Drug Safety-related Labeling Changes (SrLC)

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KYPROLIS (NDA-202714)

(CARFILZOMIB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/22/2025 (SUPPL-36)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and /or revisions underlined:

The safety and effectiveness of Kyprolis in combination with chemotherapy was evaluated, but not established in an open label trial (Study 20140106; NCT02303821) in 124 patients aged 1 to younger than 17 years with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) who have received prior targeted B-cell immune therapy or relapsed or refractory T-cell ALL.

No new safety signals were observed in these pediatric patients. The systemic exposure of carfilzomib in these pediatric patients was within range of that observed in adults given the same dose based on body surface area.

06/30/2022 (SUPPL-34)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes, please refer to label

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 2,837 patients with relapsed or refractory multiple myeloma exposed to Kyprolis in monotherapy and combination therapy studies [see Clinical Studies (14.1, 14.2, 14.3, 14.4, 14.5)], 50% were 65 years and older, while 13% were 75 years and older. The incidence of serious adverse reactions was 50% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 63% in patients greater than or equal to 75 years of age. Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older. Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients <65 years of age, 14% of patients between 65 to 74 years of age, and 14% of patients greater than or equal to 75 years of age [see Adverse Reactions (6.1)]. No overall differences in effectiveness were observed between older and younger patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Extensive changes; please refer to label

11/30/2021 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.17 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m2 based on BSA caused post-implantation loss and a decrease in fetal weight.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

5.7 Hypertension

Additions and/or revisions underlined:

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In ASPIRE, the incidence of hypertension events was 17% in the KRd arm versus 9% in the Rd arm. In ENDEAVOR, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. In CANDOR, the incidence of hypertension events was 31% in the DKd arm versus 28% in the Kd arm. Some of these events have been fatal.

Optimize blood pressure prior to starting Kyprolis. Monitor blood pressure regularly in all patients while on Kyprolis. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Conduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the last dose.

Males

Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose.

Infertility

Based on the mechanism of action, Kyprolis may have an effect on either male or female fertility [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. There are no data on the effect of Kyprolis on human fertility.

03/09/2021 (SUPPL-32)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions underlined

…, and acute pancreatitis.

08/20/2020 (SUPPL-30)

Approved Drug Label (PDF)

Boxed Warning

5.1 Cardiac Toxicities

Additions and/or revisions underlined:

… Death due to cardiac arrest has occurred within one day of Kyprolis administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus tachycardia) [see Adverse Reactions (6.1)] …

8.3 Tumor Lysis Syndrome

Additions and/or revisions underlined:

… Administer oral and intravenous fluids before administration of Kyprolis in Cycle 1 and in subsequent cycles as needed. Consider uric acid-lowering drugs in patients at risk for TLS …

8.4 Pulmonary Toxicity

Additions and/or revisions underlined:

Acute Respiratory Distress Syndrome (ARDS) and acute respiratory failure have occurred in approximately 2% of patients who received Kyprolis. In addition, acute diffuse infiltrative pulmonary disease, such as pneumonitis and interstitial lung disease, occurred in approximately 2% of patients who received Kyprolis …

5.6 Dyspnea

Additions and/or revisions underlined:

Dyspnea was reported in 25% of patients treated with Kyprolis…

5.7 Hypertension

Additions and/or revisions underlined:

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In ASPIRE, the incidence of hypertension events was 17% in the KRd arm versus 9% in the Rd arm. In ENDEAVOR, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. In CANDOR, the incidence of hypertension events was 31% in the DKd arm versus 27% in the Kd arm. Some of these events have been fatal.

Optimize blood pressure prior to starting Kyprolis. Monitor blood pressure regularly in all patients while on Kyprolis. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

5 Warnings and Precautions

5.8 Venous Thrombosis

Additions and/or revisions underlined:

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In ASPIRE, 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 ENDEAVOR, 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%.

Provide thromboprophylaxis for patients being treated with Kyprolis in combination with lenalidomide and dexamethasone; with dexamethasone; or with intravenous daratumumab and dexamethasone. Select the thromboprophylaxis regimen based the patient’s underlying risks.

For patients using oral contraceptives or hormonal contraception associated with a risk of thrombosis, consider non-hormonal contraception during treatment when Kyprolis is administered in combination [see Use in Specific Populations (8.3)].

5.11 Thrombocytopenia

Additions and/or revisions underlined:

… Hemorrhage may occur [see Adverse Reactions (6.1), Warnings and Precautions (5.10)].

Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)].

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

Additions and/or revisions underlined:

In CLARION, a clinical trial of 955 transplant-ineligible patients …

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive additions and revisions; please refer to label for complete information.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: hemolytic uremic syndrome (HUS), hepatitis B virus reactivation, gastrointestinal perforation, pericarditis, and cytomegalovirus infection, including chorioretinitis, pneumonitis, enterocolitis, viremia, and intestinal obstruction.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 2,387 patients in clinical studies of Kyprolis, 51% were 65 years and older, while 14% were 75 years and older. The incidence of serious adverse reactions was 49% in patients < 65 years of age, 58% in patients 65 to 74 years of age, and 63% in patients greater than or equal to 75 years of age. Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older. Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients <65 years of age, 14% of patients between 65 to 74 years of age, and 14% of patients greater than or equal to 75 years of age [see Adverse Reactions (6.1)] …

8.6 Hepatic Impairment

Additions and/or revisions underlined:

Reduce the dose of Kyprolis by 25% in patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin less than or equal to ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. A recommended dosage of Kyprolis has not been established for patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

05/07/2020 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Infusion-Related Reactions

(Additions and/or revisions underlined)

Infusion-related reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Administer dexamethasone prior to Kyprolis to reduce the incidence and severity of infusion-related reactions. Inform patients of the risk and of symptoms and to contact a healthcare provider immediately if symptoms of an infusion-related reaction occur.

5.15  Progressive Multifocal Leukoencephalopathy

(Newly added subsection)

Progressive multifocal leukoencephalopathy (PML), which can be fatal, has occurred with Kyprolis. In addition to Kyprolis, other possible contributary factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Kyprolis and initiate evaluation for PML including neurology consultation.

5.17 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m2 based on BSA caused post-implantation loss and a decrease in fetal weight.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the final dose. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiac Toxicities

• Acute Renal Failure

• Tumor Lysis Syndrome

• Pulmonary Toxicity

• Pulmonary Hypertension

• Dyspnea

• Hypertension

• Venous Thrombosis

• Infusion-Related Reactions

• Hemorrhage

• Thrombocytopenia

• Hepatic Toxicity and Hepatic Failure

• Thrombotic Microangiopathy

• Posterior Reversible Encephalopathy Syndrome

• Progressive Multifocal Leukoencephalopathy

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

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of Kyprolis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: hemolytic uremic syndrome (HUS), hepatitis B virus reactivation, gastrointestinal perforation, pericarditis, and cytomegalovirus infection, including chorioretinitis, pneumonitis, enterocolitis, and viremia.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Discuss the following with patients prior to treatment with Kyprolis:

Respiratory: Advise patients that they may experience cough or shortness of breath (dyspnea) during treatment with Kyprolis. This most commonly occurs within a day of dosing. Advise patients to contact their healthcare provider if they experience shortness of breath.

Infusion-Related Reactions: Advise patients of the risk of infusion-related reactions and discuss the common signs and symptoms of infusion-related reactions with the patients.

Bleeding: Inform patients that they may bruise or bleed more easily or that it may take longer to stop bleeding and to report to their healthcare provider any prolonged, unusual or excessive bleeding. Instruct patients on the signs of occult bleeding.

Hepatic: Inform patients of the risk of developing hepatic failure. Advise patients to contact their healthcare provider for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes.

Other: Inform patients to contact their healthcare provider if they experience neurologic symptoms such as headaches, confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, seizures, or visual loss.

Embryo-Fetal Toxicity: Advise females of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider immediately of a known or suspected pregnancy. Advise female patients to use effective contraceptive during treatment with Kyprolis and for 6 months following the final dose. Advise male patients with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose.

Concomitant Medications: Advise patients to discuss with their healthcare provider any medication they are currently taking prior to starting treatment with Kyprolis, or prior to starting any new medication(s) during treatment with Kyprolis.

Other

(the word “events” replaced with the word “reactions” throughout labeling)

10/04/2019 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Infusion Reactions

(additions and/or revisions are underlined)

Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Administer dexamethasone prior to Kyprolis to reduce the incidence and severity of infusion reactions.  Inform patients of the risk and of symptoms and to contact a physician immediately if symptoms of an infusion reaction occur.

6 Adverse Reactions

6.2 Postmarketing Experience

(additions and/or revisions are underlined)

The following additional adverse reactions were reported in the postmarketing experience with Kyprolis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: hemolytic uremic syndrome (HUS), gastrointestinal perforation, pericarditis, and cytomegalovirus infection including chorioretinitis, pneumonitis, enterocolitis, and viremia.

09/28/2018 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardiac Toxicities

Additions and/or revisions underlined:

… In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8%.

5.6 Dyspnea

Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of patients …

5.16 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m2 based on body surface area caused post-implantation loss and a decrease in fetal weight.

Females of reproductive potential should avoid becoming pregnant while being treated with Kyprolis. Advise females of reproductive potential that they must use contraception during treatment with Kyprolis and for 6 months following the final dose. Advise males with female sexual partners of reproductive potential that they must use contraception during treatment with Kyprolis and for 3 months following the final dose. If Kyprolis is used during pregnancy or if the patient becomes pregnant during Kyprolis treatment, the patient should be apprised of the potential risk to the fetus.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Safety Experience with Kyprolis in Combination with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma

… reported in the KRd arm as compared with the Rd arm were pneumonia (17% versus 13%), respiratory tract infection (4% versus 2%), pyrexia (4% versus 3%), and pulmonary embolism (3% versus 2%). In patients treated with Kyprolis, 47% were 65 and over and 11% were 75 years and over. The incidence of serious adverse events was 57% in patients

< 65 years of age, 73% in patients 65 to 74 years of age, and 81% in patients ? 75 years of age.

Discontinuation due to any adverse reaction … upper respiratory tract infection (0.8%). The incidence of cardiac failure events was 7% in the KRd arm versus 4% in the Rd arm.

Safety Experience with Kyprolis in Combination with Dexamethasone in Patients with Multiple Myeloma

The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.).

ENDEAVOR evaluated patients with relapsed or refractory multiple myeloma. The study treatment is described in Section 14.2. Patients received treatment for a median duration of 48 weeks in the twice weekly Kyprolis/dexamethasone (Kd) 20/56 mg/m2 arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.

… In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 9%). In patients treated with Kyprolis, 52% were 65 and over and 17% were 75 and over. The incidence of serious adverse events was 54% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 69% in patients ? 75 years of age … The most common reaction leading to discontinuation was cardiac failure in the Kd arm (n = 8, 2%) and peripheral neuropathy in the Vd arm (n = 22, 5%). The incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.

Table 12: Grades 3–4 Laboratory Abnormalities (? 10%) in Months 1–6 (20/56 mg/m2 Regimen In Combination with Dexamethasone)

A.R.R.O.W. evaluated patients with relapsed and refractory multiple myeloma. The study treatment is described in Section 14.2. Patients received treatment for a median duration of 38 weeks in the once weekly Kd 20/70 mg/m2 arm and 29.1 weeks in the twice weekly Kd 20/27 mg/m2 arm of A.R.R.O.W. The safety profile for the once weekly Kd 20/70 mg/m2 regimen was similar to the twice weekly Kd 20/27 mg/m2 regimen.

Deaths due to adverse reactions within 30 days of last study treatment occurred in 22/238 (9%) patients in the Kd 20/70 mg/m2 arm and 18/235 (8%) patients in the Kd 20/27 mg/m2 arm. The most frequent fatal adverse reactions occurring in patients (%) in the two arms (once weekly Kd 20/70 mg/m2 versus twice weekly Kd 20/27 mg/m2) were sepsis 2 (< 1%) versus 2 (< 1%), septic shock 2 (< 1%) versus 1 (< 1%), and infection 2 (< 1%) versus 0 (0%). Serious adverse reactions were reported in 43% of the patients in the Kd 20/70 mg/m2 arm and 41% of the patients in the Kd 20/27 mg/m2 arm. In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 7%). In patients treated with once weekly Kd 20/70 mg/m2, 57% were 65 and over and 19% were 75 and over. The incidence of serious adverse events was 37% in patients < 65 years of age, 50% in patients 65 to 74 years of age, and 44% in patients ? 75 years of age. Discontinuation due to any adverse reaction occurred in 13% in the Kd 20/70 mg/m2 arm versus 12% in the Kd 20/27 mg/m2   arm. The most common reaction leading to discontinuation was acute kidney injury (2% versus 2%). The incidence of cardiac failure events was 3.8% in the once weekly Kd 20/70 mg/m2 arm versus 5.1% in the twice weekly Kd 20/27 mg/m2 arm.

Common Adverse Reactions (? 10%)

Adverse reactions that occurred at a rate of 10% or greater in either Kd arm is presented in Table 13.

Adverse Reactions Occurring at a Frequency of < 10%

• Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy

• Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardia

• Ear and labyrinth disorders: tinnitus

• Eye disorders: cataract, vision blurred

• Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomiting

• General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise,   pain

• Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia

• Infections and infestations: clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infection

• Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome

• Musculoskeletal and connective tissue disorders: muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia

• Nervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathy

• Psychiatric disorders: anxiety, delirium

• Renal and urinary disorders: acute kidney injury, renal failure, renal impairment

• Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezing

• Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash

• Vascular disorders: deep vein thrombosis, flushing, hypotension

Safety Experience with Kyprolis in Patients with Multiple Myeloma who Received Monotherapy

… In patients treated with Kyprolis, 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.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

There are no studies with the use of Kyprolis in pregnant women to inform drug-associated risks of adverse developmental outcomes. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose. Advise pregnant women of the potential risk to the fetus.

8.2 Lactation

Additions and/or revisions underlined:

There are no data on the presence of Kyprolis in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from Kyprolis is unknown, advise nursing women not to breastfeed during treatment with Kyprolis and for 2 weeks after treatment.

8.3 Females and Males of Reproductive Potential

Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Conduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment.

Females

Advise females of reproductive potential to avoid pregnancy and use effective contraception during treatment with Kyprolis and for at least 6 months following the final dose.

Males

Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for at least 3 months following the final dose.

Infertility

Based on the mechanism of action, Kyprolis may have an effect on either male or female fertility. There are no data on the effect of Kyprolis on human fertility.

8.5 Geriatric Use

Of 1691 patients in clinical studies of Kyprolis, 50.4% were 65 and over, while 15.4% were 75 and over. The incidence of serious adverse events in patients was higher than in younger patients.

8.6 Hepatic Impairment

Reduce the dose of Kyprolis by 25% in patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin ? ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Embryo-Fetal Toxicity: Advise females of the potential risk to the fetus and to avoid pregnancy during treatment with Kyprolis. Advise female patients to use effective contraceptive measures to prevent pregnancy during treatment with Kyprolis and for 6 months following the final dose. Advise male patients with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose. Instruct patients to report pregnancy to their physicians immediately if they or their female partner becomes pregnant during treatment or within 6 months following the final dose.

Lactation: Advise patients to avoid breastfeeding while receiving Kyprolis and for 2 weeks after the final dose.

06/07/2018 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Pulmonary Toxicity

Approximately replaces less than.

6 Adverse Reactions

6.1 Clinical Trials Experience

Safety Experience with Kyprolis in Combination with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma

Numerous changes made to the numbers in the KRd arm; please refer to label for complete information.

Adverse Reactions Occurring at a Frequency of less than 10% (following Table 8)

Additions and/or revisions underlined:

• Ear and labyrinth disorders: deafness, tinnitus

• Infections and infestations: clostridium difficile colitis, influenza

Adverse Reactions Occurring at a Frequency of less than 10% (following Table 10)

Additions and/or revisions underlined:

• Ear and labyrinth disorders: tinnitus

Adverse Reactions Occurring at a Frequency of less than 20% (following Table 12)

Additions and/or revisions underlined:

• Ear and labyrinth disorders: tinnitus

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

… apprise the patient of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects …

8.2 Lactation

Child replaces infant

8.5 Geriatric Use

Additions and/or revisions underlined:

… The incidence of serious adverse events was 57% in patients less than 65 years of age, 73% in patients 65 to 74 years of age, and 81% in patients greater than or equal to 75 years of age …

01/17/2018 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardiac Toxicities

(Additions and/or revisions are underlined)

…In a randomized, open-label, multicenter trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd), the incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.

…These patients may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with Kyprolis and remain under close follow-up.

5.11 Thrombocytopenia

(Additions and/or revisions are underlined

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. Thrombocytopenia was reported in approximately 34% of patients in clinical trials with Kyprolis…

5.2 Acute Renal Failure

(Additions and/or revisions are underlined)

Cases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been fatal. 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. The risk of fatal renal failure was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft and Gault equation)…

5.6 Dyspnea

(Additions and/or revisions are underlined)

Dyspnea was reported in 31% of patients treated with Kyprolis and was Grade 3 or greater in 5% of patients…

5.7 Hypertension

(Additions and/or revisions are underlined)

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In a randomized, open-label, multicenter trial evaluating 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 34% in the Kd arm versus 11% in the Vd arm. Some of these events have been fatal. It is recommended to control hypertension prior to starting Kyprolis. Monitor blood pressure regularly in all patients while on Kyprolis…

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

The safety of Kyprolis in combination with dexamethasone was evaluated in an open-label, randomized trial of patients with relapsed multiple myeloma. The study treatment is described in Section 14.2. Patients received treatment for a median duration of 48 weeks in the Kyprolis/dexamethasone (Kd) arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.

Deaths due to adverse reactions within 30 days of last study treatment occurred in 32/463 (7%) patients in the Kd arm and 21/456 (5%) patients in the Vd arm. The causes of death occurring in patients (%) in the two arms (Kd versus Vd) included cardiac 4 (1%) versus 5 (1%), infections 8 (2%) versus 8 (2%), disease progression 7 (2%) versus 4 (1%), pulmonary 3 (1%) versus 2 (< 1%), renal 1 (< 1%) versus 0 (0%), and other adverse events 9 (2%) versus 2 (< 1%). Serious adverse reactions were reported in 59% of the patients in the Kd arm and 40% of the patients in the Vd arm. In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 9%). Discontinuation due to any adverse reaction occurred in 29% in the Kd arm versus 26% in the Vd arm. The most common reaction leading to discontinuation was cardiac failure in the Kd arm (n = 8, 2%) and peripheral neuropathy in the Vd arm (n = 22, 5%).

Common Adverse Reactions (greater than or equal to 10%)

The event rate of greater than or equal to Grade 2 peripheral neuropathy in the Kd arm was 7% (95% CI: 5, 9) versus 35% (95% CI: 31, 39) in the Vd arm.

Adverse Reactions Occurring at a Frequency of less than 10%

• General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise,   pain

• Infections and infestations: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection

8 Use in Specific Populations

8.2 Geriatric Use

(Additions and/or revisions are underlined)

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 54% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 70% in patients greater than or equal to 75 years of age . No overall differences in effectiveness were observed between older and younger patients.

05/25/2017 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

Addition of the following:

5.15 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.

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Addition of the following:

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

11/17/2016 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.15 Embryo-Fetal Toxicity (Addition underlined)

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.

8 Use in Specific Populations

8.6 Hepatic Impairment (New subsection added)

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.

 

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%).

 

Monitor liver enzymes regularly, regardless of baseline values, and modify dose based on toxicity.

8.7 Renal Impairment (Addition underlined)

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).

 

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.

08/04/2016 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

Hemorrhage (Subsection added)

• 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.

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Hemorrhage (added)

Clinical Trial Experience

Following Table 8: Adverse Reactions Occurring at a Frequency of < 10% (additions are bolded)

• Gastrointestinal disorders: gastrointestinal hemorrhage

• Infections and infestations: lung infection, rhinitis

• Nervous system disorders: intracranial hemorrhage

• Respiratory, thoracic and mediastinal disorders: pulmonary hemorrhage

• Vascular disorders: hemorrhage

Following Table 10: Adverse Reactions Occurring at a Frequency of < 10% (additions are bolded)

• Gastrointestinal disorders: gastrointestinal hemorrhage

• Infections and infestations: lung infection, rhinitis

Following Table 12: Adverse Reactions Occurring at a Frequency of < 20% (additions are bolded)

• Gastrointestinal disorders: gastrointestinal hemorrhage

• Infections and infestations: lung infection, rhinitis

• Nervous system disorders: intracranial hemorrhage

• Respiratory, thoracic and mediastinal disorders: pulmonary hemorrhage

• Vascular disorders: hemorrhage

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PCI - extensively revised:

• Cardiac Toxicities: Advise patients of the risks and symptoms of cardiac failure and ischemia

• Dehydration: Counsel patients to avoid dehydration, since patients receiving Kyprolis therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dehydration.

• Respiratory: Advise patients that they may experience cough or shortness of breath (dyspnea) during treatment with Kyprolis. This most commonly occurs within a day of dosing. Advise patients to contact their physician if they experience shortness of breath.

• Venous Thrombosis: Inform patients of the risk of venous thromboembolism and discuss the options for prophylaxis. Advise patients to seek immediate medical attention for symptoms of venous thrombosis or embolism.

• Infusion Reactions: Advise patients of the risk of infusion reactions, and discuss the common signs and symptoms of infusion reactions with the patients.

• Bleeding: Inform patients that they may bruise or bleed more easily or that it may take longer to stop bleeding and to report to their physician any prolonged, unusual or excessive bleeding. Instruct patients on the signs of occult bleeding.

• Hepatic: Inform patients of the risk of developing hepatic failure. Advise patients to contact their physician if they experience jaundice.

• Other: Inform patients to contact their physician if they experience neurologic symptoms such as headaches, confusion, seizures, or visual loss.

• Driving/Operating Machines: Advise patients that Kyprolis may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms.

• Pregnancy/Nursing: Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 30 days after treatment with Kyprolis. Counsel males of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 90 days after treatment with Kyprolis. Advise the patient to contact their physician immediately if pregnancy does occur during these times. Advise patients not to take Kyprolis treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician.

• Concomitant Medications: Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with Kyprolis, or prior to starting any new medication(s) during treatment with Kyprolis.

01/21/2016 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

Cardiac Toxicities

• …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

Venous Thrombosis

• … 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.

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.