Carfilzomib

Carfilzomib is used for: Multiple Myeloma

Multiple Myeloma Indicated for relapsed or refractory multiple myeloma in patients who have received 1-3 prior lines of therapy as a dual regimen with dexamethasone Also indicated as a single agent for relapsed or refractory multiple myeloma in patient who have received ?1 line of therapy Combination with dexamethasone (once weekly regimen) Each 28-day period is 1 treatment cycle Cycle 1 20 mg/m² in Cycle 1 on Day 1; if tolerated, escalate dose to 70 mg/m² on Day 8 of Cycle 1 Administer carfilzomib on Days 1, 8, and 15 Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 Administer dexamethasone 30 minutes to 4 hr before carfilzomib Cycle 2-9 Administer carfilzomib on Days 1, 8, and 15 Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22 Administer dexamethasone 30 minutes to 4 hr before carfilzomib Cycle 10 and thereafter 70 mg/m² on Day 1, 8, and 15 Dexamethasone 40 mg PO or IV on Days 1, 8, and 15 Administer dexamethasone 30 minutes to 4 hr before carfilzomib Continue until disease progression or unacceptable toxicity occurs Combination with dexamethasone (twice weekly regimen) Each 28-day period is considered 1 treatment cycle Dexamethasone: 20 mg PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each cycle; administer dexamethasone 30 minutes to 4 hr before carfilzomib Cycle 1 Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16 20 mg/² IV infused over 30 minutes, on Days 1 and 2 If tolerated, escalate to a target dose of 56 mg/m² starting on Day 8 of Cycle 1 Cycle 2 and thereafter 56 mg/m² IV infused over 30 minutes on Days 1 and 2, Days 8 and 9, and Days 15 and 16 Continue until disease progression or unacceptable toxicity occurs Combination with lenalidomide and dexamethasone Each 28-day period is considered 1 treatment cycle Lenalidomide: 25 mg PO on Days 1–21 of each cycle Dexamethasone: 40 mg PO or IV on Days 1, 8, 15, and 22 of each cycle Cycle 1 Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16 20 mg/m² IV infused over 10 minutes, on Days 1 and 2 If tolerated, escalate to a target dose of 27 mg/m² starting on Day 8 of Cycle 1 Cycles 2-12 Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16 Cycles 13 and thereafter From Cycle 13, omit Day 8 and 9 doses of carfilzomib (administer on Days 1 and 2, and Days 15 and 16) Discontinue carfilzomib after Cycle 18 Monotherapy Each 28-day period is considered 1 treatment cycle 20/27 mg/m² twice weekly regimen (10-minute infusion) Cycle 1: 20 mg/m² on Days 1 and 2; if tolerated, escalate to a target dose of 27 mg/m² starting on day 8 of cycle 1; continue with tolerated dose on Days 9 and Days 15 and 16 Cycles 2-12: Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16 Cycles 13 and thereafter: Omit Day 8 and 9 doses of carfilzomib (administer on Days 1 and 2, and Days 15 and 16) 20/56 mg/m² twice weekly regimen (30-minute infusion) Cycle 1: 20 mg/m² on Days 1 and 2; if tolerated, escalate to a target dose of 56 mg/m² starting on day 8 of cycle 1; continue with tolerated dose on Days 9 and Days 15 and 16 Cycle 2-12: Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16 Cycle 13 and thereafter: Administer carfilzomib on Days 1, 2, 15, and 16 Hepatic impairment Mild or moderate (bilirubin >1 to 3x ULN): Reduce dose by 25% Severe: Not evaluated; dose recommendation cannot be made

Renal impairment Baseline mild, moderate, severe, or patients on chronic hemodialysis: No starting dose adjustment required Patients with end stage renal disease who are on dialysis: Administer dose after hemodialysis procedure

