Kotellik® is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.
Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with Kotellik with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.
The recommended dosage regimen of Kotellik 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 Kotellik with or without food.
If a dose of Kotellik is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose.
Do not take strong or moderate CYP3A inhibitors while taking Kotellik.
If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking Kotellik 60 mg, reduce Kotellik dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume previous dose of Kotellik 60 mg.
Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of Kotellik (40 or 20 mg daily).
Review the Full Prescribing Information for vemurafenib for recommended dose modifications.
Table 1: Recommended Dose Reductions for Kotellik
|First Dose Reduction||40 mg orally once daily|
|Second Dose Reduction||20 mg orally once daily|
|Subsequent Modification||Permanently discontinue Kotellik if unable to tolerate 20 mg orally once daily|
Table 2: Recommended Dose Modifications for Kotellik for Adverse Reactions
|Severity of Adverse Reactiona||Dose Modification for Kotellik|
|New Primary Malignancies (cutaneous and non-cutaneous)||No dose modification is required.|
|Grade 3||Withhold Kotellik for up to 4 weeks. |
|Grade 4||Permanently discontinue.|
|Asymptomatic, absolute decrease in LVEF from baseline of greater than 10% and less than institutional lower limit of normal (LLN)||Withhold Kotellik for 2 weeks; repeat LVEF. Resume at next lower dose if all of the following are present |
|Symptomatic LVEF decrease from baseline||Withhold Kotellik for up to 4 weeks, repeat LVEF. Resume at next lower dose if all of the following are present: |
|Grade 2 (intolerable), Grade 3 or 4||Withhold or reduce dose.|
|Serous Retinopathy or Retinal Vein Occlusion|
|Serous retinopathy||Withhold Kotellik for up to 4 weeks. |
|Retinal vein occlusion||Permanently discontinue Kotellik.|
|Liver Laboratory Abnormalities and Hepatotoxicity|
|First occurrence Grade 4|| |
Withhold Kotellik for up to 4 weeks.
|Recurrent Grade 4||Permanently discontinue Kotellik.|
|Rhabdomyolysis and Creatine Phosphokinase (CPK) elevations|
| || |
Withhold Kotellik for up to 4 weeks.
|Grade 2 (intolerable), Grade 3 or Grade 4|| |
Withhold Kotellik for up to 4 weeks.
| || |
Withhold Kotellik for up to 4 weeks.
|First occurrence of any Grade 4 adverse reaction|| |
|Recurrent Grade 4 adverse reaction||Permanently discontinue Kotellik.|
|a National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0)|
Included as part of the PRECAUTIONS section.
Review the Full Prescribing Information for vemurafenib for information on the serious risks of vemurafenib.
New primary malignancies, cutaneous and non-cutaneous, can occur with Kotellik.
In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the Kotellik 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 Kotellik 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 Kotellik. Conduct dermatologic monitoring for 6 months following discontinuation of Kotellik when administered with vemurafenib.
Based 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 Kotellik with vemurafenib arm and 1.2% of patients in the vemurafenib arm developed non-cutaneous malignancies.
Monitor patients receiving Kotellik, when administered with vemurafenib, for signs or symptoms of non-cutaneous malignancies.
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with Kotellik.
In Trial 1, the incidence of Grade 3–4 hemorrhages was 1.2% in patients receiving Kotellik with vemurafenib and 0.8% in patients receiving vemurafenib. Hemorrhage (all grades) was 13% in patients receiving Kotellik with vemurafenib and 7% in patients receiving vemurafenib. Cerebral hemorrhage occurred in 0.8% of patients receiving Kotellik 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 Kotellik with vemurafenib compared with patients receiving vemurafenib.
Withhold Kotellik for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume Kotellik at a lower dose level. Discontinue Kotellik for Grade 4 hemorrhagic events and any Grade 3 hemorrhagic events that do not improve.
Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with Kotellik. The safety of Kotellik 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 Kotellik 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 Kotellik 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 Kotellik. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation. In patients restarting Kotellik 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 rash and other skin reactions can occur with Kotellik.
In Trial 1, Grade 3 to 4 rash, occurred in 16% of patients receiving Kotellik with vemurafenib and in 17% of patients receiving vemurafenib, including Grade 4 rash in 1.6% of patients receiving Kotellik with vemurafenib and 0.8% of the patients receiving vemurafenib. The incidence of rash resulting in hospitalization was 3.2% in patients receiving Kotellik with vemurafenib and 2.0% in patients receiving vemurafenib. In patients receiving Kotellik, 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 Kotellik.
Ocular toxicities can occur with Kotellik, 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 Kotellik 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 Kotellik until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation.
Hepatotoxicity can occur with Kotellik.
The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving Kotellik 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 Kotellik with vemurafenib and no patients receiving single-agent vemurafenib.
Monitor liver laboratory tests before initiation of Kotellik 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 Kotellik.
Rhabdomyolysis can occur with Kotellik.
In Trial 1, Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, occurred in 14% of patients receiving Kotellik 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 Kotellik 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 Kotellik with vemurafenib and in 0.4% of patients receiving vemurafenib.
Obtain baseline serum CPK and creatinine levels prior to initiating Kotellik, 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 Kotellik may be required.
Photosensitivity, including severe cases, can occur with Kotellik.
In Trial 1, photosensitivity was reported in 47% of patients receiving Kotellik 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 Kotellik 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 Kotellik 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.
Based on its mechanism of action and findings from animal reproduction studies, Kotellik 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 Kotellik, and for 2 weeks following the final dose of Kotellik.
See FDA-approved patient labeling (PATIENT INFORMATION).
Inform patients of the following:
Advise patients to contact their health care provider immediately for change in or development of new skin lesions.
Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage.
Advise patients to report any history of cardiac disease and of the requirement for cardiac monitoring prior to and during Kotellik administration. Instruct patients to immediately report any signs or symptoms of left ventricular dysfunction to their healthcare provider.
Instruct patients to contact their healthcare provider to immediately report severe skin changes.
Instruct patients to immediately contact their healthcare provider if they experience any changes in their vision.
Advise patients that treatment with Kotellik requires monitoring of their liver function. Instruct patients to report any signs or symptoms of liver dysfunction.
Instruct patients to report any signs and symptoms of muscle pain or weakness to their healthcare provider.
Advise patients to avoid sun exposure, wear protective clothing, and use broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.
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 Kotellik.
Advise females of reproductive potential to use effective contraception during treatment with Kotellik and for at least 2 weeks after the final dose of Kotellik.
Advise females not to breastfeed during treatment with Kotellik and for 2 weeks after the final dose.
Carcinogenicity 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.
Based on findings from animal reproduction studies and its mechanism of action, Kotellik can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Kotellik 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.
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.
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 Kotellik and for 2 weeks after the final dose.
Kotellik can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Kotellik and for 2 weeks after the final dose of Kotellik.
Females and Males
Based on findings in animals, Kotellik may reduce fertility in females and males of reproductive potential.
The safety and effectiveness of Kotellik have not been established in pediatric patients.
In 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.
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.
Adjustment in the starting dose of Kotellik is not required in patients with mild (Child-Pugh score A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic 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 the population pharmacokinetic analysis. A recommended dose has not been established for patients with severe renal impairment.
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 Kotellik 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 Kotellik 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 Kotellik 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 Kotellik experienced an adverse reaction that resulted in permanent discontinuation of Kotellik. 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 Kotellik, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of Kotellik 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 Kotellik were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.
Table 3: Incidence of Adverse Drug Reactions Occurring in ≥ 10% (All Grades) of Patients Receiving Kotellik with Vemurafenib and at a Higher Incidence* than Patients Receiving Vemurafenib in Trial 1
|Adverse reactions||Kotellik + Vemurafenib (n=247)||Placebo + Vemurafenib (n=246)|
|All Gradesa (%)||Grades 3-4 (%)||All Grades (%)||Grades 3-4 (%)|
|SKIN AND SUBCUTANEOUS TISSUE DISORDERS|
|GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS|
|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 Kotellik 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 Kotellik plus vemurafenib were alopecia (15%), hyperkeratosis (11%), and erythema (10%).
The following adverse reactions (all grades) of Kotellik 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||Kotellik + Vemurafenib||Placebo + Vemurafenib|
|All Gradesa %||Grades 3-4a %||All Gradesa %||Grades 3-4a %|
|Increased alkaline phosphatase||71||7||56||3.3|
|Increased creatine phosphokinaseb||79||14||16||0.5|
|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 Kotellik, and 232~243 for vemurafenib, except where indicated. |
a NCI CTCAE v4.0.
b Increase creatine phosphokinase, n=213 for Kotellik and 217 for vemurafenib.
c Lymphopenia, n=185 for Kotellik, and 181 for vemurafenib.
There is no information on overdosage of Kotellik.
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 Kotellik 60 mg once daily, steady-state was reached by 9 days with a mean accumulation ratio of 2.4-fold (44% CV).
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 Cmax was 273 ng/mL (60% CV). The absolute bioavailability of Kotellik 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 Kotellik was administered to healthy subjects.
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.
Following oral administration of Kotellik 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).
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.
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).