Carfilez

Carfilzomib is a proteasome inhibitor that is indicated:

• For the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with Lenalidomide and dexamethasone; or Dexamethasone; or Daratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone; or Isatuximab and dexamethasone.
• As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.

Clinical Studies: Effect of Carfilzomib on Sensitive CYP3A Substrate: Midazolam (a sensitive CYP3A substrate) pharmacokinetics was not affected by concomitant administration of carfilzomib.

In Vitro Studies: Effect of Carfilzomib on Cytochrome P450 (CYP) Enzymes: Carfilzomib showed direct and time-dependent inhibition of CYP3A but did not induce CYP1A2 and CYP3A4 in vitro.

Effect of Transporters on Carfilzomib: Carfilzomib is a P-glycoprotein (P-gp) substrate in vitro.

Effect of Carfilzomib on Transporters: Carfilzomib inhibits P-gp in vitro. However, given that Carfilzomib is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.

The most common adverse reactions occurring in at least 20% of patients treated with carfilzomib in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

The most common adverse reactions occurring in at least 20% of patients treated with carfilzomib in the combination therapy trials: anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia.

Carfilzomib can cause fetal harm based on findings from animal studies and its mechanism of action. There are no available data on carfilzomib use in pregnant women to evaluate for drug-associated risks. Carfilzomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose. Advise pregnant women of the potential risk to the fetus.

There are no data on the presence of Carfilzomib in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Carfilzomib and for 2 weeks after treatment.

• Cardiac Toxicities: Monitor for signs and symptoms of cardiac failure or ischemia. Withhold Kyprolis and evaluate promptly.
• Acute Renal Failure: Monitor serum creatinine regularly.
• Tumor Lysis Syndrome (TLS): Administer pre-treatment hydration. Monitor for TLS, including uric acid levels and treat promptly.
• Pulmonary Toxicity, including Acute Respiratory Distress Syndrome, Acute Respiratory Failure, and Acute Diffuse Infiltrative Pulmonary Disease: Withhold Kyprolis and evaluate promptly.
• Pulmonary Hypertension: Withhold Kyprolis and evaluate.
• Dyspnea: For severe or life-threatening dyspnea, withhold Kyprolis and evaluate.
• Hypertension, including Hypertensive Crisis: Monitor blood pressure regularly. If hypertension cannot be controlled, interrupt treatment with Kyprolis.
• Venous Thrombosis: Thromboprophylaxis is recommended.
• Infusion-related Reactions: Premedicate with dexamethasone.
• Hemorrhage: Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage. Promptly evaluate signs and symptoms of blood loss.
• Thrombocytopenia: Monitor platelet counts; interrupt or reduce Kyprolis dosing as clinically indicated.
• Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes regularly. Withhold Kyprolis if suspected.
• Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Kyprolis if suspected.
• Posterior Reversible Encephalopathy Syndrome (PRES): Consider neuro-radiological imaging (MRI) for onset of visual or neurological symptoms; discontinue Kyprolis if suspected.
• Progressive Multifocal Leukoencephalopathy: Consider PML if new or worsening neurologic manifestations. Discontinue Kyprolis in patients who develop PML. Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients.
• Embryo-Fetal Toxicity: Kyprolis can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception.

Tetrapeptide epoxyketone proteasome inhibitor

Unopened vials should be stored refrigerated 2°C to 8°C. Retain in original package to protect from light.