Carfilzomib

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 Kyprolis overdosage. In the event of overdose, the patient should be monitored, specifically for the side effects and/or adverse reactions listed in Adverse Reactions (6).

Carfilzomib is a prescription medication used to treat people with multiple myeloma. It is also approved in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.

Carfilzomib is in a class of medications called proteasome inhibitors. It works by stopping or slowing the growth of cancer cells in your body.

Carfilzomib comes as a powder to be mixed with liquid to be injected intravenously (into a vein) by a healthcare professional.

Common side effects include fatigue, anemia, and nausea. Do not drive or operate heavy machinery until you know how this medication affects you.

Carfilzomib is part of the drug class:

• OTHER ANTINEOPLASTIC AGENTS

Common side effects of carfilzomib, when given alone, include the following:

• fatigue
• anemia
• nausea
• low blood platelet counts
• difficulty breathing
• diarrhea
• fever

Common side effects of carfilzomib, when given with lenalidomide and dexamethasone, include the following:

• decreased blood cell counts
• diarrhea
• fatigue
• fever
• muscle spasm
• cough
• upper respiratory tract infection
• low potassium

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Serious side effects have been reported with carfilzomib including the following:

• heart problems including heart failure and ischemia (a restriction in blood supply to the heart). Your doctor will want to monitor for these complications.
• shortness of breath. This most commonly occurs within a day of dosing. Tell your doctor right away if you experience shortness of breath.
• high blood pressure. Your doctor will monitor your blood pressure. 
• blood clots. Your doctor will monitor you regularly and may need to add medication to prevent blood clots from forming.
• lung damage 
• pulmonary hypertension. This is a condition when there is high blood pressure in the arteries to your lungs. Your doctor may stop treatment with carfilzomib if you develop this complication. Symptoms include
  • shortness of breath during routine activity, such as climbing two flights of stairs
  • tiredness
  • chest pain
  • a racing heartbeat
  • pain on the upper right side of the abdomen
  • decreased appetite
• infusion reactions. Infusion reactions can occur with this medication. Tell your doctor or get medical help right away if you get any of these symptoms during or after an infusion this medication:
  • hives (red itchy welts) or rash
  • itching
  • swelling of your lips, tongue, throat or face
  • sudden cough
  • shortness of breath, difficulty breathing, or wheezing
  • weakness
  • dizziness or feel faint
  • palpitations (feel like your heart is racing or fluttering)
  • chest pain
• acute kidney failure. Your doctor will monitor you regularly. 
• tumor lysis syndrome (TLS). TLS is a severe, sometimes life-threatening alteration in blood chemistry that occurs with the release of materials formerly contained within cancer cells into the bloodstream. It is important to stay hydrated and follow directions with any medications your doctor may prescribe in order to prevent TLS.
• severe bleeding problems. Your doctor will monitor your signs and symptoms of blood loss.
• low platelet count (thrombocytopenia). Tell your doctor right away if you have any unusual bleeding, such as nosebleeds, or bruising under your skin.
• liver toxicity and/or failure. Your doctor will want to monitor liver with lab tests while you are taking carfilzomib.
• blood problems such as thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Your doctor will monitor for signs and symptoms of TTP/HUS.
• brain problem such as posterior reversible encephalopathy syndrome (PRES). Your doctor may order an MRI if you start to experience visual or neurological symptoms. 
• harm to your unborn baby: Carfilzomib can cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated. Use effective contraception to prevent pregnancy during treatment with carfilzomib. If you become pregnant during treatment, contact your physician immediately.

Avoid dehydration, since patients receiving carfilzomib therapy may experience vomiting and/or diarrhea. Get medical advice if you experience symptoms of dizziness, lightheadedness, or fainting spells.

Do not drive or operate heavy machinery until you know how this medication affects you.

Do not take this medication if you are allergic to carfilzomib or to any of its ingredients.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Carfilzomib can cause harm to the fetus (unborn baby). If you are a female patient with the potential to become pregnant, it is recommended that you avoid pregnancy while being treated with this medication and to use effective contraceptive (birth control) measures.

Keep all appointments with your doctor and the laboratory.

Call your doctor for instructions if you miss an appointment for your carfilzomib injection.

• Tetrapeptide epoxyketone proteasome inhibitor.1 2 6 7 8 9 21 22 23 24

• Selectively and irreversibly inhibits the 20S proteolytic core particle within the 26S proteasome1 2 6 7 8 21 (a large protein complex that degrades ubiquitinated proteins),12 which prevents targeted proteolysis and causes proteotoxic stress resulting in cell death.6 7

• Has antiproliferative and proapoptotic activity in solid and hematologic tumor cells in vitro, including in some bortezomib-resistant cell lines.1 6 8 21 27

• In animal studies, inhibits proteasome activity in blood and tissue and delays tumor growth in models of multiple myeloma, hematologic, and solid tumors.1

• Mechanism by which carfilzomib overcomes bortezomib-resistant cell line models and clinical samples not fully elucidated; however, studies suggest that carfilzomib produces more selective, potent, and durable proteasome inhibition than bortezomib.6 7 10 12 14 21 27

• Mechanism for peripheral neuropathy resulting from proteasome inhibitor therapy not fully elucidated; however, carfilzomib's selectivity for the 26S proteasome and weak activity on other protease classes may help explain the lower incidence of neurotoxicity observed in animal and clinical studies.2 6 8 12 13

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how carfilzomib affects you.
• Very bad and sometimes deadly bleeding problems have happened with this medicine. Talk with the doctor.
• Death caused by heart attack has happened within a day of getting carfilzomib. Talk with your doctor.
• A very bad and sometimes deadly brain problem called posterior reversible encephalopathy syndrome (PRES) has happened with this medicine. Call your doctor right away if you have signs like feeling confused, lowered alertness, change in eyesight, loss of eyesight, seizures, or very bad headache.
• Very bad and sometimes deadly blood problems like thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) have happened with carfilzomib in some people. Call your doctor right away if you feel very tired or weak or have any bruising or bleeding; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; change in eyesight; change in strength on 1 side is greater than the other, trouble speaking or thinking, or change in balance; or fever.
• Patients with cancer who take this medicine may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.
• Heart failure has happened with carfilzomib, as well as heart failure that has gotten worse in people who already have it. Tell your doctor if you have heart disease. Call your doctor right away if you have shortness of breath, a big weight gain, a heartbeat that is not normal, or swelling in the arms or legs that is new or worse.
• Infusion reactions have happened with this medicine. Sometimes, these could be very bad or life-threatening. Talk with the doctor.
• High blood pressure has happened with carfilzomib. Sometimes, this has been deadly. Have your blood pressure checked as you have been told by your doctor.
• Call your doctor right away if you have signs of a blood clot like chest pain or pressure; coughing up blood; shortness of breath; swelling, warmth, numbness, change of color, or pain in a leg or arm; or trouble speaking or swallowing.
• Tell your doctor if you have signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

• Antineoplastic Agent, Proteasome Inhibitor

Multiple myeloma, relapsed/refractory: Treatment (monotherapy) of relapsed or refractory multiple myeloma in patients who have received 1 or more lines of therapy; treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone or lenalidomide plus dexamethasone) in patients who have received 1 to 3 prior lines of therapy

The International Myeloma Working Group recommends the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine (Dimopoulos 2016).

Preexisting renal impairment: No initial dosage adjustment necessary (Badros 2013; Quach 2017).

Hemodialysis: No initial dosage adjustment necessary (Quach 2017). Administer after dialysis.

The International Myeloma Working Group Recommendations suggest that (based on evaluating the 20/27 mg/m2 dose), carfilzomib may be safely administered to patients with a CrCl ≥15 mL/minute; although there is less data, carfilzomib may also be administered to patients with CrCl <15 mL/minute (Dimopoulos 2016).

Renal toxicity during treatment: Serum creatinine ≥2 times baseline, CrCl <15 mL/minute or CrCl decreases to ≤50% of baseline, or patient requires dialysis: Withhold dose and monitor renal function. If renal toxicity is due to carfilzomib, resume dosing when renal function has improved to within 25% of baseline; resume with a reduced dose by 1 dose level (see Dosing- Adjustment for Toxicity for dose level reductions). If toxicity is not due to carfilzomib, restart at the discretion of the prescriber.

Preexisting hepatic impairment:

Mild (bilirubin >1 to 1.5 times ULN or AST > ULN) or moderate (bilirubin >1.5 to 3 times ULN) impairment: Reduce dose to 75% of recommended dose.

