There is no information on overdosage of COTELLIC.
None.
The following adverse reactions are discussed in greater detail in other sections of the label:
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 COTELLIC was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma. All patients received vemurafenib 960 mg twice daily on Days 1-28 and received either COTELLIC 60 mg once daily (n=247) or placebo (n=246) on Days 1-21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the COTELLIC plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year. Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies.
In Trial 1, 15% of patients receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving COTELLIC, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of COTELLIC were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). The most common ( ≥ 20%) adverse reactions with COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.
Table 3: Incidence of Adverse Drug Reactions Occurring
in ≥ 10% (All Grades) of Patients Receiving COTELLIC with Vemurafenib and
at a Higher Incidence* than Patients Receiving Vemurafenib in Trial 1
| Adverse reactions | COTELLIC + Vemurafenib (n=247) | Placebo + Vemurafenib (n=246) | ||
| All Gradesa (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
| GASTROINTESTINAL DISORDERS | ||||
| Diarrhea | 60 | 6 | 31 | 1 |
| Nausea | 41 | 1 | 25 | 1 |
| Vomiting | 24 | 1 | 13 | 1 |
| Stomatitisb | 14 | 1 | 8 | 0 |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | ||||
| Photosensitivity reactionc | 46 | 4 | 35 | 0 |
| Acneiform dermatitis | 16 | 2 | 11 | 1 |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | ||||
| Pyrexia | 28 | 2 | 23 | 0 |
| Chills | 10 | 0 | 5 | 0 |
| VASCULAR DISORDERS | ||||
| Hypertension | 15 | 4 | 8 | 2 |
| Hemorrhaged | 13 | 1 | 7 | < 1 |
| EYE DISORDERS | ||||
| Vision impairede | 15 | < 1 | 4 | 0 |
| Chorioretinopathy | 13 | < 1 | < 1 | 0 |
| Retinal detachmentf | 12 | 2 | < 1 | 0 |
| * ≥ 5% for All Grades or ≥ 2% for Grades 3–4
incidence in patients receiving COTELLIC with vemurafenib compared with
patients receiving vemurafenib as a single agent a NCI CTCAE, v4.0. b Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation c Includes solar dermatitis, sunburn, photosensitivity reaction d Includes hemorrhage, rectal hemorrhage, melena, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, hematochezia, gingival bleeding, metrorrhagia, uterine hemorrhage, hemorrhagic ovarian cyst, menometrorrhagia, menorrhagia, vaginal hemorrhage, hemoptysis, pulmonary, cerebral, subarachnoid hemorrhage, subgaleal hematoma, hematuria, epistaxis, contusion, traumatic hematoma, ecchymosis, purpura, nail bed bleeding, ocular, eye, conjunctival, and retinal hemorrhage e Includes vision blurred, visual acuity reduced, visual impairment f Includes retinal detachment, detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium |
||||
Adverse reactions of vemurafenib which occurred at a lower rate in patients receiving COTELLIC plus vemurafenib were alopecia (15%), hyperkeratosis (11%), and erythema (10%).
The following adverse reactions (all grades) of COTELLIC were reported with < 10% incidence in Trial 1:
Respiratory, thoracic and mediastinal disorders: Pneumonitis
Table 4: Incidence of
Laboratory Abnormalities Occurring in ≥ 10% (All Grades) or ≥ 2%
(Grades 3–4) of Patients in Trial 1*
| Laboratory | COTELLIC + Vemurafenib | Placebo + Vemurafenib | ||
| All Gradesa % | Grades 3-4a % | All Gradesa % | Grades 3-4a % | |
| Chemistry | ||||
| Increased creatinine | 99.6 | 3.3 | 99.6 | 0.4 |
| Increased AST | 73 | 8 | 44 | 2.1 |
| Increased ALT | 68 | 11 | 55 | 5 |
| Increased alkaline phosphatase | 71 | 7 | 56 | 3.3 |
| Increased creatine phosphokinaseb | 79 | 14 | 16 | 0.5 |
| Hypophosphatemia | 68 | 12 | 38 | 6 |
| Increased GGT | 65 | 21 | 61 | 17 |
| Hyponatremia | 38 | 6 | 33 | 2.1 |
| Hypoalbuminemia | 42 | 0.8 | 20 | 0.4 |
| Hypokalemia | 25 | 4.5 | 17 | 3.3 |
| Hyperkalemia | 26 | 2.9 | 15 | 0.4 |
| Hypocalcemia | 24 | 0.4 | 10 | 1.7 |
| Hematology | ||||
| Anemia | 69 | 2.5 | 57 | 3.3 |
| Lymphopeniac | 73 | 10 | 55 | 8 |
| Thrombocytopenia | 18 | 0 | 10 | 0 |
| AST - aspartate aminotransferase, ALT - alanine
aminotransferase, GGT - gamma-glutamyltransferase *All the percentages are
based on the number of patients who had a baseline result and at least one
on-study laboratory test. The laboratory results are available for a total of
233~244 patients for COTELLIC, and 232~243 for vemurafenib, except where
indicated. a NCI CTCAE v4.0. b Increase creatine phosphokinase, n=213 for COTELLIC and 217 for vemurafenib. c Lymphopenia, n=185 for COTELLIC, and 181 for vemurafenib. |
||||
COTELLIC® is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.
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. Review the Full Prescribing Information for vemurafenib for details.
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). Following oral administration of COTELLIC 60 mg once daily, steady-state was reached by 9 days with a mean accumulation ratio of 2.4-fold (44% CV).
AbsorptionFollowing 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 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 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.
DistributionCobimetinib 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.
EliminationFollowing oral administration of COTELLIC 60 mg once daily in cancer patients, the mean elimination half-life (t½) 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 in 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).
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. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. 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.
DataAnimal Data
Administration of cobimetinib to pregnant rats during the period of organogenesis resulted in increased post-implantation loss, including total litter loss, at exposures (AUC) of 0.9–1.4 times those in humans at the recommended dose of 60 mg. Post-implantation loss was primarily due to early resorptions. Fetal malformations of the great vessels and skull (eye sockets) occurred at the same exposures.
Tablets: 20 mg, white, round, film-coated, debossed on one side with “COB”.
Storage And HandlingCOTELLIC (cobimetinib) is supplied as 20 mg film-coated tablets debossed on one side with “COB”. COTELLIC tablets are available in bottles of 63 tablets.
NDC 50242-717-01
Storage And StabilityStore at room temperature below 30°C (86°F).
Distributed by: Genentech USA, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990. Revised: May 2016
Included as part of the PRECAUTIONS section.
PRECAUTIONSReview the Full Prescribing Information for vemurafenib for information on the serious risks of vemurafenib.
New Primary MalignanciesNew primary malignancies, cutaneous and non-cutaneous, can occur with COTELLIC.
Cutaneous MalignanciesIn Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the COTELLIC with vemurafenib arm and the vemurafenib arm, respectively: cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6% and 20%), basal cell carcinoma (4.5% and 2.4%), and second primary melanoma (0.8% and 2.4%). Among patients receiving COTELLIC with vemurafenib, the median time to detection of first cuSCC/KA was 4 months (range: 2 to 11 months), and the median time to detection of basal cell carcinoma was 4 months (range: 27 days to 13 months). The time to onset in the two patients with second primary melanoma was 9 months and 12 months.
Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. No dose modifications are recommended for COTELLIC. Conduct dermatologic monitoring for 6 months following discontinuation of COTELLIC when administered with vemurafenib.
Non-Cutaneous MalignanciesBased on its mechanism of action, vemurafenib may promote growth and development of malignancies [refer to the Full Prescribing Information for vemurafenib]. In Trial 1, 0.8% of patients in the COTELLIC with vemurafenib arm and 1.2% of patients in the vemurafenib arm developed non-cutaneous malignancies.
Monitor patients receiving COTELLIC, when administered with vemurafenib, for signs or symptoms of non-cutaneous malignancies.
HemorrhageHemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with COTELLIC.
In Trial 1, the incidence of Grade 3–4 hemorrhages was 1.2% in patients receiving COTELLIC with vemurafenib and 0.8% in patients receiving vemurafenib. Hemorrhage (all grades) was 13% in patients receiving COTELLIC with vemurafenib and 7% in patients receiving vemurafenib. Cerebral hemorrhage occurred in 0.8% of patients receiving COTELLIC with vemurafenib and in none of the patients receiving vemurafenib. Gastrointestinal tract hemorrhage (3.6% vs 1.2%), reproductive system hemorrhage (2.0% vs 0.4%), and hematuria (2.4% vs 0.8%) also occurred at a higher incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib.
