KYPROLIS 60mg powder infusion solution medication leaflet

Kyprolis 10 mg powder for solution for infusion

Kyprolis 30 mg powder for solution for infusion

Kyprolis 60 mg powder for solution for infusion

Kyprolis 10 mg powder for solution for infusion

Each vial contains 10 mg of carfilzomib.

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.

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.

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.

Powder for solution for infusion.

White to off-white lyophilised powder.

Kyprolis in combination with daratumumab and dexamethasone, with lenalidomide anddexamethasone, or with dexamethasone alone is indicated for the treatment of adult patients withmultiple myeloma who have received at least one prior therapy (see section 5.1).

Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy.

The dose is calculated using the patient’s baseline body surface area (BSA). Patients with a BSAgreater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not needto 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 a10 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 consideredone treatment cycle.

Kyprolis is administered at a starting dose of 20 mg/m2 (maximum dose 44 mg) in cycle 1 on days 1and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 27 mg/m2 (maximum dose60 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 cyclesshould be based on an individual benefit/risk assessment, as the data on the tolerability and toxicity ofcarfilzomib beyond 18 cycles are limited (see section 5.1).

In combination with Kyprolis, lenalidomide is administered as 25 mg orally on days 1-21 anddexamethasone is administered as 40 mg orally or intravenously on days 1, 8, 15, and 22 of the 28-daycycles. Appropriate dose reduction for the starting dose of lenalidomide should be consideredaccording to the recommendations in the current lenalidomide summary of product characteristics, forexample for patients with baseline renal impairment. Dexamethasone should be administered30 minutes to 4 hours before Kyprolis.

Table 1. Kyprolis in combination with lenalidomide and dexamethasone

Cycle 1

Week 1 Week 2 Week 3 Week 4

Day Days Day Day Days Day Day Days Day Days

Day 1 2 3-7 8 9 10-14 15 16 17-21 22 23-28

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

Dexamethasone40 - - 40 - - 40 - - 40 -(mg)

Lenalidomide 25 mg daily - -

Cycles 2-12

Week 1 Week 2 Week 3 Week 4

Day Days Day Day Days Day Day Days Day Days

Day 1 2 3-7 8 9 10-14 15 16 17-21 22 23-28

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

Dexamethasone40 - - 40 - - 40 - - 40 -(mg)

Lenalidomide 25 mg daily - -

Cycles 13 on

Week 1 Week 2 Week 3 Week 4

Day Days Day Day Days Day Day Days Day Days

Day 1 2 3-7 8 9 10-14 15 16 17-21 22 23-28

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

Dexamethasone40 - - 40 - - 40 - - 40 -(mg)

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 infusionon two consecutive days, each week for three weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-dayrest 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 1and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 56 mg/m2 (maximum dose123 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 mgorally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycles. Dexamethasoneshould be administered 30 minutes to 4 hours before Kyprolis.

Table 2. Kyprolis in combination with dexamethasone alone

Cycle 1

Week 1 Week 2 Week 3 Week 4

Day Day Days Days Day Days Day Day Days1 2 3-7 Day 8 Day 9 10-14 Day 15 16 17-21 22 23 24-28

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

Dexamethasone20 20 - 20 20 - 20 20 - 20 20 -(mg)

Cycle 2 and all subsequent cycles

Week 1 Week 2 Week 3 Week 4

Day Day Days Days Day Day Days Day Day Days1 2 3-7 Day 8 Day 9 10-14 15 16 17-21 22 23 24-28

Kyprolis2 a 56 56 - 56 56 - 56 56 - - - -(mg/m )

Dexamethasone20 20 - 20 20 - 20 20 - 20 20 -(mg)

a. Infusion time is 30 minutes and remains consistent throughout the regimen

Kyprolis in combination with daratumumab and dexamethasone

When combined with daratumumab and dexamethasone, Kyprolis is administered intravenously as a30-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 3. Each 28-day period is consideredone treatment cycle.

Kyprolis is administered at a starting dose of 20 mg/m2 (maximum dose 44 mg) in cycle 1 on days 1and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 56 mg/m2 (maximum dose123 mg).

Treatment may be continued until disease progression or until unacceptable toxicity occurs.

Dexamethasone is administered as 20 mg orally or intravenously on days 1, 2, 8, 9, 15 and 16 and40 mg orally or intravenously on day 22 of each 28 day cycle. For patients > 75 years of age,administer 20 mg of dexamethasone orally or intravenously weekly after the first week.

Dexamethasone should be administered 30 minutes to 4 hours before Kyprolis.

Daratumumab can be administered intravenously or subcutaneously.

If given intravenously, daratumumab is given at a dose of 16 mg/kg actual body weight; with a splitdose of 8 mg/kg in cycle 1 on days 1 and 2. Afterwards, daratumumab is administered as 16 mg/kgonce weekly on days 8, 15 and 22 of cycle 1 and days 1, 8, 15 and 22 of cycle 2, then every 2 weeksfor 4 cycles (cycles 3 to 6) and then every 4 weeks for the remaining cycles or until diseaseprogression.

Alternatively, daratumumab can be given subcutaneously at a dose of 1800 mg on days 1, 8, 15 and 22of cycle 1 and days 1, 8, 15 and 22 of cycle 2, then every 2 weeks for 4 cycles (cycles 3 to 6) and thenevery 4 weeks for the remaining cycles or until disease progression.

Refer to the daratumumab summary of product characteristics for additional information regarding theuse of the subcutaneous formulation.

On days when more than one of these medicines is administered, the recommended order ofadministration is as follows: dexamethasone, pre-infusion medications for daratumumab (see section

Concomitant medicinal products), carfilzomib, daratumumab, and post-infusion medications fordaratumumab (see section Concomitant medicinal products).

Refer to the daratumumab and dexamethasone summary of product characteristics for additionaldetails on administration.

Table 3. Kyprolis in combination with dexamethasone and daratumumab

Cycle 1

Week 1 Week 2 Week 3 Week 4

Day Day Days Day Day Days Day Day Days Day Day Days1 2 3-7 8 9 10-14 15 16 17-21 22 23 24-28

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

Dexamethasoneb 20 20 - 20 20 - 20 20 - 40 - -(mg)

Daratumumab (Intravenous OR Subcutaneous)

IV administration8 8 - 16 - - 16 - - 16 - -(mg/kg)

SCadministration 1800 - - 1800 - - 1800 - - 1800 - -(mg)

Cycle 2

Week 1 Week 2 Week 3 Week 4

Day Day Days Day Day Days Day Day Days Day Day Days1 2 3-7 8 9 10-14 15 16 17-21 22 23 24-28

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

Dexamethasoneb 20 20 - 20 20 - 20 20 - 40 - -(mg)

Daratumumab (Intravenous OR Subcutaneous)

IV administration16 - - 16 - - 16 - - 16 - -(mg/kg)

SCadministration 1800 - - 1800 - - 1800 - - 1800 - -(mg)

Cycles 3-6

Week 1 Week 2 Week 3 Week 4

Day Day Days Day Day Days Day Day Days Day Day Days1 2 3-7 8 9 10-14 15 16 17-21 22 23 24-28

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

Dexamethasoneb 20 20 - 20 20 - 20 20 - 40 - -(mg)

Daratumumab (Intravenous OR Subcutaneous)

IV administration16 - - - - - 16 - - - - -(mg/kg)

SCadministration 1800 - - - - - 1800 - - - - -(mg)

Cycles 7 and all subsequent cycles

Week 1 Week 2 Week 3 Week 4

Day Day Days Day Day Days Day Day Days Day Day Days1 2 3-7 8 9 10-14 15 16 17-21 22 23 24-28

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

Dexamethasoneb 20 20 - 20 20 - 20 20 - 40 - -(mg)

Daratumumab (Intravenous OR Subcutaneous)

IV administration16 - - - - - - - - - - -(mg/kg)

SCadministration 1800 - - - - - - - - - - -(mg)

a. Infusion time is 30 minutes and remains consistent throughout the regimen

b. For patients > 75 years of age, dexamethasone is administered as 20 mg orally or intravenously weekly afterthe first week.

Antiviral prophylaxis should be considered in patients being treated with Kyprolis to decrease the riskof herpes zoster reactivation (see section 4.8).

Thromboprophylaxis is recommended in patients being treated with Kyprolis in combination withdaratumumab and dexamethasone, with lenalidomide and dexamethasone, or with dexamethasonealone and should be based on an assessment of the patient’s underlying risks and clinical status. Forother concomitant medicinal products that may be required, such as the use of antacid prophylaxis,refer to the current lenalidomide and dexamethasone summary of product characteristics.

In patients being treated with Kyprolis in combination with daratumumab and dexamethasone, pre-infusion medications should be administered to reduce the risk of infusion-related reactions withdaratumumab.

Refer to the daratumumab summary of product characteristics for additional details on concomitantmedications including pre and post-infusion medications.

Hydration, fluid and electrolyte monitoring

Adequate hydration is required before dose administration in cycle 1, especially in patients at high riskof tumour lysis syndrome or renal toxicity. All patients should be monitored for evidence of volumeoverload and fluid requirements should be tailored to individual patient needs. The total volume offluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at riskfor 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 incycle 1). Give an additional 250 mL to 500 mL of intravenous fluids as needed following Kyprolisadministration in cycle 1. Oral and/or intravenous hydration should be continued, as needed, insubsequent cycles.

When given in combination with intravenous daratumumab, oral and/or intravenous hydration is notrequired on days when intravenous daratumumab is dosed.

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 oftreatment, concomitant therapy used (e.g. medicinal products known to increase the risk ofhypokalaemia) and associated comorbidities.

Recommended dose modifications

Dosing should be modified based on Kyprolis toxicity. Recommended actions and dose modificationsare presented in table 4. Dose level reductions are presented in table 5.

Table 4. Dose modifications during Kyprolis treatment

Haematologic toxicity Recommended action

* Absolute neutrophil count * Stop dose< 0.5 × 109/L (see section 4.4) - If recovered to ≥ 0.5 × 109/L, continue at same doselevel

* For subsequent drops to < 0.5 × 109/L, follow the samerecommendations as above and consider 1 dose levelreduction when restarting Kyprolisa

* Febrile neutropenia * Stop dose

* Absolute neutrophil count * If absolute neutrophil count returns to baseline grade and< 0.5 × 109/L and an oral fever resolves, resume at the same dose leveltemperature > 38.5°C or twoconsecutive readings of > 38.0°C

for 2 hours

* Platelet count < 10 × 109/L or * Stop doseevidence of bleeding with - If recovered to ≥ 10 × 109/L and/or bleeding isthrombocytopenia (see controlled continue at same dose levelsection 4.4) * For subsequent drops to < 10 × 109/L, follow the samerecommendations as above and consider 1 dose levelreduction when restarting Kyprolisa

Non-haematologic toxicity (renal) Recommended action

* Serum creatinine equal to or * Stop dose and continue monitoring renal function (serumgreater than 2 × baseline; or creatinine or creatinine clearance)

* Creatinine clearance < 15 mL/min - Kyprolis should be resumed when renal function has(or creatinine clearance decreases recovered to within 25% of baseline; considerto ≤ 50% of baseline) or need for resuming at 1 dose level reductionadialysis (see section 4.4) * For patients on dialysis receiving Kyprolis, the dose is to beadministered after the dialysis procedure

Other non-haematologic toxicity Recommended action

* All other grade 3 or 4 * Stop until resolved or returned to baselinenon-haematologic toxicities * Consider restarting the next scheduled treatment at 1 dose(see section 4.4) level reductiona

a. See table 5 for dose level reductions

Table 5. Dose level reductions for Kyprolis

First Kyprolis Second Kyprolis Third Kyprolis

Regimen Kyprolis Dose dose reduction dose reduction dose reduction

Kyprolis, lenalidomide, and27 mg/m2 20 mg/m2 15 mg/m2 a —dexamethasone

Kyprolis and56 mg/m2 45 mg/m2 36 mg/m2 27 mg/m2 adexamethasone

Kyprolis, daratumumab and56 mg/m2 45 mg/m2 36 mg/m2 27 mg/m2 adexamethasone

Note: Kyprolis infusion times remain unchanged during dose reduction(s)

a. If symptoms do not resolve, discontinue Kyprolis treatment

Patients with moderate or severe renal impairment were enrolled in Kyprolis-dexamethasonecombination studies, but were excluded from Kyprolis-lenalidomide combination studies. Thus, thereare limited data for Kyprolis in combination with lenalidomide and dexamethasone in patients withcreatinine clearance (CrCL < 50 mL/min). Appropriate dose reduction for the starting dose oflenalidomide in patients with baseline renal impairment should be considered according to therecommendations in the lenalidomide summary of product characteristics.

No starting dose adjustment for Kyprolis is recommended in patients with baseline mild, moderate, orsevere renal impairment or patients on chronic dialysis based on available pharmacokinetic data (seesection 5.2). However, in phase 3 clinical studies, the incidence of adverse events of acute renal failurewas higher in patients with lower baseline creatinine clearance than that among patients with higherbaseline creatinine clearance.

Renal function should be assessed at treatment initiation and monitored at least monthly or inaccordance with accepted clinical practice guidelines, particularly in patients with lower baselinecreatinine clearance (CrCL < 30 mL/min). Appropriate dose modifications based on toxicity should bemade (see table 4). There are limited efficacy and safety data on patients with baseline creatinineclearance < 30 mL/min.

Since dialysis clearance of Kyprolis concentrations has not been studied, the medicinal product shouldbe administered after the dialysis procedure.

Patients with moderate or severe hepatic impairment were excluded from Kyprolis studies incombination 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 impairmentbased on available pharmacokinetic data. However, higher subject incidence of hepatic functionabnormalities, ≥ grade 3 adverse events and serious adverse events have been reported in patients withmild 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 andmonitored monthly during treatment with carfilzomib, regardless of baseline values, and appropriatedose modifications based on toxicity should be made (see table 4). Special attention should be paid topatients with moderate and severe hepatic impairment in view of the very limited efficacy and safetydata on this population.

Overall, the subject incidence of certain adverse events (including cardiac failure) in clinical studieswas higher for patients who were ≥ 75 years of age compared to patients who were < 75 years of age(see section 4.4).

The safety and efficacy of Kyprolis in paediatric patients have not been established. No data areavailable.

Kyprolis is to be administered by intravenous infusion. The 20/27 mg/m2 dose is administered over10 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 or5% 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.

* 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 ofproduct characteristics for additional contraindications.

As Kyprolis is administered in combination with other medicinal products, the summary of productcharacteristics 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 thelenalidomide pregnancy testing and prevention requirements is needed (see section 4.6).

