DRUG INTERACTIONS--

 Avoid concomitant administration of COTELLIC with strong or moderate CYP3A inducers or inhibitors

35/15 PRODUCT DETAILS 

Name of the drug-      COTELLIC

Active ingriendents-   Cobemetinib

FDA approved use-    To be used in combination to treat advanced melanoma that                                       has spread to other parts of the body or cant be removed by                                          surgery and that has  a certain abnormal gene(BRAF                                                    V60DE OR  VR=60OK MUTATION)

 Date of Approval         10/10/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use COTELLIC safely and effectively. See full prescribing information for COTELLIC. COTELLIC (cobimetinib) tablets, for oral use

Initial U.S. Approval: 2015

 INDICATIONS AND USAGE -

 COTELLIC is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.

 Limitation of Use: COTELLIC is not indicated for treatment of patients with wild-type BRAF melanoma

 ADVERSE REACTIONS -

 Most common adverse reactions for COTELLIC (=20%) are diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. The most common (=5%) Grade 3-4 laboratory abnormalities are increased GGT, increased CPK, hypophosphatemia, increased ALT, lymphopenia, increased AST, increased alkaline phosphatase, hyponatremia.

 CONTRAINDICATIONS --

 None.

 WARNINGS AND PRECAUTIONS -

 New primary malignancies, cutaneous and non-cutaneous: Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose of COTELLIC.

Hemorrhage: Major hemorrhagic events can occur with COTELLIC. Monitor for signs and symptoms of bleeding.

 Cardiomyopathy: The risk of cardiomyopathy is increased in patients receiving COTELLIC with vemurafenib compared with vemurafenib as a single agent.

The safety of COTELLIC has not been established in patients with decreased left ventricular ejection fraction (LVEF).

Evaluate LVEF before treatment, after one month of treatment, then every 3 months thereafter during treatment with COTELLIC. (5.3, 2.4)

 Severe Dermatologic Reactions: Monitor for severe skin rashes. Interrupt, reduce, or discontinue COTELLIC.

 Serous Retinopathy and Retinal Vein Occlusion: Perform an ophthalmological evaluation at regular intervals and for any visual disturbances.

Permanently discontinue COTELLIC for retinal vein occlusion (RVO). 

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

Rhabdomyolysis: Monitor creatine phosphokinase periodically and as clinically indicated for signs and symptoms of rhabdomyolysis.

Severe Photosensitivity: Advise patients to avoid sun exposure.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

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DOSAGE AND ADMINISTRATION -

 Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of COTELLIC.

 The recommended dose is 60 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take COTELLIC with or without food.

 DOSAGE FORMS AND STRENGTHS-

 Tablets: 20 mg

 PATIENT COUNSELING INFORMATION

 See FDA-approved patient labeling (Patient Information). 

Inform patients of the following: 

New primary cutaneous malignancies: Advise patients to contact their health care provider immediately for  change in or development of new skin lesions

Hemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for 444 signs or symptoms of unusual severe bleeding or hemorrhage [

Cardiomyopathy: Advise patients to report any history of cardiac disease and of the requirement for cardiac  monitoring prior to and during COTELLIC administration.

Instruct patients to immediately report any signs  or symptoms of left ventricular dysfunction to their healthcare provider

Serious dermatologic reactions: Instruct patients to contact their healthcare provider to immediately report 450 severe skin changes

 Serous retinopathy and retinal vein occlusion: Instruct patients to immediately contact their healthcare  provider if they experience any changes in their vision 

Hepatotoxicity: Advise patients that treatment with COTELLIC requires monitoring of their liver function.                                                                                                        Instruct patients to report any signs or symptoms of liver dysfunction

Rhabdomyolysis: Instruct patients to report any signs and symptoms of muscle pain or weakness to their healthcare provider 

Severe photosensitivity: Advise patients to avoid sun exposure, wear protective clothing, and use broad  spectrum UVA/UVB sunscreen and lip balm (SPF >30) when outdoors

Embryo-fetal toxicity: Advise females of reproductive potential of the potential risk to a fetus.

Advise  females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during 462 treatment with COTELLIC

Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with COTELLIC and for at least 2 weeks after the final dose of COTELLIC 

Lactation: Advise females not to breastfeed during treatment with COTELLIC and for 2 weeks after the  final dose

Distributed by: 470 Genentech USA, Inc. 471 A Member of the Roche Group COTELLIC is a trademark of Genentech, Inc. 472 1 DNA Way ©2015 Genentech, Inc. 473 South San Francisco, CA 94080-4990

CLINICAL PHARMACOLOGY

1. Mechanism of Action -                                                                                         Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal  regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal 307 related kinase (ERK) pathway, which promotes cellular proliferation.

 2. Pharmacodynamics 

 Cardiac Electrophysiology

 Clinically relevant QT prolongation has been reported with vemurafenib, further QTc prolongation was not  observed when cobimetinib 60 mg daily was co-administered with vemurafenib.

Monitor ECG and  electrolytes before initiating treatment and routinely during treatment with cobimetinib, when administered  with vemurafenib.. 

3. Pharmacokinetics -                                                                                                    The pharmacokinetics of cobimetinib was studied in healthy subjects and cancer patients. Cobimetinib  exhibits linear pharmacokinetics in the dose range of 3.5 to 100 mg (i.e., 0.06 to 1.7 times the recommended  dosage).