Withhold COTELLIC for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume COTELLIC at a lower dose level. Discontinue COTELLIC for Grade 4 hemorrhagic events and any Grade 3 hemorrhagic events that do not improve.
CardiomyopathyCardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with COTELLIC. The safety of COTELLIC has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%.
In Trial 1, patients were assessed for decreases in LVEF by echocardiograms or MUGA at baseline, Week 5, Week 17, Week 29, Week 43, and then every 4 to 6 months thereafter while receiving treatment. Grade 2 or 3 decrease in LVEF occurred in 26% of patients receiving COTELLIC with vemurafenib and 19% of patients receiving vemurafenib. The median time to first onset of LVEF decrease was 4 months (range 23 days to 13 months). Of the patients with decreased LVEF, 22% had dose interruption and/or reduction and 14% required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 62% of patients receiving COTELLIC with a median time to resolution of 3 months (range: 4 days to 12 months).
Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of COTELLIC. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation. In patients restarting COTELLIC after a dose reduction or interruption, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated.
Severe Dermatologic ReactionsSevere rash and other skin reactions can occur with COTELLIC.
In Trial 1, Grade 3 to 4 rash, occurred in 16% of patients receiving COTELLIC with vemurafenib and in 17% of patients receiving vemurafenib, including Grade 4 rash in 1.6% of patients receiving COTELLIC with vemurafenib and 0.8% of the patients receiving vemurafenib. The incidence of rash resulting in hospitalization was 3.2% in patients receiving COTELLIC with vemurafenib and 2.0% in patients receiving vemurafenib. In patients receiving COTELLIC, the median time to onset of Grade 3 or 4 rash events was 11 days (range: 3 days to 2.8 months). Among patients with Grade 3 or 4 rash events, 95% experienced complete resolution with the median time to resolution of 21 days (range 4 days to 17 months).
Interrupt, reduce the dose, or discontinue COTELLIC.
Serous Retinopathy And Retinal Vein OcclusionOcular toxicities can occur with COTELLIC, including serous retinopathy (fluid accumulation under layers of the retina).
In Trial 1, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving COTELLIC with vemurafenib. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged between 2 days to 9 months. The reported duration of serous retinopathy ranged between 1 day to 15 months. One patient in each arm developed retinal vein occlusion.
Perform an ophthalmological evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt COTELLIC until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation.
HepatotoxicityHepatotoxicity can occur with COTELLIC.
The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving COTELLIC with vemurafenib compared to patients receiving vemurafenib were: 11% vs. 5% for alanine aminotransferase, 8% vs. 2.1% for aspartate aminotransferase, 1.6% vs. 1.2% for total bilirubin, and 7% vs. 3.3% for alkaline phosphatase. Concurrent elevation in ALT > 3 times the upper limit of normal (ULN) and bilirubin > 2 X ULN in the absence of significant alkaline phosphatase > 2 X ULN occurred in one patient (0.4%) receiving COTELLIC with vemurafenib and no patients receiving single-agent vemurafenib.
Monitor liver laboratory tests before initiation of COTELLIC and monthly during treatment, or more frequently as clinically indicated. Manage Grade 3 and 4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of COTELLIC.
RhabdomyolysisRhabdomyolysis can occur with COTELLIC.
In Trial 1, Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, occurred in 14% of patients receiving COTELLIC with vemurafenib and 0.5% of patients receiving vemurafenib. The median time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months) in patients receiving COTELLIC with vemurafenib; the median time to complete resolution was 15 days (range: 9 days to 11 months). Elevation of serum CPK increase of more than 10 times the baseline value with a concurrent increase in serum creatinine of 1.5 times or greater compared to baseline occurred in 3.6% of patients receiving COTELLIC with vemurafenib and in 0.4% of patients receiving vemurafenib.
Obtain baseline serum CPK and creatinine levels prior to initiating COTELLIC, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of COTELLIC may be required.
Severe PhotosensitivityPhotosensitivity, including severe cases, can occur with COTELLIC.
In Trial 1, photosensitivity was reported in 47% of patients receiving COTELLIC with vemurafenib: 43% of patients with Grades 1 or 2 photosensitivity and the remaining 4% with Grade 3 photosensitivity. Median time to first onset of photosensitivity of any grade was 2 months (range: 1 day to 14 months) in patients receiving COTELLIC with vemurafenib, and the median duration of photosensitivity was 3 months (range: 2 days to 14 months). Among the 47% of patients with photosensitivity reactions on COTELLIC with vemurafenib, 63% experienced resolution of photosensitivity reactions.
Advise patients to avoid sun exposure, wear protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Manage intolerable Grade 2 or greater photosensitivity with dose modifications.
Embryo-Fetal ToxicityBased on its mechanism of action and findings from animal reproduction studies, COTELLIC can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during the period of organogenesis was teratogenic and embryotoxic at doses resulting in exposures [area under the curves (AUCs)] that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with COTELLIC, and for 2 weeks following the final dose of COTELLIC.
Patient Counseling InformationSee FDA-approved patient labeling (PATIENT INFORMATION).
Inform patients of the following:
New Primary Cutaneous MalignanciesAdvise patients to contact their health care provider immediately for change in or development of new skin lesions.
HemorrhageInstruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage.
CardiomyopathyAdvise 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 ReactionsInstruct patients to contact their healthcare provider to immediately report severe skin changes.
Serious Retinopathy And Retinal Vein OcclusionInstruct patients to immediately contact their healthcare provider if they experience any changes in their vision.
HepatotoxicityAdvise patients that treatment with COTELLIC requires monitoring of their liver function. Instruct patients to report any signs or symptoms of liver dysfunction.
RhabdomyolysisInstruct patients to report any signs and symptoms of muscle pain or weakness to their healthcare provider.
Severe PhotosensitivityAdvise patients to avoid sun exposure, wear protective clothing, and use broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.
Embryo-fetal ToxicityAdvise 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 PotentialAdvise females of reproductive potential to use effective contraception during treatment with COTELLIC and for at least 2 weeks after the final dose of COTELLIC.
LactationAdvise females not to breastfeed during treatment with COTELLIC and for 2 weeks after the final dose.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityCarcinogenicity studies with cobimetinib have not been conducted. Cobimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in bone marrow of rats.
No dedicated fertility studies have been performed with cobimetinib in animals; however, effects on reproductive tissues observed in general toxicology studies conducted in animals suggest that there is potential for cobimetinib to impair fertility. In female rats, degenerative changes included increased apoptosis/necrosis of corpora lutea and vaginal epithelial cells at cobimetinib doses approximately twice those in humans at the clinically recommended dose of 60 mg based on body surface area. In male dogs, testicular degeneration occurred at exposures as low as approximately 0.1 times the exposure in humans at the clinically recommended dose of 60 mg.
Use In Specific Populations Pregnancy Risk SummaryBased 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. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. 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.
DataAnimal Data
Administration of cobimetinib to pregnant rats during the period of organogenesis resulted in increased post-implantation loss, including total litter loss, at exposures (AUC) of 0.9–1.4 times those in humans at the recommended dose of 60 mg. Post-implantation loss was primarily due to early resorptions. Fetal malformations of the great vessels and skull (eye sockets) occurred at the same exposures.
Lactation Risk SummaryThere 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.
Females And Males Of Reproductive Potential ContraceptionFemales
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.
InfertilityFemales and Males
Based on findings in animals, COTELLIC may reduce fertility in females and males of reproductive potential.
Pediatric UseThe safety and effectiveness of COTELLIC have not been established in pediatric patients.
Juvenile Animal DataIn a 4-week juvenile rat toxicology study, daily oral doses of 3 mg/kg (approximately 0.13–0.5 times the adult human AUC at the recommended dose of 60 mg) between postnatal Days 10–17 (approximately equivalent to ages 1–2 years in humans) were associated with mortality, the cause of which was not defined.
Geriatric UseClinical studies of cobimetinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.
