Crizonix250 mg

Crizonix 250 mg is a kinase inhibitor indicated for the treatment of patients with- Metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive Metastatic NSCLC whose tumors are ROS1-positive

Targeted Cancer Therapy

Crizonix 250 mg is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizonix 250 mg demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

Recommended Dose: 250 mg orally, twice daily Geriatric Use: No differences in safety or efficacy were observed between older and younger patients. Clinical studies of Crizonix 250 mg in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patientsPediatric Dose: The safety and effectiveness of Crizonix 250 mg in pediatric patients have not been established.Renal impairment: 250 mg orally, once daily in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild (ClCr 60-89 mL/min) or moderate (ClCr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis.Hepatic Impairment: Caution should be used in patients with hepatic impairment

Recommended Dose: 250 mg orally, twice daily Geriatric Use: No differences in safety or efficacy were observed between older and younger patients. Clinical studies of Crizonix 250 mg in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patientsPediatric Dose: The safety and effectiveness of Crizonix 250 mg in pediatric patients have not been established.Renal impairment: 250 mg orally, once daily in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild (ClCr 60-89 mL/min) or moderate (ClCr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis.Hepatic Impairment: Caution should be used in patients with hepatic impairment

CYP3A Inhibitors: Concurrent use of Crizonix 250 mg should be avoided with strong CYP3A inhibitors including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazoleCYP3A Inducers: Concurrent use of Crizonix 250 mg should be avoided with strong CYP3A inducers including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort CYP3A Substrates: Concurrent use of Crizonix 250 mg should be avoided with CYP3A substrates with narrow therapeutic indices including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus

The most common adverse reactions (≥25%) are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Based on its mechanism of action, Crizonix 250 mg can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Crizonix 250 mg during pregnancy. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception.There is no information regarding the presence of Crizonix 250 mg in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants patients should not breastfeed during treatment with Crizonix 250 mg and for 45 days after the final dose.

Hepatotoxicity: Patients should undergo periodic liver testing. Crizonix 250 mg should be temporarily suspended, dose reduced or permanently suspendedInterstitial lung disease (ILD)/ Pneumonitis: Drug should be permanently discontinued in patients with ILD/ PneumonitisQT interval prolongation: Electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT should be monitored. Crizonix 250 mg should be temporarily suspended, dose reduced or permanently suspendedBradycardia: Crizonix 250 mg can cause bradycardia. Heart rate and blood pressure should be regularly monitored. Crizonix 250 mg should be temporarily suspended, dose reduced or permanently suspendedSevere visual loss: Ophthalmological evaluation should be performed. Crizonix 250 mg should be discontinued in severe visual lossEmbryo-fetal toxicity: Crizonix 250 mg can cause fetal harm. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Targeted Cancer Therapy

Crizonix 250 mg is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizonix 250 mg demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.Absorption: Following oral single-dose administration, Crizonix 250 mg was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following Crizonix 250 mg 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady state systemic exposure (C.min and AUC) appeared to increase in a greater than dose proportional manner over the dose range of 200-300 mg twice daily. The mean absolute bioavailability of Crizonix 250 mg was 43% (range: 32% to 66%) following the administration of a single 250 mg oral dose. A high-fat meal reduced Crizonix 250 mg AUCinf and Cmax by approximately 14%.Distribution: The geometric mean volume of distribution (Vss) of Crizonix 250 mg was 1772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma. Binding of Crizonix 250 mg to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that Crizonix 250 mg is a substrate for P-glycoprotcin (P-gp). The blood-to-plasma concentration ratio is approximately 1.Metabolism: In vitro studies demonstrated that Crizonix 250 mg is predominantly metabolized by CYP3A4/5. The primary metabolic pathways in humans were oxidation of the piperidine ring to Crizonix 250 mg lactam and O dealkylation, with subsequent Phase 2 conjugation of O-dcalkylatcd metabolites.Elimination: Following single doses of Crizonix 250 mg, the mean apparent plasma terminal half-life of Crizonix 250 mg was 42 hours in patients. Following the administration of a single 250 mg radiolabeled Crizonix 250 mg dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged Crizonix 250 mg represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. The mean apparent clearance (CL/F) of Crizonix 250 mg was lower at steady state (60 L/hr) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/hr), which was likely due to auto inhibition of CYP3A by Crizonix 250 mg after multiple dosing.

Based on its mechanism of action, Crizonix 250 mg can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Crizonix 250 mg during pregnancy. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception.There is no information regarding the presence of Crizonix 250 mg in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants patients should not breastfeed during treatment with Crizonix 250 mg and for 45 days after the final dose.