Severe (bilirubin > 3 times ULN) impairment: There are no dosage adjustments provided in the manufacturer's labeling (the pharmacokinetics of carfilzomib have not been evaluated in patients with bilirubin >3 times ULN and any AST).

Hepatotoxicity during treatment: Grade 3 or 4 elevation of bilirubin, transaminases, or other liver abnormalities: Withhold dose until resolved or at baseline. After resolution, if appropriate to reinitiate, consider restarting at 1 dose level reduction (see Dosing: Adjustment for Toxicity for dose level reductions) with frequent monitoring of hepatic function.

Reconstitute the 60 mg vial with 29 mL, the 30 mg vial with 15 mL, and the 10 mg vial [Canadian product] with 5 mL of sterile water for injection using a 21-gauge or larger needle (0.8 mm or smaller external diameter needle), to a concentration of 2 mg/mL (directing solution onto the inside wall of the vial to avoid foaming). Gently invert and/or swirl vial slowly for ~1 minute to mix; do not shake. If foaming results, allow solution to sit for ~5 minutes until foaming resolves. Reconstituted solution should be clear and colorless. May further dilute dose by using a 21-gauge or larger needle (0.8 mm or smaller external diameter needle) to transfer the reconstituted solution into 50 or 100 mL (depending on dose and infusion duration) of D5W. Discard unused portion of the vial (do not pool unused solution from the vials).

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Contraceptives (Estrogens): Carfilzomib may enhance the thrombogenic effect of Contraceptives (Estrogens). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification

Contraceptives (Progestins): Carfilzomib may enhance the thrombogenic effect of Contraceptives (Progestins). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Concerns related to adverse effects:

• Bone marrow suppression: Thrombocytopenia (including grade 4) was observed in patients receiving carfilzomib, with platelet nadirs occurring between day 8 and day 15 of each 28-day treatment cycle, and recovery to baseline by the start of the next cycle. Monitor platelets closely and adjust dose or withhold therapy if necessary. Hemorrhage due to thrombocytopenia may occur. Anemia, lymphopenia, leukopenia, and neutropenia were also observed.

• Cardiovascular effects: Death caused by cardiac arrest has occurred within 24 hours of administration. Carfilzomib has been associated with new-onset or worsening of heart failure (HF), pulmonary edema, decreased left ventricular ejection fraction (LVEF), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction (including fatalities). Some events occurred in patients with normal ventricular function at baseline. Cardiac events typically were observed throughout the course of therapy. Patients 75 years of age and older have an increased risk of heart failure. Monitor closely for cardiac complications and for volume overload (due to pretreatment hydration), particularly in patients at risk for HF; withhold carfilzomib therapy for grade 3 or 4 cardiac events until recovery. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction (within 3 to 6 months), and conduction abnormalities, angina, or arrhythmias not managed by medication were excluded from clinical trials and may be at increased risk for cardiac complications; evaluate with a comprehensive medical assessment prior to initiation and closely monitor.

• Hemorrhage: Serious or fatal cases of hemorrhage have been reported, including gastrointestinal, intracranial and pulmonary hemorrhage and epistaxis. Bleeding may be spontaneous; intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients with and without low platelets and has also been reported in patients who were not receiving anticoagulation or antiplatelet therapy. Monitor for signs/symptoms of hemorrhage and promptly evaluate symptoms of blood loss. Reduce dose or withhold treatment as clinically indicated.

• Hepatic effects: Hepatic failure, including fatal cases, has been reported rarely. Increased transaminases and hyperbilirubinemia have also been observed. Interrupt therapy with grade 3 or higher hepatic toxicity until resolved or recovered to baseline (may require dose reduction if appropriate to reinitiate); monitor liver enzymes regularly.

• Hypertension: Hypertension has occurred with use; hypertensive crisis and hypertensive emergency have also been reported (some events were fatal). Monitor blood pressure throughout therapy; if hypertension cannot be adequately controlled, interrupt carfilzomib therapy and evaluate; assess risks versus benefits when determining to restart treatment.

• Infusion reactions: May occur immediately following or within 24 hours of carfilzomib infusion; may be life-threatening. Symptoms have included fever, chills, arthralgia, myalgia, flushing, facial edema, vomiting, weakness, dyspnea, hypotension, syncope, chest tightness, or angina. To lessen the incidence and intensity of infusion reactions, administer dexamethasone prior to drug administration.

