Comarit80 mg

Renal Cell Carcinoma: Comarit 80 mg is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).Hepatocellular Carcinoma: Comarit 80 mg is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Sorafenib.

Cytotoxic Chemotherapy

In vitro biochemical and/or cellular assays have shown that Comarit 80 mg inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Recommended Dosage for Renal Cell Carcinoma: The recommended dosage of Comarit 80 mg is 60 mg once daily without food until the patient no longer experiences clinical benefit or experiences unacceptable toxicity.Recommended Dosage for Hepatocellular Carcinoma: The recommended dosage of Comarit 80 mg is 60 mg once daily without food until disease progression or unacceptable toxicity. Or, as directed by the registered physicians. Stop treatment with Comarit 80 mg at least 28 days prior to scheduled surgery, including dental surgery. Do not substitute Comarit 80 mg tablets with Comarit 80 mg capsules. Do not administer Comarit 80 mg with food. Administer at least 1 hour before or at least 2 hours after eating. Swallow Comarit 80 mg tablets whole. Do not crush Comarit 80 mg tablets. Do not take a missed dose within 12 hours of the next dose. Modify the dose for certain patients with hepatic impairment and for patients taking drugs known to strongly induce or inhibit CYP450. Pediatric Use: The safety and effectiveness of Comarit 80 mg in pediatric patients have not been established.

Stop treatment with Comarit 80 mg at least 28 days prior to scheduled surgery, including dental surgery Do not substitute Comarit 80 mg tablets with Comarit 80 mg capsules. Do not administer Comarit 80 mg with food. Administer at least 1 hour before or at least 2 hours after eating Swallow Comarit 80 mg tablets whole. Do not crush Comarit 80 mg tablets. Do not take a missed dose within 12 hours of the next dose. Modify the dose for certain patients with hepatic impairment and for patients taking drugs known to strongly induce or inhibit CYP450

Strong CYP3A4 Inhibitors: Coadministration of a Comarit 80 mg capsule formulation with a strong CYP3A4 inhibitor increased the exposure of Comarit 80 mg, which may increase the risk of exposure-related adverse reactions. Avoid coadministration of Comarit 80 mg with strong CYP3A4 inhibitors. Reduce the dosage of Comarit 80 mg if coadministration with strong CYP3A4 inhibitors cannot be avoided. Avoid grapefruit or grapefruit juice which may also increase exposure of Comarit 80 mg.Strong CYP3A Inducers: Coadministration of a Comarit 80 mg capsule formulation with a strong CYP3A4 inducer decreased the exposure of Comarit 80 mg, which may reduce efficacy. Avoid coadministration of Comarit 80 mg with strong CYP3A4 inducers. Increase the dosage of Comarit 80 mg if coadministration with strong CYP3A4 inducers cannot be avoided. Avoid St. John's Wort which may also decrease exposure of Comarit 80 mg.

It is contraindicated in patients with known hypersensitivity to Comarit 80 mg or any other components of this product.

Hemorrhage Perforations and Fistulas Thrombotic Events Hypertension and Hypertensive Crisis Diarrhea Palmar-plantar Erythrodysesthesia Proteinuria Osteonecrosis of the Jaw Wound Complications Reversible Posterior Leukoencephalopathy Syndrome

Based on findings from animal studies and its mechanism of action, Comarit 80 mg can cause fetal harm when administered to a pregnant woman. There is no information regarding the presence of Comarit 80 mg or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Comarit 80 mg and for 4 months after the final dose.

Hemorrhage: Severe and fatal hemorrhages occurred with Comarit 80 mg. Discontinue Comarit 80 mg for Grade 3 or 4 hemorrhage. Do not administer Comarit 80 mg to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of Comarit 80 mg-treated patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of Comarit 80 mg-treated patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue Comarit 80 mg in patients who experience a fistula that cannot be appropriately managed or a GI perforation.Thrombotic Events: Comarit 80 mg increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of Comarit 80 mg-treated patients. Fatal thrombotic events occurred in Comarit 80 mg-treated patients. Discontinue Comarit 80 mg in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.Hypertension and Hypertensive Crisis: Comarit 80 mg can cause hypertension, including hypertensive crisis. Do not initiate Comarit 80 mg in patients with uncontrolled hypertension. Monitor blood pressure regularly during Comarit 80 mg treatment. Withhold Comarit 80 mg for hypertension that is not adequately controlled with medical management; when controlled, resume Comarit 80 mg at a reduced dose. Discontinue Comarit 80 mg for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.Diarrhea: Diarrhea occurred in 63% of patients treated with Comarit 80 mg. Withhold Comarit 80 mg until improvement to Grade 1 and resume Comarit 80 mg at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.Palmar-Plantar Erythrodysesthesia: Palmar-plantar erythrodysesthesia (PPE) occurred in 44% of patients treated with Comarit 80 mg. Withhold Comarit 80 mg until improvement to Grade 1 and resume Comarit 80 mg at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.Proteinuria: Proteinuria was observed in 7% of patients receiving Comarit 80 mg. Monitor urine protein regularly during Comarit 80 mg treatment. Discontinue Comarit 80 mg in patients who develop nephrotic syndrome.Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in <1% of patients treated with Comarit 80 mg. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of Comarit 80 mg and periodically during Comarit 80 mg. Advise patients regarding good oral hygiene practices. Withhold Comarit 80 mg for at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold Comarit 80 mg for development of ONJ until complete resolution.Wound Complications: Wound complications have been reported with Comarit 80 mg. Stop Comarit 80 mg at least 28 days prior to scheduled surgery. Resume Comarit 80 mg after surgery based on clinical judgment of adequate wound healing. Withhold Comarit 80 mg in patients with dehiscence or wound healing complications requiring medical intervention. Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with Comarit 80 mg. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Comarit 80 mg in patients who develop RPLS.Embryo-Fetal Toxicity: Based on data from animal studies and its mechanism of action, Comarit 80 mg can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Comarit 80 mg and for 4 months after the last dose.

One case of overdosage was reported following administration of another formulation of Comarit 80 mg; a patient inadvertently took twice the intended dose for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

Store below 30°C in a cool and dry place, away from sunlight. Keep out of reach of children.

Pediatric Use: The safety and effectiveness of Comarit 80 mg in pediatric patients have not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between these patients and younger patients. Renal Impairment: No dosage adjustment is recommended in patients with mild or moderate renal impairment.

Tyrosine Kinase Inhibitor

In vitro biochemical and/or cellular assays have shown that Comarit 80 mg inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.Absorption: Median time to peak Comarit 80 mg concentrations (Tmax) ranged from 3 to 4 hours post-dose. A 19% increase in the Cmax of Comarit 80 mg compared to a Comarit 80 mg capsule formulation was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between Comarit 80 mg and a Comarit 80 mg capsule formulation.Distribution: The oral volume of distribution (Vz/F) of Comarit 80 mg is approximately 319 L. Comarit 80 mg is highly protein-bound in human plasma (≥99.7%).Elimination: The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady state is estimated to be 2.2 L/hr.Metabolism: Comarit 80 mg is a substrate of CYP3A4 in vitro.Excretion: Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single dose of radiolabeled 14 C- Comarit 80 mg in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged Comarit 80 mg accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72-hour collection.

Pregnancy: Comarit 80 mg can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Lactation: There is no information regarding the presence of Comarit 80 mg or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with Comarit 80 mg and for 4 months after the final dose.Contraception: Comarit 80 mg can cause fetal harm when administered to a pregnant woman.Females: Females of reproductive potential should be advised to use effective contraception during treatment with Comarit 80 mg and for 4 months after the final dose.Infertility: Females and Males: Based on findings in animals, Comarit 80 mg may impair fertility in females and males of reproductive potential.