Kyprolis (carfilzomib)

If grade 3 or 4 new onset or worsening of congestive heart failure, decreased left ventricular function, or myocardial ischemia occurs, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline. Following resolution, it should be considered whether resuming carfilzomib therapy at a reduced dosage (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) is appropriate based on assessment of potential risks and benefits. If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician. (See Cardiac Effects under Cautions: Warnings/Precautions.)

Platelet counts should be monitored frequently during carfilzomib therapy. If grade 3 or 4 neutropenia or grade 4 thrombocytopenia occurs, carfilzomib therapy should be withheld. If full recovery occurs prior to the next scheduled dose, carfilzomib may be resumed at the same dosage level. If the toxicity resolves to grade 2 neutropenia or grade 3 thrombocytopenia, the dosage of carfilzomib may be reduced by one dose level (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2). If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician. (See Thrombocytopenia under Cautions: Warnings/Precautions.)

In patients who develop grade 3 or 4 elevations of serum aminotransferases (ALT or AST), bilirubin, or other liver abnormalities, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline. Following resolution, it should be considered whether resuming therapy is appropriate. Therapy may be resumed at a reduced dosage (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) with frequent monitoring of liver function tests. If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician. (See Hepatic Toxicity and Hepatic Failure under Cautions: Warnings/Precautions.)

In patients who develop elevated serum creatinine concentrations of 2 or more times the baseline value, carfilzomib therapy should be withheld until renal function recovers to grade 1 or baseline and renal function should be monitored. If nephrotoxicity is attributable to carfilzomib, therapy may then be resumed at a reduced dosage (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2). If nephrotoxicity is not attributable to carfilzomib, therapy may be resumed at the dosage used prior to the event. If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.

If other grade 3 or 4 nonhematologic toxicity occurs, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline. Resumption of therapy at a dosage reduced by one dose level (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) may then be considered. If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.

If grade 3 or 4 peripheral neuropathy occurs, carfilzomib therapy should be withheld until the condition resolves or returns to baseline. Therapy may then be resumed at the dosage used prior to the event or at a reduced dosage (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2). If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.

If grade 3 or 4 pulmonary complications (e.g., dyspnea) occur, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline. Resumption of therapy at a dosage reduced by one dose level (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) may then be considered. If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician. (See Pulmonary Complications under Cautions: Warnings/Precautions.)

If pulmonary arterial hypertension (PAH) occurs, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline. Following resolution, therapy may then be resumed at either the previous dosage or at a dosage reduced by one dose level (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) at the discretion of the clinician. If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician. (See Pulmonary Hypertension under Cautions: Warnings/Precautions.)

Carfilzomib is administered IV over 2-10 minutes. The drug should not be administered by rapid IV injection, such as IV push or bolus. Immediately prior to and following carfilzomib administration, the IV administration line should be flushed with 0.9% sodium chloride injection or 5% dextrose injection.

Unreconstituted carfilzomib powder for injection should be stored in unopened vials at 2-8degreesC. Unopened vials should be retained in the original package for protection from light.

Prior to administration, commercially available carfilzomib powder for injection must be reconstituted and the reconstituted solution of the drug may be diluted using proper aseptic technique. The powder is reconstituted by adding 29 mL of sterile water for injection to a vial labeled as containing 60 mg of the drug to provide a solution containing 2-mg/mL. The diluent should be directed toward the inside wall of the vial to minimize foaming. The vial should then be gently swirled and/or inverted for approximately 1 minute, or until complete dissolution of the cake or powder occurs, and inspected visually for particulate matter and discoloration prior to dilution and administration. The resulting solution should not be shaken. If foaming occurs, the solution should be allowed to stand for about 2-5 minutes until foaming subsides. The solution should be clear, colorless, and free of visible particulates.

The desired dose of the carfilzomib reconstituted solution may be given by IV injection or may be further diluted with 5% dextrose injection for IV infusion. The reconstituted solution is diluted by adding an appropriate volume of carfilzomib 2-mg/mL solution to a 50-mL infusion bag containing 5% dextrose injection. Reconstituted and diluted solutions of the drug are stable for up to 4 or 24 hours at room temperature (15-30degreesC) or under refrigeration (2-8degreesC), respectively, regardless of container (e.g., vial, syringe, IV bag).

Carfilzomib should not be admixed with or administered as an infusion with any other drug. Commercially available carfilzomib for injection contains no preservatives and is intended for single use; vials containing the unused portion of the reconstituted solution should be immediately discarded.

No dosing information is available for this tab.

No dosing information is available for this tab.

Carfilzomib appears to be metabolized principally by extrahepatic peptidase cleavage and epoxide hydrolysis. Cytochrome P-450 (CYP)-mediated mechanisms play a minor role in the drug's overall metabolism. In an in vitro study, carfilzomib demonstrated a modest inhibitory effect on CYP3A4/5. The drug does not induce CYP1A2 and CYP3A4 in human hepatocytes in vitro. Carfilzomib is a substrate of P-glycoprotein (P-gp). The drug has shown marginal inhibitory effects on P-gp in a Caco-2 monolayer system.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

There are no moderate interactions for this drug.

