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Carfilnat (Carfilzomib for Injection 60 mg/vial)

Carfilnat (Carfilzomib for Injection 60 mg/vial)

Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XX45

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly binds to the N terminal threonine containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome, and displays little to no activity against other protease classes. Carfilzomib had antiproliferative and proapoptotic activities in preclinical models in haematologic tumors. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma. In vitro, carfilzomib was found to have minimal neurotoxicity and minimal reaction to non-proteasomal proteases.

Carfilnat Therapeutic indications

Carfilnat 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.

Carfilnat Posology and method of administration

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

The dose is calculated using the patient’s baseline body surface area (BSA). Patients with a BSA greater than 2.2m2 should receive a dose based upon a BSA of 2.2m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

Carfilnat in combination with lenalidomide and dexamethasone

When combined with lenalidomide and dexamethasone, Carfilnat 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).

Each 28-day period is considered one treatment cycle.

Carfilnat 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 Carfilnat are omitted.

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

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Treatment with Carfilnat 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.

In combination with Carfilnat, 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 Carfilnat.

Carfilnat in combination with dexamethasone

When combined with dexamethasone, Carfilnat 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.

Carfilnat 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 Carfilnat 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 Carfilnat.

Concomitant medicinal products

Antiviral prophylaxis should be considered in patients being treated with Carfilnat to decrease the risk of herpes zoster reactivation.

Thromboprophylaxis is recommended in patients being treated with Carfilnat 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 tumor 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.

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 Carfilnat 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 Carfilnat 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.

Carfilnat Special populations

Renal impairment: Patients with moderate or severe renal impairment were enrolled in Carfilnat-dexamethasonecombination studies, but were excluded from Carfilnat-lenalidomide combination studies. Thus,there are limited data for Carfilnat in combination with lenalidomide and dexamethasone inpatients with creatinine clearance (CrCL < 50 mL/min). Appropriate dose reduction for the startingdose of lenalidomide in patients with baseline renal impairment should be considered according tothe recommendations in the lenalidomide summary of product characteristics.

No starting dose adjustment for Carfilnat is recommended in patients with baseline mild, moderate, or severe renal impairment or patients on chronic dialysis based on available pharmacokinetic data. However, in phase 3 clinical studies, the incidence of adverse events of acute renal failure was higher in patients with lower baseline creatinine clearance than that among patients with higher baseline creatinine clearance.

Renal function should be assessed at treatment initiation and monitored at least monthly or in accordance with accepted clinical practice guidelines, particularly in patients with lower baseline creatinine clearance (CrCL < 30 mL/min). Appropriate dose modifications based on toxicity should be made. There are limited efficacy and safety data on patients with baseline creatinine clearance < 30 mL/min.

Since dialysis clearance of Carfilnat concentrations has not been studied, the medicinal product should be administered after the dialysis procedure.

Hepatic impairment: Patients with moderate or severe hepatic impairment were excluded from Carfilnat studies in combination with either lenalidomide and dexamethasone or dexamethasone alone.

The pharmacokinetics of Carfilnat has not been evaluated in patients with severe hepatic impairment. No starting dose adjustment is recommended in patients with mild or moderate hepatic impairment based on available pharmacokinetic data. However, higher subject incidence of hepatic function abnormalities, ≥ grade 3 adverse events and serious adverse events have been reported in patients with mild or moderate baseline hepatic impairment compared with patients with normal hepatic function. Liver enzymes and bilirubin should be assessed at treatment initiation and monitored monthly during treatment with carfilzomib, regardless of baseline values, and appropriate dose modifications based on toxicity should be made. Special attention should be paid to patients with moderate and severe hepatic impairment in view of the very limited efficacy and safety data on this population.

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.

Paediatric population: The safety and efficacy of Carfilnat in paediatric patients have not been established. No data areavailable.

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Carfilnat Method of administration

Carfilnat 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.

Carfilnat must not be administered as an intravenous push or bolus.

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

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

Carfilnat Contraindications

  • Hypersensitivity to the active substance or to any of the excipients.
  • Women who are breast-feeding.

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

Carfilnat Undesirable effects

Serious adverse reactions that may occur during Carfilnat treatment include: cardiac failure, myocardial infarction, cardiac arrest, myocardial ischaemia, interstitial lung disease, pneumonitis, acute respiratory distress syndrome, acute respiratory failure, pulmonary hypertension, dyspnea, hypertension including hypertensive crises, acute kidney injury, tumor lysis syndrome, infusion related reaction, gastrointestinal hemorrhage, intracranial hemorrhage, pulmonary hemorrhage, thrombocytopenia, hepatic failure, PRES, thrombotic microangiopathy and TTP/HUS. In clinical studies with Carfilnat, cardiac toxicity and dyspnea typically occurred early in the course of Carfilnat therapy.

 The most common adverse reactions (occurring in > 20% of subjects) were: anaemia, fatigue, thrombocytopenia, nausea, diarrhoea, pyrexia, dyspnea, respiratory tract infection, cough and neutropenia.

Carfilnat Overdose

There is currently insufficient information to draw conclusions about the safety of doses higher than those evaluated in clinical studies. Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia has been reported following a dose of 200 mg of Carfilnat administered in error.

There is no known specific antidote for carfilzomib overdose. In the event of an overdose, the patient should be monitored, specifically for the adverse reactions to Carfilnat

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