Cotellic^® (Tablets) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

F. Hoffmann-La Roche, Ltd (Switzerland)

Labeled By

DELPHARM MILANO, S.r.l. (Italy)

Quality Control Release

F.Hoffmann-La Roche, Ltd (Switzerland)

ATC Code

L01EE02 (Cobimetinib)

Active Substance

Cobimetinib (Rec.INN registered by WHO)

Dosage Form

Cotellic®

Film-coated tablets, 20 mg: 63 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; engraved with “COB” on one side.

Excipients: lactose monohydrate, croscarmellose sodium, microcrystalline cellulose, magnesium stearate.

Film coating composition: polyvinyl alcohol, titanium dioxide (E171), macrogol, talc.

21 pcs. – blisters (3) – cardboard packs^×.

^× a protective holographic sticker is applied to the packaging to control the first opening.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent – protein kinase inhibitor

Pharmacological Action

Antitumor agent, protein kinase inhibitor.

The mitogen-activated protein kinase MAPK (Mitogen-Activated Protein Kinase)/extracellular signal-regulated kinase ERK (Extracellular signal Regulated Kinase) pathway is a key signaling pathway that regulates cell proliferation, cell cycle, cell survival, angiogenesis, and cell migration.

Cobimetinib is a highly selective allosteric oral inhibitor of MEK1/2 (MAPK/ERK Kinase) kinases. In biochemical and cytological studies, Cobimetinib demonstrated high inhibitory potency and activity against a wide range of tumors in vivo in tumor xenograft models, including tumors carrying BRAF and KRAS mutations. Biochemical and structural studies have shown the interaction of cobimetinib with MEK, with low sensitivity to the dynamic conformational changes observed during the transition of MEK to the phosphorylated form. As a result, Cobimetinib retains binding capacity and inhibitory activity upon MEK phosphorylation. Cobimetinib showed the highest activity against tumor cell lines and tumors with high levels of phosphorylated MEK, which is often observed in tumors with BRAF mutations.

In preclinical studies, treatment of MAPK-dysregulated tumor cells and tumors with cobimetinib resulted in phosphorylation of ERK1/2 kinases, the only known substrates of MEK1/2.

MAPK pathway signaling depends on the activity of ERK1/2 kinases, which phosphorylate protein targets in the cytoplasm and nucleus, in turn inducing cell cycle progression, cell proliferation, survival, and migration. Thus, Cobimetinib counteracts the promitogenic and oncogenic activity induced via the MAPK pathway by inhibiting MEK1/2.

The combination of vemurafenib and cobimetinib inhibits MAPK pathway reactivation via MEK1/2 by simultaneously targeting BRAF and MEK, leading to more pronounced suppression of signaling, apoptosis of a larger number of tumor cells, and enhanced tumor responses in preclinical models compared to vemurafenib monotherapy.

In vitro, Cobimetinib causes moderate inhibition of the hERG ion channel (concentration required for hERG channel inhibition (IC₅₀) = 0.5 µM [266 ng/ml]), which is approximately 18 times greater than the C_max in plasma at a dose of 60 mg (C_max of unbound cobimetinib = 14 ng/ml [0.03 µM]).

Pharmacokinetics

When cobimetinib is taken at a dose of 60 mg in cancer patients, moderate absorption is observed with a median T_max of 2.4 h. The mean steady-state C_max and AUC_0-24 are 273 ng/ml and 4340 ng×h/ml, respectively. The mean steady-state accumulation ratio is approximately 2.4.

Cobimetinib exhibits linear pharmacokinetics in the dose range from approximately 3.5 mg to 100 mg.

The absolute bioavailability of cobimetinib in healthy individuals is 45.9%. In healthy individuals, Cobimetinib was shown to be extensively metabolized and eliminated via the intestine. The extent of absorption is approximately 88%, indicating high absorption and presystemic metabolism.

The pharmacokinetics of cobimetinib are not altered when the drug is taken with food (including high-fat food) compared to fasting in healthy individuals. Since food does not affect the pharmacokinetics of cobimetinib, the drug can be taken regardless of meals.

In vitro, cobimetinib plasma protein binding is 94.8%. No preferential binding to human erythrocytes is observed (blood-to-plasma ratio 0.93).

V_d in healthy individuals who received Cobimetinib at a dose of 2 mg (IV) is 1050 L. According to population pharmacokinetic analysis, the apparent V_d in cancer patients is 806 L.

The ratio of cobimetinib to its metabolites was studied in a mass balance study in healthy individuals.

On average, 94% of the dose is recovered within 17 days. Cobimetinib is extensively metabolized and eliminated via the intestine; no single metabolite predominates.

The main pathways of cobimetinib metabolism are oxidation via the CYP3A isoenzyme and glucuronidation via the UGT2B7 isoenzyme. Cobimetinib is the main substance detected in plasma. The proportion of oxidized metabolites in plasma is no more than 10% of the total circulating radioactivity, with no human-specific metabolites identified.

The proportion of unchanged cobimetinib in feces and urine is 6.6% and 1.6% of the administered dose, respectively, indicating that Cobimetinib is predominantly metabolized and minimally renally excreted. In vitro data show that Cobimetinib is not an inhibitor of OAT1, OAT3, or OCT2.

After IV administration of cobimetinib at a dose of 2 mg, the mean clearance is 10.7 L/h. The mean apparent clearance in cancer patients after taking cobimetinib at a dose of 60 mg is 13.8 L/h.

The mean T_1/2 of cobimetinib is 43.6 h (range from 23.1 to 69.6 h).

Indications

Unresectable or metastatic melanoma with a BRAF V600 mutation in adult patients in combination with vemurafenib.

ICD codes

Dosage Regimen

Before initiating therapy, confirm the presence of a BRAF V600 mutation using a validated test.

The recommended dosage is 60 mg (three 20 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle.

Continue treatment until disease progression or unacceptable toxicity occurs.

Administer Cotellic in combination with vemurafenib, dosed twice daily. Take Cotellic with or without food.

If a dose is vomited, do not take an additional dose. If a dose is missed, take it only if the next scheduled dose is more than 12 hours away.

For adverse reactions, manage toxicity through treatment interruption, dose reduction, or therapy discontinuation.

The first dose reduction is to 40 mg once daily. The second dose reduction is to 20 mg once daily.

Permanently discontinue if unable to tolerate the 20 mg dose.

Adverse Reactions

Definition of categories of frequency of adverse reactions: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000) and very rare (<1/10,000), including isolated cases.

Below are the adverse reactions (all grades) reported with the use of cobimetinib in combination with vemurafenib.

From the hematopoietic system very common – anemia, lymphopenia, thrombocytopenia.

From the organ of vision very common – serous retinopathy (including phenomena of chorioretinopathy and retinal detachment, as an indicator of serous retinopathy), decreased visual acuity; common – visual disturbance.

From the digestive system very common – diarrhea, nausea, vomiting, stomatitis, increased ALT, AST, GGT, ALP activity, increased bilirubin concentration.

From metabolism very common – increased CPK activity, hypokalemia, hypoalbuminemia, hyperkalemia, hypocalcemia, increased creatinine concentration; common – dehydration, hypophosphatemia, hyponatremia, hyperglycemia.

Benign, malignant and unspecified neoplasms (including cysts and polyps) common – basal cell carcinoma, cutaneous squamous cell carcinoma, keratoacanthoma.

From the skin and subcutaneous tissues very common – photosensitivity (includes photosensitivity reactions, sunburn, solar dermatitis, actinic elastosis), rash, maculopapular rash, acneiform dermatitis, hyperkeratosis.

From the cardiovascular system very common – increased blood pressure, bleeding; common – decreased left ventricular ejection fraction (LVEF).

From the respiratory system common – pneumonitis.

General reactions very common – pyrexia, chills.

Contraindications

Severe renal impairment; concomitant use with strong and moderate inducers of the CYP3A isoenzyme and strong inhibitors of the CYP3A isoenzyme; pregnancy; lactation (breastfeeding); age under 18 years; hypersensitivity to cobimetinib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Use with caution concomitantly with moderate inhibitors of the CYP3A isoenzyme.

Patients who experience new or worsening visual disturbances are recommended to undergo an ophthalmological examination. If serous retinopathy is diagnosed, treatment with cobimetinib should be suspended until the severity of visual symptoms decreases to ≤ grade 1. Management of patients with serous retinopathy includes treatment interruption, dose reduction, or therapy discontinuation.

LVEF should be assessed before starting treatment to determine baseline values, then after 1 month of treatment and at least every 3 months or as clinically indicated until treatment is discontinued. Management of patients with a decrease in LVEF from baseline includes treatment interruption, dose reduction, or therapy discontinuation.

When resuming treatment with cobimetinib at a lower dose, LVEF measurement should be performed, if possible, at 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated.

Deviations in liver function parameters should be assessed based on laboratory test results before starting combination therapy, monthly during treatment, or more frequently (if clinically indicated). Management of patients with grade 3 liver function laboratory abnormalities includes interruption of treatment or dose reduction of vemurafenib. Management of patients with grade 4 liver function laboratory abnormalities includes interruption of treatment, dose reduction, or discontinuation of therapy with both cobimetinib and vemurafenib.

Drug Interactions

During treatment with cobimetinib, concomitant use of strong inhibitors of the CYP3A isoenzyme, including ritonavir, cobicistat, telaprevir, lopinavir, itraconazole, voriconazole, clarithromycin, telithromycin, posaconazole, nefazodone, and grapefruit juice, should be avoided. If concomitant use with a strong inhibitor of the CYP3A isoenzyme cannot be avoided, patient safety should be carefully monitored. In case of short-term (≤7 days) use of strong inhibitors of the CYP3A isoenzyme, consideration should be given to suspending cobimetinib treatment during the use of such an inhibitor.

Caution should be exercised when using cobimetinib concomitantly with moderate inhibitors of the CYP3A isoenzyme, including amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, imatinib. When cobimetinib is used concomitantly with a moderate inhibitor of the CYP3A isoenzyme, patient safety should be carefully monitored.

When cobimetinib is used concomitantly with a strong inducer of the CYP3A isoenzyme, there is a possibility of decreased exposure to cobimetinib and, consequently, its effectiveness.

Cobimetinib is a substrate of P-glycoprotein. When used concomitantly with P-glycoprotein inhibitors, such as cyclosporine and verapamil, there is a possibility of increased plasma concentration of cobimetinib.

Cobimetinib is a potential inducer of the CYP1A2 isoenzyme in vitro, thus a decrease in exposure to substrates of this enzyme, for example, theophylline, is likely. No clinical drug interaction studies have been conducted to assess the clinical significance of this phenomenon.

Cobimetinib is a moderate inhibitor of BCRP in vitro. No clinical drug interaction studies have been conducted to assess this phenomenon. The clinical significance of intestinal BCRP inhibition cannot be excluded.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.