Kyprolis^® 10 mg powder for solution for infusion

Kyprolis^® 30 mg powder for solution for infusion

Kyprolis^® 60 mg powder for solution for infusion

Kyprolis 10 mg powder for solution for infusion

Each vial contains 10 mg of carfilzomib.

Kyprolis 30 mg powder for solution for infusion

Each vial contains 30 mg of carfilzomib.

Kyprolis 60 mg powder for solution for infusion

Each vial contains 60 mg of carfilzomib.

After reconstitution, 1 mL of solution contains 2 mg of carfilzomib.

Excipient with known effect

Each mL of reconstituted solution contains 7 mg of sodium.

For the full list of excipients, see section 6.1.

Powder for solution for infusion.

White to off-white lyophilised powder.

Kyprolis in combination with either lenalidomide and dexamethasone or dexamethasone alone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (see section 5.1).

Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy.

Posology

The dose is calculated using the patient's baseline body surface area (BSA). 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%.

Kyprolis in combination with lenalidomide and dexamethasone

When combined with lenalidomide and dexamethasone, Kyprolis is administered intravenously as a 10 minute infusion, on two consecutive days, each week for three weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17 to 28) as shown in table 1. Each 28-day period is considered one treatment cycle.

Kyprolis is administered at a starting dose of 20 mg/m² (maximum dose 44 mg) in cycle 1 on days 1 and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 27 mg/m² (maximum dose 60 mg). From cycle 13, the day 8 and 9 doses of Kyprolis are omitted.

Treatment may be continued until disease progression or until unacceptable toxicity occurs.

Treatment with Kyprolis combined with lenalidomide and dexamethasone for longer than 18 cycles should be based on an individual benefit-risk assessment, as the data on the tolerability and toxicity of carfilzomib beyond 18 cycles are limited (see section 5.1).

In combination with Kyprolis, lenalidomide is administered as 25 mg orally on days 1–21 and dexamethasone is administered as 40 mg orally or intravenously on days 1, 8, 15, and 22 of the 28 day cycles. Appropriate dose reduction for the starting dose of lenalidomide should be considered according to the recommendations in the current lenalidomide summary of product characteristics, for example for patients with baseline renal impairment. Dexamethasone should be administered 30 minutes to 4 hours before Kyprolis.

Table 1 Kyprolis in combination with lenalidomide and dexamethasone^a

^a Infusion time is 10 minutes and remains consistent throughout the regimen

Kyprolis in combination with dexamethasone

When combined with dexamethasone, Kyprolis is administered intravenously as a 30-minute infusion on two consecutive days, each week for three weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17 to 28) as shown in table 2. Each 28-day period is considered one treatment cycle.

Kyprolis is administered at a starting dose of 20 mg/m² (maximum dose 44 mg) in cycle 1 on days 1 and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 56 mg/m² (maximum dose 123 mg).

Treatment may be continued until disease progression or until unacceptable toxicity occurs.

When Kyprolis is combined with dexamethasone alone, dexamethasone is administered as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycles. Dexamethasone should be administered 30 minutes to 4 hours before Kyprolis.

Table 2 Kyprolis in combination with dexamethasone alone^a

^a Infusion time is 30 minutes and remains consistent throughout the regimen

Concomitant medicinal products

Antiviral prophylaxis should be considered in patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation. The majority of patients included in studies with Kyprolis received antiviral prophylaxis; due to this fact it is not possible to calculate the true incidence of herpes zoster infection in patients treated with Kyprolis.

Thromboprophylaxis is recommended in patients being treated with Kyprolis in combination with dexamethasone or with lenalidomide and dexamethasone, and should be based on an assessment of the patient's underlying risks and clinical status. For other concomitant medicinal products that may be required, such as the use of antacid prophylaxis, refer to the current lenalidomide and dexamethasone summary of product characteristics.

Hydration, fluid and electrolyte monitoring

Adequate hydration is required before dose administration in cycle 1, especially in patients at high risk of tumour lysis syndrome or renal toxicity. All patients should be monitored for evidence of volume overload and fluid requirements should be tailored to individual patient needs. The total volume of fluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk for cardiac failure (see section 4.4).

Recommended hydration includes both oral fluids (30 mL/kg/day for 48 hours before day 1 of cycle 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid before each dose in cycle 1). Give an additional 250 mL to 500 mL of intravenous fluids as needed following Kyprolis administration in cycle 1. Oral and/or intravenous hydration should be continued, as needed, in subsequent cycles.

Serum potassium levels should be monitored monthly, or more frequently during treatment with Kyprolis as clinically indicated and will depend on the potassium levels measured before the start of treatment, concomitant therapy used (e.g. medicinal products known to increase the risk of hypokalaemia) and associated comorbidities.

Recommended dose modifications

Dosing should be modified based on Kyprolis toxicity. Recommended actions and dose modifications are presented in table 3. Dose level reductions are presented in table 4.

Table 3 Dose modifications during Kyprolis treatment

^a See table 4 for dose level reductions

Table 4 Dose level reductions for Kyprolis

Note: Kyprolis infusion times remain unchanged during dose reduction(s)

^a If symptoms do not resolve, discontinue Kyprolis treatment

Special populations

Renal impairment

Patients with moderate or severe renal impairment were excluded from Kyprolis-lenalidomide combination studies. Appropriate dose reduction for the starting dose of lenalidomide in patients with baseline renal impairment should be considered according to the recommendations in the lenalidomide summary of product characteristics.

No starting dose adjustment for Kyprolis is required in patients with baseline mild, moderate, or severe renal impairment or patients on chronic dialysis. Since dialysis clearance of Kyprolis concentrations has not been studied, the medicinal product should be administered after the dialysis procedure (see section 5.2). In phase 3 clinical studies the incidence of adverse events of acute renal failure was higher in subjects with lower baseline creatinine clearance than that among subjects with higher baseline creatinine clearance.

Renal function should be monitored at least monthly or in accordance with accepted clinical practice guidelines, particularly in patients with lower baseline creatinine clearance.

Hepatic impairment

Patients with hepatic impairment have not been systematically eva luated (see section 5.2). Liver enzymes and bilirubin should be monitored at treatment initiation and monthly during treatment with carfilzomib, regardless of baseline values.

Elderly patients

Overall, the subject incidence of certain adverse events (including cardiac failure) in clinical trials was higher for patients who were ≥ 75 years of age compared to patients who were < 75 years of age (see section 4.4).

Paediatric population

The safety and efficacy of Kyprolis in paediatric patients have not been established. No data are available.

Method of administration

Kyprolis is to be administered by intravenous infusion. The 20/27 mg/m² dose is administered over 10 minutes. The 20/56 mg/m² dose must be administered over 30 minutes.

Kyprolis must not be administered as a bolus.

The intravenous administration line should be flushed with normal sodium chloride solution or 5% glucose solution for injection immediately before and after Kyprolis administration.

Do not mix Kyprolis with or administer as an infusion with other medicinal products.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Women who are breast-feeding (see section 4.6).

As Kyprolis is administered in combination with other medicinal products, refer to their summaries of product characteristics for additional contraindications.

As Kyprolis is administered in combination with other medicinal products, the summary of product characteristics of these other medicinal products must be consulted prior to initiation of treatment with Kyprolis. As lenalidomide may be used in combination with Kyprolis, particular attention to the lenalidomide pregnancy testing and prevention requirements is needed (see section 4.6).

Cardiac disorders

New or worsening cardiac failure (e.g. congestive cardiac failure, pulmonary oedema, decreased ejection fraction), myocardial ischaemia and infarction have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration and fatal outcomes have been reported with cardiac failure and myocardial infarction.

While adequate hydration is required prior to dosing in cycle 1, all patients should be monitored for evidence of volume overload, especially patients at risk for cardiac failure. The total volume of fluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk for cardiac failure (see section 4.2).

Stop Kyprolis for grade 3 or 4 cardiac events until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment (see section 4.2).

The risk of cardiac failure is increased in elderly patients (≥ 75 years). Patients with New York Heart Association (NYHA) Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities uncontrolled by medicinal products were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Patients with signs or symptoms of NYHA Class III or IV cardiac failure, recent history of myocardial infarction (in the last 4 months), and in patients with uncontrolled angina or arrhythmias, should have a comprehensive medical assessment, prior to starting treatment with Kyprolis. This assessment should optimise the patient's status, with particular attention to blood pressure and fluid management. Subsequently patients should be treated with caution and remain under close follow-up.

Electrocardiographic changes

There have been cases of QT interval prolongation reported in clinical studies. An effect of Kyprolis on QT interval cannot be excluded (see section 5.1).

Pulmonary toxicity