Kyprolis

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kyprolis 10 mg powder for solution for infusion 
Kyprolis 30 mg powder for solution for infusion 
Kyprolis 60 mg powder for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Kyprolis 10 mg powder for solution for infusion 
Each vial contains 10 mg of carfilzomib. 
 
Excipient with known effect 
Each vial contains 37 mg sodium. 
Each vial contains 500 mg of cyclodextrin (betadex sulfobutyl ether sodium). 
 
Kyprolis 30 mg powder for solution for infusion 
Each vial contains 30 mg of carfilzomib. 
 
Excipient with known effect 
Each vial contains 109 mg sodium. 
Each vial contains 1,500 mg of cyclodextrin (betadex sulfobutyl ether sodium). 
 
Kyprolis 60 mg powder for solution for infusion 
Each vial contains 60 mg of carfilzomib. 
 
Excipient with known effect 
Each vial contains 216 mg sodium. 
Each vial contains 3,000 mg of cyclodextrin (betadex sulfobutyl ether sodium). 
 
After reconstitution, 1 mL of solution contains 2 mg of carfilzomib. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for infusion. 
 
White to off-white lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kyprolis 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 (see section 5.1). 
 



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4.2 Posology and method of administration 
 
Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy. 
 
Posology 
 
The dose is calculated using the patient’s baseline body surface area (BSA). Patients with a BSA 
greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not need 
to be made for weight changes of less than or equal to 20%. 
 
Kyprolis in combination with lenalidomide and dexamethasone 
 
When combined with lenalidomide and dexamethasone, Kyprolis 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) as shown in table 1. Each 28-day period is considered 
one treatment cycle. 
 
Kyprolis 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 Kyprolis are omitted. 
 
Treatment may be continued until disease progression or until unacceptable toxicity occurs. 
 
Treatment with Kyprolis 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 (see section 5.1). 
 
In combination with Kyprolis, 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 Kyprolis. 
 
Table 1. Kyprolis in combination with lenalidomide and dexamethasonea 
 

 

Cycle 1 
Week 1 Week 2 Week 3 Week 4 

Day 
1 

Day 
2 

Days 
3-7 

Day 
8 

Day 
9 

Days 
10-14 

Day 
15 

Day 
16 

Days 
17-21 

Day 
22 

Days 
23-28 

Kyprolis (mg/m2) 20 20 - 27 27 - 27 27 - - - 

Dexamethasone 
(mg) 

40 - - 40 - - 40 - - 40 - 

Lenalidomide 25 mg daily - - 

 

Cycles 2-12 
Week 1 Week 2 Week 3 Week 4 

Day 
1 

Day 
2 

Days 
3-7 

Day 
8 

Day 
9 

Days 
10-14 

Day 
15 

Day 
16 

Days 
17-21 

Day 
22 

Days 
23-28 

Kyprolis (mg/m2) 27 27 - 27 27 - 27 27 - - - 

Dexamethasone 
(mg) 

40 - - 40 - - 40 - - 40 - 

Lenalidomide 25 mg daily - - 



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Cycles 13 on 
Week 1 Week 2 Week 3 Week 4 

Day 
1 

Day 
2 

Days 
3-7 

Day 
8 

Day 
9 

Days 
10-14 

Day 
15 

Day 
16 

Days 
17-21 

Day 
22 

Days 
23-28 

Kyprolis (mg/m2) 27 27 - - - - 27 27 - - - 
Dexamethasone 
(mg) 

40 - - 40 - - 40 - - 40 - 

Lenalidomide 25 mg daily - - 
a. Infusion time is 10 minutes and remains consistent throughout the regimen 
 
Kyprolis in combination with dexamethasone 
 
When combined with dexamethasone, Kyprolis 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. 
 
Kyprolis 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 Kyprolis 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 Kyprolis. 
 
Table 2. Kyprolis in combination with dexamethasone alonea 
 

 

Cycle 1 
Week 1 Week 2 Week 3 Week 4 

Day 
1 

Day 
2 

Days 
3-7 

Day 
8 

Day 
9 

Days 
10-14 

Day 
15 

Day 
16 

Days 
17-21 

Day 
22 

Day 
23 

Days 
24-28 

Kyprolis 
(mg/m2) 20 20 - 56 56 - 56 56 - - - - 

Dexamethasone 
(mg) 

20 20 - 20 20 - 20 20 - 20 20 - 

 

Cycle 2 and all subsequent cycles 
Week 1 Week 2 Week 3 Week 4 

Day 
1 

Day 
2 

Days 
3-7 

Day 
8 

Day 
9 

Days 
10-14 

Day 
15 

Day 
16 

Days 
17-21 

Day 
22 

Day 
23 

Days 
24-28 

Kyprolis 
(mg/m2) 56 56 - 56 56 - 56 56 - - - - 

Dexamethasone 
(mg) 

20 20 - 20 20 - 20 20 - 20 20 - 

a. Infusion time is 30 minutes and remains consistent throughout the regimen 
 
Concomitant medicinal products 
 
Antiviral prophylaxis should be considered in patients being treated with Kyprolis to decrease the risk 
of herpes zoster reactivation (see section 4.8). 
 
Thromboprophylaxis is recommended in patients being treated with Kyprolis 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 



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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 tumour 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 (see section 4.4). 
 
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 Kyprolis 
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 
Kyprolis 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. 
 
Recommended dose modifications 
 
Dosing should be modified based on Kyprolis toxicity. Recommended actions and dose modifications 
are presented in table 3. Dose level reductions are presented in table 4. 
 
Table 3. Dose modifications during Kyprolis treatment 
 

Haematologic toxicity Recommended action 
 Absolute neutrophil count 

< 0.5 × 109/L (see section 4.4)  
 Stop dose 

- If recovered to ≥ 0.5 × 109/L, continue at same dose 
level 

 For subsequent drops to < 0.5 × 109/L, follow the same 
recommendations as above and consider 1 dose level 
reduction when restarting Kyprolisa

 Febrile neutropenia 
 Absolute neutrophil count 

< 0.5 × 109/L and an oral 
temperature > 38.5°C or two 
consecutive readings of > 38.0°C 
for 2 hours 

 Stop dose 
 If absolute neutrophil count returns to baseline grade and 

fever resolves, resume at the same dose level 

 Platelet count < 10 × 109/L or 
evidence of bleeding with 
thrombocytopenia (see 
section 4.4) 

 Stop dose 
- If recovered to ≥ 10 × 109/L and/or bleeding is 

controlled continue at same dose level 
 For subsequent drops to < 10 × 109/L, follow the same 

recommendations as above and consider 1 dose level 
reduction when restarting Kyprolisa

Non-haematologic toxicity (renal) Recommended action 
 Serum creatinine equal to or 

greater than 2 × baseline; or 
 Creatinine clearance < 15 mL/min 

(or creatinine clearance decreases 
to ≤ 50% of baseline) or need for 
dialysis (see section 4.4) 

 Stop dose and continue monitoring renal function (serum 
creatinine or creatinine clearance) 
- Kyprolis should be resumed when renal function has 

recovered to within 25% of baseline; consider 
resuming at 1 dose level reductiona 

 For patients on dialysis receiving Kyprolis, the dose is to be 
administered after the dialysis procedure 



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Other non-haematologic toxicity Recommended action 
 All other grade 3 or 4 

non-haematologic toxicities  
(see section 4.4) 

 Stop until resolved or returned to baseline 
 Consider restarting the next scheduled treatment at 1 dose 

level reductiona
a. See table 4 for dose level reductions 
 
Table 4. Dose level reductions for Kyprolis 
 

Regimen Kyprolis Dose 
First Kyprolis 
dose reduction 

Second Kyprolis 
dose reduction 

Third Kyprolis 
dose reduction 

Kyprolis, lenalidomide, and 
dexamethasone 27 mg/m

2 20 mg/m2 15 mg/m2 a — 

Kyprolis and 
dexamethasone 56 mg/m

2 45 mg/m2 36 mg/m2 27 mg/m2 a 

Note: Kyprolis infusion times remain unchanged during dose reduction(s) 
a. If symptoms do not resolve, discontinue Kyprolis treatment 
 
Special populations 
 
Renal impairment 
 
Patients with moderate or severe renal impairment were enrolled in Kyprolis-dexamethasone 
combination studies, but were excluded from Kyprolis-lenalidomide combination studies. Thus, there 
are limited data for Kyprolis 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 Kyprolis is recommended in patients with baseline mild, moderate, or 
severe renal impairment or patients on chronic dialysis based on available pharmacokinetic data (see 
section 5.2). 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 (see table 3). There are limited efficacy and safety data on patients with baseline creatinine 
clearance < 30 mL/min. 
 
