Carfilzomib

In vitro, carfilzomib inhibits OATP1B1 with an IC₅₀ = 2.01 μM whereas it is unknown whether carfilzomib may or not inhibit other transporters OATP1B3, OAT1, OAT3, OCT2 and BSEP, at the systemic level. Carfilzomib does not inhibit human UGT2B7 but inhibits human UGT1A1 with an IC₅₀ of 5.5 μM. Nonetheless, considering the fast elimination of carfilzomib, notably a rapid decline in systemic concentration 5 minutes after the end of infusion, the risk of clinically relevant interactions with substrates of OATP1B1 and UGT1A1 is probably low.

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

The pharmacokinetics of carfilzomib 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.

In vitro, at concentrations (3 μM) lower than those expected at therapeutic doses, carfilzomib inhibits the efflux transport of digoxin, a P-gp substrate, by 25%. Caution should be observed when carfilzomib is combined with substrates of P-gp (e.g. digoxin, colchicine).

The risk of cardiac failure is increased in elderly patients (≥75 years). The risk of cardiac failure is also increased in Asian patients.

A thorough assessment for cardiovascular risk factors prior to starting treatment is recommended.

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 cardiological assessment, prior to starting treatment with carfilzomib. This assessment should optimise the patient's status, with particular attention to blood pressure control and fluid management. Subsequently patients should be treated with caution and remain under close follow-up.

All patients should be screened for HBV before initiation of treatment with carfilzomib. For patients with positive HBV serology, prophylaxis with antivirals should be considered. They should be monitored for clinical and laboratory signs of HBV reactivation during and after the end of treatment. Experts in the treatment of HBV infection should be consulted, as necessary. The safety of resuming carfilzomib, after HBV reactivation is adequately controlled, is not known. Therefore, resumption of therapy should be discussed with experts in managing HBV.

Patients with moderate or severe renal impairment were enrolled in carfilzomib-dexamethasone combination studies, but were excluded from carfilzomib-lenalidomide combination studies. Thus, there are limited data for carfilzomib in combination with lenalidomide and dexamethasone in patients with creatinine clearance (CrCL <50 mL/min). 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 carfilzomib 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 carfilzomib concentrations has not been studied, the medicinal product should be administered after the dialysis procedure.

There are no data from the use of carfilzomib in pregnant women.

Studies in animals have shown reproductive toxicity.

Based on its mechanism of action and findings in animals, carfilzomib can cause foetal harm when administered to a pregnant woman. carfilzomib should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. If carfilzomib is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be apprised of the potential hazard to the foetus.

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected. The conditions of the Pregnancy Prevention Programme for lenalidomide must be fulfilled for all patients unless there is reliable evidence that the patient does not have child bearing potential. Please refer to the current lenalidomide summary of product characteristics.

It is unknown whether carfilzomib or its metabolites are excreted in human milk. Based on its pharmacological properties, a risk to the suckling child cannot be excluded. Consequently, as a precautionary measure, breast-feeding is contra-indicated during and for at least 2 days after treatment with carfilzomib.

Women of childbearing potential/Contraception in males and females

Female patients of child bearing potential treated with carfilzomib (and/or their partners) must use effective contraception measures during and for one month following treatment.

It cannot be excluded that the efficacy of oral contraceptives may be reduced during carfilzomib treatment. In addition, due to an increased risk of venous thromboembolic events associated with carfilzomib, females should avoid the use of hormonal contraceptives that are associated with a risk of thrombosis during treatment with carfilzomib. If a patient is currently using oral contraceptives or a hormonal method of contraception that is associated with a risk of thrombosis, the patient should switch to an alternative method of effective contraception.

Male patients must use effective contraception measures during and for 3 months following treatment if their partner is pregnant or of child bearing potential not using effective contraception.

Fertility

No fertility studies have been performed in animals.

Carfilzomib has minor influence on the ability to drive and use machines. Fatigue, dizziness, fainting, blurred vision, somnolence and/or a drop in blood pressure have been observed in clinical trials. Patients being treated with carfilzomib should be advised not to drive or operate machines in the event that they experience any of these symptoms.