Absorption-                                                                                                             Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels  (Tmax) was 2.4 (range:1–24) hours, geometric mean steady-state AUC0-24h was 4340 ng·h/mL (61% CV) and 329 330 Cmax was 273 ng/mL (60% CV).

Distribution-                                                                                                            Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. No preferential binding to human red blood cells was observed (blood to plasma ratio of 0.93). The estimated  apparent volume of distribution was 806 L in cancer patients based on a population PK analysis. 

Elimination -                                                                                                                    Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean elimination half-life (t1/2) was 44 (range: 23–70) hours and the mean apparent clearance (CL/F) was 13.8 L/h (61% CV).

 Metabolism-                                                                                                                    CYP3A oxidation and UGT2B7 glucuronidation were the major pathways of cobimetinib metabolism in2 vitro. Following oral administration of a single 20 mg radiolabeled cobimetinib dose, no oxidative  metabolites >10% of total circulating radioactivity were observed. 

Excretion -                                                                                                                         Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76% of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was recovered in the urine  (with 1.6% as unchanged drug). 

Specific Populations -                                                                                                        Age, Sex, and Race/Ethnicity: Based on the population pharmacokinetic analysis, age (19–88 years), sex, or race/ethnicity does not have a clinically important effect on the systemic exposure of cobimetinib. 

Hepatic Impairment -                                                                                                        The pharmacokinetics of cobimetinib has not been studied in patients with moderate to severe hepatic  impairment.

Renal Impairment -                                                                                                         Cobimetinib undergoes minimal renal elimination. Cobimetinib exposures were similar in 151 patients with  mild renal impairment (CLcr 60 to 89 mL/min), 48 patients with moderate renal impairment (CLcr 30 to 59 361 mL/min) and 286 patients with normal renal function (CLcr =90 mL/min)

Drug Interaction-                                                                                                       Studies 364 Vemurafenib: Coadministration of COTELLIC 60 mg once daily and vemurafenib 960 mg twice daily  resulted in no clinically relevant pharmacokinetic drug interactions.

 Effect of Inducrs  Cobimetinib:                                                                                      In vitro studies show that cobimetinib is a 7 substrate of CYP3A. Coadministration of itraconazole (a strong CYP3A inhibitor) 200 mg once daily for 14  days with a single 10 mg cobimetinib dose increased mean cobimetinib AUC (90% CI) by 6.7-fold (5.6.0) and mean Cmax (90% CI) by 3.2-fold (2.7, 3.7) in 15 healthy subjects.

Effect of Strong and Moderate CYP3A Inducers on Cobimetinib:                               Based on simulations, cobimetinib  exposures would decrease by 83% when coadministered with a strong CYP3A inducer and by 73% when 375 coadministered with a moderate CYP3A inducer [see Drug Interactions 

 Effect of Cobimetinib on CYP Substrates:                                                           Coadministration of cobimetinib 60 mg once daily for 15 days  with a single 30 mg dose of dextromethorphan (sensitive CYP2D6 substrate) or a single 2 mg dose of  midazolam (sensitive CYP3A substrate) to 20 patients with solid tumors did not change dextromethorphan 379 or midazolam systemic exposure.

Effect of Transporters on Cobimetinib: Cobimetinib is a substrate of efflux transporter P-glycoprotein 383 (P-gp), but is not a substrate of Breast Cancer Resistance Protein (BCRP), Organic Anion Transporting 384 Polypeptide (OATP1B1 or OATP1B3) or Organic Cation Transporter (OCT1) in vitro.

 Effect of Cobimetinib on Transporters: In vitro data suggest that cobimetinib at clinically relevant  concentrations does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, or OCT1. 

Effect of Gastric Acid Reducing Drugs on Cobimetinib: Coadministration of a proton pump inhibitor,  rabeprazole 20 mg once daily for 5 days, with a single dose of 20 mg COTELLIC under fed and fasted  conditions did not result in a clinically important change in cobimetinib exposure. 

1. Pregnancy Risk Summary -                                                                                            Based on findings from animal reproduction studies and its mechanism of action, COTELLIC can cause fetal harm when administered to a pregnant woman

There are no available data on the use of COTELLIC 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 2–4% and 15–20%, respectively.

2. Lactation Risk Summary -                                                                                         There is no information regarding the presence of cobimetinib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman not to breastfeed during treatment with COTELLIC and for 2 weeks after the final dose

3. Females and Males of Reproductive Potential

Contraception Females COTELLIC can cause fetal harm when administered to a pregnant woman 

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

Infertility Females and Males Based on findings in animals, COTELLIC may reduce fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)]

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

5. Geriatric Use-                                                                                                              Clinical studies of cobimetinib did not include sufficient numbers of patients aged 65 years and older to 277 determine whether they respond differently from younger patients. 

6. Hepatic Impairment -                                                                                                        Pharmacokinetics of cobimetinib has not been studied in patients with moderate or severe hepatic  impairment. Dose adjustment is not recommended for patients with mild hepatic impairment (total bilirubin  less than or equal to ULN and AST greater than ULN or total bilirubin >ULN but = 1.5 times ULN and any  AST) based on results of the population pharmacokinetic analysis 

7. Renal Impairment -                                                                                                         No dedicated pharmacokinetic trial in patients with renal impairment has been conducted.

Dose adjustment  is not recommended for mild to moderate renal impairment (CLcr 30 to 89 mL/min) based on the results of 286 the population pharmacokinetic analysis

. A recommended dose has not been established for patients with  severe renal impairment

OVERDOSAGE -

 There is no information on overdosage of COTELLIC