Since dialysis clearance of Kyprolis 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 Kyprolis studies in 
combination with either lenalidomide and dexamethasone or dexamethasone alone. 
 
The pharmacokinetics of Kyprolis 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 
(see sections 4.4 and 5.2). 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 (see table 3). Special attention should be paid to 



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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 studies 
was higher for patients who were ≥ 75 years of age compared to patients who were < 75 years of age 
(see section 4.4). 
 
Paediatric population 
 
The safety and efficacy of Kyprolis in paediatric patients have not been established. No data are 
available. 
 
Method of administration 
 
Kyprolis 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. 
 
Kyprolis 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 Kyprolis administration. 
 
Do not mix Kyprolis with or administer as an infusion with other medicinal products. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 Women who are breast-feeding (see section 4.6). 
 
As Kyprolis is administered in combination with other medicinal products, refer to their summaries of 
product characteristics for additional contraindications. 
 
4.4 Special warnings and precautions for use 
 
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). 
 
Cardiac disorders 
 
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). 
 



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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. 
 
Electrocardiographic changes 
 
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). 
 
Pulmonary toxicity 
 
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 
 
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 
 
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 
 
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). 
 
Acute renal failure 
 
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 



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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). 
 
Tumour lysis syndrome 
 
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 
 
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). 
 
Haemorrhage and thrombocytopenia 
 
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). 
 
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 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. 
 
Hepatic toxicity 
 
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 



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enzymes and bilirubin should be monitored at treatment initiation and monthly during treatment with 
carfilzomib, regardless of baseline values. 
 
Thrombotic microangiopathy 
 
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. 
 
Posterior reversible encephalopathy syndrome 
 
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. 
 
Hepatitis B Virus (HBV) Reactivation 
 
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. 
 
Progressive Multifocal Leukoencephalopathy 
 
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. 
 
Contraception 
 
Female patients of childbearing 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). 
 



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Sodium content 
 
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. 
 
Cyclodextrin content 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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). 
 



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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. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of child bearing potential/Contraception in males and females 
 
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. 
 
Pregnancy 
 
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. 
 
Breast-feeding 
 
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. 
 
Fertility 
 
No fertility studies have been performed in animals (see section 5.3). 
 



13 

4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
Summary of safety profile 
 
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%). 
 
Tabulated list of adverse reactions 
 
Adverse reactions are presented below by system organ class and frequency category (see 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. 
 
Table 5. 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 

 



14 

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) 

Blood and 
lymphatic 
system 
disorders 

Thrombocytopenia 
Neutropenia 
Anaemia 
Lymphopenia 
Leukopenia 

Febrile neutropenia 
 

HUS TTP 
Thrombotic 
microangiopathy 

Metabolism and 
nutrition 
disorders 

Hypokalaemia 
Hyperglycaemia 
Decreased appetite 

Dehydration 
Hyperkalaemia 
Hypomagnesaemia 
Hyponatraemia 
Hypercalcaemia 
Hypocalcaemia 
Hypophosphataemia 
Hyperuricaemia 
Hypoalbuminaemia

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 

 

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 

 



15 

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) 

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 
 
Description of selected adverse reactions 
 
Cardiac failure, myocardial infarction and myocardial ischaemia 
 
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. 
 



16 

Dyspnoea 
 
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. 
 
Hypertension including hypertensive crises 
 
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 
 
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. 
 
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 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. 
 
Hepatic failure 
 
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. 
 
Peripheral neuropathy 
 
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. 
 



17 

Other special populations 
 
Elderly patients (≥ 75 years) 
 
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. 
 
Reporting of suspected adverse reactions 
 
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. 
 
4.9 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 Kyprolis 
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 Kyprolis listed in section 4.8. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX45 
 
Mechanism of action 
 
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 tumours. In 
animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumour growth in 
models of multiple myeloma. In vitro, carfilzomib was found to have minimal neurotoxicity and 
minimal reaction to non-proteasomal proteases. 
 
Pharmacodynamic effects 
 
Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like 
(CT-L) activity when measured in blood 1 hour after the first dose. Doses of ≥ 15 mg/m2 consistently 
induced an (≥ 80%) inhibition of the CT-L activity of the proteasome. In addition, carfilzomib 
administration resulted in inhibition of the latent membrane protein 2 (LMP2) and multicatalytic 
endopeptidase complex-like 1 (MECL1) subunits of the immunoproteasome ranging from 26% to 32% 
and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours 
following the first dose of carfilzomib for each week of dosing. Combination dosing with 
lenalidomide and dexamethasone did not affect proteasome inhibition. 
 
At the higher dose of 56 mg/m2, there was not only a greater inhibition of CT-L subunits (≥ 90%) 
compared to those at 15 to 20 mg/m2, but also a greater inhibition of other proteasome subunits 
(LMP7, MECL1, and LMP2). There was an approximately 8%, 23% and 34% increase in the 
inhibition of LMP7, MECL1, and LMP2 subunits respectively at the dose of 56 mg/m2 compared to 



18 

those at 15 to 20 mg/m2. Similar proteasome inhibition by carfilzomib was achieved with 
2 to 10 minute and 30 minute infusions at the 2 dose levels (20 and 36 mg/m2) at which it was tested. 
 
Clinical efficacy and safety 
 
Kyprolis in combination with lenalidomide and dexamethasone for the treatment of patients with 
relapsed multiple myeloma – study PX-171-009 (ASPIRE) 
 
The safety and efficacy of Kyprolis were evaluated in a randomised, open-label, multicentre study of 
792 patients with relapsed multiple myeloma, which evaluated the combination of Kyprolis with 
lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone, randomised 1:1. 
 
This study evaluated Kyprolis at an initial dose of 20 mg/m2, which was increased to 27 mg/m2 on 
cycle 1, day 8, administered twice weekly for 3 out of 4 weeks as a 10 minute infusion. Kyprolis 
treatment was administered for a maximum of 18 cycles unless discontinued early for disease 
progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue 
until progression or unacceptable toxicity. 
 
Patients who had the following were excluded from the study: creatinine clearance rates < 50 mL/min, 
NYHA Class III to IV congestive heart failure, or myocardial infarction within the last 4 months, 
disease progression during the treatment with a bortezomib-containing regimen, or progression during 
the first 3 months of initiating treatment with lenalidomide and dexamethasone, or progression at any 
time during treatment with lenalidomide and dexamethasone if this was the subject’s most recent line 
of therapy. Study eligibility criteria allowed a small subset of patients with myeloma refractory to 
bortezomib (n = 118) or lenalidomide (n = 57) to be enrolled. Enrolled subjects were defined as 
refractory to a therapy if they met any of the following 3 criteria: nonresponsive (< minimal response) 
to any regimen; progression during any regimen; or progression within 60 days of completion of any 
regimen. This study did not evaluate the benefit/risk ratio in the broader refractory population. 
 
The disease status and other baseline characteristics were well-balanced between the two arms, 
including age (64 years, range 31-91 years), gender (56% male), ECOG performance status (48% with 
performance status 1), high risk genetic mutations, consisting of the genetic subtypes t(4;14), t(14;16), 
or deletion 17p in ≥ 60% of plasma cells (13%), unknown-risk genetic mutations, which included 
subjects with results not collected or not analysed (47%), and baseline ISS stage III disease (20%). 
Subjects had received 1 to 3 prior lines of therapy (median of 2), including prior treatment with 
bortezomib (66%), thalidomide (44%) and lenalidomide (20%). 
 
The results of study PX-171-009 are summarised in table 6 and in figure 1 and figure 2. 
 