New or worsening cardiac failure (e.g. congestive cardiac failure, pulmonary oedema, decreasedejection 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 fataloutcomes have been reported with cardiac failure and myocardial infarction. For potential dose-relatedeffects, see section 4.8.

While adequate hydration is required prior to dosing in cycle 1, all patients should be monitored forevidence of volume overload, especially patients at risk for cardiac failure. The total volume of fluidsmay be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk forcardiac failure (see section 4.2).

Stop Kyprolis for grade 3 or 4 cardiac events until recovery and consider whether to restart Kyprolis at1 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 isalso 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 myocardialinfarction, and conduction abnormalities uncontrolled by medicinal products were not eligible for theclinical studies. These patients may be at greater risk for cardiac complications. Patients with signs orsymptoms of NYHA Class III or IV cardiac failure, recent history of myocardial infarction (in the last4 months), and in patients with uncontrolled angina or arrhythmias, should have a comprehensivecardiological assessment, prior to starting treatment with Kyprolis. This assessment should optimisethe 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 and post-marketing.

Cases of ventricular tachycardia have been reported in patients receiving Kyprolis.

Acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrativepulmonary disease such as pneumonitis and interstitial lung disease have occurred in patientsreceiving Kyprolis. Some of these events have been fatal. Evaluate and stop Kyprolis until resolvedand consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2).

Pulmonary hypertension has been reported in patients treated with Kyprolis. Some of these eventshave been fatal. Evaluate as appropriate. Stop Kyprolis for pulmonary hypertension until resolved orreturned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (seesection 4.2).

Dyspnoea was commonly reported in patients treated with Kyprolis. Evaluate dyspnoea to excludecardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis forgrade 3 and 4 dyspnoea until resolved or returned to baseline and consider whether to restart Kyprolisbased on a benefit/risk assessment (see sections 4.2 and 4.8).

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with

Kyprolis. Some of these events have been fatal. Hypertension was reported more frequently in patientswho received Kyprolis in combination with daratumumab in study 20160275. It is recommended tocontrol hypertension prior to starting and during treatment. All patients should be routinely evaluatedfor 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 orreturned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (seesection 4.2).

Cases of acute renal failure have been reported in patients who received Kyprolis. Some of theseevents have been fatal. Acute renal failure was reported more frequently in patients with advancedrelapsed and refractory multiple myeloma who received Kyprolis monotherapy. In phase 3 clinicalstudies the incidence of adverse events of acute renal failure was higher in subjects with lowerbaseline creatinine clearance than that among subjects with higher baseline creatinineclearance. Creatinine clearance was stable over time for the majority of patients. Renal function shouldbe monitored at least monthly or in accordance with accepted clinical practice guidelines, particularlyin patients with lower baseline creatinine clearance. Reduce or stop dose as appropriate (seesection 4.2).

Cases of tumour lysis syndrome (TLS), including with fatal outcome, have been reported in patientswho received Kyprolis. Patients with a high tumour burden should be considered to be at greater riskfor TLS. Ensure that patients are well hydrated before administration of Kyprolis in cycle 1, and insubsequent cycles as needed (see section 4.2). Uric acid lowering medicinal products should beconsidered in patients at high risk for TLS. Evidence of TLS during treatment should be monitoredfor, 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, bradycardia, chest tightness, orangina. 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 andseverity of reactions (see section 4.2).

Haemorrhage and thrombocytopenia

Cases of haemorrhage (e.g. gastrointestinal, pulmonary and intracranial haemorrhage) have beenreported in patients treated with Kyprolis, often associated with thrombocytopenia. Some of theseevents have been fatal (see section 4.8).

Kyprolis causes thrombocytopenia with platelet nadirs observed on day 8 or day 15 of each 28-daycycle with recovery to baseline platelet count by the start of the next cycle (see section 4.8). Plateletcounts should be monitored frequently during treatment with Kyprolis. Reduce or stop dose asappropriate (see section 4.2).

Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolismwith fatal outcomes, have been reported in patients who received Kyprolis.

Patients with known risk factors for thromboembolism - including prior thrombosis - should beclosely 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 otheragents that may increase the risk of thrombosis (e.g. erythropoietic agents or hormone replacementtherapy). Patients and physicians are advised to be observant for the signs and symptoms ofthromboembolism. Patients should be instructed to seek medical care if they develop symptoms suchas shortness of breath, chest pain, haemoptysis, arm or leg swelling or pain.

Thromboprophylaxis should be considered based on an individual benefit/risk assessment.

Cases of hepatic failure, including fatal cases, have been reported. Kyprolis can cause elevations ofserum transaminases (see section 4.8). Reduce or stop dose as appropriate (see section 4.2). Liverenzymes and bilirubin should be monitored at treatment initiation and monthly during treatment withcarfilzomib, regardless of baseline values.

Thrombotic microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura andhaemolytic 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. Ifthe diagnosis is suspected, stop Kyprolis and evaluate patients for possible TTP/HUS. If the diagnosisof TTP/HUS is excluded, Kyprolis can be restarted. The safety of reinitiating Kyprolis therapy inpatients previously experiencing TTP/HUS is not known.

Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patientsreceiving 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 withhypertension, and the diagnosis is confirmed by neuro-radiological imaging. Kyprolis should bediscontinued if PRES is suspected. The safety of reinitiating Kyprolis therapy in patients previouslyexperiencing 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 patientswith positive HBV serology, prophylaxis with antivirals should be considered. They should bemonitored 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 resumingcarfilzomib, after HBV reactivation is adequately controlled, is not known. Therefore, resumption oftherapy should be discussed with experts in managing HBV.

Progressive Multifocal Leukoencephalopathy

Cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients receivingcarfilzomib who have had prior or concurrent immunosuppressive therapy.

Patients receiving carfilzomib should be monitored for any new or worsening neurologic, cognitive orbehavioural 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 aspecialist with appropriate diagnostic testing. If PML is confirmed, carfilzomib must be discontinued.

Female patients of childbearing potential (and/or their partners) must use effective contraceptionmeasures during and for one month following treatment. Male patients must use effectivecontraception measures during and for 3 months following treatment if their partner is pregnant or ofchildbearing potential and not using effective contraception (refer to section 4.6). Carfilzomib maydecrease the efficacy of oral contraceptives (refer to section 4.5).

Kyprolis 10 mg powder for solution for infusion

This medicinal product contains 37 mg sodium per 10 mg vial which is equivalent to 1.9% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Kyprolis 30 mg powder for solution for infusion

This medicinal product contains 109 mg sodium per 30 mg vial which is equivalent to 5.5% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Kyprolis 60 mg powder for solution for infusion

This medicinal product contains 216 mg sodium per 60 mg vial which is equivalent to 11% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Cyclodextrin content

Kyprolis 10 mg powder for solution for infusion

This medicinal product contains 500 mg cyclodextrin (betadex sulfobutyl ether sodium) per 10 mg vialwhich 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 mgvial 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 mgvial which is equivalent to 88 mg/kg for a 70 kg adult.

Carfilzomib is primarily metabolised via peptidase and epoxide hydrolase activities, and as a result,the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration ofcytochrome P450 inhibitors and inducers.

