Cobimetinib

Cobimetinib is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Cobimetinib is used to treat a certain type of metastatic melanoma (skin cancer) that has spread to other parts of the body and cannot be removed with surgery. Cobimetinib is usually given together with another medicine called vemurafenib (Zelboraf).

Cobimetinib is used only if your tumor has a specific genetic marker that your doctor will test for.

Cobimetinib may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use cobimetinib if you are allergic to it.

To make sure cobimetinib is safe for you, tell your doctor if you have:

• heart disease, heart rhythm disorder;
• a history of eye problems (especially a problem with your retina);
• liver or kidney disease;
• skin problems not related to melanoma;
• a muscle disorder;
• a bleeding or blood clotting disorder such as hemophilia; or
• a condition for which you take a blood thinner such as warfarin (Coumadin, Jantoven).

Using cobimetinib may increase your risk of developing other types of skin cancer. Ask your doctor about your specific risk. Tell your doctor if you notice any new skin symptoms such as redness, sores that will not heal, a new wart, or a mole that has changed in size or color.

Do not use cobimetinib if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment. Use effective birth control while you are using this medication and for at least 2 weeks after your last dose.

It is not known whether cobimetinib passes into breast milk or if it could harm a nursing baby. Do not breast-feed while taking cobimetinib, and for 2 weeks after your last dose.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if cobimetinib crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, you should not breastfeed while taking cobimetinib or for 2 weeks after finishing cobimetinib.

Talk to your healthcare provider about the best way to feed your baby during this time.

• Store cobimetinib at room temperature.
• Keep this and all medicines out of the reach of children.

Your doctor will perform blood tests to make sure you have the correct tumor type to be treated with cobimetinib.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Cobimetinib is given in a 28-day treatment cycle. You may need to use the medicine only during the first 21 days of each cycle. Your doctor will determine how long to treat you with cobimetinib.

Do not change your doses or medication schedule without your doctor's advice.

You may take cobimetinib with or without food.

Check your skin on a regular basis while you are using cobimetinib. Tell your doctor if you notice any new skin symptoms such as redness, sores that will not heal, a new wart, or a mole that has changed in size or color.

Your heart function may need to be checked with an electrocardiograph or ECG (sometimes called an EKG) while you are using this medicine. You may also need regular vision examinations.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using cobimetinib and call your doctor at once if you have:

• vision changes, partial vision loss, seeing halos around lights;

• unexplained muscle pain, tenderness, or weakness (especially if you also have fever and dark colored urine);

• easy bruising or bleeding (nosebleeds, bleeding gums);

• signs of bleeding inside the body--weakness, dizziness, headache, red or pink urine, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• signs of a heart problem--cough, wheezing, shortness of breath (even with mild exertion), chest pain, fast heartbeats, swelling in your feet or ankles;

• low levels of sodium in the body--headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;

• liver problems--nausea, upper stomach pain, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• severe skin reaction--skin pain, itching, redness, bumps or pimples, thickened or wrinkled skin, skin rash that spreads and causes blistering and peeling.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• nausea, vomiting, diarrhea;

• fever;

• sunburn or increased sensitivity to sunlight;

• low sodium levels; or

• abnormal laboratory tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain or tenderness
• bleeding gums
• blurred vision or any other change in vision
• chest discomfort or pain
• chills
• clay colored stools
• coughing up blood
• dark urine
• decreased appetite
• difficulty in breathing or swallowing
• dizziness
• faintness
• fast irregular or pounding heartbeat
• fever
• headache
• increased menstrual flow or vaginal bleeding
• increased sensitivity of the skin to sunlight
• itching or skin rash
• loss of appetite
• muscle cramps or spasms
• muscle pain or stiffness
• nausea and vomiting
• nervousness
• nosebleeds
• paralysis
• pounding in the ears
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• redness or other discoloration of the skin
• seeing flashes or sparks of light
• seeing floating spots before the eyes, or a veil or curtain appearing across part of vision
• severe sunburn
• slow or fast heartbeat
• swelling of the feet or lower legs
• unusual tiredness or weakness
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acne or pimples
• diarrhea
• nausea
• swelling or inflammation of the mouth
• vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Exposure was decreased by 31% in patients with severe hepatic impairment compared to patients with normal hepatic function.

CrCl ≥30 mL/minute: No dosage adjustment is necessary.

CrCl <30 mL/minute: There is no dosage adjustment provided in the manufacturer’s labeling (has not been studied).

Concerns related to adverse effects:

• Cardiomyopathy: Symptomatic or asymptomatic declines in left ventricular ejection fraction (LVEF) may occur with cobimetinib. Safety has not been established in patients with baseline LVEF below the institutional lower limit of normal (LLN) or below 50%. Assess LVEF (by echocardiogram or MUGA scan) prior to therapy initiation, 1 month after initiation, and every 3 months thereafter until cobimetinib is discontinued. May require treatment interruption, dose reduction and/or discontinuation. Also assess LVEF at ~2 weeks, 4 weeks, 10 weeks, 16 weeks, and then as clinically indicated after a dose reduction or treatment interruption. The median time to first onset of LVEF decline was 4 months (range: 23 days to 13 months). Decreased LVEF resolved to >LLN or within 10% of baseline at nearly two-thirds of patients with a median time to resolution of 3 months (range: 4 days to 12 months).

• Dermatologic toxicity: Severe rash and other skin reactions (including grades 3 and 4 toxicity) may occur; some events required hospitalization. The median time to onset of grade 3 and 4 rash events was 11 days (range: 3 days to ~3 months); most patients with grades 3 and 4 rash experienced complete resolution at a median time of 21 days (range: 4 days to 17 months). May require treatment interruption, dose reduction and/or discontinuation. Photosensitivity was reported in nearly one-half of patients (may be severe). The median time to first onset of photosensitivity was 2 months (range: 1 day to 14 months); the median duration was 3 months (range: 2 days to 14 months). Photosensitivity resolved in nearly two-thirds of patients. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF 30 or higher) when outdoors. Photosensitivity may require treatment interruption, dose reduction, and/or discontinuation.

• Hemorrhage: Hemorrhage, including major symptomatic bleeding in a critical area/organ, may occur with cobimetinib. Grade 3 to 4 bleeding has occurred. Cerebral hemorrhage, gastrointestinal bleeding, reproductive system hemorrhage, and hematuria have been reported. May require treatment interruption, dose reduction, and/or discontinuation.

• Hepatotoxicity: Hepatotoxicity (including grades 3 or 4 transaminase, total bilirubin, or alkaline phosphatase elevations) may occur with cobimetinib. Monitor liver function test at baseline and monthly during treatment, or as clinically necessary. Grade 3 and 4 elevations may require treatment interruption, dose reduction, and/or discontinuation.

• Hypertension: Hypertension has been observed with cobimetinib in combination with vemurafenib, including grades 3 or 4 hypertension.

• Malignancy: New primary cutaneous malignancies may occur. Malignancies included cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA), basal cell carcinoma (BCC), and second primary melanoma. The median time to detection of first cuSCC or KA was 4 months (range: 2 to 11 months); the median time to first detection of BCC was 4 months (range: 1 to 13 months). Dermatologic exams should be performed prior to initiation, every 2 months during treatment, and for 6 months following discontinuation of cobimetinib/vemurafenib combination therapy. Suspicious lesions should be managed with excision and dermatopathologic evaluation. Dosage adjustment is not recommended for new cutaneous malignancies. Vemurafenib may be associated with the development of noncutaneous malignancy; monitor for signs/symptoms of noncutaneous malignancy during combination treatment.

• Ophthalmic effects: Ocular toxicities may occur, including serous retinopathy (fluid accumulation under retina layers). Chorioretinopathy and retinal detachment have been reported; retinal vein occlusion has also been reported (case reports); permanently discontinue if retinal vein occlusion occurs. The time to first onset of serous retinopathy ranged between 2 days to 9 months with a duration of 1 day to 15 months. Perform ophthalmic examinations regularly during treatment, and with reports of new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt treatment until visual symptoms improve; may require treatment interruption, dose reduction, and/or discontinuation.

• Rhabdomyolysis: Rhabdomyolysis and creatine phosphokinase (CPK) elevations may occur with cobimetinib. The median time to first occurrence of grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months), with a median time to resolution of 15 days (range: 9 days to 11 months). Obtain baseline serum CPK and creatinine levels at baseline, periodically during treatment and as clinically indicated. If CPK is elevated, evaluate for signs/symptoms of rhabdomyolysis or other etiology. Depending on severity, may require treatment interruption, dose reduction, and/or discontinuation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Prior to initiating therapy, confirm BRAF V600K or V600E mutation status with an approved test; approved for use in patients with BRAF V600K and BRAF V600E mutations. Not indicated for use in patients with wild-type BRAF melanoma.

BRAF V600K or V600E mutation status (prior to treatment); liver function tests (baseline and monthly during treatment, more frequently if clinically indicated); creatine phosphokinase (CPK) and serum creatinine (baseline and periodically during treatment, more frequently if clinically indicated); electrolytes (prior to and routinely during treatment). Assess left ventricular ejection fraction (LVEF) by echocardiogram or MUGA scan prior to therapy initiation, 1 month after initiation, and every 3 months thereafter until cobimetinib is discontinued; also assess LVEF at ~2 weeks, 4 weeks, 10 weeks, 16 weeks, and then as clinically indicated after a dose reduction or treatment interruption. Monitor ECG prior to and routinely during treatment.

