Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands
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).
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. For potential dose-related effects, see section 4.8.
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). 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 Kyprolis. 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.
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).
Acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some of these events have been fatal. Evaluate and stop Kyprolis until resolved and consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2).
Pulmonary hypertension has been reported in patients treated with Kyprolis. Some of these events have been fatal. Evaluate as appropriate. Stop Kyprolis for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2).
Dyspnoea was commonly reported in patients treated with Kyprolis. Evaluate dyspnoea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for grade 3 and 4 dyspnoea until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (see sections 4.2 and 4.8).
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. It is recommended to control hypertension prior to starting and during treatment. All patients should be routinely evaluated for hypertension while on Kyprolis and treated as needed. If the hypertension cannot be controlled, the Kyprolis dose should be reduced. In case of hypertensive crises, stop Kyprolis until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2).
Cases of acute renal failure have been reported in patients who received Kyprolis. 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 Kyprolis 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 (see section 4.2).
Cases of tumour lysis syndrome (TLS), including with fatal outcome, have been reported in patients who received Kyprolis. Patients with a high tumour burden should be considered to be at greater risk for TLS. Ensure that patients are well hydrated before administration of Kyprolis in cycle 1, and in subsequent cycles as needed (see section 4.2). Uric acid lowering medicinal products should be considered in patients at high risk for TLS. Evidence of TLS during treatment should be monitored for, including regular measurement of serum electrolytes, and managed promptly. Stop Kyprolis until TLS is resolved (see section 4.2).
Infusion reactions, including life-threatening reactions, have been reported in patients who received Kyprolis. Symptoms may include fever, chills, arthralgia, myalgia, facial flushing, facial oedema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Dexamethasone should be administered prior to Kyprolis to reduce the incidence and severity of reactions (see section 4.2).
Cases of haemorrhage (e.g. gastrointestinal, pulmonary and intracranial haemorrhage) have been reported in patients treated with Kyprolis, often associated with thrombocytopenia. Some of these events have been fatal (see section 4.8).
Kyprolis causes thrombocytopenia with platelet nadirs observed on day 8 or day 15 of each 28-day cycle with recovery to baseline platelet count by the start of the next cycle (see section 4.8). Platelet counts should be monitored frequently during treatment with Kyprolis. Reduce or stop dose as appropriate (see section 4.2).
Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported in patients who received Kyprolis.
Patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia). Caution should be used in the concomitant administration of other agents that may increase the risk of thrombosis (e.g. erythropoietic agents or hormone replacement therapy). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, haemoptysis, arm or leg swelling or pain.
Thromboprophylaxis should be considered based on an individual benefit/risk assessment.
Cases of hepatic failure, including fatal cases, have been reported. Kyprolis can cause elevations of serum transaminases (see section 4.8). Reduce or stop dose as appropriate (see section 4.2). Liver enzymes and bilirubin should be monitored at treatment initiation and monthly during treatment with carfilzomib, regardless of baseline values.
Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome (TTP/HUS) have been reported in patients who received Kyprolis. Some of these events have been fatal. Signs and symptoms of TTP/HUS should be monitored for. If the diagnosis is suspected, stop Kyprolis and evaluate patients for possible TTP/HUS. If the diagnosis of TTP/HUS is excluded, Kyprolis can be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Kyprolis. PRES, formerly termed reversible posterior leukoencephalopathy syndrome (RPLS), is a rare, neurological disorder, which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging. Kyprolis should be discontinued if PRES is suspected. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.
Cases of Hepatitis B Virus (HBV) reactivation have been reported in patients receiving carfilzomib.
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.
Cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients receiving carfilzomib who have had prior or concurrent immunosuppressive therapy.
Patients receiving carfilzomib should be monitored for any new or worsening neurologic, cognitive or behavioural signs and symptoms that may be suggestive of PML as part of the differential diagnosis of CNS disorders.
If PML is suspected, further administration must be suspended until PML has been excluded by a specialist with appropriate diagnostic testing. If PML is confirmed, carfilzomib must be discontinued.
Female patients of child bearing potential (and/or their partners) must use effective contraception measures during and for one month following treatment. Male patients must use effective contraception measures during and for 3 months following treatment if their partner is pregnant or of childbearing potential and not using effective contraception (refer to section 4.6). Carfilzomib may decrease the efficacy of oral contraceptives (refer to section 4.5).
This medicinal product contains 0.3 mmols (7 mg) of sodium per mL of reconstituted solution. This should be taken into consideration for patients on a controlled sodium diet.
Carfilzomib is primarily metabolised via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers.
In vitro studies indicated that carfilzomib did not induce human CYP3A4 in cultured human hepatocytes. A clinical trial using oral midazolam as a CYP3A probe conducted with carfilzomib at a dose of 27 mg/m² (2-10 minute infusion) demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration, indicating that carfilzomib is not expected to inhibit the metabolism of CYP3A4/5 substrates and is not a CYP3A4 inducer in human subjects. No clinical trial was conducted with a dose of 56 mg/m². However, it is unknown whether carfilzomib is an inducer of CYP1A2, 2C8, 2C9, 2C19 and 2B6 at therapeutic concentrations. Caution should be observed when carfilzomib is combined with medicinal products that are substrates of these enzymes, such as oral contraceptives. Effective measures to avoid pregnancy should be taken (see section 4.6, and refer also to the current lenalidomide summary of product characteristics), an alternative method of effective contraception should be used if the patient is using oral contraceptives.
Carfilzomib does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19 and 2D6 in vitro and is therefore not expected to influence exposure of medicinal products that are substrates of these enzymes as a result of inhibition.
Carfilzomib is a P-glycoprotein (P-gp) but not a BCRP substrate. However, given that Kyprolis is administrated intravenously and is extensively metabolised, the pharmacokinetic profile of carfilzomib is unlikely to be affected by P-gp or BCRP inhibitors or inducers. 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).
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.
Female patients of child bearing potential treated with Kyprolis (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 (see section 4.5). 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 (see sections 4.4 and 4.8). 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.
There are no data from the use of carfilzomib in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3).
Based on its mechanism of action and findings in animals, Kyprolis can cause foetal harm when administered to a pregnant woman. Kyprolis should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. If Kyprolis 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 Kyprolis.
No fertility studies have been performed in animals (see section 5.3).
Kyprolis 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 Kyprolis 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 Kyprolis 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 Kyprolis, cardiac toxicity and dyspnoea typically occurred early in the course of Kyprolis therapy (see section 4.4). 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 (see section 5.1). A cross-study comparison of the adverse reactions occurring in the Kyprolis and dexamethasone (Kd) arm of study 2011-003 vs the Kyprolis, 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 (table 5). 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)
Table 5. Tabulated list of adverse reactions:
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 Kyprolis, 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 Kyprolis therapy (<5 cycles). For clinical management of cardiac disorders during Kyprolis treatment, see section 4.4.
Dyspnoea was reported in approximately 30% of subjects in clinical studies with Kyprolis. 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 Kyprolis treatment, see section 4.4.
Hypertensive crises (hypertensive urgency or hypertensive emergency) have occurred following administration of Kyprolis. 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 Kyprolis treatment, see section 4.4.
Thrombocytopenia was reported in approximately 34% of subjects in clinical studies with Kyprolis and approximately 20% of subjects had grade ≥3 events. Kyprolis 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 Kyprolis treatment, see section 4.4.
Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported in patients who received Kyprolis (see section 4.4). The overall incidence of venous thromboembolic events was higher in the Kyprolis 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 Kyprolis. For clinical management of hepatic toxicity during Kyprolis treatment, see section 4.4.
In a randomised, open-label multicentre study in patients receiving Kyprolis 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 (see section 4.4), dyspnoea, leukopenia and thrombocytopenia) in clinical trials with Kyprolis was higher for patients who were ≥75 years of age compared to patients who were <75 years of age.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Kyprolis powder for solution for infusion must not be mixed with sodium chloride 9 mg/mL (0.9%) solution for injection.
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