Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Amgen Europe B.V., Minervum 7061, 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 studies. 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 and post-marketing. Cases of ventricular tachycardia have been reported in patients receiving Kyprolis.
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. Hypertension was reported more frequently in patients who received Kyprolis in combination with daratumumab in study 20160275. 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, bradycardia, 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).
Kyprolis 10 mg powder for solution for infusion:
This medicinal product contains 37 mg sodium per 10 mg vial which is equivalent to 1.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Kyprolis 30 mg powder for solution for infusion:
This medicinal product contains 109 mg sodium per 30 mg vial which is equivalent to 5.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Kyprolis 60 mg powder for solution for infusion:
This medicinal product contains 216 mg sodium per 60 mg vial which is equivalent to 11% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Kyprolis 10 mg powder for solution for infusion:
This medicinal product contains 500 mg cyclodextrin (betadex sulfobutyl ether sodium) per 10 mg vial which is equivalent to 88 mg/kg for a 70 kg adult.
Kyprolis 30 mg powder for solution for infusion:
This medicinal product contains 1,500 mg cyclodextrin (betadex sulfobutyl ether sodium) per 30 mg vial which is equivalent to 88 mg/kg for a 70 kg adult.
Kyprolis 60 mg powder for solution for infusion:
This medicinal product contains 3,000 mg cyclodextrin (betadex sulfobutyl ether sodium) per 60 mg vial which is equivalent to 88 mg/kg for a 70 kg adult.
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 study 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 study 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 IC~50~ = 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 IC~50~ 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 studies. 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 versus 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%).
In study 20160275 (see section 5.1), in which the administration of Kyprolis in combination with daratumumab and dexamethasone (KdD) was compared to Kyprolis 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%).
Adverse reactions are presented below by system organ class and frequency category (see table 6). 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.
Table 6. Tabulated list of adverse reactions:
| MedDRA system organ class | 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) |
|---|---|---|---|---|
| Infections and infestations | Pneumonia Respiratory tract infection | Sepsis Lung infection Influenza Herpes zoster* Urinary tract infection Bronchitis Gastroenteritis Viral infection Nasopharyngitis Rhinitis | Clostridium difficile colitis Cytomegalovirus infection Hepatitis B virus reactivation | |
| Immune system disorders | Drug hypersensitivity | |||
| Blood and lymphatic system disorders | Thrombocytopenia Neutropenia Anaemia Lymphopenia Leukopenia | Febrile neutropenia | HUS TTP | Thrombotic microangiopathy |
| Metabolism and nutrition disorders | Hypokalaemia Decreased appetite | Dehydration Hyperkalaemia Hypomagnesaemia Hyponatraemia Hypercalcaemia Hypocalcaemia Hypophosphataemia Hyperuricaemia Hypoalbuminaemia Hyperglycaemia | Tumour lysis syndrome | |
| Psychiatric disorders | Insomnia | Anxiety Confusional state | ||
| Nervous system disorders | Dizziness Peripheral neuropathy Headache | Paraesthesia Hypoaesthesia | Intracranial haemorrhage Cerebrovascular accident PRES | |
| Eye disorders | Cataract Blurred vision | |||
| Ear and labyrinth disorders | Tinnitus | |||
| Cardiac disorders | Cardiac failure Myocardial infarction Atrial fibrillation Tachycardia Ejection fraction decreased Palpitations | Cardiac arrest Cardiomyopathy Myocardial ischaemia Pericarditis Pericardial effusion Ventricular tachycardia | ||
| Vascular disorders | Hypertension | Deep vein thrombosis Hypotension Flushing | Hypertensive crisis Haemorrhage | Hypertensive emergency |
| Respiratory, thoracic, and mediastinal disorders | Dyspnoea Cough | Pulmonary embolism Pulmonary oedema Epistaxis Oropharyngeal pain Dysphonia Wheezing Pulmonary hypertension | ARDS Acute respiratory failure Pulmonary haemorrhage Interstitial lung disease Pneumonitis | |
| Gastrointestinal disorders | Vomiting Diarrhoea Constipation Abdominal pain Nausea | Gastrointestinal haemorrhage Dyspepsia Toothache | Gastrointestinal perforation Pancreatitis acute | |
| Hepatobiliary disorders | Increased alanine aminotransferase Increased aspartate aminotransferase Gamma- glutamyltransferase increased Hyperbilirubinaemia | Hepatic failure Cholestasis | ||
| Skin and subcutaneous tissue disorders | Rash Pruritus Erythema Hyperhidrosis | Angioedema | ||
| Musculoskeletal and connective tissue disorders | Back pain Arthralgia Pain in extremity Muscle spasms | Musculoskeletal pain Musculoskeletal chest pain Bone pain Myalgia Muscular weakness | ||
| Renal and urinary disorders | Increased blood creatinine | Acute kidney injury Renal failure Renal impairment Decreased creatinine renal clearance | ||
| General disorders and administration site conditions | Pyrexia Peripheral oedema Asthenia Fatigue Chills | Chest pain Pain Infusion site reactions Influenza like illness Malaise | Multi-organ dysfunction syndrome | |
| Investigations | Increased c-reactive protein Increased blood uric acid | |||
| Injury, poisoning and procedural complications | Infusion related reaction |
* Frequency is calculated based on data from clinical studies in which most patients used prophylaxis
In clinical studies with Kyprolis, 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 Kyprolis 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.
For clinical management of cardiac disorders during Kyprolis treatment, see section 4.4.
Dyspnoea was reported in approximately 24% 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 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. For clinical management of hypertension during Kyprolis treatment, see section 4.4.
Thrombocytopenia was reported in approximately 33% of subjects in clinical studies with Kyprolis 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. 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 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.
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) 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.
In study 20160275, there was a higher risk of infusion reaction when carfilzomib is administered with daratumumab.
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.
In study 20160275, secondary primary malignancies in each treatment group (1.9% in KdD arm and 1.3% in Kd arm) have been reported.
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.
In study 20160275, the incidence of hepatitis B reactivation was 0.6% in the KdD arm versus 0% in the Kd arm.
Overall, the subject incidence of certain adverse events (including cardiac arrhythmias, cardiac failure (see section 4.4), dyspnoea, leukopenia and thrombocytopenia) in clinical studies with Kyprolis 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.
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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