Chemical formula: C₄₀H₅₇N₅O₇ Molecular mass: 719.91 g/mol PubChem compound: 11556711
Carfilzomib interacts in the following cases:
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.
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).
Cases of acute renal failure have been reported in patients who received carfilzomib. Some of these events have been fatal. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received carfilzomib monotherapy. 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. Creatinine clearance was stable over time for the majority of patients. Renal function should be monitored at least monthly or in accordance with accepted clinical practice guidelines, particularly in patients with lower baseline creatinine clearance. Reduce or stop dose as appropriate.
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.
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.
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.
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.
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 vs 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%).
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=2,944). Within each system organ class and frequency category, adverse reactions are presented in order of decreasing seriousness.
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very common: Pneumonia, Respiratory tract infection
Common: Sepsis, Lung infection, Influenza, Herpes zoster*, Urinary tract infection, Bronchitis, Gastroenteritis, Viral infection, Nasopharyngitis, Rhinitis
Uncommon: Clostridium difficile colitis, Cytomegalovirus infection, Hepatitis B virus reactivation
Uncommon: Drug hypersensitivity
Very common: Thrombocytopenia, Neutropenia, Anaemia, Lymphopenia, Leukopenia
Common: Febrile neutropenia
Uncommon: HUS
Rare: TTP, Thrombotic microangiopathy
Very common: Hypokalaemia, Hyperglycaemia, Decreased appetite
Common: Dehydration, Hyperkalaemia, Hypomagnesaemia, Hyponatraemia, Hypercalcaemia, Hypocalcaemia, Hypophosphataemia, Hyperuricaemia, Hypoalbuminaemia
Uncommon: Tumour lysis syndrome
Very common: Insomnia
Common: Anxiety, Confusional state
Very common: Dizziness, Peripheral neuropathy Headache
Common: Paraesthesia, Hypoaesthesia
Uncommon: Intracranial haemorrhage, Cerebrovascular accident
Rare: PRES
Common: Cataract, Blurred vision
Common: Tinnitus
Common: Cardiac failure, Myocardial infarction, Atrial fibrillation, Tachycardia, Ejection fraction decreased, Palpitations
Uncommon: Cardiac arrest, Myocardial ischaemia, Pericarditis, Pericardial effusion
Very common: Hypertension
Common: Deep vein thrombosis, Hypotension, Flushing
Uncommon: Hypertensive crisis, Haemorrhage
Rare: Hypertensive emergency
Very common: Dyspnoea, Cough
Common: Pulmonary embolism, Pulmonary oedema, Epistaxis, Oropharyngeal pain, Dysphonia, Wheezing, Pulmonary hypertension
Uncommon: ARDS, Acute respiratory failure, Pulmonary haemorrhage, Interstitial lung disease, Pneumonitis
Very common: Vomiting, Diarrhoea, Constipation, Abdominal pain, Nausea
Common: Gastrointestinal haemorrhage, Dyspepsia, Toothache
Uncommon: Gastrointestinal perforation
Common: Increased alanine aminotransferase, Increased aspartate aminotransferase, Gamma-glutamyltransferase increased, Hyperbilirubinaemia
Uncommon: Hepatic failure, Cholestasis
Common: Rash, Pruritus, Erythema, Hyperhidrosis
Rare: Angioedema
Very common: Back pain, Arthralgia, Pain in extremity, Muscle spasms
Common: Musculoskeletal pain, Musculoskeletal chest pain, Bone pain, Myalgia, Muscular weakness
Very common: Increased blood creatinine
Common: Acute kidney injury, Renal failure, Renal impairment, Decreased creatinine renal clearance
Very common: Pyrexia, Peripheral oedema, Asthenia, Fatigue, Chills
Common: Chest pain, Pain, Infusion site reactions, Influenza like illness, Malaise
Uncommon: Multi-organ dysfunction syndrome
Common: Increased c-reactive protein, Increased blood uric acid
Common: Infusion related reaction
* Frequency is calculated based on data from clinical trials in which most patients used prophylaxis
In clinical studies with carfilzomib, cardiac failure was reported in approximately 7% of subjects (5% of subjects had grade ≥3 events), myocardial infarction was reported in approximately 2% of subjects (1.5% of subjects had grade ≥3 events) and myocardial ischaemia was reported in approximately 1% of subjects (<1% of subjects had grade ≥3 events). These events typically occurred early in the course of carfilzomib therapy (<5 cycles). For clinical management of cardiac disorders during carfilzomib treatment.
Dyspnoea was reported in approximately 30% 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). For clinical management of dyspnoea during carfilzomib treatment.
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 20% of subjects and 7.5% 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. For clinical management of hypertension during carfilzomib treatment.
Thrombocytopenia was reported in approximately 34% of subjects in clinical studies with carfilzomib and approximately 20% of subjects had grade ≥3 events. 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. For clinical management of thrombocytopenia during carfilzomib treatment.
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 two 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.
Cases of hepatic failure, including fatal cases, have been reported in <1% of subjects in clinical studies with carfilzomib. For clinical management of hepatic toxicity during carfilzomib treatment.
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) vs 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.
Overall, the subject incidence of certain adverse events (including cardiac arrhythmias, cardiac failure, dyspnoea, leukopenia and thrombocytopenia) in clinical trials with carfilzomib was higher for patients who were ≥75 years of age compared to patients who were <75 years of age.
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