• Posterior reversible encephalopathy syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported rarely with use; symptoms include seizure, headache, lethargy, confusion, blindness, altered consciousness, hypertension, and other visual/neurological disturbances. Discontinue therapy if PRES diagnosis is suspected; the safety of reinitiating therapy after PRES diagnosis is not known.

• Pulmonary toxicities: Acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse-infiltrative pulmonary disease (eg, pneumonitis and interstitial lung disease) have occurred in a small number of patients (some events were fatal); discontinue therapy if any of these drug-induced pulmonary toxicities occur. In clinical trials, pulmonary arterial hypertension (PAH) was observed (including grade 3 or higher events); perform cardiac imaging or other testing as appropriate, and withhold carfilzomib until PAH is resolved or returns to baseline. Dyspnea (including grade 3 or higher events) has been reported; monitor closely. Withhold carfilzomib for grade 3 or 4 dyspnea until pulmonary symptom resolution or return to baseline.

• Renal toxicity: Renal toxicity (eg, renal insufficiency, acute renal failure, renal failure) has been reported with carfilzomib. Acute renal failure was observed more frequently in patients receiving carfilzomib monotherapy for advanced relapsed/refractory multiple myeloma; renal failure risk is greater when patients have a baseline reduced creatinine clearance. Monitor renal function closely; may require therapy interruption or dose reduction.

• Thrombotic microangiopathy: Thrombotic microangiopathy, including cases of thrombocytopenic thrombotic purpura/hemolytic uremic syndrome (TTP/HUS) has been reported (some fatal); monitor for signs/symptoms. Interrupt therapy if TTP/HUS diagnosis is suspected and manage appropriately (eg, plasma exchange as clinically necessary). If TTP/HUS diagnosis is excluded, may consider reinitiating therapy; the safety of restarting carfilzomib after a TTP/HUS diagnosis is not known.

• Thromboembolic events: Venous thromboembolism (eg, deep vein thrombosis and pulmonary embolism) has been observed, particularly when used as part of combination therapy with dexamethasone or with lenalidomide plus dexamethasone. Thromboprophylaxis is recommended with combination therapy, and should be based on patients’ underlying risk factors, treatment regimen, and clinical status. Due to risk of thrombosis with hormonal contraception, consider an alternative method of effective contraception during combination treatment of carfilzomib with dexamethasone or lenalidomide plus dexamethasone.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS), including fatalities, has been observed. TLS risk is increased in multiple myeloma patients with a high tumor burden. Adequately hydrate patients prior to carfilzomib therapy and monitor closely for signs and symptoms of TLS; consider use of antihyperuricemic agents. If TLS occurs, interrupt treatment until resolved.

Concurrent drug therapy issues:

• Combination therapy toxicity: An increased incidence of serious and fatal adverse events was observed in a clinical trial comparing the combination of carfilzomib, melphalan, and prednisone (KMP) to bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed multiple myeloma (MM) in transplant-ineligible patients. Cardiac failure, hypertension, acute renal failure, and dyspnea were observed more frequently in the KMP arm. KMP is not an approved carfilzomib combination regimen.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Injection: Vials contain the excipient cyclodextrin (sulfobutyl ether beta-cyclodextrin), which may accumulate in patients with renal insufficiency, although the clinical significance of this finding is uncertain (Luke 2010).

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, adverse fetal events would be expected to occur with use in pregnant women. Females and males of reproductive potential are advised to avoid pregnancy during therapy; women of reproductive potential should abstain from sexual activity or use effective contraception during treatment and for at least 30 days following therapy completion. Male patients of reproductive potential should abstain from sexual activity or use effective contraception during treatment and for at least 90 days following therapy completion.

Use should be avoided. US FDA pregnancy category: Not assigned Comments: -This drug can harm a developing fetus based on animal studies and its mechanism of action. -Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during therapy and for at least 30 days following completion of therapy. -Advise male patients of reproductive potential to use effective contraception to prevent pregnancy during therapy and for at least 90 days following completion of therapy. -Apprise the patient of the potential hazard to the fetus if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug.

Animal studies have revealed evidence of embryofetal toxicity at doses that were lower than in patients receiving the recommended dose, but have failed to show teratogenicity. No effects on reproductive tissues were noted during animal toxicity studies. There are no controlled data in human pregnancy. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.