19 

Table 6. Summary of efficacy analysis in relapsed multiple myeloma study PX-171-009 
 

 

KRd combination therapy 
KRd arma 

 
(N = 396) 

Rd arma 
 

(N = 396) 
PFS months median (95% CI) 26.3 (23.3, 30.5) 17.6 (15.0, 20.6) 

HR (95% CI); 1-sided p-valueb 0.69 (0.57, 0.83); < 0.0001 
OS months median (95% CI) 48.3 (42.4, 52.8) 40.4 (33.6, 44.4) 

HR (95% CI); 1-sided p-valueb 0.79 (0.67, 0.95); 0.0045 
ORR, n (%) 345 (87.1) 264 (66.7) 

sCR 56 (14.1) 17 (4.3) 
CR 70 (17.7) 20 (5.1) 
VGPR 151 (38.1) 123 (31.1) 
PR 68 (17.2) 104 (26.3) 

95% CI of ORR 83.4, 90.3 61.8, 71.3 
1-sided p-value < 0.0001
KRd = Kyprolis, lenalidomide and dexamethasone; Rd = lenalidomide and dexamethasone; 
PFS = progression-free survival; HR = hazard ratio; CI = confidence interval; OS = overall survival; 
ORR = overall response rate; sCR = stringent complete response; CR = complete response; VGPR = very good 
partial response; PR = partial response; IMWG = international myeloma working group; EBMT = European 
society for blood and marrow transplantation 
a. As determined by an Independent Review Committee using standard objective IMWG/EBMT response criteria 
b. Statistically significant 
 
Patients in the Kyprolis, lenalidomide, and dexamethasone (KRd) arm demonstrated improved 
progression-free survival (PFS) compared with those in the lenalidomide and dexamethasone (Rd) 
arm, (HR = 0.69, with 1-sided p-value < 0.0001) which represents a 45% improvement in PFS or a 
31% reduction in the risk of event as determined using standard objective International Myeloma 
Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by 
an Independent Review Committee (IRC). 
 
The PFS benefit of KRd was consistently observed in all subgroups, including patients ≥ 75 years of 
age (n = 96), patients with high risk (n = 100) or unknown (n = 375) risk genetic mutations, and 
patients with baseline creatinine clearance of 30 - < 50 mL/min (n = 56). 
 



20 

Figure 1. Kaplan-Meier curve of progression-free survival in relapsed multiple myelomaa 

 

KRd = Kyprolis, lenalidomide and dexamethasone; Rd = lenalidomide, dexamethasone; PFS = progression-free 
survival; HR = hazard ratio; CI = confidence interval; IMWG = International Myeloma Working Group; 
EBMT = European blood and marrow transplantation; mo = months 
Note: The response and PD outcomes were determined using standard objective IMWG/EBMT response criteria. 
a. Study PX-171-009 
 
A pre-planned overall survival (OS) analysis was performed after 246 deaths in the KRd arm and 
267 deaths in the Rd arm. The median follow-up was approximately 67 months. A statistically 
significant advantage in OS was observed in patients in the KRd arm compared to patients in the Rd 
arm. Patients in the KRd arm had a 21% reduction in the risk of death compared with those in the Rd 
arm (HR = 0.79; 95% CI: 0.67, 0.95; p-value = 0.0045). The median OS improved by 7.9 months in 
patients in the KRd arm compared with those in the Rd arm (see table 6 and figure 2). 
 

Number of Subjects at Risk: 

Months from Randomisation 

Pr
op

or
tio

n s
ur

viv
ing

 w
ith

ou
t p

ro
gr

es
sio

n 

KRd 396 332 279 222 179 112 24 1  
Rd 396 287 206 151 117 72 18 1  

0 6 12 18 24 30 36 42 48 

 KRd  Rd 
 

GRH0219EN v1 

1.0 

0.8 

0.6 

0.4 

0.2 

0.0 

 
Progression/Death, n (%) 207 (52.3%)  224 (56.6%) 
Median PFS, mo 26.3  17.6 
HR (KRd/Rd) (95% CI)  0.690 (0.570, 0.834)  
p-value (1-sided)  <.0001  

 

KRd (N=396) Rd (N=396) 



21 

Figure 2. Kaplan-Meier curve of overall survival in relapsed multiple myelomaa 
 

 
KRd = Kyprolis, lenalidomide and dexamethasone; Rd = lenalidomide and dexamethasone; OS = overall 
survival; HR = hazard ratio; CI = confidence interval; mo = months 
a. Study PX-171-009 
 
Patients treated with KRd reported improved Global Health Status, with higher Global Health 
Status/Quality of Life (QoL) scores compared with Rd over 18 cycles of treatment (multiplicity 
unadjusted 1-sided p-value = 0.0001) measured with the EORTC QLQ-C30, an instrument validated 
in multiple myeloma. 
 
Kyprolis in combination with dexamethasone for the treatment of patients with relapsed multiple 
myeloma – study 2011-003 (ENDEAVOR) 
 
The safety and efficacy of Kyprolis were evaluated in a phase 3, randomised, open-label, multicentre 
study of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd). A total of 
929 patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of 
therapy were enrolled and randomised (464 in the Kd arm; 465 in the Vd arm). 
 
This study evaluated Kyprolis at an initial dose of 20 mg/m2, which was increased to 56 mg/m2 on 
cycle 1, day 8, administered twice weekly for 3 out of 4 weeks as a 30 minute infusion until 
progression or unacceptable toxicity. 
 
Patients randomised to the Vd arm could receive bortezomib either by the intravenous (n = 108) or 
subcutaneous (n = 357) route. Patients who had the following were excluded from the study: creatinine 
clearance rates < 15 mL/min, NYHA Class III to IV congestive heart failure, myocardial infarction 
within the last 4 months or those with left ventricular ejection fraction (LVEF) < 40%. Study 
eligibility criteria allowed patients previously treated with carfilzomib (n = 3) or bortezomib (n = 502) 
to be enrolled as long as patients had at least a partial response (PR) to prior proteasome inhibitor 
therapy, were not removed from proteasome inhibitor therapy due to toxicity, and had at least a 
6-month proteasome inhibitor treatment-free interval from last dose. 
 
The demographics and baseline characteristics for study 2011-003 were well-balanced between the 
two arms, including prior treatment with bortezomib (54%), prior treatment with lenalidomide (38%), 
lenalidomide refractory (25%), age (65 years, range 30-89 years), gender (51% male), ECOG 
performance status (45% with performance status 1), high risk genetic mutations, consisting of the 
genetic subtypes t(4;14) or t(14;16) in 10% or more of screened plasma cells, or deletion 17p in ≥ 20% 

Number of Subjects at Risk: 

Months from Randomisation 

Pr
op

or
tio

n S
ur

viv
ing

 

KRd 396 369 343 316 282 259 232 211 190 166 149 88 22 0 
Rd 396 356 313 281 243 220 199 176 149 133 113 69 20 3 

0 6 12 18 24 30 36 42 48 54 60 66 72 78 

 KRd 
 Rd 

 

GR
H0

46
3v

1 

1.0 

0.8 

0.6 

0.4 

0.2 

0.0 

 

Death, n (%) 246 (62.1%) 267 (67.4%) 
Median OS, mo 48.3 40.4 
HR (KRd/Rd) (95% CI) 0.794 (0.667, 0.945)  
p-value (1-sided) 0.0045  

KRd (N=396) Rd (N=396) 



22 

of plasma cells (23%) unknown-risk genetic mutations, which included subjects with results not 
collected or not analysed (9%) and baseline ISS stage III disease (24%). 
 
The results of study 2011-003 are summarised in table 7. 
 