In vitro studies indicated that carfilzomib did not induce human CYP3A4 in cultured humanhepatocytes. A clinical study using oral midazolam as a CYP3A probe conducted with carfilzomib at adose of 27 mg/m2 (2-10 minute infusion) demonstrated that the pharmacokinetics of midazolam wereunaffected by concomitant carfilzomib administration, indicating that carfilzomib is not expected toinhibit the metabolism of CYP3A4/5 substrates and is not a CYP3A4 inducer in human subjects. Noclinical study was conducted with a dose of 56 mg/m2. However, it is unknown whether carfilzomib isan inducer of CYP1A2, 2C8, 2C9, 2C19 and 2B6 at therapeutic concentrations. Caution should beobserved 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 methodof 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 notexpected to influence exposure of medicinal products that are substrates of these enzymes as a resultof inhibition.

Carfilzomib is a P-glycoprotein (P-gp) but not a BCRP substrate. However, given that Kyprolis isadministrated intravenously and is extensively metabolised, the pharmacokinetic profile of carfilzomibis unlikely to be affected by P-gp or BCRP inhibitors or inducers. In vitro, at concentrations (3 µM)lower than those expected at therapeutic doses, carfilzomib inhibits the efflux transport of digoxin, a

P-gp substrate, by 25%. Caution should be observed when carfilzomib is combined with substrates of

P-gp (e.g. digoxin, colchicine).

In vitro, carfilzomib inhibits OATP1B1 with an IC50 = 2.01 µM whereas it is unknown whethercarfilzomib may or not inhibit other transporters OATP1B3, OAT1, OAT3, OCT2 and BSEP, at thesystemic 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 insystemic concentration 5 minutes after the end of infusion, the risk of clinically relevant interactionswith substrates of OATP1B1 and UGT1A1 is probably low.

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

It cannot be excluded that the efficacy of oral contraceptives may be reduced during carfilzomibtreatment (see section 4.5). In addition, due to an increased risk of venous thromboembolic eventsassociated with carfilzomib, females should avoid the use of hormonal contraceptives that areassociated with a risk of thrombosis during treatment with carfilzomib (see sections 4.4 and 4.8). If apatient is currently using oral contraceptives or a hormonal method of contraception that is associatedwith 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 treatmentif their partner is pregnant or of child bearing potential not using effective contraception.

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

Studies in animals have shown reproductive toxicity (see section 5.3).

Based on its mechanism of action and findings in animals, Kyprolis can cause foetal harm whenadministered to a pregnant woman. Kyprolis should not be used during pregnancy unless the potentialbenefit outweighs the potential risk to the foetus. If Kyprolis is used during pregnancy, or if the patientbecomes pregnant while taking this medicinal product, the patient should be apprised of the potentialhazard to the foetus.

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic activesubstance that causes severe life-threatening birth defects. If lenalidomide is taken during pregnancy, ateratogenic 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 thepatient does not have child bearing potential. Please refer to the current lenalidomide summary ofproduct characteristics.

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

No fertility studies have been performed in animals (see section 5.3).

Kyprolis has minor influence on the ability to drive and use machines.

Fatigue, dizziness, fainting, blurred vision, somnolence and/or a drop in blood pressure have beenobserved in clinical studies. Patients being treated with Kyprolis should be advised not to drive oroperate machines in the event that they experience any of these symptoms.

Serious adverse reactions that may occur during Kyprolis treatment include: cardiac failure,myocardial infarction, cardiac arrest, myocardial ischaemia, interstitial lung disease, pneumonitis,acute respiratory distress syndrome, acute respiratory failure, pulmonary hypertension, dyspnoea,hypertension including hypertensive crises, acute kidney injury, tumour lysis syndrome, infusionrelated reaction, gastrointestinal haemorrhage, intracranial haemorrhage, pulmonary haemorrhage,thrombocytopenia, hepatic failure, hepatitis B virus reactivation, PRES, thrombotic microangiopathyand TTP/HUS. In clinical studies with Kyprolis, cardiac toxicity and dyspnoea typically occurredearly 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 theadverse reactions occurring in the Kyprolis and dexamethasone (Kd) arm of study 2011-003 versus the

Kyprolis, lenalidomide and dexamethasone (KRd) arm of study PX-171-009 suggest that there may bea 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 pulmonaryhypertension (Kd 1.3%, KRd 0.8%).

In study 20160275 (see section 5.1), in which the administration of Kyprolis in combination withdaratumumab and dexamethasone (KdD) was compared to Kyprolis in combination withdexamethasone (Kd), deaths due to adverse events within 30 days of the last dose of any studytreatment occurred in 10% of patients in the KdD arm compared with 5% of patients in the Kd arm.

The most common cause of death occurring in patients in the two arms (KdD versus Kd) wasinfections (5% versus 3%). The risk of fatal treatment-emergent adverse events was higher amongsubjects ≥ 65 years of age. Serious adverse events were reported in 56% of the patients in the KdDarm and 46% of the patients in the Kd arm. The most common serious adverse events reported in the

KdD arm as compared with the Kd arm were anaemia (2% versus 1%), diarrhoea (2% versus 0%),pyrexia (4% versus 2%), pneumonia (12% versus 9%), influenza (4% versus 1%), sepsis (4% versus1%) and bronchitis (2% versus 0%).

Adverse reactions are presented below by system organ class and frequency category (see table 6).

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

Table 6. Tabulated list of adverse reactions

MedDRA Very common Common Uncommon Raresystem organ (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1,000 to (≥ 1/10,000 toclass < 1/100) < 1/1,000)

Infections and Pneumonia Sepsis Clostridiuminfestations Respiratory tract Lung infection difficile colitisinfection Influenza Cytomegalovirus

Herpes zoster* infection

Urinary tract infection Hepatitis B virus

Bronchitis reactivation

Gastroenteritis

Viral infection

Nasopharyngitis

Rhinitis

Immune system Drugdisorders hypersensitivity

Blood and Thrombocytopenia Febrile neutropenia HUS Thromboticlymphatic system Neutropenia TTP microangiopathydisorders Anaemia

Lymphopenia

Leukopenia

Metabolism and Hypokalaemia Dehydration Tumour lysisnutrition Decreased appetite Hyperkalaemia syndromedisorders Hypomagnesaemia

Hyponatraemia

Hypercalcaemia

Hypophosphataemia

Hyperuricaemia

Hypoalbuminaemia

Psychiatric Insomnia Anxietydisorders Confusional state

Nervous system Dizziness Paraesthesia Intracranialdisorders Peripheral Hypoaesthesia haemorrhageneuropathy Cerebrovascular

Headache accident

PRES

Eye disorders Cataract

Blurred vision

Ear and labyrinth Tinnitusdisorders

Cardiac disorders Cardiac failure Cardiac arrest

Myocardial infarction Cardiomyopathy

Atrial fibrillation Myocardial

Tachycardia ischaemia

Ejection fraction Pericarditisdecreased Pericardial effusion

Palpitations Ventriculartachycardia

Vascular Hypertension Deep vein thrombosis Hypertensive crisis Hypertensivedisorders Hypotension Haemorrhage emergency

Flushing

MedDRA Very common Common Uncommon Raresystem organ (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1,000 to (≥ 1/10,000 toclass < 1/100) < 1/1,000)

Respiratory, Dyspnoea Pulmonary embolism ARDSthoracic, and Cough Pulmonary oedema Acute respiratorymediastinal Epistaxis failuredisorders Oropharyngeal pain Pulmonary

Dysphonia haemorrhage

Wheezing Interstitial lung

Pulmonary diseasehypertension Pneumonitis

Gastrointestinal Vomiting Gastrointestinal Gastrointestinaldisorders Diarrhoea haemorrhage perforation

Constipation Dyspepsia Pancreatitis acute

Abdominal pain Toothache

Nausea

Hepatobiliary Increased alanine Hepatic failuredisorders aminotransferase Cholestasis

Increased aspartateaminotransferase

Gamma-glutamyltransferaseincreased

Skin and Rash Angioedemasubcutaneous Pruritustissue disorders Erythema

Hyperhidrosis

Musculoskeletal Back pain Musculoskeletal painand connective Arthralgia Musculoskeletal chesttissue disorders Pain in extremity pain

Muscle spasms Bone pain

Myalgia

Muscular weakness

Renal and Increased blood Acute kidney injuryurinary disorders creatinine Renal failure

Decreased creatininerenal clearance

General Pyrexia Chest pain Multi-organdisorders and Peripheral oedema Pain dysfunctionadministration Asthenia Infusion site reactions syndromesite conditions Fatigue Influenza like illness

Chills Malaise

Investigations Increased c-reactiveprotein

Increased blood uricacid

Injury, poisoning Infusion relatedand procedural reactioncomplications

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

Cardiac failure, myocardial infarction and myocardial ischaemia

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

In study 20160275, the overall incidence of cardiac disorders (any and all grade events) in thesubgroup of patients with baseline vascular disorders or baseline hypertension was 29.9% versus19.8% (KdD versus Kd), and 30.6% versus 18.1%, respectively. For fatal cardiac events, the incidencewas 1.9% versus 0.0% (KdD versus Kd) and 1.5% versus 0.0%, respectively. No single type of cardiacevent accounted for the difference reported between the KdD versus Kd arms in the subgroup ofpatients with baseline vascular disorders or baseline hypertension.

For clinical management of cardiac disorders during Kyprolis treatment, see section 4.4.

Dyspnoea was reported in approximately 24% of subjects in clinical studies with Kyprolis. Themajority 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 followingadministration of Kyprolis. Some of these events have been fatal. In clinical studies, hypertensionadverse events occurred in approximately 21% of subjects and 8% of subjects had grade ≥ 3hypertension events, but hypertensive crises occurred in < 0.5% of subjects. The incidence ofhypertension adverse events was similar between those with or without a prior medical history ofhypertension. For clinical management of hypertension during Kyprolis treatment, see section 4.4.

Thrombocytopenia was reported in approximately 33% of subjects in clinical studies with Kyprolisand approximately 20% of subjects had grade ≥ 3 events. In study 20160275, the incidence of grade≥ 3 thrombocytopenia was 24.4% in the KdD arm and 16.3% in the Kd arm. Kyprolis causesthrombocytopenia through inhibition of platelet budding from megakaryocytes resulting in a classiccyclical thrombocytopenia with platelet nadirs occurring on day 8 or 15 of each 28-day cycle andusually associated with recovery to baseline by the start of the next cycle. For clinical management ofthrombocytopenia during Kyprolis treatment, see section 4.4.

Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolismwith fatal outcomes, have been reported in patients who received Kyprolis (see section 4.4). Theoverall incidence of venous thromboembolic events was higher in the Kyprolis arms of three phase 3studies. In study PX-171-009 the incidence of venous thromboembolic events was 15.6% in the KRdarm and 9.0% in the Rd arm. Grade ≥ 3 venous thromboembolic events were reported in 5.6% ofpatients in the KRd arm and 3.9% of patients in the Rd arm. In study 2011-003 the incidence ofvenous thromboembolic events was 12.5% in the Kd arm and 3.3% in the bortezomib plusdexamethasone (Vd) arm. Grade ≥ 3 venous thromboembolic events were reported in 3.5% of patientsin the Kd arm and 1.8% of patients in the Vd arm. In study 20160275 the incidence of venousthromboembolic events was 6.2% in the KdD arm and 11.1% in the Kd arm. Grade ≥ 3 venousthromboembolic events were reported in 1.9% of patients in the KdD arm and 6.5% of patients in the

Kd arm.

Hepatic failure

Cases of hepatic failure, including fatal cases, have been reported in < 1% of subjects in clinicalstudies with Kyprolis. For clinical management of hepatic toxicity during Kyprolis treatment, seesection 4.4.

In a randomised, open-label multicentre study in patients receiving Kyprolis 20/56 mg/m2 infused over30 minutes in combination with dexamethasone (Kd, n = 464) versus bortezomib plus dexamethasone(Vd, n = 465), cases of grade 2 and higher peripheral neuropathy were reported in 7% of patients withrelapsed multiple myeloma in the Kd arm, compared with 35% in the Vd arm at the time of thepre-planned OS analysis. In study 20160275, cases of grade 2 and higher peripheral neuropathy werereported in 10.1% of patients with relapsed multiple myeloma in the KdD arm compared with 3.9% inthe Kd arm.

Infusion reaction

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

Respiratory tract infections

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

Secondary primary malignancies

In study 20160275, secondary primary malignancies in each treatment group (1.9% in KdD arm and1.3% in Kd arm) have been reported.

In study 20160275, opportunistic infections in each treatment group (9.4% in KdD arm and 3.9% in

Kd arm) have been reported. Opportunistic infections occurring in ≥ 1% of subjects in the KdD armincluded herpes zoster, oral candidiasis, oral herpes, and herpes simplex.

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

Overall, the subject incidence of certain adverse events (including cardiac arrhythmias, cardiac failure(see section 4.4), dyspnoea, leukopenia and thrombocytopenia) in clinical studies with Kyprolis washigher for patients who were ≥ 75 years of age compared to patients who were < 75 years of age.

In study 20160275, 47% of the 308 patients who received KdD 20/56 mg/m2 twice weekly were≥ 65 years of age. In the KdD arm of the study, fatal treatment-emergent adverse events occurred in6% of patients < 65 years of age and 14% of patients ≥ 65 years of age. In the Kd arm, these eventsoccurred in 8% of patients < 65 years of age and 3% of patients ≥ 65 years of age.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is currently insufficient information to draw conclusions about the safety of doses higher thanthose evaluated in clinical studies. Acute onset of chills, hypotension, renal insufficiency,thrombocytopenia and lymphopenia has been reported following a dose of 200 mg of Kyprolisadministered in error.

There is no known specific antidote for carfilzomib overdose. In the event of an overdose, the patientshould be monitored, specifically for the adverse reactions to Kyprolis listed in section 4.8.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XG02

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly bindsto the N terminal threonine containing active sites of the 20S proteasome, the proteolytic core particlewithin the 26S proteasome, and displays little to no activity against other protease classes. Carfilzomibhad antiproliferative and proapoptotic activities in preclinical models in haematologic tumours. Inanimals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumour growth inmodels of multiple myeloma. In vitro, carfilzomib was found to have minimal neurotoxicity andminimal reaction to non-proteasomal proteases.

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 consistentlyinduced an (≥ 80%) inhibition of the CT-L activity of the proteasome. In addition, carfilzomibadministration resulted in inhibition of the latent membrane protein 2 (LMP2) and multicatalyticendopeptidase 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 hoursfollowing the first dose of carfilzomib for each week of dosing. Combination dosing withlenalidomide 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 theinhibition of LMP7, MECL1, and LMP2 subunits respectively at the dose of 56 mg/m2 compared tothose at 15 to 20 mg/m2. Similar proteasome inhibition by carfilzomib was achieved with2 to 10 minute and 30 minute infusions at the 2 dose levels (20 and 36 mg/m2) at which it was tested.

Kyprolis in combination with lenalidomide and dexamethasone for the treatment of patients withrelapsed multiple myeloma - study PX-171-009 (ASPIRE)

The safety and efficacy of Kyprolis were evaluated in a randomised, open-label, multicentre study of792 patients with relapsed multiple myeloma, which evaluated the combination of Kyprolis withlenalidomide 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 oncycle 1, day 8, administered twice weekly for 3 out of 4 weeks as a 10 minute infusion. Kyprolistreatment was administered for a maximum of 18 cycles unless discontinued early for diseaseprogression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continueuntil 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 duringthe first 3 months of initiating treatment with lenalidomide and dexamethasone, or progression at anytime during treatment with lenalidomide and dexamethasone if this was the subject’s most recent lineof therapy. Study eligibility criteria allowed a small subset of patients with myeloma refractory tobortezomib (n = 118) or lenalidomide (n = 57) to be enrolled. Enrolled subjects were defined asrefractory 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 anyregimen. 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% withperformance 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 includedsubjects 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 withbortezomib (66%), thalidomide (44%) and lenalidomide (20%).

The results of study PX-171-009 are summarised in table 7 and in figure 1 and figure 2.

Table 7. Summary of efficacy analysis in relapsed multiple myeloma study PX-171-009

KRd combination therapy

KRd arma Rd arma(N = 396) (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, 71.31-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 goodpartial response; PR = partial response; IMWG = international myeloma working group; EBMT = Europeansociety 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 improvedprogression-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 a31% reduction in the risk of event as determined using standard objective International Myeloma

Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria byan Independent Review Committee (IRC).

The PFS benefit of KRd was consistently observed in all subgroups, including patients ≥ 75 years ofage (n = 96), patients with high risk (n = 100) or unknown (n = 375) risk genetic mutations, andpatients with baseline creatinine clearance of 30 - < 50 mL/min (n = 56).

Figure 1. Kaplan-Meier curve of progression-free survival in relapsed multiple myelomaa1.0 KRd (N=396) Rd (N=396)

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)0.8p-value (1-sided) <.00010.60.40.20.00 6 12 18 24 30 36 42 48

Months from Randomisation

KRd Rd

Number of Subjects at Risk:

KRd 396 332 279 222 179 112 24 1

Rd 396 287 206 151 117 72 18 1

GRH0219EN v1

KRd = Kyprolis, lenalidomide and dexamethasone; Rd = lenalidomide, dexamethasone; PFS = progression-freesurvival; 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 and267 deaths in the Rd arm. The median follow-up was approximately 67 months. A statisticallysignificant advantage in OS was observed in patients in the KRd arm compared to patients in the Rdarm. Patients in the KRd arm had a 21% reduction in the risk of death compared with those in the Rdarm (HR = 0.79; 95% CI: 0.67, 0.95; p-value = 0.0045). The median OS improved by 7.9 months inpatients in the KRd arm compared with those in the Rd arm (see table 7 and figure 2).

Proportion surviving without progression

Figure 2. Kaplan-Meier curve of overall survival in relapsed multiple myelomaa1.0 KRd (N=396) Rd (N=396)

Death, n (%) 246 (62.1%) 267 (67.4%)0.8 Median OS, mo 48.3 40.4

HR (KRd/Rd) (95% CI) 0.794 (0.667, 0.945)p-value (1-sided) 0.00450.60.40.20.00 6 12 18 24 30 36 42 48 54 60 66 72 78

Months from Randomisation

KRd

Rd

Number of Subjects at Risk:

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

KRd = Kyprolis, lenalidomide and dexamethasone; Rd = lenalidomide and dexamethasone; OS = overallsurvival; 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 (multiplicityunadjusted 1-sided p-value = 0.0001) measured with the EORTC QLQ-C30, an instrument validatedin multiple myeloma.

Kyprolis in combination with dexamethasone for the treatment of patients with relapsed multiplemyeloma - study 2011-003 (ENDEAVOR)

The safety and efficacy of Kyprolis were evaluated in a phase 3, randomised, open-label, multicentrestudy of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd). A total of929 patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines oftherapy 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 oncycle 1, day 8, administered twice weekly for 3 out of 4 weeks as a 30 minute infusion untilprogression or unacceptable toxicity.

Patients randomised to the Vd arm could receive bortezomib either by the intravenous (n = 108) orsubcutaneous (n = 357) route. Patients who had the following were excluded from the study: creatinineclearance rates < 15 mL/min, NYHA Class III to IV congestive heart failure, myocardial infarctionwithin the last 4 months or those with left ventricular ejection fraction (LVEF) < 40%. Studyeligibility 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 inhibitortherapy, were not removed from proteasome inhibitor therapy due to toxicity, and had at least a6-month proteasome inhibitor treatment-free interval from last dose.

The demographics and baseline characteristics for study 2011-003 were well-balanced between thetwo 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), ECOGperformance status (45% with performance status 1), high risk genetic mutations, consisting of thegenetic subtypes t(4;14) or t(14;16) in 10% or more of screened plasma cells, or deletion 17p in ≥ 20%

Proportion Surviving

GRH0463v1of plasma cells (23%) unknown-risk genetic mutations, which included subjects with results notcollected or not analysed (9%) and baseline ISS stage III disease (24%).

The results of study 2011-003 are summarised in table 8.

Table 8. Summary of efficacy analysis in relapsed multiple myeloma study 2011-003

Kd Arm Vd Arm(N = 464) (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, 67.01-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 = verygood 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 creatinineclearance of 30 - < 50 mL/min (n = 128).

In patients who received prior bortezomib (54%), median PFS was 15.6 months in the Kd arm versus8.1 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 versus7.3 months in the Vd arm (HR = 0.69, 95% CI: 0.52, 0.92), ORR was 70.1% versus 59.3%. In patientsrefractory 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%.

Figure 3. Kaplan-Meier plot of progression-free survival as determined by the IRC(intent-to-treat population) study 2011-0031.0

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

Progression/Death, n (%) 171 (36.9%) 243 (52.3%)

Median PFS, mo 18.7 9.40.8 HR (Kd/Vd) (95% CI) 0.533 (0.437, 0.651)p-value (1-sided) <.00010.60.40.20.00 6 12 18 24 30

Months from Randomisation

Kd Vd

Number of Subjects at Risk:

Kd 464 331 144 41 4 0

Vd 465 252 81 12 1 0

GRH0129 v2

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 and209 deaths in the Vd arm. At the time of the analysis, 80% of the targeted events were registered. Themedian follow-up was approximately 37 months. A statistically significant advantage in OS wasobserved 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 2011-0031.0

Kd (black)

Vd (grey)0.80.6

Kd (N=464) Vd (N=465)0.4

Death, n (%) 189 (40.7%) 209 (44.9%)0.2 Median OS, mo 47.6 40.0

HR (Kd/Vd) (95% CI) 0.791 (0.648, 0.964)p-value (1-sided) 0.01000.00 6 12 18 24 30 36 42 48

Months from Randomisation

Number of Subjects at Risk:

Kd 464 423 373 335 308 270 162 66 10

Vd 465 402 351 293 256 228 140 39 5

GRH0131 v4

Kd = Kyprolis plus dexamethasone; Vd = bortezomib plus dexamethasone; OS = overall survival; mo = months;

HR = hazard ratio; CI = confidence interval

Proportion Surviving Proportion Surviving without Progression

Kyprolis in combination with daratumumab and dexamethasone for the treatment of patients withrelapsed or refractory multiple myeloma - study 20160275 (CANDOR)

The safety and efficacy of Kyprolis were evaluated in a phase 3, randomised, open-label, multicentresuperiority trial of Kyprolis with daratumumab plus dexamethasone (KdD) versus Kyprolis plusdexamethasone (Kd). A total of 466 patients with relapsed or refractory multiple myeloma who hadreceived 1 to 3 prior lines of therapy were enrolled and randomised in a 2:1 randomisation (312 in

KdD arm and 154 in Kd arm).

In the KdD and Kd arms, Kyprolis was evaluated at a starting dose of 20 mg/m2, which was increasedto 56 mg/m2 on cycle 1, day 8 administered twice weekly for 3 out of 4 weeks as a 30-minute infusion.

Patients who had the following were excluded from the trial: known moderate or severe persistentasthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1< 50% of predicted normal, active congestive heart failure.

Demographics and baseline characteristics were generally consistent between the two arms, includinggender (57.5% male), race (78.5% white subjects), age (64 years, range 29-84 years), prior treatmentwith bortezomib (90%), bortezomib refractory (29%), high-risk genetic mutations, consisting of thegenetic subtypes t(4; 14), t(14; 16), or deletion17p (16%) and unknown-risk genetic-mutations whichincluded subjects with results not done, failed or quantity insufficient (51%). A smaller proportion ofsubjects were aged ≥ 75 years in the KdD group (9.0%) than in the Kd group (14.3%). Subjects had amedian (range) of 2.0 (1 to 4) prior lines of therapy. A higher percent of subjects had a prior transplantin the KdD group (62.5%) compared with the Kd group (48.7%). Only 1 patient in KdD groupreceived previous anti-CD38 monoclonal antibody therapy.

The results of the primary analysis of study 20160275 are summarised in table 9 and figure 5 andfigure 6.

Table 9. Summary of efficacy in study 20160275 at primary analysis

KdD arm Kd arm(N=312) (N=154)

PFS months median (95% CI)a NE (NE, NE) 15.8 (12.1, NE)

HR (95% CI); 1-sided p-valueb 0.630 (0.464, 0.854); 0.0014

ORR (%) (95% CI)a, c 84.3 (79.8, 88.1) 74.7 (67.0, 81.3)

Response category, n(%)

N with response 263 115

CR 89 (28.5) 16 (10.4)

MRD [-] CR 43 (13.8) 5 (3.2)

VGPR 127 (40.7) 59 (38.3)

PR 47 (15.1) 40 (26.0)

Odds ratio 1.925 (1.184, 3.129)1-sided p-valueb 0.0040

MRD[-]CR at 12 months 12.5 (9.0, 16.7) 1.3 (0.2, pct. 4.6)

Odds ratio 11.329 (2.703, 47.476)1-sided p-valueb < 0.0001

KdD = Kyprolis plus dexamethasone and daratumumab; Kd = Kyprolis plus dexamethasone; CI = confidenceinterval; NE = not estimable; HR = Hazard Ratio; ORR = overall response rate; CR = complete response;

VGPR = very good partial response; MRD[-]CR = complete response with negative (or no) minimal residualdisease.

a. These endpoints were determined by an Independent Review Committee using IMWG response criteria.

b. Statistically significant

c. Overall response is defined as achieving a best overall response of PR, VGPR, CR, or better.

Data cut off for primary analysis: 14 July 2019

At the time of the primary PFS analysis the trial demonstrated an improvement in PFS in the KdD armas compared to the Kd arm (hazard ratio [HR]=0.630; 95% CI: 0.464, 0.854; p=0.0014) whichrepresents a 37% reduction in the risk of disease progression or death in patients treated with KdD.

The median PFS was not estimable for the KdD arm and was 15.8 months in the Kd arm.

In patients who received prior lenalidomide (42.3%), median PFS was NE in the KdD arm versus12.1 months in the Kd arm (HR = 0.52, 95% CI: 0.34, 0.80), ORR was 78.9% versus 74.3%(OR=1.29, 95% CI: 0.65, 2.54), and MRD[-]CR at 12 months was 11.4% versus 0.0% (OR=NE, 95%

CI: NE, NE). In patients refractory to lenalidomide (33%), median PFS was NE in the KdD arm versus11.1 months in the Kd arm (HR = 0.45, 95% CI: 0.28, 0.74), ORR was 79.8% versus 72.7%(OR=1.48, 95%CI: 0.69, 3.20), and MRD[-]CR at 12 months 13.1% versus 0.0% (OR=NE, 95% CI:

NE, NE).

Limited data are available in elderly patients (≥ 75 years). A total of 43 patients above 75 years of agewere enrolled in study 20160275 (25 patients in the KdD group and 18 patients in the Kd group). A

HR of 1.459 (95% CI: 0.504, 4.223) in PFS was observed. The risk of fatal treatment-emergentadverse events was higher among subjects ≥ 65 years of age (see section 4.8). KdD should be usedwith caution in patients ≥ 75 years after careful consideration of the potential benefit/risk on anindividual basis.

Figure 5. Kaplan-Meier plot of progression-free survival (intent-to-treat-population) asdetermined by IRC study 201602751.00.80.60.40.20.0 Kd (N=154) KdD (N=312)

Progression/Death, n (%) 68 (44.2%) 110 (35.3%)

Median PFS, months 15.8 NE

HR (KdD/Kd) (95% CI) 0.630 (0.464, 0.854)p-value (1-sided) 0.00140 3 6 9 12 15 18 21 24

Months from Randomisation

Kd KdD

Number of Subjects at Risk:

Kd 154 122 100 85 70 55 13 2 0

KdD 312 279 236 211 189 165 57 14 0

Proportion Surviving Without Progression

ORR was 84.3% for patients in the KdD arm and 74.7% in the Kd arm (see table 9). The medianduration of response was not estimable for the KdD arm and was 16.6 months (13.9, NE) for the Kdgroup. The median time to response was 1.0 (1, 14) months for the KdD arm and 1.0 (1, 10) monthsfor the Kd arm.

At the time of final analysis, 148 subjects (47.4%) in the KdD group and 80 subjects (51.9%) in the

Kd group had died. Median OS (95% CI) was 50.8 (44.7, NE) months for the KdD group and 43.6(35.3, NE) months for the Kd group, with a HR (KdD/Kd) of 0.784 (95% CI: 0.595, 1.033; 1-sidedp = 0.0417). This one-sided p-value did not meet the statistical significance level of 0.021 for this finalanalysis. Median follow-up time was 50.6 months in the KdD group and 50.1 months in the Kd group.

Figure 6. Kaplan-Meier plot of overall survival in study 20160275

Kyprolis monotherapy in patients with relapsed and refractory multiple myeloma

Additional clinical experience has been generated with Kyprolis monotherapy in patients with relapsedand 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 moreheavily 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 andcyclophosphamide). The study did not meet its primary efficacy endpoint of demonstrating superiorityof 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 ≥ 2prior therapies required), which met its primary efficacy endpoint of IRC-assessed ORR (22.9%).

