Kyprolis^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Amgen Europe, B.V. (Netherlands)

Manufactured By

Patheon Manufacturing Services, LLC (USA)

Or

Amgen Technology (Ireland), Unlimited Company (Ireland)

Packaging and Quality Control Release

AMGEN EUROPE, B.V. (Netherlands)

Or

AMGEN TECHNOLOGY (Ireland), Unlimited Company (Ireland)

Or

PHARMSTANDARD-UfaVITA, JSC (Russia)

ATC Code

L01XG02 (Carfilzomib)

Active Substance

Carfilzomib (Rec.INN registered by WHO)

Dosage Form

Kyprolis®

Lyophilizate for preparation of solution for infusion 60 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for infusion in the form of a lyophilisate or powder from white to yellowish, free from visible particulates; reconstituted solution: a clear solution from colorless to light yellow, free from visible particulates.

Excipients: sulfobutyl ether beta-cyclodextrin sodium (sulfobutyl ether beta-cyclodextrin) – 3090 mg, citric acid – 59.4 mg, sodium hydroxide (for pH adjustment).

Glass vials with a capacity of 50 ml (1) – rigid plastic containers (1) – cardboard packs^×.

^× each pack has two transparent protective labels – first opening control, with a longitudinal colored stripe.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents; proteasome inhibitors

Pharmacological Action

Antineoplastic agent. It is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly binds to the N-terminal threonine of the active sites of the main proteolytic 20S subunit, which is part of the 26S proteasome, and has no or minimal effect on proteases of other classes.

Carfilzomib demonstrated antiproliferative and pro-apoptotic effects in preclinical models of hematologic malignancies. In animals, Carfilzomib inhibited proteasome activity in blood and tissues and slowed tumor growth in multiple myeloma models. In vitro experiments showed that Carfilzomib is characterized by minimal neurotoxicity and minimal reactivity towards non-proteasomal proteases.

Intravenous administration of carfilzomib led to suppression of the chymotrypsin-like activity (CT-L) of the proteasome, measured in blood 1 hour after administration of the first dose of the drug. Administration at doses ≥15 mg/m² caused sustained (≥80%) inhibition of CT-L proteasome activity.

Additionally, administration of carfilzomib at a dose of 20 mg/m² led to inhibition of the latent membrane protein 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits of the immunoproteasome in the range of 26% to 32% and 41% to 49%, respectively. Proteasome inhibition persisted for 48 hours or more after the first dose of carfilzomib when administered weekly. Combined use with lenalidomide and dexamethasone did not affect the degree of proteasome inhibition.

When using a higher dose – 56 mg/m², not only more pronounced inhibition of CT-L subunits (≥90%) was noted, compared to doses of 15-20 mg/m², but also more pronounced inhibition of other proteasome subunits (LMP7, MECL1 and LMP2). Inhibition of LMP7, MECL1 and LMP2 subunits with carfilzomib at a dose of 56 mg/m² increased by approximately 8%, 23%, and 34%, respectively, compared to doses of 15-20 mg/m². The level of proteasome inhibition was equivalent for the 2-10-minute and 30-minute infusion regimens for both studied doses of 20 and 36 mg/m².

Pharmacokinetics

After IV administration of carfilzomib at a dose of 27 mg/m² over 2-10 min, C_max and AUC were 4232 ng/ml and 379 ng×h/ml, respectively. With repeated administration at doses of 15 and 20 mg/m², systemic exposure (AUC) and T_1/2 values on days 1 and 15 or 16 of the first therapy cycle were similar, indicating no systemic accumulation of carfilzomib. When used at doses from 20 to 56 mg/m², a dose-dependent increase in exposure was noted. With a 30-minute infusion, similar T_1/2 and AUC parameters were achieved, but a 2-3-fold decrease in C_max was noted compared to the C_max achieved with a 2-10-minute infusion of the same dose. After a 30-minute infusion of a 56 mg/m² dose, a 2.5-fold increase in AUC (948 ng×h/ml) was noted compared to the 27 mg/m² dose, and C_max (2079 ng/ml) was lower compared to the 27 mg/m² dose administered as an infusion over 2 to 10 minutes.

The binding of carfilzomib to human plasma proteins averaged 97% in the concentration range from 0.4 to 4 µmol. The mean V_d of carfilzomib at steady state at a dose of 20 mg/m² was 28 L.

Carfilzomib undergoes extensive metabolism followed by renal excretion.

Carfilzomib is rapidly and extensively metabolized. The main metabolites present in human plasma and urine in measurable amounts and formed by human hepatocytes in vitro were peptide fragments and carfilzomib diol, indicating that the main pathways of carfilzomib metabolism are cleavage by peptidases and hydrolysis of epoxy groups. Mechanisms mediated by the cytochrome P450 system play a minor role in the overall metabolism of carfilzomib. The metabolites of the drug have no known biological activity.

After IV administration at doses >15 mg/m², Carfilzomib is rapidly eliminated from the systemic circulation with T_1/2 values <1 h on the first day of the first therapy cycle. The systemic clearance of the drug ranged from 151 to 263 L/h and exceeded hepatic blood flow, indicating that Carfilzomib is predominantly eliminated by extrahepatic routes.

Indications

In combination with daratumumab and dexamethasone, with lenalidomide and dexamethasone, or with dexamethasone only: treatment of multiple myeloma in adult patients who have received at least one prior line of antineoplastic therapy.

As monotherapy for relapsed and refractory multiple myeloma in patients who have received at least 2 prior lines of therapy, including bortezomib and an immunomodulatory agent.

ICD codes

Dosage Regimen

Therapy should be carried out under the supervision of a physician experienced in the use of antineoplastic drugs.

Administered intravenously as an infusion.

Initial dose – 20 mg/m² (maximum dose – 44 mg). Dose escalation is carried out in accordance with the treatment regimen and tolerability.

Treatment may continue until disease progression or unacceptable toxicity develops.

Adverse Reactions

Infections and infestations very common – pneumonia, respiratory tract infection; common – sepsis, lung infection, viral infection, herpes zoster, urinary tract infection, bronchitis, gastroenteritis, viral infection, nasopharyngitis, rhinitis; uncommon – Clostridium difficile-associated colitis.

Immune system disorders uncommon – hypersensitivity reactions.

Blood and lymphatic system disorders: very common – thrombocytopenia, neutropenia, anemia, lymphopenia, leukopenia; common – febrile neutropenia; uncommon – hemolytic-uremic syndrome; rare – thrombotic thrombocytopenic purpura, thrombotic microangiopathy.

Metabolism and nutrition disorders very common – hypokalemia, hyperglycemia, decreased appetite; common – dehydration, hyperkalemia, hypomagnesemia, hyponatremia, hypercalcemia, hypocalcemia, hypophosphatemia, hyperuricemia, hypoalbuminemia; uncommon – tumor lysis syndrome.

Psychiatric disorders very common – insomnia; common – anxiety, confusion.

Nervous system disorders: very common – dizziness, peripheral neuropathy, headache; common – paresthesia, hypesthesia; uncommon – intracranial hemorrhage, cerebrovascular accident; rare – posterior reversible encephalopathy syndrome.

Eye and ear disorders common – cataract, blurred vision, tinnitus.

Cardiac disorders very common – hypertension; common – heart failure, myocardial infarction, atrial fibrillation, tachycardia, decreased ejection fraction, palpitations, deep vein thrombosis, hypotension, hyperemia; uncommon – cardiac arrest, myocardial ischemia, pericarditis, pericardial effusion, hypertensive crisis, hemorrhage; rare – complicated hypertensive crisis.

Respiratory, thoracic and mediastinal disorders very common – dyspnea, cough; common – pulmonary embolism, pulmonary edema, epistaxis, oropharyngeal pain, dysphonia, wheezing, pulmonary hypertension; uncommon – acute respiratory distress syndrome, acute respiratory failure, pulmonary hemorrhage, interstitial lung disease, pneumonitis.

Gastrointestinal disorders very common – vomiting, diarrhea, constipation, abdominal pain, nausea; common – gastrointestinal hemorrhage, dyspepsia, toothache; uncommon – gastrointestinal perforation.

Hepatobiliary disorders common – increased ALT and AST, increased gamma-glutamyltransferase, hyperbilirubinemia; uncommon – hepatic failure, cholestasis.

Skin and subcutaneous tissue disorders common – skin rash, pruritus, erythema, hyperhidrosis.

Musculoskeletal and connective tissue disorders very common – back pain, arthralgia, limb pain, muscle spasms; common – musculoskeletal pain, musculoskeletal chest pain, bone pain, myalgia, muscle weakness.

Renal and urinary disorders very common – increased plasma creatinine; common – acute kidney injury, renal failure, renal impairment, decreased creatinine renal clearance.

General disorders and administration site conditions very common – pyrexia, peripheral edema, asthenia, fatigue, chills; common – chest pain, pain, infusion site reactions, influenza-like illness, malaise; uncommon – multiple organ failure.

Investigations common – increased C-reactive protein, increased plasma uric acid.

Other: common – infusion-related reaction.

Contraindications

Hypersensitivity to carfilzomib, pregnancy, breastfeeding period.

With caution

When used concomitantly with drugs that increase the risk of thrombosis (in particular, hormonal contraceptives), with drugs that are substrates of CYP1A2, 2C8, 2C9, 2C19 and 2B6 isoenzymes, substrates of P-glycoprotein (in particular, digoxin, colchicine), in moderate and severe hepatic impairment.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Women of reproductive potential (and/or their partners) should use effective methods of contraception throughout the entire course of treatment and for one month after its completion. Men should use effective methods of contraception during treatment and for another 3 months after its completion if their partner is pregnant or capable of conception and is not using effective means of contraception.

Use in Hepatic Impairment

Use with caution in moderate and severe hepatic impairment.

Pediatric Use

Should not be used in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Since Carfilzomib is used in combination with other drugs, the instructions for use of these drugs should also be reviewed before starting treatment.

Cases of new onset or worsening of heart failure (in particular, chronic heart failure, pulmonary edema, decreased left ventricular ejection fraction), myocardial ischemia and myocardial infarction have been reported with Carfilzomib administration. Fatal outcomes due to cardiac arrest occurred within one day after administration, and fatal cases of heart failure and myocardial infarction have been reported.

Although adequate hydration is required before the start of administration in cycle 1, all patients should also be monitored for hypervolemia, especially patients at risk of developing heart failure. If necessary, in patients with heart failure or at high risk for this condition, adjustment of the total volume of infusion therapy may be required.

If cardiac adverse events of grade 3 or 4 severity develop, Carfilzomib should be discontinued until the events resolve and resumption of carfilzomib at a dose reduced by one level should be considered based on a benefit/risk assessment. The risk of heart failure increases in elderly patients (> 75 years). Patients with symptoms of NYHA class III-IV heart failure, those who have recently had a myocardial infarction (within the last 4 months), as well as patients with uncontrolled angina or arrhythmia should undergo a complete medical examination before starting carfilzomib therapy. This assessment should optimize the patient’s condition with particular attention to blood pressure control and infusion therapy. Subsequently, patients should be treated with caution and should be under close observation.

The possibility of an effect of carfilzomib on the QT interval cannot be excluded.

If pulmonary toxicity develops, the patient should be clinically evaluated and carfilzomib should be discontinued until this condition resolves. The decision to resume therapy is made based on the results of a benefit/risk assessment.

If pulmonary hypertension develops, the patient should be clinically evaluated and carfilzomib should be discontinued until this condition resolves. The decision to resume therapy is made based on the results of a benefit/risk assessment.

If dyspnea occurs, an examination should be performed to rule out cardiopulmonary complications, including heart failure and pulmonary syndromes. If dyspnea of grade 3 or 4 severity develops, carfilzomib should be discontinued until the dyspnea resolves or respiratory parameters return to baseline. The decision to resume therapy is made based on the results of a benefit/risk assessment.

It is recommended to control hypertension before starting treatment. All patients should be regularly examined for hypertension and treated if necessary. If hypertension cannot be controlled, a dose adjustment of carfilzomib is required. If a hypertensive crisis is diagnosed, carfilzomib should be discontinued until the hypertensive crisis is resolved or blood pressure parameters return to baseline. The decision to resume therapy is made based on the results of a benefit/risk assessment.

Acute renal failure was more frequently diagnosed in patients with advanced relapsed or refractory multiple myeloma receiving carfilzomib monotherapy. Renal function parameters should be monitored at least once a month or as often as recommended by clinical guidelines, especially in patients with lower baseline CrCl. If necessary, the dose of carfilzomib should be reduced or discontinued.

Patients with high tumor burden appear to have a higher risk of tumor lysis syndrome (TLS). Adequate hydration should be ensured before administration of carfilzomib in cycle I of therapy, and, if necessary, in subsequent cycles. In patients at high risk of developing TLS, the use of uric acid-lowering agents should be considered. During treatment, monitoring for signs of TLS is necessary, including regular assessment of serum electrolyte levels and adequate correction of identified abnormalities. Carfilzomib should be discontinued until TLS symptoms resolve.

Infusion reactions may develop immediately after or within 24 hours of carfilzomib administration. To reduce the frequency and severity of reactions, dexamethasone is administered as premedication before carfilzomib administration.

Carfilzomib causes thrombocytopenia with a nadir observed on day 8 and day 15 of each 28-day cycle, followed by recovery to baseline by the start of the next cycle. Frequent monitoring of platelet counts is necessary during treatment with carfilzomib. If necessary, dose reduction or discontinuation of carfilzomib is required.

Patients with known risk factors for thromboembolism, including a history of thrombosis, should be carefully monitored. All modifiable risk factors (e.g., smoking, hypertension and hyperlipidemia) should be minimized. Caution should also be exercised when concomitantly using other drugs that may increase the risk of thrombosis (e.g., erythropoiesis-stimulating agents or hormone replacement therapy drugs). Patients and treating physicians are advised to be especially attentive to signs and symptoms of thromboembolism. Patients should be instructed to seek immediate medical attention if symptoms such as difficulty breathing, chest pain, hemoptysis, swelling in the arms or legs, or limb pain develop. Thromboprophylaxis should be considered in each individual case after a benefit/risk assessment.

If serum hepatic transaminase levels increase, dose reduction or discontinuation of carfilzomib may be required. Monitoring of hepatic enzyme activity and bilirubin should be performed at the start of treatment and monthly during treatment with carfilzomib, regardless of baseline values.

Cases of thrombotic microangiopathy, including cases of thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS), have been reported in patients receiving Carfilzomib. Some of these cases were fatal.

Close monitoring for the appearance of symptoms of thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS) is necessary. If this diagnosis is suspected, Carfilzomib should be discontinued and an appropriate examination should be performed. If the TTP/HUS diagnosis is not confirmed, Carfilzomib may be resumed. The safety of re-administering carfilzomib in patients who have experienced TTP/HUS has not been established.

Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Carfilzomib. PRES, previously known as reversible posterior leukoencephalopathy syndrome, is a rare neurological disorder that can manifest with seizures, headache, lethargy, confusion, blindness, altered level of consciousness, and other visual and neurological disturbances, along with elevated blood pressure; neuroimaging is performed to confirm the diagnosis.

If posterior reversible encephalopathy syndrome (PRES) is suspected, administration of carfilzomib should be discontinued. The safety of re-administering carfilzomib in patients who have experienced PRES has not been established.

Effect on the Ability to Drive and Operate Machinery

Carfilzomib has a minor influence on the ability to drive and operate machinery.
Considering possible adverse reactions, patients are advised to refrain from driving vehicles and operating machinery during treatment.

Drug Interactions

It is unknown whether Carfilzomib is an inducer of CYP1A2, 2C8, 2C9, 2C19, and 2B6 isoenzymes at therapeutic concentrations. Caution should be exercised with the concomitant use of carfilzomib and drugs that are substrates of these isoenzymes, in particular oral contraceptives.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.