes or hyperglycemia. Instruct patients to report symptoms of severe hyperglycemia (eg, polydipsia, polyuria).

• Malignancy: Cutaneous squamous cell carcinoma and keratoacanthoma (cuSCC) and new primary melanoma were observed during single-agent dabrafenib therapy at an increased incidence compared with control therapy in clinical trials. The median time to the first occurrence of cuSCC was 2.1 months (range: 1 to 53 weeks); approximately one-third of patients who developed cuSCC had more than one occurrence (with continued treatment). The median time between diagnosis of the first and second lesions was 6 weeks. When used in combination with trametinib, cuSCC occurred less frequently than with single-agent dabrafenib therapy; time to diagnosis ranged from 1.8 to 16.8 months after the initiation of combination treatment, and from 9 days to ~21 months for single-agent therapy. Basal cell carcinoma (BCC) may also occur with combination or single-agent therapy; the incidence of BCC is ~3% for combination therapy versus 6% for single-agent dabrafenib. The time to BCC diagnosis ranged from ~3 to ~24 months for patients receiving combination therapy. Dermatologic evaluations should be performed prior to initiating therapy, every 2 months during therapy, and for up to 6 months post discontinuation. There are case reports of noncutaneous malignancies, including pancreatic cancer (KRAS mutation-positive), colorectal cancer (recurrent NRAS mutation-positive), hand and neck cancer, and glioblastoma, with combination therapy; monitor for signs/symptoms of noncutaneous malignancies. Dabrafenib should be permanently discontinued if RAS mutation-positive noncutaneous malignancies develop (no trametinib dosage reduction is required).

• Ocular toxicity: Retinal pigment epithelial detachments (RPED) were seen in clinical trials when used in combination with trametinib (a known complication of trametinib single-agent therapy). Detachments were typically bilateral and multifocal and occurred in the central macular area of the retina. Promptly (within 24 hours) refer patients for ophthalmological evaluations if loss of vision or other visual disturbances occur; dabrafenib dosage modification is not necessary for RPED (trametinib therapy modification may be required). Ophthalmic exams (including retinal evaluation) should be performed periodically during treatment with combination therapy. Uveitis, including iritis and iridocyclitis, has been reported with dabrafenib single-agent therapy and when used in combination with trametinib; manage symptomatically with local ophthalmic steroid and mydriatic drops. May require dabrafenib treatment interruption or permanent discontinuation (does not require alteration in trametinib therapy). Monitor for signs/symptoms of uveitis (eg, eye pain, photophobia, vision changes).

• QT prolongation: QTcF prolongation >60 msec above baseline or to >500 msec was reported (rare), both as a single agent or when used in combination with trametinib. Use with caution in patients who may be at increased risk for arrhythmias.

• Venous thromboembolism: Venous thromboembolism events (some fatal) may occur when dabrafenib is used in combination with trametinib. DVT and PE occurred at an increased incidence with combination therapy. Patients should seek immediate medical attention with symptoms of DVT or PE (shortness of breath, chest pain, arm/leg swelling). Dabrafenib therapy may be continued for uncomplicated DVT or PE; permanently discontinue trametinib for life-threatening PE.

Concurrent drug therapy issues:

• Combination therapy with trametinib: Serious adverse reactions (retinal vein occlusion, interstitial lung disease) that occur with single-agent trametinib may also occur when dabrafenib is administered in combination with trametinib.

• Drugs affecting gastric pH: Drugs affecting gastric pH (eg, proton pump inhibitors, H2-receptor antagonists, antacids) may alter dabrafenib solubility, resulting in decreased bioavailability. Clinical trials have not been performed to evaluate concomitant administration and its effect on dabrafenib efficacy.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Glucose-6-phosphate dehydrogenase deficiency: Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be at risk for hemolytic anemia when administered dabrafenib; use with caution and closely observe for signs/symptoms of hemolytic anemia.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• Appropriate use: Not indicated for treatment of patients with wild-type BRAF melanoma. Exposing wild-type cells to BRAF inhibitors such as dabrafenib may result in paradoxical activation of MAP-kinase signaling and increased cell proliferation. Prior to initiating therapy, confirm BRAF V600E or BRAF V600K mutations (US labeling) or BRAF V600 mutations (Canadian labeling) status with an approved test. Data regarding single agent use in patients with BRAF V600K mutation is limited; compared to BRAF V600E mutation, lower response rates have been observed with BRAF V600K mutation. Data regarding other less common BRAF V600 mutations is lacking.

Monitoring Parameters

BRAFV600 mutation status (prior to treatment); serum glucose (particularly in patients with preexisting diabetes mellitus or hyperglycemia); electrolytes; renal function; dermatologic evaluations prior to initiation, every 2 months during therapy, and for up to 6 months following discontinuation to assess for new cutaneous malignancies; monitor for febrile drug reactions and signs/symptoms of infections; signs/symptoms of uveitis (eg, eye pain, photophobia, vision changes), monitor for signs/symptoms of hemolytic anemia.

For patients receiving combination therapy with trametinib: Hepatic function (Canadian labeling recommends approximately every 4 weeks for 6 months after initiation then periodically as clinically indicated); CBC (baseline and periodically during therapy); assess LVEF (by echocardiogram or MUGA scan) at baseline, 1 month after therapy initiation, and then at 2- to 3-month intervals; monitor for signs/symptoms of hemorrhage, venous thromboembolism, interstitial lung disease, and RPED, or retinal vein occlusion.

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. Based on its mechanism of action, dabrafenib would be expected to cause fetal harm if administered to a pregnant woman. Females of reproductive potential should use a highly effective nonhormonal contraceptive during therapy and for at least 2 weeks [US labeling] or at least 4 weeks [Canadian labeling] (for single-agent therapy) or 4 months (for combination therapy with trametinib) after treatment is complete; hormonal contraceptives may not be effective. Spermatogenesis may be impaired in males (observed in animal studies); family planning and fertility counseling should be considered prior to therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hair loss, hard or thick skin, headache, joint pain, muscle pain, back pain, constipation, cough, rhinitis, or pharyngitis. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), acne, rash, skin redness, redness or irritation of palms or soles of feet, chills, jaundice, dark urine, blurred vision, blindness, vision changes, visual halos or bright colors around lights, eye pain, sensitivity to lights, severe headache, or angina (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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