Cobimetinib - Cotellic -@-(Nov 2015)- Anti-cancer
Drug Name:Cobimetinib - Cotellic -@-(Nov 2015)- Anti-cancer
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
Effect of Strong or Moderate CYP3A Inhibitors on Cobimetinib
Coadministration of COTELLIC with itraconazole (a strong CYP3A4 inhibitor)
increased cobimetinib systemic exposure by 6.7-fold.
Avoid concurrent use of COTELLIC and strong or moderate CYP3A inhibitors.
If concurrent short term (14 days or less) use of moderate CYP3A inhibitors
including certain antibiotics (e.g., erythromycin, ciprofloxacin)
is unavoidable for patients who are taking COTELLIC 60 mg,
reduce COTELLIC dose to 20 mg
After discontinuation of a moderate CYP3A inhibitor resume COTELLIC
at the previous dose
Use an alternative to a strong or moderate CYP3A inhibitor in patients
who are taking a reduced dose of 230 COTELLIC (40 or 20 mg daily)
Effect of Strong or Moderate CYP3A Inducers on Cobimetinib
Coadministration of COTELLIC with a strong CYP3A inducer may decrease
cobimetinib systemic exposure by more than 80% and reduce its efficacy.
Avoid concurrent use of COTELLIC and strong or moderate CYP3A inducers
including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and
St. John’s Wort
Indication:
COTELLIC (cobimetinib) tablets, for oral use
Initial U.S. Approval: 2015
NEW MOLECULAR ENTITY AND NEW THERAPEUTIC BIOLOGICAL
PRODUCTS APPROVED FOR 2015
Certain drugs are classified as New molecular Emtities- NME- for FDA review
Many of these products contain active moieties that have not been approved
by FDA previously, either as a single ingredient or as part of a combination
products; these products frequently provide important new therapies for the
patients.
Some drugs are characterized as NMEs for administrative purposes ,but
nonetheless contain certain active moieties in products that have been
previously approved by FDA. For example, CDER classifies biological
products submitted in an application under section 351(a) of the Public
Service Act as NME for purposes of FDA review, regardless of whether
the agency previously approved a related active moiety in a different
product.
FDAs classification of a drug as an -NME- for review purposes is distinct
from FDAs determination of whether a drug is a - New Chemical Entity or - NCE-
within the meaning of the Federal Food,Drug, and Cosmetic Act
No.35
Drug Name - Cobimetinib
Active Ingredient- Cotellic
Date of approval - 11/10/2015
FDA-approved use - To be used in combination with Vemurafenib
to treat Advanced Mellanoma that has spread to other parts of the
body or cant be removed by surgery, and that a certain type of
abnormal gene(BRAF V 600E V600E or V600K mutation)
Approved by US FDA on 11/10/2015- (Ref- FDA approved List- 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 Reaction:
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.
Contra-Indications:
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.
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.
Dosages/ Overdosage Etc:
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.
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 Information:
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 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
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 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:
Genentech USA, Inc.
A Member of the Roche Group COTELLIC is a trademark of Genentech, Inc.
1 DNA Way ©2015 Genentech, Inc.
South San Francisco, CA 94080-4990
Pharmacology/ Pharmacokinetics:
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 related kinase (ERK) pathway, which promotes cellula
proliferation. BRAF V600E and K mutations result in constitutive activation of the
BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines
expressing BRAF V600E, cobimetinib inhibited tumor cell growth.
2. 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 324 dosage).
Following oral administration of COTELLIC 60 mg once daily, steady-state was
reached by 9 days 325 with a mean accumulation ratio of 2.4-fold (44% CV).
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 ngEh/mL (61% CV) and Cmax was 273 ng/mL
(60% CV).
The absolute bioavailability of COTELLIC was 46% (90% CI: 40%, 53%) in healthy
subjects. A high]fat meal (comprised of approximately 150 calories from protein,
250 calories 331 from carbohydrate, and 500.600 calories from fat) had no effect on
cobimetinib AUC and Cmax after a single 20 mg COTELLIC was administered to healthy
subjects.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
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
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 to4%
and 15 to20%, 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.
4. Geriatric Use
Clinical studies of cobimetinib did not include sufficient numbers of patients aged
65 years and older to determine whether they respond differently from
younger patients.
