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Encorafenib Capsules

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Encorafenib is a kinase inhibitor. The chemical name is methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate. The chemical structure of encorafenib is shown below:

Empirical formula: C22H27ClFN7O4S - Molecular weight: 540 daltons

Encorafenib is a white to almost white powder. In aqueous media, encorafenib is slightly soluble at pH 1, very slightly soluble at pH 2, and insoluble at pH 3 and higher.

Encorafenib capsules for oral use contain 50 mg or 75 mg of encorafenib with the following inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, magnesium stearate (vegetable origin). The capsule shell contains gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol).

2. INDICATIONS AND USAGE

Encorafenib is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test [see Dosage and Administration (3.1)].

Limitations of Use:

Encorafenib is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

3. DOSAGE AND ADMINISTRATION

3.1 Patient Selection

Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating encorafenib [see Warnings and Precautions (5.2), Clinical Studies]. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

3.2 Recommended Dosage

The recommended dosage of encorafenib is 450 mg orally taken once daily in combination with binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information for recommended binimetinib dosing information.

Encorafenib may be taken with or without food [see Clinical Pharmacology]. Do not take a missed dose of encorafenib within 12 hours of the next dose of encorafenib.

Do not take an additional dose if vomiting occurs after encorafenib administration but continue with the next scheduled dose.

3.3 Dosage Modifications for Adverse Reactions

If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg once daily until binimetinib is resumed [see Warnings and Precautions (5.7)].

Dose reductions for adverse reactions associated with encorafenib are presented in Table 1.

Table 1: Recommended Dose Reductions for Encorafenib for Adverse Reactions

Dosage modifications for adverse reactions associated with encorafenib are presented in Table 2.

Table 2: Recommended Dosage Modifications for Encorafenib for Adverse Reactions

a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

b Dose modification of encorafenib when administered with binimetinib is not recommended for new primary cutaneous malignancies; ocular events other than uveitis, iritis, and iridocyclitis; interstitial lung disease/pneumonitis; cardiac dysfunction; creatine phosphokinase (CPK) elevation; rhabdomyolysis; and venous thromboembolism.

Refer to the binimetinib prescribing information for dose modifications for adverse reactions associated with binimetinib.

3.4 Dose Modifications for Coadministration of Strong or Moderate CYP3A4 Inhibitors

Avoid concurrent use of strong or moderate CYP3A4 inhibitors during treatment with encorafenib. If concomitant use of a strong or moderate CYP3A4 inhibitor is unavoidable, reduce the encorafenib dose to one-third of the encorafenib dose prior to concurrent use of strong CYP3A4 inhibitors or one-half of the encorafenib dose prior to concurrent use of moderate CYP3A4 inhibitors. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology].

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib.

Cutaneous Malignancies

In COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received encorafenib in combination with binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months) [see Adverse Reactions (6.1)].

For patients who received encorafenib as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients.

Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies.

Non-Cutaneous Malignancies

Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving encorafenib for signs and symptoms of non-cutaneous malignancies. Discontinue encorafenib for RAS mutation-positive non-cutaneous malignancies [see Dosage and Administration (3.3)].

5.2 Tumor Promotion in BRAF Wild-Type Tumors

In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating encorafenib [see Indications and Usage (2), Dosage and Administration (3.1)].

5.3 Hemorrhage

Hemorrhage can occur when encorafenib is administered in combination with binimetinib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving encorafenib in combination with binimetinib; Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (3.3), Adverse Reactions (6.1)].

5.4 Uveitis

Uveitis, including iritis and iridocyclitis, has been reported in patients treated with encorafenib in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with encorafenib in combination with binimetinib was 4%.

Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (3.3), Adverse Reactions (6.1)].

5.5 QT Prolongation

Encorafenib is associated with dose-dependent QTc interval prolongation in some patients [see Clinical Pharmacology]. In COLUMBUS, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients who received encorafenib in combination with binimetinib.

Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during encorafenib administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms [see Dosage and Administration (3.3), Adverse Reactions (6.1)].

5.6 Embryo-Fetal Toxicity

Based on its mechanism of action, encorafenib can cause fetal harm when administered to a pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses.

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective, non-hormonal method of contraception since encorafenib can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the final dose of encorafenib [see Use in Specific Populations (8.1, 8.3)].

5.7 Risks Associated with Encorafenib as a Single Agent

Encorafenib when used as a single agent is associated with an increased risk of certain adverse reactions compared to when encorafenib is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with encorafenib single agent compared to 2% of patients treated with encorafenib in combination with binimetinib [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of encorafenib as recommended [see Dosage and Administration (3.3)].

5.8 Risks Associated with Combination Treatment

Encorafenib is indicated for use in combination with binimetinib. Refer to the binimetinib prescribing information for additional risk information that applies to combination use treatment.

6. ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

 New Primary Malignancies [see Warnings and Precautions (5.1)]

 Hemorrhage [see Warnings and Precautions (5.3)]

 Uveitis [see Warnings and Precautions (5.4)]

 QT Prolongation [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of encorafenib in combination with binimetinib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received encorafenib (450 mg once daily) in combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial (COLUMBUS).

The COLUMBUS trial [see Clinical Studies] excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with encorafenib in combination with binimetinib and 6.2 months for patients treated with vemurafenib.

The most common (≥ 25%) adverse reactions in patients receiving encorafenib in combination with binimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia.

Adverse reactions leading to dose interruptions of encorafenib occurred in 30% of patients receiving encorafenib in combination with binimetinib; the most common were nausea (7%), vomiting (7%) and pyrexia (4%). Adverse reactions leading to dose reductions of encorafenib occurred in 14% of patients receiving encorafenib in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%) and nausea (2%). Five percent (5%) of patients receiving encorafenib in combination with binimetinib experienced an adverse reaction that resulted in permanent discontinuation of encorafenib; the most common were hemorrhage in 2% and headache in 1% of patients.

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for encorafenib in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3.

Table 3: Adverse Reactions Occurring in ≥ 10% of Patients Receiving Encorafenib in Combination with Binimetinib in COLUMBUSa

a Grades per National Cancer Institute CTCAE v4.03.

b Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1) and rash (n=1) in the encorafenib with binimetinib arm.

c Represents a composite of multiple, related preferred terms.

Encorafenib when used as a single agent increases the risk of certain adverse reactions compared to encorafenib in combination with binimetinib. In patients receiving encorafenib 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥ 5%) compared to patients receiving encorafenib in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%).

Other clinically important adverse reactions occurring in < 10% of patients who received encorafenib in combination with binimetinib were:

Nervous system disorders: Facial paresis

Gastrointestinal disorders: Pancreatitis

Skin and subcutaneous tissue disorders: Panniculitis

Immune system disorders: Drug hypersensitivity

Table 4: Laboratory Abnormalities Occurring in ≥ 10% (All Grades) of Patients Receiving Encorafenib in Combination with Binimetinib in COLUMBUSa

a Grades per National Cancer Institute CTCAE v4.03.

7. DRUG INTERACTIONS

7.1 Effect of Other Drugs on Encorafenib

Strong or Moderate CYP3A4 Inhibitors

Concomitant administration of encorafenib with a strong or moderate CYP3A4 inhibitor increased encorafenib plasma concentrations and may increase encorafenib adverse reactions [see Clinical Pharmacology]. Avoid coadministration of encorafenib with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration of strong or moderate CYP3A4 inhibitors cannot be avoided, modify dose as recommended [see Dosage and Administration (3.4)].

Strong or Moderate CYP3A4 Inducers

Concomitant administration of encorafenib with a strong or moderate CYP3A4 inducer may decrease encorafenib plasma concentrations and may decrease encorafenib efficacy [see Clinical Pharmacology]. Avoid concomitant administration of strong or moderate CYP3A4 inducers with encorafenib.

7.2 Effect of Encorafenib on Other Drugs

Sensitive CYP3A4 Substrates

Concomitant administration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

Coadministration of encorafenib with hormonal contraceptives (CYP3A4 substrates) can result in decreased concentrations and loss of hormonal contraceptive efficacy. Avoid hormonal contraceptives [see Use in Specific Populations (8.3)].

7.3 Drugs That Prolong the QT Interval

Encorafenib is associated with dose-dependent QTc interval prolongation. Avoid coadministration of encorafenib with medicinal products with a known potential to prolong QT/QTc interval [see Warnings and Precautions (5.5), Clinical Pharmacology].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, encorafenib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. There are no available clinical data on the use of encorafenib during pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time curve [AUC] at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure.

8.2 Lactation

Risk Summary

There are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from encorafenib in breastfed infants, advise women not to breastfeed during treatment with encorafenib and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating encorafenib [see Use in Specific Populations (8.1)].

Contraception

Encorafenib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with encorafenib and for 2 weeks after the final dose. Counsel patients to use a non-hormonal method of contraception since encorafenib has the potential to render hormonal contraceptives ineffective [see Drug Interactions (7.2)].

Infertility

Males

Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of encorafenib may impact fertility in males [see Nonclinical Toxicology].

8.4 Pediatric Use

The safety and effectiveness of encorafenib have not been established in pediatric patients.

8.5 Geriatric Use

Of the 690 patients with BRAF mutation-positive melanoma who received encorafenib at doses between 300 mg and 600 mg once daily in combination with binimetinib (45 mg twice daily) across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of encorafenib plus binimetinib were observed in elderly patients as compared to younger patients [see Clinical Pharmacology].

8.6 Hepatic Impairment

Dose adjustment for encorafenib is not recommended in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology]. A recommended dose has not been established for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

8.7 Renal Impairment

No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min) [see Clinical Pharmacology]. A recommended dose has not been established for patients with severe renal impairment (CLcr < 30 mL/min).

9. OVERDOSAGE

Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with encorafenib.

10. MECHANISM OF ACTION

Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and substantially reduce ligand binding to these kinases at clinically achievable concentrations (≤ 0.9 μM).

Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression.

Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone.

11. PHARMACODYNAMICS

Cardiac Electrophysiology

A dedicated study to evaluate the QT prolongation potential of encorafenib has not been conducted. Encorafenib is associated with dose-dependent QTc interval prolongation. Following administration of the recommended dose of encorafenib in combination with binimetinib, based on a central tendency analysis of QTc in a study of adult patients with melanoma, the largest mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (14 to 22) ms [see Warnings and Precautions (5.5)].

12. PHARMACOKINETICS

The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation. After a single dose, systemic exposure of encorafenib was dose proportional over the dose range of 50 mg to 700 mg. After once-daily dosing, systemic exposure of encorafenib was less than dose proportional over the dose range of 50 mg to 800 mg. Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%.

Absorption

After oral administration, the median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed.

Effect of Food

Administration of a single dose of encorafenib 100 mg (0.2 times the recommended dose) with a high-fat, high-calorie meal (comprised of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) decreased the mean maximum encorafenib concentration (Cmax) by 36% with no effect on AUC.

Distribution

Encorafenib is 86% bound to human plasma proteins in vitro. The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%).

Elimination

The mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%), and the apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state.

Metabolism

The primary metabolic pathway is N-dealkylation, with CYP3A4 as the main contributor (83%) to total oxidative clearance of encorafenib in human liver microsomes, followed by CYP2C19 (16%) and CYP2D6 (1%).

Excretion

Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine.

Specific Populations

Age (19 to 89 years), sex, body weight, mild hepatic impairment (Child-Pugh Class A), and mild or moderate renal impairment (CLcr 30 to < 90 mL/min) do not have a clinically meaningful effect on the pharmacokinetics of encorafenib. The effect of race or ethnicity, moderate or severe hepatic impairment (Child-Pugh Class B or C), and severe renal impairment (CLcr < 30 mL/min) on encorafenib pharmacokinetics have not been studied.

Drug Interaction Studies

Clinical Studies

Effect of CYP3A4 Inhibitors on Encorafenib: Coadministration of a strong (posaconazole) or moderate (diltiazem) CYP3A4 inhibitor with encorafenib increased the AUC of encorafenib by 3- and 2-fold, respectively, and increased the Cmax by 68% and 45%, respectively, after a single encorafenib dose of 50 mg (0.1 times the recommended dose).

Effect of CYP3A4 Inducers on Encorafenib: The effect of coadministration of a CYP3A4 inducer on encorafenib exposure has not been studied. In clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.

Effect of Acid Reducing Agents on Encorafenib: Coadministration of a proton pump inhibitor, rabeprazole, had no effect on AUC and Cmax of encorafenib.

Combination Treatment: Coadministration of encorafenib (UGT1A1 inhibitor) with binimetinib (UGT1A1 substrate) had no effect on binimetinib exposure.

In Vitro Studies

Effect of Encorafenib on CYP/UGT Substrates: Encorafenib is a reversible inhibitor of UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, and CYP3A, and a time-dependent inhibitor of CYP3A4 at clinically relevant plasma concentrations. Encorafenib induced CYP2B6, CYP2C9, and CYP3A4 at clinically relevant plasma concentrations.

Effect of Transporters on Encorafenib: Encorafenib is a substrate of P-glycoprotein (P-gp). Encorafenib is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), organic anion transporting polypeptide (OATP1B1, OATP1B3) or organic cation transporter (OCT1) at clinically relevant plasma concentrations.

Effect of Encorafenib on Transporters: Encorafenib inhibited P-gp, BCRP, OCT2, organic anion transporter (OAT1, OAT3), OATP1B1, and OATP1B3, but not OCT1 or MRP2 at clinically relevant plasma concentrations.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

BRAFTOVI (encorafenib) is supplied as 50 mg and 75 mg hard gelatin capsules.

50 mg: stylized “A” on orange cap and “LGX 50mg” on beige body, available in cartons (NDC 70255-020-01) containing two bottles of 60 capsules each (NDC 70255-020-02).

75 mg: stylized “A” on beige cap and “LGX 75mg” on white body, available in cartons (NDC 70255-025-01) containing two bottles of 90 capsules each (NDC 70255-025-02)

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Do not use if safety seal under cap is broken or missing. Dispense in original bottle. Do not remove desiccant. Protect from moisture. Keep container tightly closed.

Rx only

Rev 06/18