Table 7. Summary of efficacy analysis in relapsed multiple myeloma study 2011-003 
 

 

Kd Arm 
 

(N = 464) 

Vd Arm 
 

(N = 465) 
PFS months median (95% CI)a 18.7 (15.6, NE) 9.4 (8.4, 10.4) 

HR (95% CI); 1-sided p-valueb 0.533 (0.44, 0.65); < 0.0001 
Overall survival months median (95% CI) 47.6 (42.5, NE) 40.0 (32.6, 42.3)

HR (95% CI); 1-sided p-valueb 0.791 (0.65, 0.96); 0.010 
ORR n (%)a, c 357 (76.9) 291 (62.6) 

≥ CRd 58 (12.5) 29 (6.2) 
≥ VGPRe 252 (54.3) 133 (28.6) 

95% CI of ORR 72.8, 80.7 58.0, 67.0 
1-sided p-valueb < 0.0001

Kd = Kyprolis plus dexamethasone; Vd = bortezomib and dexamethasone; CI = confidence interval; 
NE = not estimable; HR = Hazard Ratio; ORR = overall response rate; CR = complete response; VGPR = very 
good partial response 
a. These endpoints were determined by an Independent Review Committee 
b. Statistically significant 
c. Overall response is defined as achieving a best overall response of PR, VGPR, CR, or sCR 
d. Statistically significant, 1-sided p-value = 0.0005 
e. Statistically significant, 1-sided p-value = 0.0001 
 
The study showed significant improvement in PFS for patients in the Kd arm over those in the Vd arm 
(HR: 0.53, 95% CI: 0.44, 0.65 [p-value < 0.0001]) (see figure 3). 
 
Similar PFS results were observed in patients who had received prior treatment with bortezomib 
(HR 0.56, 95% CI: 0.44, 0.73) and patients who had not received prior treatment with bortezomib 
(HR 0.48, 95% CI: 0.36, 0.66). 
 
The PFS benefit of Kd was consistently observed in all subgroups, including patients ≥ 75 years of age 
(n = 143), patients with high risk (n = 210) genetic mutations, and patients with baseline creatinine 
clearance of 30 - < 50 mL/min (n = 128). 
 
In patients who received prior bortezomib (54%), median PFS was 15.6 months in the Kd arm versus 
8.1 months in the Vd arm (HR = 0.56, 95% CI: 0.44, 0.73), ORR was 71.2% versus 60.3%. 
 
In patients who received prior lenalidomide (38%), median PFS was 12.9 months in the Kd arm versus 
7.3 months in the Vd arm (HR = 0.69, 95% CI: 0.52, 0.92), ORR was 70.1% versus 59.3%. In patients 
refractory to lenalidomide (25%), median PFS was 8.6 months in the Kd arm versus 6.6 months in the 
Vd arm (HR = 0.80, 95% CI: 0.57, 1.11), ORR was 61.9% versus 54.9%. 
 



23 

Figure 3. Kaplan-Meier plot of progression-free survival as determined by the IRC 
(intent-to-treat population) study 2011-003 

 
Kd = Kyprolis plus dexamethasone; Vd = bortezomib plus dexamethasone; PFS = progression-free survival; 
mo = months; HR = hazard ratio; CI = confidence interval 
 
A pre-planned second interim OS analysis was performed after 189 deaths in the Kd arm and 
209 deaths in the Vd arm. At the time of the analysis, 80% of the targeted events were registered. The 
median follow-up was approximately 37 months. A statistically significant advantage in OS was 
observed in patients in the Kd arm compared to patients in the Vd arm (HR = 0.791; 95% CI: 0.65, 
0.96; p-value = 0.010) (see figure 4). 
 
Figure 4. Kaplan-Meier curve of overall survival in relapsed multiple myeloma study 2011-003 
 

 
Kd = Kyprolis plus dexamethasone; Vd = bortezomib plus dexamethasone; OS = overall survival; mo = months; 
HR = hazard ratio; CI = confidence interval 
 

Number of subjects at risk: 

Months from Randomisation 

Pr
op

or
tio

n s
ur

viv
ing

 w
ith

ou
t p

ro
gr

es
sio

n 

Kd 464 331 144 41 4 0 
Vd 465 252 81 12 1 0 

 

0 6 12 18 24 30 

 Kd  Vd 

GRH0129 v2 

1.0 

0.8 

0.6 

0.4 

0.2 

0.0 

Progression/Death, n (%) 171 (36.9%) 243 (52.3%) 
Median PFS, mo 18.7 9.4 
HR (Kd/Vd) (95% CI) 0.533 (0.437, 0.651)  
p-value (1-sided)  <.0001  

Kd (N=464) Vd (N=465) 

GRH0131 v4 

Number of subjects at risk: 
Months from Randomisation 

Pr
op

or
tio

n s
ur

viv
ing

 

Kd 464 423 373 335 308 270 162 66 10 
Vd 465 402 351 293 256 228 140 39 5 

0 6 12 18 24 30 36 42 48 

 Kd (black) 
 Vd (grey) 

 

1.0 

0.8 

0.6 

0.4 

0.2 

0.0 

Death, n (%) 189 (40.7%) 209 (44.9%) 
Median OS, mo 47.6 40.0 
HR (Kd/Vd) (95% CI) 0.791 (0.648, 0.964)  
p-value (1-sided) 0.0100  

Kd (N=464) Vd (N=465) 



24 

Kyprolis monotherapy in patients with relapsed and refractory multiple myeloma 
 
Additional clinical experience has been generated with Kyprolis monotherapy in patients with relapsed 
and refractory multiple myeloma. Study PX-171-011 was an open-label randomised phase 3 study 
(N = 315; exposure to ≥ 3 prior therapies required). Patients enrolled to study PX-171-011 were more 
heavily pre-treated with lower organ and marrow function as compared to those enrolled in study 
PX-171-009. PX-171-011 evaluated Kyprolis monotherapy versus a control arm (corticosteroids and 
cyclophosphamide). The study did not meet its primary efficacy endpoint of demonstrating superiority 
of Kyprolis monotherapy over the active control arm in overall survival (HR = 0.975 
[95% CI: 0.760, 1.249]). PX-171-003A1 was a single-arm phase 2 study (N = 266; exposure to ≥ 2 
prior therapies required), which met its primary efficacy endpoint of IRC-assessed ORR (22.9%). 
 
Cardiac electrophysiology 
 
An evaluation of possible effects of carfilzomib on cardiac function was performed by analysing, via 
central blind reading, triplicate ECG in 154 subjects with advanced malignancies, including multiple 
myeloma. The effect of carfilzomib on cardiac repolarisation using the QT interval with Fridericia’s 
correction (QTcF interval) and the analysis of concentration-QTc relationships show no clear signal of 
any dose-related effect. The upper bound of one-sided 95% confidence interval (CI) for predicted 
effect on QTcF at Cmax was 4.8 msec. With Bazett’s correction (QTcB interval), the upper bound of 
one-sided 95% confidence interval (CI) for predicted effect on QTcB at Cmax was 5.9 msec. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Kyprolis in all subsets of the paediatric population in multiple myeloma (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
The Cmax and AUC following a 2 to 10 minute intravenous infusion of 27 mg/m2 was 4,232 ng/mL and 
379 ng•hr/mL, respectively. Following repeated doses of Kyprolis at 15 and 20 mg/m2, systemic 
exposure (AUC) and half-life were similar on days 1 and 15 or 16 of cycle 1, suggesting there was no 
systemic carfilzomib accumulation. At doses between 20 and 56 mg/m2, there was a dose-dependent 
increase in exposure. 
 
A 30 minute infusion resulted in a similar half-life and AUC, but 2- to 3-fold lower Cmax compared to 
that observed with a 2 to 10 minute infusion of the same dose. Following a 30 minute infusion of the 
56 mg/m2 dose, the AUC (948 ng•hr/mL) was approximately 2.5-fold that observed at the 27 mg/m2 
level, and Cmax (2,079 ng/mL) was lower compared to that of 27 mg/m2 over the 2 to 10 minute 
infusion. 
 
Distribution 
 
The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. When 
tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the 
concentration range of 0.4 to 4 micromolar. 
 



25 

Biotransformation 
 
Carfilzomib was rapidly and extensively metabolised. The predominant metabolites measured in 
human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and 
the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal 
pathways of metabolism. Cytochrome P450 mediated mechanisms played a minor role in overall 
carfilzomib metabolism. The metabolites have no known biologic activity. 
 
Elimination 
 
Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib was rapidly cleared from the 
systemic circulation with a half-life of ≤ 1 hour on day 1 of cycle 1. The systemic clearance ranged 
from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely 
cleared extrahepatically. Carfilzomib is eliminated primarily via metabolism with subsequent 
excretion of its metabolites in urine. 
 
Special populations 
 
Population pharmacokinetic analyses indicate there are no effects of age, gender or race on the 
pharmacokinetics of carfilzomib. 
 
Hepatic impairment 
 
A pharmacokinetic study evaluated 33 patients with relapsed or progressive advanced malignancies 
(solid tumours; n = 31 or haematologic malignancies; n = 2) who had normal hepatic function 
(bilirubin ≤ upper limit of normal [ULN]; aspartate aminotransferase [AST] ≤ ULN, n = 10), mild 
hepatic impairment (bilirubin > 1-1.5 × ULN or AST > ULN, but bilirubin ≤ ULN, n = 14), or 
moderate hepatic impairment (bilirubin > 1.5-3 × ULN; any AST, n = 9). The pharmacokinetics of 
carfilzomib has not been studied in patients with severe hepatic impairment (bilirubin > 3 × ULN and 
any AST). Kyprolis, as a single agent, was administered intravenously over 30 minutes at 20 mg/m2 on 
days 1 and 2 and at 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1. If tolerated, patients received 
56 mg/m2 starting in cycle 2. Baseline hepatic function status had no marked effect on the total 
systemic exposure (AUClast) of carfilzomib following single or repeat-dose administration (geometric 
mean ratio in AUClast at the 27 mg/m2 dose in cycle 1, day 16 for mild and moderate impairment 
versus normal hepatic function were 144.4% and 126.1%, respectively; and at the 56 mg/m2 dose in 
cycle 2, day 1 were 144.7% and 121.1%). However, in patients with mild or moderate baseline hepatic 
impairment, all of whom had solid tumours, there was a higher subject incidence of hepatic function 
abnormalities, ≥ grade 3 adverse events and serious adverse events compared with subjects with 
normal hepatic function (see section 4.2). 
 
Renal impairment 
 
The pharmacokinetics of carfilzomib was studied in two dedicated renal impairment studies. 
 
The first study was conducted in 50 multiple myeloma patients with normal renal function 
(CrCL > 80 mL/min, n = 12), mild (CrCL 50-80 mL/min, n = 12), moderate (CrCL 30-49 mL/min, 
n = 10), and severe (CrCL < 30 mL/min, n = 8) renal impairment, and patients on chronic dialysis 
(n = 8). Kyprolis, as a single agent, was administered intravenously over 2 to 10 minutes at doses up to 
20 mg/m2. Pharmacokinetic data were collected from patients following the 15 mg/m2 dose in cycle 1 
and the 20 mg/m2 dose in cycle 2. The second study was conducted in 23 relapsed multiple myeloma 
patients with creatinine clearance ≥ 75 mL/min (n = 13) and patients with end stage renal disease 
(ESRD) requiring dialysis (n = 10). Pharmacokinetic data were collected from patients following 
administration of a 27 mg/m2 dose as a 30 minute infusion on cycle 1, day 16 and the 56 mg/m2 dose 
on cycle 2, day 1. 
 
Results from both studies show that renal function status had no marked effect on the exposure of 
carfilzomib following single or repeat-dose administration. The geometric mean ratio in AUClast at the 



26 

15 mg/m2 dose cycle 1, day 1 for mild, moderate, severe renal impairment and chronic dialysis versus 
normal renal function were 124.36%, 111.07%, 84.73% and 121.72%, respectively. The geometric 
mean ratios in AUClast at the 27 mg/m2 dose cycle 1, day 16 and at the 56 mg/m2 dose cycle 2, day 1 
for ESRD versus normal renal function were 139.72% and 132.75%, respectively. In the first study the 
M14 metabolite, a peptide fragment and the most abundant circulating metabolite, increased 2- and 
3-fold in patients with moderate and severe renal impairment, respectively, and 7-fold in patients 
requiring dialysis (based on AUClast). In the second study, the exposures for M14 were greater 
(approximately 4-fold) in subjects with ESRD than in subjects with normal renal function. This 
metabolite has no known biological activities. Serious adverse events related to worsening renal 
function were more common in subjects with baseline renal dysfunction (see section 4.2). 
 
5.3 Preclinical safety data 
 
Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood 
lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and 
was not clastogenic in the in vivo mouse bone marrow micronucleus assay. 
 
Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (which corresponds 
to 36 mg/m2 and is similar to the recommended dose in humans of 27 mg/m2 based on BSA) 
experienced hypotension, increased heart rate, and increased serum levels of troponin T. The repeated 
bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in 
monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to 
toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid 
accumulation, cardiac haemorrhage/degeneration), gastrointestinal (necrosis/haemorrhage), renal 
(glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (haemorrhage/inflammation) 
systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 
27 mg/m2 based on BSA. The highest non-severely toxic dose of 0.5 mg/kg in monkeys resulted in 
interstitial inflammation in the kidney along with slight glomerulopathy and slight heart inflammation. 
Those findings were reported at 6 mg/m2 which are below the recommended dose in humans of 
27 mg/m2. 
 
Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were 
noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month 
monkey chronic toxicity studies. Carfilzomib caused embryo-foetal toxicity in pregnant rabbits at 
doses that were lower than in patients receiving the recommended dose. Carfilzomib administered to 
pregnant rats during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day, 
which is approximately half the recommended dose in humans of 27 mg/m2 based on BSA. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Betadex sulfobutyl ether sodium 
Anhydrous citric acid (E330) 
Sodium hydroxide (for pH adjustment) 
 
6.2 Incompatibilities 
 
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. 
 



27 

6.3 Shelf life 
 
Powder vial (unopened) 
 
3 years. 
 
Reconstituted solution 
 
Chemical and physical in-use stability of reconstituted solutions in the vial, syringe or intravenous bag 
has been demonstrated for 24 hours at 2°C - 8°C or for 4 hours at 25°C. The elapsed time from 
reconstitution to administration should not exceed 24 hours. 
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions are the responsibility of the user and should not be 
longer than 24 hours at 2°C – 8°C. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). 
Do not freeze. 
Store in the original carton in order to protect from light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Kyprolis 10 mg powder for solution for infusion 
10 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium 
seal with a light blue plastic flip off cap. 
 
Kyprolis 30 mg powder for solution for infusion 
30 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium 
seal with an orange plastic flip off cap. 
 
Kyprolis 60 mg powder for solution for infusion 
50 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium 
seal with a purple plastic flip off cap. 
 
Pack size of one vial. 
 
6.6 Special precautions for disposal and other handling 
 
General precautions 
 
Carfilzomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of 
Kyprolis. Use of gloves and other protective equipment is recommended. 
 
Reconstitution and preparation for intravenous administration 
 
Kyprolis vials contain no antimicrobial preservatives and are intended for single use only. Proper 
aseptic technique must be observed. 
 



28 

The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete 
preparation instructions prior to reconstitution: 
 
1. Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patient’s BSA at 

baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 
2.2 m2. Dose adjustments do not need to be made for weight changes of ≤ 20%. 

 
2. Remove vial from refrigerator just prior to use. 
 
3. Use only a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to 

aseptically reconstitute each vial by slowly injecting 5 mL (for 10 mg vial), 15 mL (for 30 mg 
vial) or 29 mL (for 60 mg vial) sterile water for injections through the stopper and directing the 
solution onto the INSIDE WALL OF THE VIAL to minimise foaming. 

 
4. Gently swirl and/or invert the vial slowly for approximately 1 minute, or until complete 

dissolution. DO NOT SHAKE. If foaming occurs, allow the solution to settle in the vial until 
foaming subsides (approximately 5 minutes) and the solution is clear. 

 
5. Visually inspect for particulate matter and discolouration prior to administration. The 

reconstituted product should be a clear, colourless to slightly yellow solution and should not be 
administered if any discolouration or particulate matter is observed. 

 
6. Discard any unused portion left in the vial. 
 
7. Kyprolis can be administered directly by intravenous infusion or optionally administered in an 

intravenous bag. Do not administer as an intravenous push or bolus. 
 
8. When administering in an intravenous bag, use only a 21-gauge or larger gauge needle (0.8 mm 

or smaller external diameter needle) to withdraw the calculated dose from the vial and dilute 
into a 50 or 100 mL intravenous bag containing 5% glucose solution for injection. 