The manufacturer states there are no known contraindications to the use of carfilzomib.

• Acute respiratory distress syndrome
• Lactation
• Posterior reversible encephalopathy syndrome
• Progressive multifocal leukoencephalopathy

• Acute myocardial infarction
• Acute renal failure
• Cardiac arrest
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic heart failure
• Disease of liver
• Dyspnea
• Hemolytic uremic syndrome
• Herpes zoster
• Hypertension
• Myocardial ischemia
• Neutropenic disorder
• Pregnancy
• Pulmonary hypertension
• Thrombocytopenic disorder
• Thromboembolic disorder

• Pneumonia

Adverse effects reported in 30% or more of multiple myeloma patients receiving carfilzomib include fatigue, anemia, nausea, dyspnea, diarrhea, and pyrexia. Serious adverse effects occurred in 45% of patients, and included pneumonia, acute renal failure, pyrexia, and congestive heart failure.

Laboratory abnormalities reported in 10% or more of patients receiving carfilzomib include anemia, thrombocytopenia, increased creatinine concentrations, lymphopenia, neutropenia, hypokalemia, hypomagnesemia, leukopenia, increased AST concentrations, hyperglycemia, hypercalcemia, hypophosphatemia, and hyponatremia.

More Frequent

• Anemia
• Dyspnea
• Fever
• Hypertension
• Hypokalemia
• Hypomagnesemia
• Leukopenia
• Lymphopenia
• Neutropenic disorder
• Thrombocytopenic disorder

Less Frequent

• Abnormal hepatic function tests
• Acute renal failure
• Deep venous thrombosis
• Gastroenteritis
• Gastrointestinal hemorrhage
• Heart failure
• Hyperbilirubinemia
• Hypercalcemia
• Hyperkalemia
• Hypersensitivity drug reaction
• Hypoalbuminemia
• Hyponatremia
• Hypophosphatemia
• Hypotension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Multiple organ failure
• Pneumonia
• Pulmonary edema
• Pulmonary hypertension
• Pulmonary thromboembolism
• Sepsis
• Septic shock
• Tumor lysis syndrome
• Viral infection
• Worsening of chronic heart failure

Rare or Very Rare

• Acute myocardial infarction
• Acute pancreatitis
• Acute respiratory distress syndrome
• Auditory neurotoxicity
• Bradycardia
• Cardiac arrest
• Cholestasis
• Chronic heart failure
• Clostridioides difficile infection
• Cytomegalovirus disease
• Dehydration
• Enterocolitis
• Gastrointestinal obstruction
• Gastrointestinal perforation
• Hemolytic uremic syndrome
• Hemorrhage
• Hepatic failure
• Herpes zoster
• Hypertensive crisis
• Ileus
• Interstitial pneumonitis
• Intracranial bleeding
• Laryngeal edema
• Myocardial ischemia
• Pericardial effusion
• Pericarditis
• Posterior reversible encephalopathy syndrome
• Progressive multifocal leukoencephalopathy
• Pulmonary hemorrhage
• Reactivation of hepatitis B
• Thromboembolic disorder
• Thrombotic thrombocytopenic purpura
• Ventricular tachycardia

More Frequent

• Back pain
• Constipation
• Cough
• Diarrhea
• Fatigue
• Headache disorder
• Insomnia
• Muscle spasm
• Nausea
• Pain
• Peripheral edema
• Peripheral neuropathy
• Upper respiratory infection
• Vomiting

Less Frequent

• Acute abdominal pain
• Angina
• Anorexia
• Arthralgia
• Blurred vision
• Cataracts
• Chest tightness
• Chills
• Delirium
• Dizziness
• Dyspepsia
• Epistaxis
• Erythema
• Facial edema
• Flushing
• General weakness
• Hyperglycemia
• Hyperhidrosis
• Hypoesthesia
• Influenza
• Malaise
• Muscle weakness
• Myalgia
• Pain in oropharynx
• Palpitations
• Paresthesia
• Pharyngitis
• Pruritus of skin
• Rhinitis
• Symptoms of anxiety
• Syncope
• Tachycardia
• Toothache
• Urinary tract infection
• Voice change
• Wheezing

Rare or Very Rare

• Acute cognitive impairment
• Tinnitus

No enhanced messaging available.

Safety and efficacy of carfilzomib have not been established in pediatric patients.

Category D. (See Users Guide and see Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

It is not known whether carfilzomib is distributed into human milk. Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to carfilzomib in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

In a population pharmacokinetic analysis, carfilzomib exposure in patients 65 years of age and older did not differ substantially from that in adult patients younger than 65 years of age following a single 20-mg/m2 IV dose of the drug. In clinical studies, no clinically important differences in safety or efficacy were observed between patients 65 years of age and older and younger adults. (See Dosage and Administration: Special Populations.)