An evaluation of possible effects of carfilzomib on cardiac function was performed by analysing, viacentral blind reading, triplicate ECG in 154 subjects with advanced malignancies, including multiplemyeloma. The effect of carfilzomib on cardiac repolarisation using the QT interval with Fridericia’scorrection (QTcF interval) and the analysis of concentration-QTc relationships show no clear signal ofany dose-related effect. The upper bound of one-sided 95% confidence interval (CI) for predictedeffect on QTcF at Cmax was 4.8 msec. With Bazett’s correction (QTcB interval), the upper bound ofone-sided 95% confidence interval (CI) for predicted effect on QTcB at Cmax was 5.9 msec.

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 forinformation on paediatric use).

The C 2max and AUC following a 2 to 10 minute intravenous infusion of 27 mg/m was 4,232 ng/mL and379 ng*hr/mL, respectively. Following repeated doses of Kyprolis at 15 and 20 mg/m2, systemicexposure (AUC) and half-life were similar on days 1 and 15 or 16 of cycle 1, suggesting there was nosystemic carfilzomib accumulation. At doses between 20 and 56 mg/m2, there was a dose-dependentincrease in exposure.

A 30 minute infusion resulted in a similar half-life and AUC, but 2- to 3-fold lower Cmax compared tothat observed with a 2 to 10 minute infusion of the same dose. Following a 30 minute infusion of the56 mg/m2 dose, the AUC (948 ng*hr/mL) was approximately 2.5-fold that observed at the 27 mg/m2level, and Cmax (2,079 ng/mL) was lower compared to that of 27 mg/m2 over the 2 to 10 minuteinfusion.

The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. Whentested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over theconcentration range of 0.4 to 4 micromolar.

Carfilzomib was rapidly and extensively metabolised. The predominant metabolites measured inhuman plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments andthe diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principalpathways of metabolism. Cytochrome P450 mediated mechanisms played a minor role in overallcarfilzomib metabolism. The metabolites have no known biologic activity.

Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib was rapidly cleared from thesystemic circulation with a half-life of ≤ 1 hour on day 1 of cycle 1. The systemic clearance rangedfrom 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largelycleared extrahepatically. Carfilzomib is eliminated primarily via metabolism with subsequentexcretion of its metabolites in urine.

Population pharmacokinetic analyses indicate there are no effects of age, gender or race on thepharmacokinetics of carfilzomib.

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), mildhepatic impairment (bilirubin > 1-1.5 × ULN or AST > ULN, but bilirubin ≤ ULN, n = 14), ormoderate hepatic impairment (bilirubin > 1.5-3 × ULN; any AST, n = 9). The pharmacokinetics ofcarfilzomib has not been studied in patients with severe hepatic impairment (bilirubin > 3 × ULN andany AST). Kyprolis, as a single agent, was administered intravenously over 30 minutes at 20 mg/m2 ondays 1 and 2 and at 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1. If tolerated, patients received56 mg/m2 starting in cycle 2. Baseline hepatic function status had no marked effect on the totalsystemic exposure (AUClast) of carfilzomib following single or repeat-dose administration (geometricmean ratio in AUClast at the 27 mg/m2 dose in cycle 1, day 16 for mild and moderate impairmentversus normal hepatic function were 144.4% and 126.1%, respectively; and at the 56 mg/m2 dose incycle 2, day 1 were 144.7% and 121.1%). However, in patients with mild or moderate baseline hepaticimpairment, all of whom had solid tumours, there was a higher subject incidence of hepatic functionabnormalities, ≥ grade 3 adverse events and serious adverse events compared with subjects withnormal hepatic function (see section 4.2).

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 to20 mg/m2. Pharmacokinetic data were collected from patients following the 15 mg/m2 dose in cycle 1and the 20 mg/m2 dose in cycle 2. The second study was conducted in 23 relapsed multiple myelomapatients 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 followingadministration of a 27 mg/m2 dose as a 30 minute infusion on cycle 1, day 16 and the 56 mg/m2 doseon cycle 2, day 1.

Results from both studies show that renal function status had no marked effect on the exposure ofcarfilzomib following single or repeat-dose administration. The geometric mean ratio in AUClast at the15 mg/m2 dose cycle 1, day 1 for mild, moderate, severe renal impairment and chronic dialysis versusnormal renal function were 124.36%, 111.07%, 84.73% and 121.72%, respectively. The geometricmean ratios in AUClast at the 27 mg/m2 dose cycle 1, day 16 and at the 56 mg/m2 dose cycle 2, day 1for 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- and3-fold in patients with moderate and severe renal impairment, respectively, and 7-fold in patientsrequiring 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. Thismetabolite has no known biological activities. Serious adverse events related to worsening renalfunction were more common in subjects with baseline renal dysfunction (see section 4.2).

Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral bloodlymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test andwas 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 correspondsto 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 repeatedbolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose inmonkeys using dosing schedules similar to those used clinically resulted in mortalities that were due totoxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluidaccumulation, 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 of27 mg/m2 based on BSA. The highest non-severely toxic dose of 0.5 mg/kg in monkeys resulted ininterstitial 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 of27 mg/m2.

Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues werenoted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-monthmonkey chronic toxicity studies. Carfilzomib caused embryo-foetal toxicity in pregnant rabbits atdoses that were lower than in patients receiving the recommended dose. Carfilzomib administered topregnant 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.

Betadex sulfobutyl ether sodium

Anhydrous citric acid (E330)

Sodium hydroxide (for pH adjustment)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Kyprolis powder for solution for infusion must not be mixed with sodium chloride 9 mg/mL (0.9%)solution for injection.

Powder vial (unopened)3 years.

Chemical and physical in-use stability of reconstituted solutions in the vial, syringe or intravenous baghas been demonstrated for 24 hours at 2°C - 8°C or for 4 hours at 25°C. The elapsed time fromreconstitution to administration should not exceed 24 hours.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user and should not belonger than 24 hours at 2°C - 8°C.

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.

Kyprolis 10 mg powder for solution for infusion10 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminiumseal with a light blue plastic flip off cap.

Kyprolis 30 mg powder for solution for infusion30 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminiumseal with an orange plastic flip off cap.

Kyprolis 60 mg powder for solution for infusion50 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminiumseal with a purple plastic flip off cap.

Pack size of one vial.

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. Properaseptic technique must be observed.

The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the completepreparation instructions prior to reconstitution:

1. Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patient’s BSA atbaseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of2.2 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) toaseptically reconstitute each vial by slowly injecting 5 mL (for 10 mg vial), 15 mL (for 30 mgvial) or 29 mL (for 60 mg vial) sterile water for injections through the stopper and directing thesolution 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 completedissolution. DO NOT SHAKE. If foaming occurs, allow the solution to settle in the vial untilfoaming subsides (approximately 5 minutes) and the solution is clear.

5. Visually inspect for particulate matter and discolouration prior to administration. Thereconstituted product should be a clear, colourless to slightly yellow solution and should not beadministered 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 anintravenous 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 mmor smaller external diameter needle) to withdraw the calculated dose from the vial and diluteinto a 50 or 100 mL intravenous bag containing 5% glucose solution for injection.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

EU/1/15/1060/002

EU/1/15/1060/003

EU/1/15/1060/001

Date of first authorisation: 19 November 2015

Date of latest renewal: 25 June 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.