Dermatologic exams (baseline, every 2 months during treatment, and for 6 months following discontinuation); ophthalmic examinations (baseline, regularly during treatment and with reports of new or worsening visual disturbances); monitor for signs/symptoms of dermatologic toxicity, hemorrhage, noncutaneous malignancy, photosensitivity, and rhabdomyolysis.

Applies to cobimetinib: oral tablet

Along with its needed effects, cobimetinib may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking cobimetinib:

• Abdominal or stomach pain or tenderness
• bleeding gums
• blurred vision or any other change in vision
• chest discomfort or pain
• chills
• clay colored stools
• coughing up blood
• dark urine
• decreased appetite
• difficulty in breathing or swallowing
• dizziness
• faintness
• fast irregular or pounding heartbeat
• fever
• headache
• increased menstrual flow or vaginal bleeding
• increased sensitivity of the skin to sunlight
• itching or skin rash
• loss of appetite
• muscle cramps or spasms
• muscle pain or stiffness
• nausea and vomiting
• nervousness
• nosebleeds
• paralysis
• pounding in the ears
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• redness or other discoloration of the skin
• seeing flashes or sparks of light
• seeing floating spots before the eyes, or a veil or curtain appearing across part of vision
• severe sunburn
• slow or fast heartbeat
• swelling of the feet or lower legs
• unusual tiredness or weakness
• yellow eyes or skin

Some side effects of cobimetinib may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acne or pimples
• diarrhea
• nausea
• swelling or inflammation of the mouth
• vomiting

Applies to cobimetinib: oral tablet

General

The most commonly reported adverse reactions (more than 35%) were increased creatinine, increased CPK, lymphopenia, increased AST, increased alkaline phosphatase, increased ALT, hypophosphatemia, anemia, increased gamma-glutamyltransferase, diarrhea, photosensitivity reactions, hypoalbuminemia, nausea, and hyponatremia.[Ref]

Renal

Very common (10% or more): Increased creatinine (99.6%)[Ref]

Musculoskeletal

Very common (10% or more): Increased CPK (79%)[Ref]

Hepatic

Very common (10% or more): Increased AST (73%), increased alkaline phosphatase (71%), increased ALT (68%), increased gamma-glutamyltransferase (65%)
Frequency not reported: Increased total bilirubin[Ref]

Hematologic

Very common (10% or more): Lymphopenia (73%), anemia (69%), thrombocytopenia (18%)[Ref]

Metabolic

Very common (10% or more): Hypophosphatemia (68%), hypoalbuminemia (42%), hyponatremia (38%), hyperkalemia (26%), hypokalemia (25%), hypocalcemia (24%)[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (60%), nausea (41%), vomiting (24%), stomatitis (14%)[Ref]

Dermatologic

Very common (10% or more): Photosensitivity reactions (47%), acneiform dermatitis (16%), alopecia (15%), hyperkeratosis (11%), erythema (10%)
Frequency not reported: Rash[Ref]

Other

Very common (10% or more): Pyrexia (28%), hemorrhage (13%), chills (10%)[Ref]

Reported hemorrhage cases included various types of hemorrhages (rectal, hemorrhoidal, gastrointestinal tract, uterine, vaginal, pulmonary, cerebral, subarachnoid, ocular, eye, conjunctival, retinal; reproductive system); melena, hematemesis; hematochezia; gingival bleeding; metrorrhagia; hemorrhagic ovarian cyst; menometrorrhagia; menorrhagia; hemoptysis; subgaleal hematoma; hematuria; epistaxis; contusion; traumatic hematoma; ecchymosis; purpura; and nail bed bleeding.[Ref]

Cardiovascular

Very common (10% or more): Decreased LVEF (26%), hypertension (15%)[Ref]

Ocular

Very common (10% or more): Serous retinopathy (26%), impaired vision (15%), chorioretinopathy (13%), retinal detachment (12%)
Uncommon (0.1% to 1%): Retinal vein occlusion[Ref]

Oncologic

Common (1% to 10%): Cutaneous squamous cell carcinoma/keratoacanthoma, basal cell carcinoma
Uncommon (0.1% to 1%): Second primary melanoma, non-cutaneous malignancies[Ref]

Some side effects of cobimetinib may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

60 mg orally once a day for first 21 days of each 28-day cycle

Duration of therapy: Until disease progression or unacceptable toxicity

Comments: The presence of BRAF V600E or V600K mutation in tumor specimens should be confirmed with an FDA-approved test prior to treatment initiation; information on FDA-approved tests available at http://www.fda.gov/CompanionDiagnostics.

Use: In combination with vemurafenib, indicated for treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

Data not available