Hepatic ImpairmentAdjustment in the starting dose of COTELLIC is not required in patients with mild (Child-Pugh score A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
Renal ImpairmentNo 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 the population pharmacokinetic analysis. A recommended dose has not been established for patients with severe renal impairment.
Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with COTELLIC with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.
Recommended DoseThe recommended dosage regimen of COTELLIC is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.
Take COTELLIC with or without food.
If a dose of COTELLIC is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose.
Dose Modifications Concurrent CYP3A InhibitorsDo not take strong or moderate CYP3A inhibitors while taking COTELLIC.
If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking COTELLIC 60 mg, reduce COTELLIC dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume previous dose of COTELLIC 60 mg.
Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily) .
Adverse ReactionsReview the Full Prescribing Information for vemurafenib for recommended dose modifications.
Table 1: Recommended Dose Reductions for COTELLIC
| First Dose Reduction | 40 mg orally once daily |
| Second Dose Reduction | 20 mg orally once daily |
| Subsequent Modification | Permanently discontinue COTELLIC if unable to tolerate 20 mg orally once daily |
Table 2: Recommended Dose
Modifications for COTELLIC for Adverse Reactions
| Severity of Adverse Reactiona | Dose Modification for COTELLIC |
| New Primary Malignancies (cutaneous and non-cutaneous) | No dose modification is required. |
| Hemorrhage | |
| Grade 3 | Withhold COTELLIC for up to 4 weeks.
|
| Grade 4 | Permanently discontinue. |
| Cardiomyopathy | |
| Asymptomatic, absolute decrease in LVEF from baseline of greater than 10% and less than institutional lower limit of normal (LLN) | Withhold COTELLIC for 2 weeks; repeat LVEF. Resume at next lower dose if all of the following are present
|
| Symptomatic LVEF decrease from baseline | Withhold COTELLIC for up to 4 weeks, repeat LVEF. Resume at next lower dose if all of the following are present:
|
| Dermatologic Reactions | |
| Grade 2 (intolerable), Grade 3 or 4 | Withhold or reduce dose. |
| Serous Retinopathy or Retinal Vein Occlusion | |
| Serous retinopathy | Withhold COTELLIC for up to 4 weeks.
|
| Retinal vein occlusion | Permanently discontinue COTELLIC. |
| Liver Laboratory Abnormalities and Hepatotoxicity | |
| First occurrence Grade 4 | Withhold COTELLIC for up to 4 weeks.
|
| Recurrent Grade 4 | Permanently discontinue COTELLIC. |
| Rhabdomyolysis and Creatine Phosphokinase (CPK) elevations | |
|
Withhold COTELLIC for up to 4 weeks.
|
| Photosensitivity | |
| Grade 2 (intolerable), Grade 3 or Grade 4 | Withhold COTELLIC for up to 4 weeks.
|
| Other | |
|
Withhold COTELLIC for up to 4 weeks.
|
| First occurrence of any Grade 4 adverse reaction |
|
| Recurrent Grade 4 adverse reaction | Permanently discontinue COTELLIC. |
| a National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0) | |
The following adverse reactions are discussed in greater detail in other sections of the label:
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 COTELLIC was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma. All patients received vemurafenib 960 mg twice daily on Days 1-28 and received either COTELLIC 60 mg once daily (n=247) or placebo (n=246) on Days 1-21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the COTELLIC plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year. Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies.
In Trial 1, 15% of patients receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving COTELLIC, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of COTELLIC were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). The most common ( ≥ 20%) adverse reactions with COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.
Table 3: Incidence of Adverse Drug Reactions Occurring
in ≥ 10% (All Grades) of Patients Receiving COTELLIC with Vemurafenib and
at a Higher Incidence* than Patients Receiving Vemurafenib in Trial 1
| Adverse reactions | COTELLIC + Vemurafenib (n=247) | Placebo + Vemurafenib (n=246) | ||
| All Gradesa (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
| GASTROINTESTINAL DISORDERS | ||||
| Diarrhea | 60 | 6 | 31 | 1 |
| Nausea | 41 | 1 | 25 | 1 |
| Vomiting | 24 | 1 | 13 | 1 |
| Stomatitisb | 14 | 1 | 8 | 0 |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | ||||
| Photosensitivity reactionc | 46 | 4 | 35 | 0 |
| Acneiform dermatitis | 16 | 2 | 11 | 1 |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | ||||
| Pyrexia | 28 | 2 | 23 | 0 |
| Chills | 10 | 0 | 5 | 0 |
| VASCULAR DISORDERS | ||||
| Hypertension | 15 | 4 | 8 | 2 |
| Hemorrhaged | 13 | 1 | 7 | < 1 |
| EYE DISORDERS | ||||
| Vision impairede | 15 | < 1 | 4 | 0 |
| Chorioretinopathy | 13 | < 1 | < 1 | 0 |
| Retinal detachmentf | 12 | 2 | < 1 | 0 |
| * ≥ 5% for All Grades or ≥ 2% for Grades 3–4
incidence in patients receiving COTELLIC with vemurafenib compared with
patients receiving vemurafenib as a single agent a NCI CTCAE, v4.0. b Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation c Includes solar dermatitis, sunburn, photosensitivity reaction d Includes hemorrhage, rectal hemorrhage, melena, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, hematochezia, gingival bleeding, metrorrhagia, uterine hemorrhage, hemorrhagic ovarian cyst, menometrorrhagia, menorrhagia, vaginal hemorrhage, hemoptysis, pulmonary, cerebral, subarachnoid hemorrhage, subgaleal hematoma, hematuria, epistaxis, contusion, traumatic hematoma, ecchymosis, purpura, nail bed bleeding, ocular, eye, conjunctival, and retinal hemorrhage e Includes vision blurred, visual acuity reduced, visual impairment f Includes retinal detachment, detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium |
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Adverse reactions of vemurafenib which occurred at a lower rate in patients receiving COTELLIC plus vemurafenib were alopecia (15%), hyperkeratosis (11%), and erythema (10%).
The following adverse reactions (all grades) of COTELLIC were reported with < 10% incidence in Trial 1:
Respiratory, thoracic and mediastinal disorders: Pneumonitis
Table 4: Incidence of
Laboratory Abnormalities Occurring in ≥ 10% (All Grades) or ≥ 2%
(Grades 3–4) of Patients in Trial 1*
| Laboratory | COTELLIC + Vemurafenib | Placebo + Vemurafenib | ||
| All Gradesa % | Grades 3-4a % | All Gradesa % | Grades 3-4a % | |
| Chemistry | ||||
| Increased creatinine | 99.6 | 3.3 | 99.6 | 0.4 |
| Increased AST | 73 | 8 | 44 | 2.1 |
| Increased ALT | 68 | 11 | 55 | 5 |
| Increased alkaline phosphatase | 71 | 7 | 56 | 3.3 |
| Increased creatine phosphokinaseb | 79 | 14 | 16 | 0.5 |
| Hypophosphatemia | 68 | 12 | 38 | 6 |
| Increased GGT | 65 | 21 | 61 | 17 |
| Hyponatremia | 38 | 6 | 33 | 2.1 |
| Hypoalbuminemia | 42 | 0.8 | 20 | 0.4 |
| Hypokalemia | 25 | 4.5 | 17 | 3.3 |
| Hyperkalemia | 26 | 2.9 | 15 | 0.4 |
| Hypocalcemia | 24 | 0.4 | 10 | 1.7 |
| Hematology | ||||
| Anemia | 69 | 2.5 | 57 | 3.3 |
| Lymphopeniac | 73 | 10 | 55 | 8 |
| Thrombocytopenia | 18 | 0 | 10 | 0 |
| AST - aspartate aminotransferase, ALT - alanine
aminotransferase, GGT - gamma-glutamyltransferase *All the percentages are
based on the number of patients who had a baseline result and at least one
on-study laboratory test. The laboratory results are available for a total of
233~244 patients for COTELLIC, and 232~243 for vemurafenib, except where
indicated. a NCI CTCAE v4.0. b Increase creatine phosphokinase, n=213 for COTELLIC and 217 for vemurafenib. c Lymphopenia, n=185 for COTELLIC, and 181 for vemurafenib. |
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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 COTELLIC (40 or 20 mg daily).
Effect Of Strong Or Moderate CYP3A Inducers On CobimetinibCoadministration 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.