 
Disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061 
4817 ZK Breda 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1060/002 
EU/1/15/1060/003 
EU/1/15/1060/001 
 
 



29 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 November 2015 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



31 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
Amgen Europe B.V. 
Minervum 7061 
4817 ZK Breda 
The Netherlands 
 
Amgen Technology (Ireland) Unlimited Company 
Pottery Road 
Dun Laoghaire 
Co Dublin 
Ireland 
 
Amgen NV 
Telecomlaan 5-7 
1831 Diegem 
Belgium 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A. LABELLING 



34 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kyprolis 10 mg powder for solution for infusion 
carfilzomib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 10 mg of carfilzomib. 
After reconstitution, 1 mL of solution contains 2 mg of carfilzomib. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Betadex sulfobutyl ether sodium, anhydrous citric acid (E330), sodium hydroxide. See 
leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion. 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use. 
Single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



35 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard unused portions in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1060/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



36 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kyprolis 10 mg powder for solution for infusion 
carfilzomib 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 mg 
 
 
6. OTHER 
 
 



37 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kyprolis 30 mg powder for solution for infusion 
carfilzomib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 30 mg of carfilzomib. 
After reconstitution, 1 mL of solution contains 2 mg of carfilzomib. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Betadex sulfobutyl ether sodium, anhydrous citric acid (E330), sodium hydroxide. See 
leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion. 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use. 
Single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



38 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard unused portions in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1060/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



39 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kyprolis 30 mg powder for solution for infusion 
carfilzomib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 30 mg of carfilzomib. 
After reconstitution, 1 mL of solution contains 2 mg of carfilzomib. 
 
 
3. LIST OF EXCIPIENTS 
 
Betadex sulfobutyl ether sodium, anhydrous citric acid (E330), sodium hydroxide. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use. 
Single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



40 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard unused portions in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1060/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 



41 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kyprolis 60 mg powder for solution for infusion 
carfilzomib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 60 mg of carfilzomib. 
After reconstitution, 1 mL of solution contains 2 mg of carfilzomib. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Betadex sulfobutyl ether sodium, anhydrous citric acid (E330), sodium hydroxide. See 
leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion. 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use. 
Single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



42 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard unused portions in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1060/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



43 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kyprolis 60 mg powder for solution for infusion 
carfilzomib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 60 mg of carfilzomib. 
After reconstitution, 1 mL of solution contains 2 mg of carfilzomib. 
 
 
3. LIST OF EXCIPIENTS 
 
Betadex sulfobutyl ether sodium, anhydrous citric acid (E330), sodium hydroxide. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use. 
Single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



44 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard unused portions in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Amgen Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1060/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 



45 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



46 

Package leaflet: Information for the patient 
 

Kyprolis 10 mg powder for solution for infusion 
Kyprolis 30 mg powder for solution for infusion 
Kyprolis 60 mg powder for solution for infusion 

carfilzomib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how 
to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Kyprolis is and what it is used for 
2. What you need to know before you use Kyprolis 
3. How to use Kyprolis 
4. Possible side effects 
5. How to store Kyprolis 
6. Contents of the pack and other information 
 
 
1. What Kyprolis is and what it is used for 
 
Kyprolis is a medicine that contains the active substance carfilzomib. 
 
Carfilzomib works by blocking the proteasome. The proteasome is a system within the cells that 
breaks down proteins when they are damaged or no longer needed. By preventing the breakdown of 
proteins in cancer cells, which are more likely to contain more abnormal proteins, Kyprolis causes the 
death of cancer cells. 
 
Kyprolis is used to treat adult patients with multiple myeloma who have had at least one previous 
treatment for this disease. Multiple myeloma is a cancer of plasma cells (a type of white blood cell). 
 
Kyprolis will be given to you together with lenalidomide and dexamethasone, or only with 
dexamethasone. Lenalidomide and dexamethasone are other medicines used to treat multiple 
myeloma. 
 
 
2. What you need to know before you use Kyprolis 
 
Your doctor will examine you and review your full medical history. You will be monitored closely 
during treatment. Before starting Kyprolis, and during treatment, you will undergo blood testing. This 
is to check that you have enough blood cells and your liver and kidneys are working properly. Your 
doctor or nurse will check if you are getting enough fluids. 
 
You must read the package leaflet of all medicines that you take in combination with Kyprolis so that 
you understand the information related to those medicines. 
 



47 

Do not use Kyprolis if you are allergic to carfilzomib or any of the other ingredients of this medicine 
(listed in section 6). 
 
Warnings and precautions 
 
Talk to your doctor or nurse before using Kyprolis if you have any of the conditions listed below. 
You may need extra tests to check that your heart, kidneys and liver are working properly. 
 
 Heart problems, including a history of chest pain (angina), heart attack, irregular heartbeat, high 

blood pressure or if you have ever taken a medicine for your heart 
 Lung problems, including a history of shortness of breath at rest or with activity (dyspnoea) 
 Kidney problems, including kidney failure or if you have ever received dialysis 
 Liver problems, including a history of hepatitis, fatty liver, or if you have ever been told your 

liver is not working properly 
 Unusual bleeding, including easy bruising, bleeding from an injury, such as a cut, that takes 

longer than expected to stop, or internal bleeding such as coughing up blood, vomiting up 
blood, dark tarry stools, or bright red blood in your stools; or bleeding in the brain leading to 
sudden numbness or paralysis on one side of the face, legs or arms, sudden severe headache or 
trouble seeing or difficulty speaking or swallowing. This can indicate you have low numbers of 
platelets (cells that help the blood to clot) 

 A history of blood clots in your veins 
 Leg or arm pain or swelling (which could be a symptom of blood clots in the deep veins of the 

leg or arm), chest pain or shortness of breath (which may be a symptom of blood clots in the 
lungs) 

 Any other major disease for which you were hospitalised or received any medicine. 
 
Conditions you need to look out for 
 
You must look out for certain symptoms while you are taking Kyprolis to reduce the risk of any 
problems. Kyprolis can make some conditions worse or cause serious side effects, which may be fatal, 
such as heart problems, lung problems, kidney problems, tumour lysis syndrome (a life-threatening 
condition that occurs when cancer cells break and release their content to the bloodstream), reactions 
to the Kyprolis infusion, unusual bruising or bleeding, (including internal bleeding), blood clots in 
your veins, liver problems, certain blood conditions, or a neurological condition known as PRES. See 
‘Conditions you need to look out for’ in section 4. 
 
Tell your doctor if you have ever had or might now have a hepatitis B infection. This is because this 
medicine could cause hepatitis B virus to become active again. Your doctor will check you for signs of 
this infection before, during and for some time after treatment with this medicine. Tell your doctor 
right away if you get worsening tiredness, or yellowing of your skin or white part of your eyes. 
 
At any time during or after your treatment, tell your doctor or nurse immediately if you: experience 
blurred, loss of or double vision, difficulty speaking, weakness in an arm or a leg, a change in the way 
you walk or problems with your balance, persistent numbness, decreased sensation or loss of 
sensation, memory loss or confusion. These may all be symptoms of a serious and potentially fatal 
brain condition known as Progressive Multifocal Leukoencephalopathy (PML). If you had these 
symptoms prior to treatment with carfilzomib, tell your doctor about any change in these symptoms. 
 
Other medicines and Kyprolis 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines. This 
includes any medicines obtained without a prescription, such as vitamins or herbal remedies. 
 
Tell your doctor or nurse if you are taking medicines used to prevent pregnancy such as oral 
contraceptives or other hormonal contraceptives, as these may not be suitable for use with Kyprolis. 
 



48 

Pregnancy and breast-feeding 
 
For women taking Kyprolis 
 
Do not take Kyprolis if you are pregnant, think you may be pregnant or are planning to have a baby. 
Treatment with Kyprolis has not been evaluated in pregnant women. While taking Kyprolis, and for 
30 days after stopping treatment you should use a suitable method of contraception to ensure you do 
not become pregnant. You should talk to your doctor or nurse about suitable methods of contraception. 
 
If you become pregnant while taking Kyprolis, notify your doctor or nurse immediately. 
 
Do not take Kyprolis if you are breast-feeding. It is not known if Kyprolis passes into breast milk in 
humans. 
 
