DRUG INTERACTIONS

· Strong or moderate CYP3A4 inhibitors: Concomitant use may increase encorafenib plasma concentration. If concomitant use cannot be avoided, modify BRAFTOVI dose.

· Strong or moderate CYP3A4 inducers: Concomitant use may decrease encorafenib plasma concentrations. Avoid concomitant use.

 ·Sensitive CYP3A4 substrates: Concomitant use with BRAFTOVI may increase toxicity or decrease efficacy of these agents. Avoid hormonal contraceptives.

BRIEF SUMMARY

ENCORAFENIB-(June 2018)

Indn-     To treat unresectable or metastatic melanoma    

Comp-         Capsules: 50 mg and 75 mg  is a kinase inhibitor indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic me  

ADR-  Most common adverse reactions, in combination with binimetinib, are fatigue, nausea, vomiting, abdominal pain, and arthralgia.

CI-    None.

WARNINGS-                                                                                                                -New Primary Malignancies, cutaneous and non-cutaneous:  Can occur. Monitor for malignancies and perform dermatologic evaluations prior to, while on therapy, and following discontinuation of treatment. 

Pat Inform-                                                                                                           

Inform patients-

  New Primary Cutaneous Malignancies-                                                                           Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions

Hemorrhage-                                                                                                                      Advise patients to notify their healthcare provider immediately with any symptoms suggestive of hemorrhage, such as unusual bleeding

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  20

ADVERSE REACTIONS

Most common adverse reactions (>25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, vomiting, abdominal pain, and arthralgia.

   CONTRAINDICATIONS-                                                                                                    · None.

WARNINGS AND PRECAUTIONS-                                                                                    -New Primary Malignancies, cutaneous and non-cutaneous:  Can occur. Monitor for malignancies and perform dermatologic evaluations prior to, while on therapy, and following discontinuation of treatment. 

 - Tumor Promotion in BRAF Wild-Type Tumors: Increased cell proliferation can occur with BRAF inhibitors.                                                                                                   -

Hemorrhage: Major hemorrhagic events can occur.                                                         -

Uveitis: Perform ophthalmologic evaluation at regular intervals and for any visual disturbances.

-QT Prolongation: Monitor electrolytes before and during treatment. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. Withhold BRAFTOVI for QTc of 500 ms or greater.                                                                                                                                                                                                         - Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective non-hormonal method of contraception.

INDICATIONS AND USAGE-                                                                             BRAFTOVI is a kinase inhibitor 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. (1, 2.1)

 Limitations of Use:                                                                                                             BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma.

DOSAGE AND ADMINISTRATION -                                                                                  - Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI.                                                                                                  - The recommended dose is 450 mg orally once daily in combination with binimetinib. Take BRAFTOVI with or without food.

DOSAGE FORMS AND STRENGTHS-                                                                    - Capsules: 50 mg and 75 mg

PATIENT COUNSELING INFORMATION

 Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients of the following:   

 New Primary Cutaneous Malignancies-                                                                           Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions

Hemorrhage-                                                                                                                      Advise patients to notify their healthcare provider immediately with any symptoms suggestive of hemorrhage, such as unusual bleeding

 Uveitis-                                                                                                                                 Advise patients to contact their healthcare provider if they experience any changes in their vision

QT Prolongation-                                                                                                                 Advise patients that BRAFTOVI can cause QTc interval prolongation and to inform their physician if they have any QTc interval prolongation symptoms, such as syncope.

Females and Males of Reproductive Potential Embryo-Fetal Toxicity:                         Advise females with reproductive potential of the potential risk to a fetus.

 Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose.

 Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with BRAFTOVI’

Lactation:                                                                                                                             Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose.

Infertility:                                                                                                                             Advise males of reproductive potential that BRAFTOVI may impair fertility.

Strong or Moderate CYP3A Inducers or Inhibitors                                                          Coadministration of BRAFTOVI with a strong or moderate CYP3A inhibitor may increase encorafenib concentrations; while coadministration of BRAFTOVI with a strong or moderate CYP3A inducer may decrease encorafenib concentrations.  

  Advise patients that they need to avoid certain medications while taking BRAFTOVI and to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

 Advise patients to avoid grapefruit or grapefruit juice while taking BRAFTOVI

Storage-                                                                                                                                BRAFTOVI is moisture sensitive. Advise patients to store BRAFTOVI in the original bottle with desiccant and to keep the cap of the bottle tightly closed. Do not remove the desiccants from the bottle.

Distributed by:

 Array BioPharma Inc. 3200 Walnut Street Boulder, CO 80301 © 2018 Array BioPharma Inc. All rights reserved. BRAFTOVI™ is a trademark of Array BioPharma Inc.

CLINICAL PHARMACOLOGY-

1.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.

2. Pharmacodynamics-                                                                                                        Cardiac Electrophysiology -A dedicated study to evaluate the QT prolongation potential of BRAFTOVI has not been conducted. BRAFTOVI is associated with dose-dependent QTc interval prolongation.

3. 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.

 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 BRAFTOVI 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 BRAFTOVI increased the AUC of encorafenib by 3- and 2-fold, respectively, and increased the Cmax by 68% and 45%, respectively, after a single BRAFTOVI 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 BRAFTOVI (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.

USE IN SPECIFIC POPULATIONS

1.Pregnancy- Risk summary-                                                                                             Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of BRAFTOVI during pregnancy.                                                                                                                                                                                                                                                     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.

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 BRAFTOVI in breastfed infants, advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose.

3. Females and Males of Reproductive Potential Pregnancy Testing-                            Verify the pregnancy status of females of reproductive potential prior to initiating BRAFTOVI

Contraception- BRAFTOVI can cause fetal harm when administered to a pregnant woman.

 Females -Advise females of reproductive potential to use effective contraception during treatment with BRAFTOVI and for 2 weeks after the final dose

Counsel patients to use a non-hormonal method of contraception since BRAFTOVI has the potential to render hormonal contraceptives ineffective

 Infertility Males- Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of BRAFTOVI may impact fertility in males .

4. Pediatric Use The safety and effectiveness of BRAFTOVI have not been established in pediatric patients.

5. Geriatric Use- Of the 690 patients with BRAF mutation-positive melanoma who received BRAFTOVI 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 BRAFTOVI plus binimetinib were observed in elderly patients as compared to younger patients

6. Hepatic Impairment- Dose adjustment for BRAFTOVI is not recommended in patients with mild hepatic impairment (Child-Pugh Class A).

A recommended dose has not been established for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

7. Renal Impairment- No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min) . A recommended dose has not been established for patients with severe renal impairment (CLcr < 30 mL/min).

 OVERDOSAGE

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