Note: Confirm BRAF V600 mutation status prior to treatment initiation. Correct hypokalemia or hypomagnesemia prior to treatment initiation.
Colorectal cancer, metastatic, BRAF V600E mutation-positive: Oral: 300 mg once daily (in combination with cetuximab) until disease progression or unacceptable toxicity (Kopetz 2019; Tabernero 2021).
Melanoma, unresectable or metastatic, with BRAF V600E or BRAF V600K mutation: Oral: 450 mg once daily (in combination with binimetinib) until disease progression or unacceptable toxicity (Dummer 2018).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Missed doses: Do not administer a missed dose if <12 hours until the next dose. Do not take an additional dose if vomiting occurs after encorafenib administration; resume with the next scheduled dose.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hemodialysis: Not likely dialyzed due to extensive protein binding.
Preexisting hepatic impairment:
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate to severe impairment (Child-Pugh class B or C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment:
Grade 2 AST or ALT elevations: Maintain encorafenib dose; if no improvement within 4 weeks, withhold encorafenib until improvement to ≤ grade 1 or to pretreatment/baseline levels and then resume at the same dose.
Grade 3 AST or ALT elevation: For the first occurrence of grade 3 AST or ALT elevations, withhold encorafenib for up to 4 weeks; if improves to ≤ grade 1 or to pretreatment/baseline level, resume encorafenib at a reduced dose. If no improvement, permanently discontinue encorafenib. For recurrent grade 3 toxicity, consider permanently discontinuing encorafenib.
Grade 4 AST or ALT elevation: For the first occurrence of grade 4 AST or ALT elevations, permanently discontinue encorafenib or withhold encorafenib for up to 4 weeks; if improves to ≤ grade 1 or to pretreatment/baseline level, resume encorafenib at a reduced dose. If no improvement, permanently discontinue encorafenib. For recurrent grade 4 toxicity, permanently discontinue encorafenib.
Refer to adult dosing.
Note: In metastatic melanoma, if encorafenib is permanently discontinued, discontinue binimetinib. If binimetinib is withheld, reduce encorafenib dose to a maximum of 300 mg once daily until binimetinib therapy is resumed. In metastatic colorectal cancer, if cetuximab is discontinued, discontinue encorafenib. Refer to the Binimetinib or Cetuximab monographs for recommended dose reductions.
When used in combination with binimetinib or cetuximab, encorafenib dosage modification is not recommended for new primary cutaneous malignancies, ocular events (other than uveitis, iritis, and iridocyclitis), interstitial lung disease/pneumonitis, cardiac dysfunction (other than QTc prolongation), creatine phosphokinase elevation, rhabdomyolysis, and venous thromboembolism.
Recommended encorafenib dose reductions for toxicity:
Colorectal cancer, metastatic:
Initial dose: 300 mg once daily.
First dose reduction: 225 mg once daily.
Second dose reduction: 150 mg once daily.
Subsequent modifications (if unable to tolerate 150 mg once daily): Permanently discontinue encorafenib.
Melanoma, unresectable or metastatic:
Initial dose: 450 mg once daily.
First dose reduction: 300 mg once daily.
Second dose reduction: 225 mg once daily.
Subsequent modifications (if unable to tolerate 225 mg once daily): Permanently discontinue encorafenib.
Dermatologic toxicity (excluding hand-foot skin reaction):
Grade 2 toxicity: If no improvement within 2 weeks, withhold encorafenib until ≤ grade 1, then resume at the same dose.
Grade 3 toxicity: Withhold encorafenib until ≤ grade 1; resume at the same dose if first occurrence, or reduce the dose if recurrent grade 3 toxicity.
Grade 4 toxicity: Permanently discontinue encorafenib.
Ocular toxicity:
Uveitis including iritis and iridocyclitis: If grade 1 or 2 uveitis does not respond to specific ocular therapy (or for grade 3 uveitis), interrupt encorafenib therapy for up to 6 weeks. If improves within 6 weeks following therapy interruption, resume at the same dose or a lower dose. If does not improve, permanently discontinue encorafenib. Permanently discontinue for grade 4 uveitis.
QTc prolongation:
QTcF >500 msec and ≤60 msec increase from baseline: Withhold encorafenib until QTcF is ≤500 msec; then resume at a reduced dose. If more than 1 recurrence, permanently discontinue encorafenib.
QTcF >500 msec and >60 msec increase from baseline: Permanently discontinue encorafenib.
Other toxicity (including hemorrhage and hand-foot skin reaction):
Recurrent grade 2 or first occurrence of any grade 3 toxicity: Interrupt encorafenib therapy for up to 4 weeks; if improves to ≤ grade 1 or to pretreatment/baseline level, resume at a reduced dose. If no improvement, permanently discontinue encorafenib.
Grade 3 toxicity (recurrent): Consider permanently discontinuing encorafenib.
Grade 4 toxicity (first occurrence): Permanently discontinue encorafenib or withhold encorafenib therapy for up to 4 weeks until improvement to ≤ grade 1 or to pretreatment/baseline level, then resume at a reduced dose (permanently discontinue if no improvement).
Grade 4 toxicity (recurrent): Permanently discontinue encorafenib.
New primary noncutaneous malignancy (RAS mutation-positive): Permanently discontinue encorafenib.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Braftovi: 50 mg [DSC], 75 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Braftovi: 75 mg
Encorafenib is available through a network of select specialty pharmacies. Refer to https://www.braftovimektovi.com/hcp/ for more information.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210496s013lbl.pdf#page=22, must be dispensed with this medication.
Oral: Administer once daily with or without food.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Encorafenib may cause carcinogenicity and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Colorectal cancer, metastatic: Treatment of metastatic colorectal cancer in adults with a BRAF V600E mutation (in combination with cetuximab) as detected by an approved test, after prior therapy.
Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation (in combination with binimetinib) as detected by an approved test.
Limitations of use: Encorafenib is not indicated for treatment of wild-type BRAF melanoma or wild-type BRAF colorectal cancer.
Encorafenib may be confused with binimetinib, cobimetinib, dabrafenib, dasatinib, enasidenib, enfortumab vedotin, entrectinib, erdafitinib, erlotinib, trametinib, vemurafenib
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence of adverse reactions for encorafenib are in combination therapy with either binimetinib or cetuximab, unless otherwise noted. Encorafenib as a single agent is associated with an increased risk of certain adverse reactions.
>10%:
Dermatologic: Acneiform eruption (combination therapy: 3% to 32%; single agent: 8%), alopecia (single agent: 56%; combination therapy: 14%), dermatological reaction (grades 3/4: single agent: 21%; combination therapy: 2%), erythema of skin (single agent: 16%; combination therapy: 7%), hyperkeratosis (single agent: 57%; combination therapy: 23%), melanocytic nevus (14%), palmar-plantar erythrodysesthesia (single agent: 51%; combination therapy: 7%), pruritus (single agent: 31%; combination therapy: 13% to 14%), skin rash (single agent: 41%; combination therapy: 22% to 26%), xeroderma (single agent: 38%; combination therapy: 13% to 16%)
Endocrine & metabolic: Hyperglycemia (28%), hypokalemia (12%), hypomagnesemia (19%), hyponatremia (11% to 18%), increased gamma-glutamyl transferase (45%)
Gastrointestinal: Abdominal pain (28% to 30%), constipation (15% to 22%), decreased appetite (27%), diarrhea (33%), dysgeusia (single agent: 13%, combination therapy: 6%), nausea (34% to 41%), vomiting (21% to 30%)
Hematologic & oncologic: Anemia (34% to 36%; grades 3/4: 4%), hemorrhage (19%; grades 3/4: 2% to 3%), leukopenia (13%), lymphocytopenia (13% to 24%; grades 3/4: 2% to 7%), neutropenia (13%; grades 3/4: 3%), prolonged partial thromboplastin time (13%; grades 3/4: 1%)
Hepatic: Increased serum alanine aminotransferase (17% to 29%), increased serum alkaline phosphatase (18% to 21%), increased serum aspartate aminotransferase (15% to 27%)
Nervous system: Dizziness (15%), fatigue (43% to 51%), headache (20% to 22%), insomnia (13%), peripheral neuropathy (12%; grades 3/4: 1%)
Neuromuscular & skeletal: Arthralgia (single agent: 44%; combination therapy: 26% to 27%), back pain (single agent: 15%; combination therapy: 9%), limb pain (10% to 11%), myopathy (single agent: 33%; combination therapy: 15% to 23%)
Renal: Increased serum creatinine (93%)
Miscellaneous: Fever (17% to 18%)
1% to 10%:
Endocrine & metabolic: Hypermagnesemia (10%)
Gastrointestinal: Hematochezia (2% to 3%), hemorrhoidal bleeding (1% to 2%), pancreatitis (<10%)
Hematologic & oncologic: Basal cell carcinoma of skin (combination therapy: 2%; single agent: 1%), keratoacanthoma (single agent: ≤8%; combination therapy: ≤3%), malignant melanoma (single agent: 5%; combination therapy: 1%), rectal hemorrhage (4%), squamous cell carcinoma of skin (single agent: ≤8%; combination therapy: ≤3%)
Hypersensitivity: Hypersensitivity reaction (<10%)
Nervous system: Facial paresis (<10%)
Neuromuscular & skeletal: Panniculitis (<10%)
Ophthalmic: Uveitis (4%, including iritis and iridocyclitis)
Respiratory: Epistaxis (7%)
<1%: Cardiovascular: Prolonged QT interval on ECG
Frequency not defined:
Gastrointestinal: Gastrointestinal hemorrhage
Nervous system: Intracranial hemorrhage
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to encorafenib or any component of the formulation.
Concerns related to adverse effects:
• Dermatologic toxicity: Grade 3 or 4 dermatologic toxicity occurred in ~20% of patients receiving encorafenib as a single agent, compared to 2% of patients receiving the combination of encorafenib and binimetinib.
• Hemorrhage: Hemorrhage, including ≥ grade 3 events, may occur when administered in combination with other agents. The most frequent hemorrhagic events in melanoma patients were GI in nature, including rectal hemorrhage, hematochezia, and hemorrhoidal hemorrhage. Fatal intracranial hemorrhage (in the setting of new or progressive brain metastases) was also reported. In a study of metastatic colorectal cancer, epistaxis, hematochezia, and rectal hemorrhage occurred most frequently; fatal GI hemorrhage also was reported (rarely).
• Malignancy: New primary malignancies (cutaneous and noncutaneous) have been observed in patients treated with BRAF inhibitors and may occur with encorafenib. Cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), as well as basal cell carcinoma and new primary melanoma occurred in patients receiving encorafenib in combination with other agents; the median time to first onset of cuSCC/KA in patients with melanoma was ~6 months (range: 1 to 9 months). Cases of cuSCC/KA, basal cell carcinoma, and new primary melanoma were also observed in patients receiving encorafenib monotherapy. Due to its mechanism of action (activation of RAS through mutation or other mechanisms), other noncutaneous malignancies may develop with encorafenib use.
• Ocular toxicity: Uveitis, including iritis and iridocyclitis, has been observed with the combination of encorafenib and binimetinib.
• QT prolongation: Encorafenib is associated with dose dependent QTc interval prolongation. In a clinical trial, QTcF prolongation to >500 msec was reported (rare) when used in combination with binimetinib. Patients at risk for developing QTc prolongation include those with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, or concomitant use of medications associated with QT prolongation.
Concurrent drug therapy issues:
• Combination therapy: Additional toxicities may occur when used in combination with binimetinib or cetuximab.
Other warnings/precautions:
• Appropriate use: Encorafenib is not indicated for treatment of patients with wild-type BRAF melanoma or wild-type BRAF colorectal cancer. Exposing BRAF wild-type cells to BRAF inhibitors such as encorafenib may result in paradoxical activation of MAP-kinase signaling and increased cell proliferation. Prior to initiating therapy, confirm BRAF V600E or BRAF V600K mutation status with an approved test. Information on approved tests for detection of BRAF V600 mutations is available at http://www.fda.gov/companiondiagnostics.
Substrate of CYP2C19 (minor), CYP2D6 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BCRP/ABCG2, OATP1B1/1B3 (SLCO1B1/1B3)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Risk D: Consider therapy modification
Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy
Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Risk X: Avoid combination
Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Atogepant. Management: The recommended dose of atogepant when coadministered with OATP1B1/1B3 inhibitors is 10 mg once daily or 30 mg once daily. Risk D: Consider therapy modification
Azithromycin (Systemic): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors): Encorafenib may increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Berotralstat: BCRP/ABCG2 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with BCRP inhibitors. Risk D: Consider therapy modification
Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider therapy modification
Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Risk D: Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Encorafenib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Encorafenib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and moderate CYP3A4 inhibitors when possible. If combined, decrease the encorafenib dose from 450 mg to 225 mg; 300 mg to 150 mg; and 225 mg or 150 mg to 75 mg. Resume prior dose once inhibitor discontinued for 3 to 5 half-lives. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and strong CYP3A4 inhibitors when possible. If combined, decrease encorafenib from 450 mg to 150 mg; or from 300 mg, 225 mg, or 150 mg to 75 mg. Once the CYP3A4 inhibitor is discontinued for 3 to 5 half-lives, resume prior dose. Risk D: Consider therapy modification
Dabrafenib: May enhance the QTc-prolonging effect of Encorafenib. Dabrafenib may decrease the serum concentration of Encorafenib. Risk X: Avoid combination
Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Dronedarone: Encorafenib may enhance the QTc-prolonging effect of Dronedarone. Dronedarone may increase the serum concentration of Encorafenib. Management: Avoid use of dronedarone and encorafenib if possible. If combined, reduce the encorafenib dose (if 450 mg, decrease to 225 mg; if 300 mg decrease to 150 mg; if 225 mg or 150 mg decrease to 75 mg) and monitor the QT interval. Risk D: Consider therapy modification
Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Risk X: Avoid combination
Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid combination
Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination
Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with OATP1B1/1B3 inhibitors and monitor patients for increased eluxadoline effects/toxicities. Risk D: Consider therapy modification
Fexinidazole: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fexinidazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Fluorouracil Products: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Grapefruit Juice: May increase the serum concentration of Encorafenib. Risk X: Avoid combination
Haloperidol: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Hormonal Contraceptives: Encorafenib may decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination
Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination
Midostaurin: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors): Encorafenib may increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
OLANZapine: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
PAZOPanib: Encorafenib may enhance the QTc-prolonging effect of PAZOPanib. Encorafenib may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination
QT-prolonging Agents (Highest Risk): Encorafenib may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-Prolonging Inhalational Anesthetics (Moderate Risk): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): Encorafenib may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and moderate CYP3A4 inhibitors when possible. If combined, decrease encorafenib dose from 450 mg to 225 mg; 300 mg to 150 mg; and 225 mg or 150 mg to 75 mg. Monitor closely for QT interval prolongation. Risk D: Consider therapy modification
QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Encorafenib. QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk) may increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and strong CYP3A4 inhibitors when possible. If combined, decrease encorafenib dose from 450 mg to 150 mg; or from 300 mg, 225 mg, or 150 mg to 75 mg. Monitor closely for QT interval prolongation. Risk D: Consider therapy modification
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Encorafenib may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and strong CYP3A4 inhibitors when possible. If combined, decrease encorafenib dose from 450 mg to 150 mg; or from 300 mg, 225 mg, or 150 mg to 75 mg. Monitor closely for QT interval prolongation. Risk D: Consider therapy modification
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Risk X: Avoid combination
RisperiDONE: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Rosuvastatin: BCRP/ABCG2 Inhibitors may increase the serum concentration of Rosuvastatin. Risk C: Monitor therapy
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Taurursodiol. Risk X: Avoid combination
Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a BCRP inhibitor. Risk D: Consider therapy modification
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination
Coadministration with a grapefruit or grapefruit juice may increase encorafenib concentrations. Management: Avoid grapefruit or grapefruit juice while taking encorafenib.
Verify pregnancy status prior to initiating encorafenib therapy in patients who can become pregnant. Patients who can become pregnant should use a highly effective nonhormonal contraceptive during therapy and for at least 2 weeks after the last encorafenib dose; hormonal contraceptives may not be effective.
Based on its mechanism of action and on findings in animal reproduction studies, encorafenib may cause fetal harm if administered during pregnancy.
It is not known if encorafenib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 2 weeks after the last encorafenib dose.
BRAFV600K or V600E mutation status (prior to treatment). Monitor electrolytes. Verify pregnancy status (in females of reproductive potential) prior to treatment initiation. Conduct dermatologic evaluations prior to treatment initiation, every 2 months during therapy, and for up to 6 months following discontinuation to assess for new cutaneous malignancies. Monitor for QT prolongation in patients with or at risk for developing QTc prolongation. Assess for visual symptoms at each visit; perform an ophthalmologic evaluation regularly and for new or worsening visual disturbances (and to follow new or persistent ophthalmologic findings); monitor for signs/symptoms of uveitis (eg, eye pain, photophobia, vision changes). Monitor for signs/symptoms of hemorrhage, dermatologic toxicity (conduct dermatopathologic evaluations for suspicious lesions), and for noncutaneous malignancies. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Encorafenib is an ATP-competitive inhibitor of protein kinase B-raf (BRAF) which suppresses the MAPK pathway (Dummer 2018). Encorafenib targets BRAF V600E, V600 D, and V600 K, and has a longer dissociation half-life than other BRAF inhibitors, allowing for sustained inhibition (Dummer 2018). BRAF V600 mutations result in constitutive activation of the BRAF pathway (which may stimulate tumor growth); BRAF inhibition inhibits tumor cell growth. The combination of encorafenib and binimetinib allows for greater antitumor activity in BRAF V600 mutant cell lines; in animal studies, the combination also delayed the emergence of resistance in BRAF V600E mutant cells compared to either drug alone. In BRAF-mutant colorectal cancer, EGFR-mediated MAPK pathway activation is a resistance mechanism to BRAF inhibitors; the combination of a BRAF inhibitor and anti-EGFR agents has been shown to overcome this resistance mechanism (in nonclinical models). The combination of encorafenib and cetuximab had an anti-tumor effect greater than either agent alone (in an animal model).
Absorption: At least 86% of the dose is absorbed.
Distribution: 164 L.
Protein binding: 86% to plasma proteins.
Metabolism: Primarily via CYP3A4 and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%).
Half-life elimination: 3.5 hours.
Time to peak: 2 hours.
Excretion: Feces (47%; 5% as unchanged drug); urine (47%; 2% as unchanged drug).
Capsules (Braftovi Oral)
75 mg (per each): $133.74
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