Lenalidomide is expected to be harmful to the unborn child. As Kyprolis is given in combination with 
lenalidomide, you must follow the Pregnancy Prevention Programme (see package leaflet for 
lenalidomide for information on pregnancy prevention and discuss with your doctor, pharmacist or 
nurse). 
 
For men taking Kyprolis 
 
While taking Kyprolis and for 90 days after stopping treatment, you should use a condom even if your 
partner is pregnant. 
 
If your partner becomes pregnant whilst you are taking Kyprolis or within 90 days after stopping 
treatment, notify your doctor or nurse immediately. 
 
Driving and using machines 
 
While you are being treated with Kyprolis you may experience fatigue, dizziness, fainting, and/or a 
drop in blood pressure. This may impair your ability to drive or operate machines. Do not drive a car 
or operate machines if you have these symptoms. 
 
Kyprolis contains sodium 
 
This medicine contains 37 mg sodium per 10 mg vial. This is equivalent to 1.9% of the WHO 
recommended maximum daily intake of 2 g sodium for an adult. 
 
This medicine contains 109 mg sodium per 30 mg vial. This is equivalent to 5.5% of the WHO 
recommended maximum daily intake of 2 g sodium for an adult. 
 
This medicine contains 216 mg sodium per 60 mg vial. This is equivalent to 11% of the WHO 
recommended maximum daily intake of 2 g sodium for an adult. 
 
Kyprolis contains cyclodextrin 
 
This medicine contains 500 mg cyclodextrin (betadex sulfobutyl ether sodium) per 10 mg vial. This is 
equivalent to 88 mg/kg for a 70 kg adult. 
 
This medicine contains 1,500 mg cyclodextrin (betadex sulfobutyl ether sodium) per 30 mg vial. This 
is equivalent to 88 mg/kg for a 70 kg adult. 
 
This medicine contains 3,000 mg cyclodextrin (betadex sulfobutyl ether sodium) per 60 mg vial. This 
is equivalent to 88 mg/kg for a 70 kg adult. 
 
 



49 

3. How to use Kyprolis 
 
Kyprolis will be given to you by a doctor or nurse. The dose will be calculated based on your height 
and weight (body surface area). Your doctor or nurse will determine the dose of Kyprolis that you 
receive. 
 
Kyprolis will be given as an infusion into a vein. The infusion may last up to 30 minutes. Kyprolis is 
given 2 days in a row each week, for 3 weeks, followed by one week without treatment. 
 
Each 28-day period is one treatment cycle. This means that Kyprolis will be given to you on days 1, 2, 
8, 9, 15, and 16 of each 28-day cycle. The doses on day 8 and 9 of each cycle will not be given from 
cycle 13 onwards if you are treated with Kyprolis in combination with lenalidomide and 
dexamethasone. 
 
Most patients will receive treatment for as long as their disease improves or remains stable. However, 
Kyprolis treatment may also be stopped if you experience side effects that cannot be managed. 
 
Together with Kyprolis you will also be given either lenalidomide and dexamethasone, or only 
dexamethasone. You may also be given other medicines. 
 
If you are given too much Kyprolis 
 
As this medicine is being given by a doctor or nurse, it is unlikely that you will be given too much. 
However, if you are given too much Kyprolis your doctor will monitor you for side effects. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Conditions you need to look out for 
 
Some side effects could be serious. Tell your doctor straight away if you get notice any of the 
following symptoms: 
 
 Chest pains, shortness of breath, or if there is swelling of your feet, which may be symptoms of 

heart problems 
 Difficulty breathing, including shortness of breath at rest or with activity or a cough (dyspnoea), 

rapid breathing, feeling like you can't breathe in enough air, wheezing, or cough, which can be 
signs of lung toxicity 

 Very high blood pressure, severe chest pain, severe headache, confusion, blurred vision, nausea 
and vomiting, or severe anxiety, which may be signs of a condition known as hypertensive crisis 

 Shortness of breath with everyday activities or at rest, irregular heartbeat, racing pulse, 
tiredness, dizziness, and fainting spells, which can be signs of a condition known as pulmonary 
hypertension 

 Swollen ankles, feet or hands, loss of appetite, passing less urine, or abnormal blood test results, 
which may be symptoms of kidney problems or kidney failure 

 A side effect called tumour lysis syndrome, which can be caused by the rapid breakdown of 
tumour cells and may cause irregular heartbeat, kidney failure or abnormal blood test results 

 Fever, chills or shaking, joint pain, muscle pain, facial flushing, or swelling of the face, lips, 
tongue and/or throat which may cause difficulty breathing or swallowing (angioedema), 
weakness, shortness of breath, low blood pressure, fainting, chest tightness, or chest pain can 
occur as a reaction to the infusion 

 Unusual bruising or bleeding, such as a cut, that takes longer than usual to stop bleeding; or 
internal bleeding such as coughing up blood, vomiting up blood, dark tarry stools, or bright red 



50 

blood in your stools; or bleeding in the brain leading to sudden numbness or paralysis on one 
side of the face, legs or arms, sudden severe headache or trouble seeing or difficulty speaking or 
swallowing 

 Leg or arm pain or swelling (which could be a symptom of blood clots in the deep veins of the 
leg or arm), chest pain or shortness of breath (which may be a symptom of blood clots in the 
lungs) 

 Yellowing of your skin and eyes (jaundice), abdominal pain or swelling, nausea or vomiting, 
which could be symptoms of liver problems including liver failure. If you have ever had 
hepatitis B infection, treatment with this medicine may cause the hepatitis B infection to 
become active again 

 Bleeding, bruising, weakness, confusion, fever, nausea, vomiting and diarrhoea, and acute 
kidney failure, which may be signs of a blood condition known as thrombotic microangiopathy 

 Headaches, confusion, seizures (fits), visual loss, and high blood pressure (hypertension), which 
may be symptoms of a neurologic condition known as posterior reversible encephalopathy 
syndrome (PRES). 

 
Other possible side effects 
 
Very common side effects (may affect more than 1 in 10 people) 
 Serious lung infection (pneumonia) 
 Respiratory tract infection (infection of the airways) 
 Low platelets, which may cause easy bruising or bleeding (thrombocytopenia) 
 Low white blood cell count, which may decrease your ability to fight infection and may be 

associated with fever 
 Low red blood cell count (anaemia) which may cause tiredness and fatigue 
 Changes to blood tests (decreased blood levels of potassium, increased blood levels of sugar 

and/or creatinine) 
 Decreased appetite 
 Difficulty sleeping (insomnia) 
 Headache 
 Numbness, tingling, or decreased sensation in hands and/or feet 
 Dizziness 
 High blood pressure (hypertension) 
 Shortness of breath 
 Cough 
 Diarrhoea 
 Nausea 
 Constipation 
 Vomiting 
 Stomach pain 
 Back pain 
 Joint pain 
 Pain in limbs, hands or feet 
 Muscle spasms 
 Fever 
 Chills 
 Swelling of the hands, feet or ankles 
 Feeling weak 
 Tiredness (fatigue) 
 
Common side effects (may affect up to 1 in 10 people) 
 Infusion reaction 
 Heart failure and heart problems including rapid, strong or irregular heartbeat 
 Heart attack 
 Kidney problems, including kidney failure 



51 

 Blood clots in the veins (deep vein thrombosis) 
 Feeling too hot 
 Blood clot in the lungs 
 Fluid in the lungs 
 Wheezing 
 Serious infection including infection in the blood (sepsis) 
 Lung infection 
 Liver problems including an increase in liver enzymes in the blood 
 Flu-like symptoms (influenza) 
 Reactivation of the chicken pox virus (shingles) that can cause a skin rash and pain (herpes 

zoster) 
 Urinary tract infection (infection of structures that carry urine) 
 Cough which could include chest tightness or pain, nasal congestion (bronchitis) 
 Sore throat 
 Inflammation of the nose and throat 
 Runny nose, nasal congestion or sneezing 
 Viral infection 
 Infection of the stomach and intestine (gastroenteritis) 
 Bleeding in the stomach and bowels 
 Changes to blood tests (decreased blood levels of sodium, magnesium, protein, calcium or 

phosphate, increased blood levels of calcium, uric acid, potassium, bilirubin or c-reactive 
protein) 

 Dehydration 
 Anxiety 
 Feeling confused 
 Blurred vision 
 Cataract 
 Low blood pressure (hypotension) 
 Nose bleed 
 Change in voice or hoarseness 
 Indigestion 
 Toothache 
 Rash 
 Bone pain, muscle pain, chest pain 
 Muscle weakness 
 Aching muscles 
 Itchy skin 
 Redness of the skin 
 Increased sweating 
 Pain 
 Pain, swelling, irritation or discomfort where you received the injection into your vein 
 Ringing in the ears (tinnitus) 
 A general feeling of illness or discomfort 
 
 
Uncommon side effects (may affect up to 1 in 100 people) 
 Bleeding in the lungs 
 Inflammation of the colon caused by a bacteria called Clostridium difficile 
 Allergic reaction to Kyprolis 
 Multi-organ failure 
 Reduced blood flow to the heart 
 Bleeding in the brain 
 Stroke 



52 

 Difficulty breathing, rapid breathing and/or fingertips and lips looking slightly blue (acute 
respiratory distress syndrome) 

 Swelling of the lining of the heart (pericarditis), symptoms include pain behind the breast bone, 
sometimes spreading across to the neck and shoulders, sometimes with a fever 

 Fluid build-up in the lining of the heart (pericardial effusion), symptoms include chest pain or 
pressure and shortness of breath 

 A blockage in the flow of bile from the liver (cholestasis), which can cause itchy skin, yellow 
skin, very dark urine and very pale stools 

 Perforation of the digestive system 
 Cytomegalovirus infection 
 Hepatitis B infection activated again (viral inflammation of the liver) 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Kyprolis 
 
Kyprolis will be stored in the pharmacy. 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Kyprolis after the expiry date printed on the vial and the carton. The expiry date refers to 
the last day of that month. 
 
Store refrigerated (2°C - 8°C). 
Do not freeze. 
Store in the original carton in order to protect from light. 
 
The reconstituted product should be a clear, colourless to slightly yellow solution and should not be 
administered if any discolouration or particulate matter is observed. 
 
Kyprolis is for single use only. Any unused product or waste material should be disposed of in 
accordance with local requirements. 
 
 
6. Contents of the pack and other information 
 
What Kyprolis contains 
 
- The active substance is carfilzomib. Each vial contains 10 mg, 30 mg or 60 mg of carfilzomib. 

After reconstitution, 1 mL of solution contains 2 mg of carfilzomib. 
- The other ingredients are betadex sulfobutyl ether sodium, anhydrous citric acid (E330) and 

sodium hydroxide (see section 2 ‘Kyprolis contains sodium’). 
 
What Kyprolis looks like and contents of the pack 
 
Kyprolis is supplied in a glass vial as a white to off-white powder for solution for infusion, which is 
reconstituted (dissolved) before use. The reconstituted solution is a clear, colourless or slightly yellow 
solution. 
 
Each pack contains 1 vial. 
 



53 

Marketing Authorisation Holder and Manufacturer 
Amgen Europe B.V. 
Minervum 7061, 
4817 ZK Breda, 
The Netherlands 
 
Marketing Authorisation Holder 
Amgen Europe B.V. 
Minervum 7061 
4817 ZK Breda 
The Netherlands 
 
Manufacturer 
Amgen Technology (Ireland) Unlimited Company 
Pottery Road 
Dun Laoghaire 
Co Dublin 
Ireland 
 
Manufacturer 
Amgen NV 
Telecomlaan 5-7 
1831 Diegem 
Belgium 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
s.a. Amgen n.v. 
Tel/Tél: +32 (0)2 7752711 
 

Lietuva 
Amgen Switzerland AG Vilniaus filialas 
Tel: +370 5 219 7474  

България 
Амджен България ЕООД 
Тел.: +359 (0)2 424 7440  

Luxembourg/Luxemburg 
s.a. Amgen 
Belgique/Belgien 
Tel/Tél: +32 (0)2 7752711 

Česká republika 
Amgen s.r.o. 
Tel: +420 221 773 500  

Magyarország 
Amgen Kft. 
Tel.: +36 1 35 44 700  

Danmark 
Amgen, filial af Amgen AB, Sverige 
Tlf: +45 39617500 
 

Malta 
Amgen B.V. 
The Netherlands 
Tel: +31 (0)76 5732500 
 

Deutschland 
AMGEN GmbH 
Tel.: +49 89 1490960 
 

Nederland 
Amgen B.V. 
Tel: +31 (0)76 5732500 

Eesti 
Amgen Switzerland AG Vilniaus filialas 
Tel: +372 586 09553  

Norge 
Amgen AB 
Tel: +47 23308000 



54 

Ελλάδα 
Amgen Ελλάς Φαρμακευτικά Ε.Π.Ε. 
Τηλ.: +30 210 3447000 
 

Österreich 
Amgen GmbH 
Tel: +43 (0)1 50 217 
 

España 
Amgen S.A. 
Tel: +34 93 600 18 60 
 

Polska 
Amgen Biotechnologia Sp. z o.o. 
Tel.: +48 22 581 3000 

France 
Amgen S.A.S. 
Tél: +33 (0)9 69 363 363   

Portugal 
Amgen Biofarmacêutica, Lda. 
Tel: +351 21 4220606 

Hrvatska 
Amgen d.o.o. 
Tel: +385 (0)1 562 57 20  

România 
Amgen România SRL 
Tel: +4021 527 3000 

Ireland 
Amgen Ireland Limited 
Tel: +353 1 8527400 
 

Slovenija 
AMGEN zdravila d.o.o. 
Tel: +386 (0)1 585 1767 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
Amgen Slovakia s.r.o. 
Tel: +421 2 321 114 49 

Italia 
Amgen S.r.l. 
Tel: +39 02 6241121  

Suomi/Finland 
Amgen AB, sivuliike Suomessa/Amgen AB, filial 
i Finland 
Puh/Tel: +358 (0)9 54900500 
 

Kύπρος 
C.A. Papaellinas Ltd 
Τηλ.: +357 22741 741  

Sverige 
Amgen AB 
Tel: +46 (0)8 6951100 

Latvija 
Amgen Switzerland AG Rīgas filiāle 
Tel: +371 257 25888 
 

United Kingdom 
Amgen Limited 
Tel: +44 (0)1223 420305  

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 



55 

--------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Instructions for reconstitution and preparation of Kyprolis powder for solution for infusion for 
intravenous administration 
 
Carfilzomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of 
Kyprolis. Use of gloves and other protective equipment is recommended. 
 
Kyprolis vials contain no antimicrobial preservatives and are intended for single use only. Proper 
aseptic technique must be observed. 
 
The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete 
preparation instructions prior to reconstitution: 
 
1. Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patient’s BSA at 

baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 
2.2 m2. Dose adjustments do not need to be made for weight changes of ≤ 20%. 

 
2. Remove vial from refrigerator just prior to use. 
 
3. Use only a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to 

aseptically reconstitute each vial by slowly injecting 5 mL (for 10 mg vial), 15 mL (for 30 mg 
vial) or 29 mL (for 60 mg vial) sterile water for injections through the stopper and directing the 
solution onto the INSIDE WALL OF THE VIAL to minimise foaming. 

 
4. Gently swirl and/or invert the vial slowly for approximately 1 minute, or until complete 

dissolution. DO NOT SHAKE. If foaming occurs, allow the solution to settle in the vial until 
foaming subsides (approximately 5 minutes) and the solution is clear. 

 
5. Visually inspect for particulate matter and discolouration prior to administration. The 

reconstituted product should be a clear, colourless to slightly yellow solution and should not be 
administered if any discolouration or particulate matter is observed. 

 
6. Discard any unused portion left in the vial. 
 
7. Kyprolis can be administered directly by intravenous infusion or optionally administered in an 

intravenous bag. Do not administer as an intravenous push or bolus. 
 
8. When administering in an intravenous bag, use only a 21-gauge or larger gauge needle (0.8 mm 

or smaller external diameter needle) to withdraw the calculated dose from the vial and dilute 
into a 50 or 100 mL intravenous bag containing 5% glucose solution for injection. 

 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions are the responsibility of the user and should not be 
longer than 24 hours at 2°C – 8°C. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET