DRUG INTERACTIONS

No clinically important drug interactions have been observed with MEKTOVI.

BRIEF SUMMARY

BINIMETINIB- (June  2018)

Indn-   To treat unresectable or metastatic melanoma                                                                                           

Comp-  Tablets: 15 mg.  The recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food

CI-   None. 

Pat Inform-                                                                                                    Cardiomyopathy-                                                                                                     Advise patients to report any symptoms of heart failure to their healthcare provider                                                                                                                                                Venous hrombosis-                                                                                                           Advise patients to contact their healthcare provider if they experience symptoms of venous thrombosis or pulmonary embolism. Advise patients to seek medical attention for sudden onset of difficulty breathing, leg pain, or swelling

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  19

ADVERSE REACTIONS

Most common adverse reactions (= 25%) for MEKTOVI, in combination with encorafenib, are fatigue, nausea, diarrhea, vomiting, and abdominal pain.

 Ocular Toxicities: Serous retinopathy, retinal vein occlusion (RVO) and uveitis have occurred. Perform an ophthalmologic evaluation at regular intervals and for any visual disturbances. 

 Interstitial Lung Disease (ILD): Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. 

 Hepatotoxicity: Monitor liver function tests before and during treatment and as clinically indicated. 

 Rhabdomyolysis: Monitor creatine phosphokinase and creatinine periodically and as clinically indicated. 

 Hemorrhage: Major hemorrhagic events can occur. (5.7) ? Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. 

PATIENT COUNSELING INFORMATION

 Advise the patient to read the FDA-approved patient labeling (Patient Information).

 Inform patients of the following:                                                                                     

  Cardiomyopathy-                                                                                                     Advise patients to report any symptoms of heart failure to their healthcare provider

Venous hrombosis-                                                                                                           Advise patients to contact their healthcare provider if they experience symptoms of venous thrombosis or pulmonary embolism. Advise patients to seek medical attention for sudden onset of difficulty breathing, leg pain, or swelling

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

Interstitial Lung Disease-                                                                                                 Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including cough or dyspnea.

Hepatotoxicity-                                                                                                                     Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with MEKTOVI.                                                                Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding

Rhabdomyolysis-                                                                                                                 Advise patients to contact their healthcare provider as soon as possible if they experience unusual or new onset weakness, myalgia, or darkened urine

Hemorrhage-                                                                                                                      Advise patients to notify their healthcare provider if they experience symptoms suggestive of hemorrhage, such as unusual bleeding

 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 contraception during treatment with MEKTOVI and for 30 days after the final dose.

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

 Lactation:                                                                                                                           Advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the final dose 

Distributed by:                                                                                                                    Array BioPharma Inc.                                                                                                        3200 Walnut Street Boulder, CO 80301                                                                           © 2018 Array BioPharma Inc. All rights reserved.                                                         

    MEKTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries.

CLINICAL PHARMACOLOGY-

1.Mechanism of Action-                                                                                                      Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway.

2. Pharmacokinetics-                                                                                                        The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is < 40% at steady state. The systemic exposure of binimetinib is approximately dose proportional.

Absorption-                                                                                                                         After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours.

Effect of Food --                                                                                                                  The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure.

Distribution-                                                                                                                     Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%).

Elimination-                                                                                                                        The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%).

Metabolism-                                                                                                                        The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure.

Excretion-                                                                                                                             Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine.

 Specific Populations Age (20 to 94 years), sex, or body weight-                                    do not have a clinically important effect on the systemic exposure of binimetinib. The effect of race or ethnicity on the pharmacokinetics of binimetinib is unknown.

 Hepatic Impairment:                                                                                                            No clinically meaningful changes in binimetinib exposure (AUC and Cmax) were observed in subjects with mild hepatic impairment (total bilirubin > 1 and = 1.5 × ULN and any AST or total bilirubin = ULN and AST > ULN) as compared to subjects with normal liver function (total bilirubin = ULN and AST = ULN).

Renal Impairment:                                                                                                               In subjects with severe renal impairment (eGFR = 29 mL/min/1.73 m2), no clinically important changes in binimetinib exposure were observed as compared to subjects with normal renal function. 

Drug Interaction Studies-

Clinical Studies Effect of UGT1A1 Inducers or Inhibitors on Binimetinib:                    UGT1A1 genotype and smoking (UGT1A1 inducer) do not have a clinically important effect on binimetinib exposure..

 No differences in binimetinib exposure have been observed when MEKTOVI is coadministered with encorafenib.

 Effect of Binimetinib on CYP Substrates: Binimetinib did not alter the exposure of a sensitive CYP3A4 substrate (midazolam).

 Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered in the presence of a gastric acid reducing agent (rabeprazole). In Vitro Studies Effect of Binimetinib on CYP Substrates: Binimetinib is not a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A.

 Effect of Transporters on Binimetinib: Binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter 1 (OCT1).

USE IN SPECIFIC POPULATIONS-       

 1.Pregnancy Risk Summary-                                                                                            Based on findings from animal reproduction studies and its mechanism of action,   MEKTOVI can cause fetal harm when administered to a pregnant woman.                       There are no available clinical data on the use of MEKTOVI during pregnancy.

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 binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed infant, or on milk production                         

 Because of the potential for serious adverse reactions from MEKTOVI in breastfed infants, advise women not to breastfeed during treatment with MEKTOVI and for 3 days 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 MEKTOVI

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

Females-                                                                                                                               Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose.

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

5. Geriatric Use-                                                                                                                   Of the 690 patients with BRAF mutation-positive melanoma who received MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once 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 MEKTOVI plus encorafenib were observed in elderly patients as compared to younger patients

6. Hepatic Impairment-                                                                                                                      Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Dose adjustment for MEKTOVI is not recommended in patients with mild hepatic impairment (total bilirubin > 1 and = 1.5 × ULN and any AST or total bilirubin = ULN and AST > ULN).                                                             

 Reduce the dose of MEKTOVI for patients with moderate (total bilirubin > 1.5 and = 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment

OVERDOSAGE-                                                                                                                 Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKTOVI.