Kyprolis

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

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

Common side effects of Kyprolis, 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.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if this medication crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using this medication.

You should not use carfilzomib if you are allergic to it.

To make sure carfilzomib is safe for you, tell your doctor if you have:

• kidney disease (or if you are on dialysis);

• heart disease, high blood pressure; or

• liver disease, or abnormal liver function tests.

Carfilzomib can harm an unborn baby. Use effective birth control to prevent pregnancy while you are using this medicine, whether you are a man or a woman. Carfilzomib use by either parent may cause birth defects.

If you are a woman, keep using birth control for at least 30 days after your last dose of carfilzomib. If you are a man, keep using birth control for at least 90 days after your last dose. Tell your doctor right away if a pregnancy occurs while either the mother or the father is using carfilzomib.

It is not known whether carfilzomib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some side effects may occur within 24 hours after the injection. Tell your caregiver right away if you feel dizzy, weak, nauseated, light-headed, feverish, sweaty, or if you have joint or muscle pain, a headache, chest tightness, back pain, trouble breathing, or swelling in your face.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;

• easy bruising, unusual bleeding, or any bleeding that will not stop;

• headache, confusion, change in mental status, vision loss, seizure (convulsions);

• vomiting, diarrhea, stomach pain, weakness, blood in your stools;

• coughing up blood or vomit that looks like coffee grounds;

• heart problems--chest pain or pressure, pounding heartbeats or fluttering in your chest, pain spreading to your jaw or shoulder, nausea, sweating;

• liver problems--upper stomach pain, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes);

• low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, rapid heart rate, pale skin, weakness;

• lung problems--shortness of breath (even with mild exertion or while lying down), swelling of your hands or feet, wheezing, gasping for breath, blue colored lips and skin, cough with foamy mucus;

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• signs of a blood clot in the lung--chest pain, sudden cough, wheezing, rapid breathing;

• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs; or

• signs of tumor cell breakdown--lower back pain, blood in your urine, little or no urinating; numbness or tingly feeling around your mouth; muscle weakness or tightness; fast or slow heart rate, weak pulse.

Common side effects may include:

• fever, bruising, pale skin or other signs of low blood cell counts;

• nausea;

• diarrhea; or

• feeling tired.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Cardiac Effects

Death from cardiac arrest within a day of administration reported.1 2

New onset or worsening of preexisting CHF with decreased left ventricular function or myocardial ischemia also reported.1 2 Heart failure-related events (e.g., CHF, pulmonary edema, decreased left ventricular ejection fraction) occurred in 7% of carfilzomib-treated patients.1

Patients with NYHA class III or IV heart failure, history of MI in the preceding 6 months, or conduction abnormalities not controlled by medication may be at greater risk for cardiac complications.1

Monitor for cardiac complications and manage promptly if they occur.1 If grade 3 or 4 cardiac toxicity occurs, withhold therapy until toxicity resolves or returns to baseline; may resume therapy at reduced dosage if benefit outweighs risk.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Pulmonary Hypertension

PAH reported in 2% of patients.1 Evaluate patients for PAH using cardiac imaging and/or other tests as indicated.1

If PAH is suspected, withhold therapy until signs and symptoms resolve or return to baseline; may resume therapy at previous or reduced dosage if benefit outweighs risk.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Pulmonary Complications

Dyspnea reported in approximately 35% of patients.1 2 6 Grade 3 dyspnea occurred in 5% of patients; no grade 4 cases and one fatal case reported.1 2 6 Generally occurs early in therapy and is transient; risk does not increase with cumulative exposure and is not associated with progressive lung injury.2 6

Monitor patients for dyspnea and manage immediately.1 If grade 3 or 4 pulmonary toxicity (i.e., dyspnea) occurs, withhold therapy until toxicity resolves or returns to baseline; may resume therapy at reduced dosage if benefit outweighs risk.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Infusion Reactions

Infusion-related reactions (e.g., pyrexia, chills, arthralgia, myalgia, flushing, facial edema, emesis, weakness, dyspnea, hypoxia, hypotension, syncope, chest tightness, angina) reported; may occur immediately following or up to 24–48 hours following IV administration.1 5

To minimize incidence and severity of infusion-related reactions, administer premedication with dexamethasone.1 (See Premedication under Dosage and Administration and also see Advice to Patients.)

Tumor Lysis Syndrome

Tumor lysis syndrome reported rarely.1 2 Increased risk in patients with multiple myeloma and high tumor burden.1

Hydrate well prior to administration.1 Some clinicians also concurrently administer allopurinol to reduce risk.22 Monitor for manifestations of tumor lysis syndrome during therapy; if present, manage promptly.1 Interrupt carfilzomib therapy until tumor lysis syndrome resolves.1 (See Hydration under Dosage and Administration.)

Thrombocytopenia

Thrombocytopenia, usually transient and rarely requiring dosage reduction or discontinuance, reported.1 2 Nadir platelet count occurs around day 8 of each 4-week cycle; recovery to baseline typically occurs by start of subsequent cycle.1 2

Monitor platelet counts frequently during therapy.1 If thrombocytopenia occurs, reduce dosage or interrupt therapy as clinically indicated.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Hepatic Toxicity and Hepatic Failure

Hepatic failure, including fatal cases, reported rarely.1 2 5 6 Elevated serum aminotransferase (ALT or AST) and bilirubin concentrations also reported.1 6

Monitor liver function tests frequently.1 If grade 3 or greater elevations of liver function tests occur, withhold therapy until toxicity resolves or returns to baseline; may resume therapy at reduced dosage if appropriate.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals.1

Avoid pregnancy during therapy.1 If used during pregnancy or if the patient becomes pregnant during therapy, apprise of potential fetal hazard.1 (See Advice to Patients.)

Specific Populations

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether carfilzomib is distributed into human milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established.1

No clinically important differences in safety and efficacy relative to younger adults.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Efficacy, safety, and pharmacokinetics not studied in patients with baseline hepatic impairment.1 Patients with baseline ALT or AST concentrations ≥3 times ULN or bilirubin concentrations ≥2 times ULN were excluded from clinical trials.1 2

Pharmacokinetics (i.e., clearance, exposure) and safety not affected by baseline mild to severe renal impairment, including chronic hemodialysis; no dosage adjustment necessary.1 19 Because dialysis clearance not specifically studied to date, administer carfilzomib after the hemodialysis session.1

Pharmacokinetics (e.g., AUC, peak plasma concentrations) not affected by gender.1

Common Adverse Effects

Fatigue,1 2 anemia,1 2 nausea,1 2 dyspnea,1 2 diarrhea,1 2 pyrexia.1 2

Laboratory abnormalities: Anemia,1 2 thrombocytopenia,1 2 increased Scr,1 2 lymphopenia,1 2 neutropenia,1 2 hypokalemia,1 hypomagnesemia,1 leukopenia,1 2 increased AST concentrations,1 hyperglycemia,1 hypercalcemia,1 hypophosphatemia,1 hyponatremia.1

Metabolism appears to occur primarily by extrahepatic peptidase cleavage and epoxide hydrolysis.1 26 CYP-mediated mechanisms play a minor role in overall metabolism.1

Has modest inhibitory effect on CYP3A4/5 in vitro.1 26

Does not induce CYP1A2 or CYP3A4 in human hepatocytes in vitro.1

Substrate of P-glycoprotein (P-gp).1 Has shown marginal inhibitory effects on P-gp in a Caco-2 monolayer system.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP inhibitors or inducers: Clinically important pharmacokinetic interactions unlikely.1 26

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4/5: Clinically important pharmacokinetic interactions not expected.1

Drugs Affecting the P-glycoprotein Transport System

P-gp inhibitors or inducers: Clinically important pharmacokinetic interactions not expected.1

Specific Drugs

In the U.S.

• Kyprolis

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Proteasome Inhibitor

Carfilzomib injection is used alone or together with other medicines (eg, dexamethasone, lenalidomide) to treat multiple myeloma (a type of bone marrow cancer) in patients who have received other treatments that did not work well. It interferes with the growth of cancer cells, which are eventually destroyed by the body. Carfilzomib is an antineoplastic agent (cancer medicine).

This medicine is to be given only by or under the supervision of your doctor.

A nurse or other trained health professional will give you this medicine in a hospital or cancer clinic. This medicine is given through a needle placed in a vein.

This medicine needs to be given on a fixed schedule. Be sure to keep all appointments.

Drink extra fluids so you will pass more urine while you are receiving this medicine. This may help prevent kidney problems and other unwanted effects.

You might also receive medicines (eg, dexamethasone, antivirals) to help prevent unwanted reactions to the injection and decrease the risk of virus infection (eg, herpes zoster) reactivation.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Agitation
• black, tarry stools
• bleeding gums
• bloating or swelling of the face, arms, hands, lower legs, or feet
• blood in the urine or stools
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain
• coma
• confusion
• cough or hoarseness
• decreased urine output
• depression
• difficult or labored breathing
• difficulty with moving
• dizziness
• drowsiness
• fast, slow, or irregular heartbeat
• headache
• hostility
• irregular heartbeat
• irritability
• lower back or side pain
• muscle spasms (tetany) or twitching
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• rapid weight gain
• seizures
• stupor
• tightness in the chest
• tingling of the hands or feet
• trembling
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• unusual tiredness or weakness
• unusual weight gain or loss

• Chills
• fever
• muscle pain or cramps
• painful blisters on the trunk of the body
• weakness in the arms, hands, legs, or feet

• Dark-colored urine
• general feeling of discomfort or illness
• general feeling of tiredness or weakness
• light-colored stools
• stomach pain, continuing
• thickening of bronchial secretions
• yellow eyes or skin

• Blindness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• joint pain, stiffness, or swelling
• stomach pain
• sweating

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• body aches or pain
• bone pain
• constipation
• diarrhea
• dry mouth
• ear congestion
• flushed, dry skin
• fruit-like breath odor
• increased hunger
• increased thirst
• increased urination
• loss of appetite
• loss of voice
• metallic taste
• muscle weakness
• pain in the arms or legs
• runny nose
• sneezing
• sore throat
• trouble sleeping
• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

• 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 this medicine (Kyprolis) 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 this medicine (Kyprolis). 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 this medicine (Kyprolis) 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 this medicine (Kyprolis), 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 this medicine (Kyprolis). 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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Hard stools (constipation).
• Loose stools (diarrhea).
• Not hungry.
• Feeling tired or weak.
• Back pain.
• Headache.
• Not able to sleep.
• Upset stomach or throwing up.
• Nose or throat irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

      Administration Precautions

• Hydration - Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high risk of tumor lysis syndrome 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 [see Warnings and Precautions (5.1, 5.3)].

• 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 [see Dosage and Administration (2.2)].  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 [see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.

• Administration - Infuse over 10 or 30 minutes depending on the Kyprolis dose regimen [see Dosage and Administration (2.2)]. Do not administer as a bolus. 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 [see Dosage and Administration (2.2)] using the patient’s actual body surface area at baseline. In patients with a body surface area greater than 2.2 m2, calculate the dose based upon a body surface area 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 [see Warnings and Precautions (5.8)].

• 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 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 1. 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 [see Dosage and Administration (2.3)]. 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 in Combination with Dexamethasone

For the combination regimen with dexamethasone, administer Kyprolis 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. Each 28-day period is considered one treatment cycle. Administer Kyprolis by 30-minute infusion 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 [see Dosage and Administration (2.3)]. Refer to the dexamethasone Prescribing Information for other concomitant medications.

Kyprolis Monotherapy

For monotherapy, administer Kyprolis intravenously as a 10-minute or 30-minute infusion depending on the regimen as described below.

20/27 mg/m2 regimen by 10-minute infusion

For monotherapy using the 20/27 mg/m2 regimen, administer Kyprolis intravenously as a 10-minute infusion [see Clinical Studies (14.3)]. 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 3. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis (see Table 3). 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 [see Dosage and Administration (2.1)]. 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.

20/56 mg/m2 regimen by 30-minute infusion

For monotherapy using the 20/56 mg/m2 regimen, administer Kyprolis intravenously as a 30-minute infusion [see Clinical Studies (14.3)].  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. 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 8 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to help prevent infusion reactions [see Dosage and Administration (2.1)].  The recommended starting dose of Kyprolis is 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.  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.  Dose level reductions are presented in Table 6. See the lenalidomide and dexamethasone Prescribing Information respectively for dosing recommendations.

      Dose Modifications for Use in Hepatic Impairment

For patients with mild or moderate hepatic impairment, reduce the dose of Kyprolis by 25%. Dosing recommendation cannot be made in patients with severe hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

      Dosing in Patients with End Stage Renal Disease

For patients with end stage renal disease who are on dialysis, administer Kyprolis after the hemodialysis procedure.

      Reconstitution and Preparation for Intravenous Administration

Kyprolis vials contain no antimicrobial preservatives and are intended for single use only. Unopened vials of Kyprolis are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL.

Read the complete preparation instructions prior to reconstitution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution/Preparation Steps:

1. Remove vial from refrigerator just prior to use.

2. Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patient’s body surface area (BSA) at baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

3. Use a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to aseptically reconstitute each vial by slowly injecting 29 mL (for 60 mg vial) or 15 mL (for 30 mg vial) Sterile Water for Injection, USP, through the stopper and directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming.

4. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately 5 minutes) and the solution is clear.

5. Visually inspect for particulate matter and discoloration prior to administration. The reconstituted product should be a clear, colorless solution and should not be administered if any discoloration or particulate matter is observed.

6. Discard any unused portion left in the vial. DO NOT pool unused portions from the vials. DO NOT administer more than one dose from a vial.

7. Optionally, Kyprolis can be administered in an intravenous bag.

8. When administering in an intravenous bag, use a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose [see Dosage and Administration (2)] from the vial and dilute into 50 mL or 100 mL intravenous bag containing 5% Dextrose Injection, USP (based on the calculated total dose and infusion time).

The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 7.

      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 of Kyprolis.  Some events occurred in patients with normal baseline ventricular function.  In clinical studies with Kyprolis, these events occurred throughout the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of Kyprolis administration.  In a randomized, open-label, multicenter trial evaluating Kyprolis in combination with lenalidomide and dexamethasone (KRd) versus lenalidomide/dexamethasone (Rd), the incidence of cardiac failure events was 6% in the KRd arm versus 4% in the Rd arm.  In a randomized, open-label, multicenter trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd), the incidence of cardiac failure events was 8% in the Kd arm versus 3% in the Vd arm.

Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia.  Evaluate promptly if cardiac toxicity is suspected.  Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment [see Dosage and Administration (2.3)].

While adequate hydration is required prior to each dose in Cycle 1, all patients should also be monitored for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure [see Dosage and Administration (2.1)].

In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to patients ˂ 75 years of age. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with Kyprolis and remain under close follow-up [see Use in Specific Populations (8.5)].

      Acute Renal Failure

Cases of acute renal failure have occurred in patients receiving Kyprolis. Renal insufficiency adverse events (including renal failure) have occurred in approximately 10% of patients treated with Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft and Gault equation). Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)].

      Tumor Lysis Syndrome

Cases of tumor lysis syndrome (TLS), including fatal outcomes, have been reported in patients who received Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Ensure that patients are well hydrated before administration of Kyprolis in Cycle 1, and in subsequent cycles as needed [see Dosage and Administration (2.1)]. Consider uric acid-lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, including interruption of Kyprolis until TLS is resolved [see Dosage and Administration (2.1)].

      Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in less than 1% of patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis [see Dosage and Administration (2.3)].

      Pulmonary Hypertension

Pulmonary arterial hypertension was reported in approximately 1% of patients treated with Kyprolis and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated.  Withhold Kyprolis for pulmonary hypertension until resolved or returned to baseline, and consider whether to restart Kyprolis based on a benefit/risk assessment [see Dosage and Administration (2.3)].

      Dyspnea

Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of patients. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes.  Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline.  Consider whether to restart Kyprolis based on a benefit/risk assessment [see Dosage and Administration (2.3), Warnings and Precautions (5.1 and 5.4), and Adverse Reactions (6.1)].

      Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis.  In a randomized, open-label, multicenter trial evaluating Kyprolis in combination with KRd versus Rd, the incidence of hypertension events was 16% in the KRd arm versus 8% in the Rd arm.  In a randomized, open-label, multicenter trial of Kd versus Vd, the incidence of hypertension events was 26% in the Kd arm versus 10% in the Vd arm. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment [see Dosage and Administration (2)].

      Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In a randomized, open-label, multicenter trial evaluating KRd versus Rd (with thromboprophylaxis used in both arms), the incidence of venous thromboembolic events in the first 12 cycles was 13% in the KRd arm versus 6% in the Rd arm. In a randomized, open-label, multicenter trial of Kd versus Vd, the incidence of venous thromboembolic events in months 1–6 was 9% in the Kd arm versus 2% in the Vd arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%.

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.

Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with Kyprolis in combination with dexamethasone or lenalidomide plus dexamethasone [see Use in Specific Population (8.3)].

      Infusion Reactions

Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial 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 Kyprolis. Administer dexamethasone prior to Kyprolis to reduce the incidence and severity of infusion reactions [see Dosage and Administration (2)]. Inform patients of the risk and of symptoms and to contact a physician immediately if symptoms of an infusion reaction occur.

      Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. The bleeding can be spontaneous, and intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in patients who were not on antiplatelet therapy or anticoagulation. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

      Thrombocytopenia

Kyprolis causes 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 [see Adverse Reactions (6.1)]. Thrombocytopenia was reported in approximately 40% of patients in clinical trials with Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)]. Hemorrhage may occur [see Adverse Reactions (6.1) and Warnings and Precautions (5.10)].

      Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported (< 1%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

      Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received Kyprolis.  Some of these events have been fatal. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known [see Dosage and Administration (2.3)].

      Posterior Reversible Encephalopathy Syndrome

Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Kyprolis. 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 Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

      Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients

In a clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to Kyprolis (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 for the KMP arm. Kyprolis in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.

      Embryo-Fetal Toxicity

Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using Kyprolis.

Advise females of reproductive potential to avoid becoming pregnant while being treated with Kyprolis.  Advise males of reproductive potential to avoid fathering a child while being treated with Kyprolis.  Advise women who use Kyprolis during pregnancy or become pregnant during treatment with Kyprolis of the potential hazard to the fetus [see Use in Specific Populations (8.1, 8.3)].

      Pregnancy

Risk Summary

Kyprolis can cause fetal harm based on findings from animal studies [see Data] and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are no adequate and well-controlled studies in pregnant women using Kyprolis.

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis. Males of reproductive potential should be advised to avoid fathering a child while being treated with Kyprolis. Consider the benefits and risks of Kyprolis and possible risks to the fetus when prescribing Kyprolis to a pregnant woman.  If Kyprolis is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.  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.

Data

Animal Data

Carfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area.

      Lactation

Risk Summary

There is no information regarding the presence of Kyprolis in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Kyprolis and any potential adverse effects on the breastfed infant from Kyprolis or from the underlying maternal condition.

      Females and Males of Reproductive Potential

Contraception

Kyprolis can cause fetal harm [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment with Kyprolis and for at least 30 days following completion of therapy. Advise male patients of reproductive potential to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment with Kyprolis and for at least 90 days following completion of therapy.

      Pediatric Use

The safety and effectiveness of Kyprolis in pediatric patients have not been established.

      Geriatric Use

Of 598 patients in clinical studies of Kyprolis monotherapy dosed at 20/27 mg/m2 by up to 10-minute infusion, 49% were 65 and over, while 16% were 75 and over. The incidence of serious adverse events was 44% in patients < 65 years of age, 55% in patients 65 to 74 years of age, and 56% in patients ≥ 75 years of age [see Warnings and Precautions (5.1)].  In a single-arm, multicenter clinical trial of Kyprolis monotherapy dosed at 20/27 mg/m2 (N = 266), no overall differences in effectiveness were observed between older and younger patients.

Of 392 patients treated with Kyprolis in combination with lenalidomide and dexamethasone, 47% were 65 and over and 11% were 75 years and over. The incidence of serious adverse events was 50% in patients < 65 years of age, 70% in patients 65 to 74 years of age, and 74% in patients ≥ 75 years of age [see Warnings and Precautions (5.1)].  No overall differences in effectiveness were observed between older and younger patients.

Of 463 patients treated with Kyprolis dosed at 20/56 mg/m2 by 30-minute infusion in combination with dexamethasone, 52% were 65 and over and 17% were 75 and over. The incidence of serious adverse events was 44% in patients < 65 years of age, 50% in patients 65 to 74 years of age, and 57% in patients ≥ 75 years of age [see Warnings and Precautions (5.1)].  No overall differences in effectiveness were observed between older and younger patients.

      Hepatic Impairment

Reduce the dose of Kyprolis by 25% in patients with mild or moderate hepatic impairment.  Dosing recommendation cannot be made for patients with severe hepatic function [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

The pharmacokinetics and safety of Kyprolis were evaluated in patients with advanced malignancies who had either normal hepatic function, or mild (bilirubin > 1 to 1.5×ULN or AST > ULN), moderate (bilirubin > 1.5 to 3×ULN), or severe (bilirubin > 3×ULN) hepatic impairment.  The AUC of carfilzomib increased by approximately 50% in patients with mild and moderate hepatic impairment compared to patients with normal hepatic function. PK data were not collected in patients with severe hepatic impairment.  The incidence of serious adverse events was higher in patients with mild, moderate, and severe hepatic impairment combined (22/35 or 63%) than in patients with normal hepatic function (3/11 or 27%) [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)].

Monitor liver enzymes regularly, regardless of baseline values, and modify dose based on toxicity [see Dosage and Administration (2.3)].

      Renal Impairment

No starting dose adjustment is required in patients with baseline mild, moderate, or severe renal impairment or patients on chronic hemodialysis.  The pharmacokinetics and safety of Kyprolis were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic hemodialysis. In addition, a pharmacokinetic study was conducted in patients with normal renal function and end-stage renal disease (ESRD) [see Clinical Pharmacology (12.3)].

In these studies, the pharmacokinetics of Kyprolis was not influenced by the degree of baseline renal impairment, including the patients on hemodialysis. Since dialysis clearance of Kyprolis concentrations has not been studied, the drug should be administered after the hemodialysis procedure [see Clinical Pharmacology (12.3)].

Common side effects of Kyprolis include: asthenia, arthralgia, dyspnea, fever, thrombocytopenia, vomiting, and chills. Other side effects include: congestive heart failure, pulmonary edema, and reduced ejection fraction. See below for a comprehensive list of adverse effects.