Kyprolis

/ Amgen

Administration Precautions
Hydration: Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. The recommended hydration includes both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles. Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure.
Electrolyte Monitoring: Monitor serum potassium levels regularly during treatment with Kyprolis.
Premedications: Premedicate with the recommended dose of dexamethasone for monotherapy or the recommended dexamethasone dose if on combination therapy. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion reactions. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.
Administration: Kyprolis can be administered in a 50 mL or 100 mL intravenous bag of 5% Dextrose Injection, USP. Infuse over 10 or 30 minutes depending on the Kyprolis dose regimen. Administer as an intravenous infusion. Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration. Do not mix Kyprolis with or administer as an infusion with other medicinal products.
Dose Calculation: Calculate the Kyprolis dose using the patient’s actual body surface area (BSA) at baseline. In patients with a BSA greater than 2.2 m², calculate the dose based upon a BSA of 2.2 m².
Thromboprophylaxis: Thromboprophylaxis is recommended for patients being treated with the combination of Kyprolis with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Infection Prophylaxis: Consider antiviral prophylaxis for patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation.
Patients on Hemodialysis: Administer Kyprolis after the hemodialysis procedure.
Recommended Dosing
Kyprolis in Combination with Dexamethasone: For the combination regimen with dexamethasone alone, administer Kyprolis intravenously once weekly or twice weekly as a 30-minute infusion as described in Table 1 & 2 at the attached doctor’s leaflet.
Once weekly 20/70 mg/m² regimen by 30-minute infusion: Kyprolis is administered intravenously as a 30-minute infusion once weekly for three weeks followed by a 13-day rest period as shown in Table 1. Each 28-day period is considered one treatment cycle. Administer Kyprolis at a starting dose of 20 mg/m² in Cycle 1 on Day 1. If tolerated, escalate the dose to 70 mg/m² on Day 8 of Cycle 1. Dexamethasone 40 mg is taken by mouth or intravenously on Days 1, 8, and 15 of all cycles and on Day 22 of Cycles 1 to 9. Administer dexamethasone 30 minutes to 4 hours before Kyprolis.
Treatment may be continued until disease progression or unacceptable toxicity occurs. Refer to the dexamethasone Prescribing Information for other information on that product.
Twice weekly 20/56 mg/m² regimen by 30-minute infusion: Kyprolis is administered intravenously as a 30-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 2 at the attached doctor’s leaflet. Each 28-day period is considered one treatment cycle. Administer Kyprolis at a starting dose of 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 56 mg/m² on Day 8 of Cycle 1. Dexamethasone 20 mg is taken by mouth or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. Administer dexamethasone 30 minutes to 4 hours before Kyprolis.
Treatment may be continued until disease progression or unacceptable toxicity occurs. Refer to the dexamethasone Prescribing Information for other information on that product.
Kyprolis in Combination with Lenalidomide and Dexamethasone: For the combination regimen with lenalidomide and dexamethasone, administer Kyprolis intravenously as a 10-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 3 at the attached doctor’s leaflet. Each 28-day period is considered one treatment cycle. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m² on Day 8 of Cycle 1. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis. Discontinue Kyprolis after Cycle 18. Lenalidomide 25 mg is taken orally on Days 1–21 and dexamethasone 40 mg by mouth or intravenously on Days 1, 8, 15, and 22 of the 28-day cycles.
Continue treatment until disease progression or unacceptable toxicity occurs. Refer to the lenalidomide and dexamethasone Prescribing Information for other concomitant medications, such as the use of anticoagulant and antacid prophylaxis, that may be required with those agents.
Kyprolis Monotherapy: For monotherapy, administer Kyprolis intravenously as a 10-minute infusion. In Cycles 1 through 12, administer Kyprolis on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 4 at the attached doctor’s leaflet. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis (see Table 4). Premedicate with dexamethasone 4 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to help prevent infusion reactions. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m² on Day 8 of Cycle 1. Treatment may continue until disease progression or unacceptable toxicity occurs.
Dose Modifications Based on Toxicities: Modify dosing based on toxicity. Recommended actions and dose modifications for Kyprolis are presented in Table 5 at the attached doctor’s leaflet. Dose level reductions are presented in Table 6. See the lenalidomide and dexamethasone Prescribing Information respectively for dosing recommendations.
Dosing in Patients with End Stage Renal Disease: For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.
See prescribing information for full details.

Relapsed or Refractory Multiple Myeloma:
• Treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy in combination with:
o Lenalidomide and dexamethasone; or
o Dexamethasone; or
o Daratumumab (I.V. or S.C.) and dexamethasone.
• As a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Hypersensitivity to the active substance or to any of the excipients.

Cardiac Toxicities: New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration. Some events occurred in patients with normal baseline ventricular function. In clinical studies with Carfilzomib , these events occurred throughout the course of therapy. Death due to cardiac arrest has occurred within one day of drug administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus tachycardia).
Acute Renal Failure: Cases of acute renal failure have occurred in patients receiving Carfilzomib . Some of these events have been fatal. Renal insufficiency adverse events (including renal failure) have occurred in approximately 9% of patients who receivedthe drug. .  Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Carfilzomib  monotherapy.  The risk of fatal renal failure was greater in patients with a baseline reduced estimated creatinine clearance
Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome: Cases of tumor lysis syndrome (TLS), including fatal outcomes, have been reported in patients who received Carfilzomib . Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Administer oral and intravenous fluids before administration of the drug in Cycle 1, and in subsequent cycles as needed.
Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute respiratory failure have occurred in approximately 2% of patients received the drug. In addition, acute diffuse infiltrative pulmonary disease, such as pneumonitis and interstitial lung disease, occurred in approximately 2% of patients who received the drug. Some events were fatal. In the event of drug-induced pulmonary toxicity, discontinue treatment.
Pulmonary Hypertension:
Pulmonary arterial hypertension was reported in approximately 2% of patients who received Carfilzomib , with Grade 3 or greater in less than 1%.
Evaluate with cardiac imaging and/or other tests as indicated. Withhold Carfilzomib  for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Carfilzomib  based on a benefit/risk assessment.
Dyspnea:
Dyspnea was reported in 25% of patients treated with Carfilzomib , with Grade 3 or greater in 4%.
Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Carfilzomib  for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Carfilzomib  based on a benefit/risk assessment.
Hypertension:
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Carfilzomib . Some of these events have been fatal. Optimize blood pressure prior to starting Carfilzomib . Monitor blood pressure regularly in all patients while on Carfilzomib . If hypertension cannot be adequately controlled, withhold Carfilzomib  and evaluate. Consider whether to restart Carfilzomib  based on a benefit/risk assessment.
Venous Thrombosis:
Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Carfilzomib . Provide thromboprophylaxis for patients being treated with Carfilzomib  in combination with lenalidomide and dexamethasone; with dexamethasone; or with intravenous daratumumab and dexamethasone. Select the thromboprophylaxis regimen based on the patient’s underlying risks.
For patients using oral contraceptives or hormonal contraception associated with a risk of thrombosis, consider non-hormonal contraception during treatment when Carfilzomib  is administered in combination.
Infusion-Related Reactions:
Infusion-related reactions, including life threatening reactions, have occurred in patients receiving Carfilzomib . Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Carfilzomib.
Administer dexamethasone prior to Carfilzomib  to reduce the incidence and severity of infusion-related reactions.
Hemorrhage:
Fatal or serious cases of hemorrhage have been reported in patients treated with Carfilzomib . Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis.
Hepatic Toxicity and Hepatic Failure:
Cases of hepatic failure, including fatal cases, have been reported (2%) during treatment with this medicinal product. Carfilzomib can cause increased serum transaminases. Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy:
Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received carfilzomib. Some of these events have been fatal.
Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop carfilzomib and evaluate. If the diagnosis of TTP/HUS is excluded, carfilzomib may be restarted. The safety of reinitiating carfilzomib therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome:
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving carfilzomib. PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro radiological imaging (MRI).
Discontinue carfilzomib if PRES is suspected and evaluate. The safety of reinitiating carfilzomib therapy in patients previously experiencing PRES is not known.
Progressive Multifocal Leukoencephalopathy:
Progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported with carfilzomib. In addition to carfilzomib, other possible contributaory factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression.
Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue carfilzomib and initiate evaluation for PML including neurology consultation.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients:
In CLARION, a clinical trial of 955 transplant ineligible patients with newly diagnosed multiple myeloma randomized to Carfilzomib (20/36 mg/m2 by 30 minute infusion twice weekly for four of each six week cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone (VMP), a higher incidence of fatal adverse reactions (7%  versus  4%) and serious adverse reactions (50% versus 42%) were observed in the KMP arm compared to patients in the VMP arm, respectively. Patients in the KMP arm were observed to have a higher incidence of any grade adverse reactions involving cardiac failure (11%  versus 4%), hypertension (25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% versus 9%). This study did not meet its primary outcome measure of superiority in progression free survival (PFS) for the KMP arm. Carfilzomib in combination with melphalan and prednisone is not indicated for transplant ineligible patients with newly diagnosed multiple myeloma.
Embryo-Fetal Toxicity:
Based on the mechanism of action and findings in animals, Carfilzomib  can cause fetal harm when administered to a pregnant woman.
See prescribing information for full details.

Most commonly reported adverse reactions (incidence ≥ 20%) with monotherapy are: fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea and pyrexia.
See prescribing information for full details.

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.
Cytochrome P450: In an in vitro study using human liver microsomes, carfilzomib showed modest direct (Ki = 1.7 micromolar) and time-dependent inhibition (Ki = 11 micromolar) of human cytochrome CYP3A4/5. In vitro studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. A clinical trial of 17 patients using oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration.
Kyprolis is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 substrates.
P-gp: Carfilzomib is a P-glycoprotein (P-gp) substrate. In vitro, carfilzomib inhibited the efflux transport of P-gp substrate digoxin by 25% in a Caco-2 monolayer system. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.

Pregnancy:
Carfilzomib can cause fetal harm based on findings from animal studies and the drug’s mechanism of action. There are no studies with the use of the drug in pregnant women to inform drug-associated risks of adverse developmental outcomes. Advise pregnant women of the potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
Lactation: 
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.
See prescribing information for full details.  

Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error.
There is no known specific antidote for carfilzomib overdosage. In the event of overdose, monitor patients for adverse reactions and provide supportive care as appropriate.