Summary of safety profile

Serious adverse reactions that may occur during carfilzomib treatment include: cardiac failure, myocardial infarction, cardiac arrest, myocardial ischaemia, interstitial lung disease, pneumonitis, acute respiratory distress syndrome, acute respiratory failure, pulmonary hypertension, dyspnoea, hypertension including hypertensive crises, acute kidney injury, tumour lysis syndrome, infusion related reaction, gastrointestinal haemorrhage, intracranial haemorrhage, pulmonary haemorrhage, thrombocytopenia, hepatic failure, hepatitis B virus reactivation, PRES, thrombotic microangiopathy and TTP/HUS. In clinical studies with carfilzomib, cardiac toxicity and dyspnoea typically occurred early in the course of carfilzomib therapy. The most common adverse reactions (occurring in >20% of subjects) were: anaemia, fatigue, thrombocytopenia, nausea, diarrhoea, pyrexia, dyspnoea, respiratory tract infection, cough and neutropenia.

Following initial doses of carfilzomib at 20 mg/m², the dose was increased to 27 mg/m² in study PX-171-009 and to 56 mg/m² in study 2011-003. A cross-study comparison of the adverse reactions occurring in the carfilzomib and dexamethasone (Kd) arm of study 2011-003 versus the carfilzomib, lenalidomide and dexamethasone (KRd) arm of study PX-171-009 suggest that there may be a potential dose relationship for the following adverse reactions: cardiac failure (Kd 8.2%, KRd 6.4%), dyspnoea (Kd 30.9%, KRd 22.7%), hypertension (Kd 25.9%, KRd 15.8%), and pulmonary hypertension (Kd 1.3%, KRd 0.8%).

In study 20160275, in which the administration of carfilzomib in combination with daratumumab and dexamethasone (KdD) was compared to carfilzomib in combination with dexamethasone (Kd), deaths due to adverse events within 30 days of the last dose of any study treatment occurred in 10% of patients in the KdD arm compared with 5% of patients in the Kd arm. The most common cause of death occurring in patients in the two arms (KdD versus Kd) was infections (5% versus 3%). The risk of fatal treatment-emergent adverse events was higher among subjects ≥65 years of age. Serious adverse events were reported in 56% of the patients in the KdD arm and 46% of the patients in the Kd arm. The most common serious adverse events reported in the KdD arm as compared with the Kd arm were anaemia (2% versus 1%), diarrhoea (2% versus 0%), pyrexia (4% versus 2%), pneumonia (12% versus 9%), influenza (4% versus 1%), sepsis (4% versus 1%) and bronchitis (2% versus 0%).

Tabulated list of adverse reactions

Adverse reactions are presented below by system organ class and frequency category. Frequency categories were determined from the crude incidence rate reported for each adverse reaction in a dataset of pooled clinical studies (n=3,878). Within each system organ class and frequency category, adverse reactions are presented in order of decreasing seriousness.

Tabulated list of adverse reactions:

^* Frequency is calculated based on data from clinical studies in which most patients used prophylaxis

Description of selected adverse reactions

Cardiac failure, myocardial infarction and myocardial ischaemia

In clinical studies with carfilzomib, cardiac failure was reported in approximately 5% of subjects (approximately 3% of subjects had grade ≥3 events), myocardial infarction was reported in approximately 1% of subjects (approximately 1% of subjects had grade ≥3 events) and myocardial ischaemia was reported in <1% of subjects (<1% of subjects had grade ≥3 events). These events typically occurred early in the course of carfilzomib therapy (<5 cycles).

In study 20160275, the overall incidence of cardiac disorders (any and all grade events) in the subgroup of patients with baseline vascular disorders or baseline hypertension was 29.9% versus 19.8% (KdD versus Kd), and 30.6% versus 18.1%, respectively. For fatal cardiac events, the incidence was 1.9% versus 0.0% (KdD versus Kd) and 1.5% versus 0.0%, respectively. No single type of cardiac event accounted for the difference reported between the KdD versus Kd arms in the subgroup of patients with baseline vascular disorders or baseline hypertension.

Dyspnoea

Dyspnoea was reported in approximately 24% of subjects in clinical studies with carfilzomib. The majority of dyspnoea adverse reactions were non-serious (<5% of subjects had grade ≥3 events), resolved, rarely resulted in treatment discontinuation, and had an onset early in the course of study (<3 cycles).

Hypertension including hypertensive crises

Hypertensive crises (hypertensive urgency or hypertensive emergency) have occurred following administration of carfilzomib. Some of these events have been fatal. In clinical studies, hypertension adverse events occurred in approximately 21% of subjects and 8% of subjects had grade ≥3 hypertension events, but hypertensive crises occurred in <0.5% of subjects. The incidence of hypertension adverse events was similar between those with or without a prior medical history of hypertension.

Thrombocytopenia

Thrombocytopenia was reported in approximately 33% of subjects in clinical studies with carfilzomib and approximately 20% of subjects had grade ≥3 events. In study 20160275, the incidence of grade ≥3 thrombocytopenia was 24.4% in the KdD arm and 16.3% in the Kd arm. Carfilzomib causes thrombocytopenia through inhibition of platelet budding from megakaryocytes resulting in a classic cyclical thrombocytopenia with platelet nadirs occurring on day 8 or 15 of each 28-day cycle and usually associated with recovery to baseline by the start of the next cycle.

Venous thromboembolic events

Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported in patients who received carfilzomib. The overall incidence of venous thromboembolic events was higher in the carfilzomib arms of three phase 3 studies. In study PX-171-009 the incidence of venous thromboembolic events was 15.6% in the KRd arm and 9.0% in the Rd arm. Grade ≥3 venous thromboembolic events were reported in 5.6% of patients in the KRd arm and 3.9% of patients in the Rd arm. In study 2011-003 the incidence of venous thromboembolic events was 12.5% in the Kd arm and 3.3% in the bortezomib plus dexamethasone (Vd) arm. Grade ≥3 venous thromboembolic events were reported in 3.5% of patients in the Kd arm and 1.8% of patients in the Vd arm. In study 20160275 the incidence of venous thromboembolic events was 6.2% in the KdD arm and 11.1% in the Kd arm. Grade ≥3 venous thromboembolic events were reported in 1.9% of patients in the KdD arm and 6.5% of patients in the Kd arm.

Hepatic failure

Cases of hepatic failure, including fatal cases, have been reported in <1% of subjects in clinical studies with carfilzomib.

Peripheral neuropathy

In a randomised, open-label multicentre study in patients receiving carfilzomib 20/56 mg/m² infused over 30 minutes in combination with dexamethasone (Kd, n=464) versus bortezomib plus dexamethasone (Vd, n=465), cases of grade 2 and higher peripheral neuropathy were reported in 7% of patients with relapsed multiple myeloma in the Kd arm, compared with 35% in the Vd arm at the time of the pre-planned OS analysis. In study 20160275, cases of grade 2 and higher peripheral neuropathy were reported in 10.1% of patients with relapsed multiple myeloma in the KdD arm compared with 3.9% in the Kd arm.

Infusion reaction

In study 20160275, there was a higher risk of infusion reaction when carfilzomib is administered with daratumumab.

Respiratory tract infections

In study 20160275, respiratory tract infections reported as serious adverse reactions occurred in each treatment group (27.6% in KdD arm and 15.0% in Kd arm). In study 20160275, pneumonia reported as serious adverse reactions occurred in each treatment group (15.3% in KdD arm and 9.8% in Kd arm). 1.3% and 0% events have been fatal in the KdD and Kd arms, respectively.

Secondary primary malignancies

In study 20160275, secondary primary malignancies in each treatment group (1.9% in KdD arm and 1.3% in Kd arm) have been reported.

Opportunistic infections

In study 20160275, opportunistic infections in each treatment group (9.4% in KdD arm and 3.9% in Kd arm) have been reported. Opportunistic infections occurring in ≥1% of subjects in the KdD arm included herpes zoster, oral candidiasis, oral herpes, and herpes simplex.

Hepatitis B reactivation

In study 20160275, the incidence of hepatitis B reactivation was 0.6% in the KdD arm versus 0% in the Kd arm.

Other special populations

Elderly patients

Overall, the subject incidence of certain adverse events (including cardiac arrhythmias, cardiac failure, dyspnoea, leukopenia and thrombocytopenia) in clinical studies with carfilzomib was higher for patients who were ≥75 years of age compared to patients who were <75 years of age.

In study 20160275, 47% of the 308 patients who received KdD 20/56 mg/m² twice weekly were ≥65 years of age. In the KdD arm of the study, fatal treatment-emergent adverse events occurred in 6% of patients <65 years of age and 14% of patients ≥65 years of age. In the Kd arm, these events occurred in 8% of patients <65 years of age and 3% of patients ≥65 years of age.