IV Preparation Remove vial from refrigerator just prior to use Reconstitute each vial by slowly injecting 29 mL (60-mg vial) or 15 mL (30-mg vial) or 5 mL (10-mg vial) Sterile Water for Injection, direct solution onto the inside wall of the vial to minimize foaming; resulting concentration of reconstituted vial is 2 mg/mL There is no data to support use of closed system transfer devices with carfilzomib Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs Do not shake to avoid foam generation; if foaming occurs, allow solution to rest in vial for about 2-5 minutes, until foaming subsides Reconstituted product should be a clear, colorless solution; if any discoloration or particulate matter is observed, do not use the reconstituted product Can be administered directly by slow IV infusion or optionally, may dilute further by adding calculated dose to 50-100 mL D5W IV bag When administering in an IV bag, use ?21-gauge needle (?0.8 mm external diameter needle) to withdraw calculated dose Immediately discard vial containing unused portion IV Administration Do not administer by IV push or bolus Administer IV over 10 or 30 minutes depending on the dose regimen Flush IV live with 0.9% NaCl or D5W immediately before and after carfilzomib administration Do not mix with or administer as an infusion with other medicinal products

Hypersensitivity. Lactation.

Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) and premedicate to avoid infusion reactions; maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely (see Administration) Tumor lysis syndrome, including fatal outcomes, reported; patients with multiple myeloma and a high tumor burden are at greater risk; ensure adequate hydration and consider uric acid-lowering drugs Monitor for pulmonary hypertension and other pulmonary complications (eg, ARDS) during and after treatment completion; dyspnea reported in 31% of patients Dyspnea reported; evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes Inform patient of the risk and symptoms of infusion reactions Consider neuroradiological imaging (MRI) for onset of visual or neurological symptoms of posterior reversible encephalopathy syndrome (PRES); discontinue therapy if suspected Monitor platelet counts; interrupt or reduce dosing as clinically indicated if thrombocytopenia occurs Cases of hepatic failure, including fatal cases, reported; monitor liver enzymes regularly, regardless of baseline values, and modify dose based on toxicity Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage; promptly evaluate signs and symptoms of blood loss Increased fatal and serious toxicities reported in combination with melphalan and prednisone in newly diagnosed transplant-ineligible patients Thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day cycle, with recovery to baseline platelet count usually by the start of the next cycle; thrombocytopenia reported in ~34% of patients in clinical trials with carfilzomib Hypertension, including hypertensive crisis and hypertensive emergency, has been observed Can cause fetal harm

Pregnancy Can cause fetal harm based on findings from animal studies and the drug’s mechanism of action Females of reproductive potential should be advised to avoid becoming pregnant while being treated Males of reproductive potential should be advised to avoid fathering a child while being treated Contraception Advise females of reproductive potential to use contraception during treatment and for 6 months following final dose; if drug used during pregnancy or if patient becomes pregnant during treatment, patient should be apprised of potential risk to fetus Advise male patients with female sexual partners to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment and for at least 90 days following completion of therapy Lactation There are no data on presence of drug in human milk, effects on breastfed child, or on milk production; because many drugs are excreted in human milk and potential for serious adverse reactions in breastfed child unknown, advise nursing women not to breastfeed during treatment and for 2 weeks after treatment

Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs.

Side effects of Carfilzomib : >10% Fatigue (55.5%) Anemia (46.8%) Nausea (44.9%) Thrombocytopenia (36.3%) Dyspnea (34.6%) Diarrhea (32.7%) Pyrexia (30.4%) Upper respiratory tract infection (28.3%) Headache (27.6%) Cough (26%) Increase in blood creatinine (24.1%) Lymphopenia (24%) Peripheral Edema (24%) Vomiting (22.2%) Constipation (20.9%) Neutropenia (20.7%) Back pain (20.2%) Insomnia (17.9%) Chills (16%) Arthralgia (15.8%) Muscle spasms (14.4%) Hypertension (14.3%) Asthenia (13.9%) Hypokalemia (13.7%) Hypomagnesemia (13.5%) Leukopenia (13.5%) Pain in extremity (13.3%) Pneumonia (12.7%) Increase in aspartate aminotransferase (12.5%) Dizziness (12.5%) Hypoesthesia (12.2%) Anorexia (12%) Pain (12%) Hyperglycemia (11.8%) Chest wall pain (11.4%) Hypercalcemia (11%) Hypophosphatemia (10.5%) Hyponatremia (10.3%) 1-10% Pneumonia (10%) Acute renal failure (4%) Pyrexia (3%) Congestive heart failure (3%)

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; has antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells