4.1. Therapeutic indications

Kyprolis in combination with daratumumab and dexamethasone, with lenalidomide and dexamethasone, or with 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).

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 dexamethasone

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)a

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)a

27

27

-

27

27

-

27

27

-

-

-

Dexamethasone (mg)

40

-

-

40

-

-

40

-

-

40

-

Lenalidomide

25 mg daily

-

-

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)a

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 alone

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)a

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)a

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

Kyprolis in combination with daratumumab and dexamethasone

When combined with daratumumab and 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 3. 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.

Dexamethasone is administered as 20 mg orally or intravenously on days 1, 2, 8, 9, 15 and 16 and 40 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 split dose of 8 mg/kg in cycle 1 on days 1 and 2. Afterwards, daratumumab is administered as 16 mg/kg once weekly on days 8, 15 and 22 of cycle 1 and days 1, 8, 15 and 22 of cycle 2, then every 2 weeks for 4 cycles (cycles 3 to 6) and then every 4 weeks for the remaining cycles or until disease progression.

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

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

On days when more than one of these medicines is administered, the recommended order of administration is as follows: dexamethasone, pre-infusion medications for daratumumab (see section Concomitant medicinal products), carfilzomib, daratumumab, and post-infusion medications for daratumumab (see section Concomitant medicinal products).

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

Table 3. Kyprolis in combination with dexamethasone and daratumumab

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)a

20

20

-

56

56

-

56

56

-

-

-

-

Dexamethasone (mg)b

20

20

-

20

20

-

20

20

-

40

-

-

Daratumumab (Intravenous OR Subcutaneous)

IV administration (mg/kg)

8

8

-

16

-

-

16

-

-

16

-

-

SC administration (mg)

1800

-

-

1800

-

-

1800

-

-

1800

-

-

Cycle 2

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)a

56

56

-

56

56

-

56

56

-

-

-

-

Dexamethasone (mg)b

20

20

-

20

20

-

20

20

-

40

-

-

Daratumumab (Intravenous OR Subcutaneous)

IV administration (mg/kg)

16

-

-

16

-

-

16

-

-

16

-

-

SC administration (mg)

1800

-

-

1800

-

-

1800

-

-

1800

-

-

Cycles 3-6

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)a

56

56

-

56

56

-

56

56

-

-

-

-

Dexamethasone (mg)b

20

20

-

20

20

-

20

20

-

40

-

-

Daratumumab (Intravenous OR Subcutaneous)

IV administration (mg/kg)

16

-

-

-

-

-

16

-

-

-

-

-

SC administration (mg)

1800

-

-

-

-

-

1800

-

-

-

-

-

Cycles 7 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)a

56

56

-

56

56

-

56

56

-

-

-

-

Dexamethasone (mg)b

20

20

-

20

20

-

20

20

-

40

-

-

Daratumumab (Intravenous OR Subcutaneous)

IV administration (mg/kg)

16

-

-

-

-

-

-

-

-

-

-

-

SC administration (mg)

1800

-

-

-

-

-

-

-

-

-

-

-

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 after the first week.

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 daratumumab and dexamethasone, with lenalidomide and dexamethasone, or with dexamethasone alone and should be based on an assessment of the patient's underlying risks and clinical status. For other 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 with daratumumab.

Refer to the daratumumab summary of product characteristics for additional details on concomitant medications 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 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.

When given in combination with intravenous daratumumab, oral and/or intravenous hydration is not required 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 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 4. Dose level reductions are presented in table 5.

Table 4. 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

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 5 for dose level reductions

Table 5. 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/m2

20 mg/m2

15 mg/m2 a

—

Kyprolis and dexamethasone

56 mg/m2

45 mg/m2

36 mg/m2

27 mg/m2 a

Kyprolis, daratumumab and dexamethasone

56 mg/m2

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 4). 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 4). Special attention should be paid to 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).

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 and post-marketing. Cases of ventricular tachycardia have been reported in patients receiving Kyprolis.

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. Hypertension was reported more frequently in patients who received Kyprolis in combination with daratumumab in study 20160275. It is recommended to control hypertension prior to starting and during treatment. All patients should be routinely evaluated for hypertension while on Kyprolis and treated as needed. If the hypertension cannot be controlled, the Kyprolis dose should be reduced. In case of hypertensive crises, stop Kyprolis until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2).

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 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, bradycardia, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Dexamethasone should be administered prior to Kyprolis to reduce the incidence and severity of reactions (see section 4.2).

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 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).

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).

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 childbearing 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).

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 versus the Kyprolis, lenalidomide and dexamethasone (KRd) arm of study PX-171-009 suggest that there may be a potential dose relationship for the following adverse reactions: cardiac failure (Kd 8.2%, KRd 6.4%), dyspnoea (Kd 30.9%, KRd 22.7%), hypertension (Kd 25.9%, KRd 15.8%), and pulmonary hypertension (Kd 1.3%, KRd 0.8%).

In study 20160275 (see section 5.1), in which the administration of Kyprolis in combination with daratumumab and dexamethasone (KdD) was compared to Kyprolis in combination with dexamethasone (Kd), deaths due to adverse events within 30 days of the last dose of any study treatment occurred in 10% of patients in the KdD arm compared with 5% of patients in the Kd arm. The most common cause of death occurring in patients in the two arms (KdD versus Kd) was infections (5% versus 3%). The risk of fatal treatment-emergent adverse events was higher among subjects ≥ 65 years of age. Serious adverse events were reported in 56% of the patients in the KdD arm and 46% of the patients in the Kd arm. The most common serious adverse events reported in the KdD arm as compared with the Kd arm were anaemia (2% versus 1%), diarrhoea (2% versus 0%), pyrexia (4% versus 2%), pneumonia (12% versus 9%), influenza (4% versus 1%), sepsis (4% versus 1%) and bronchitis (2% versus 0%).

Tabulated list of adverse reactions

Adverse reactions are presented below by system organ class and frequency category (see table 6). Frequency categories were determined from the crude incidence rate reported for each adverse reaction in a dataset of pooled clinical studies (n = 3,878). Within each system organ class and frequency category, adverse reactions are presented in order of decreasing seriousness.

Table 6. Tabulated list of adverse reactions

MedDRA system organ class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Rare

(≥ 1/10,000 to < 1/1,000)

Infections and infestations

Pneumonia

Respiratory tract infection

Sepsis

Lung infection

Influenza

Herpes zoster*

Urinary tract infection

Bronchitis

Gastroenteritis

Viral infection

Nasopharyngitis

Rhinitis

Clostridium difficile colitis

Cytomegalovirus infection

Hepatitis B virus reactivation

Immune system disorders

Drug hypersensitivity

Blood and lymphatic system disorders

Thrombocytopenia

Neutropenia

Anaemia

Lymphopenia

Leukopenia

Febrile neutropenia

HUS

TTP

Thrombotic microangiopathy

Metabolism and nutrition disorders

Hypokalaemia

Decreased appetite

Dehydration

Hyperkalaemia

Hypomagnesaemia

Hyponatraemia

Hypercalcaemia

Hypocalcaemia

Hypophosphataemia

Hyperuricaemia

Hypoalbuminaemia

Hyperglycaemia

Tumour lysis syndrome

Psychiatric disorders

Insomnia

Anxiety

Confusional state

Nervous system disorders

Dizziness

Peripheral neuropathy

Headache

Paraesthesia

Hypoaesthesia

Intracranial haemorrhage

Cerebrovascular accident

PRES

Eye disorders

Cataract

Blurred vision

Ear and labyrinth disorders

Tinnitus

Cardiac disorders

Cardiac failure

Myocardial infarction

Atrial fibrillation

Tachycardia

Ejection fraction decreased

Palpitations

Cardiac arrest

Cardiomyopathy

Myocardial ischaemia

Pericarditis

Pericardial effusion

Ventricular tachycardia

Vascular disorders

Hypertension

Deep vein thrombosis

Hypotension

Flushing

Hypertensive crisis

Haemorrhage

Hypertensive emergency

Respiratory, thoracic, and mediastinal disorders

Dyspnoea

Cough

Pulmonary embolism

Pulmonary oedema

Epistaxis

Oropharyngeal pain

Dysphonia

Wheezing

Pulmonary hypertension

ARDS

Acute respiratory failure

Pulmonary haemorrhage

Interstitial lung disease

Pneumonitis

Gastrointestinal disorders

Vomiting

Diarrhoea

Constipation

Abdominal pain

Nausea

Gastrointestinal haemorrhage

Dyspepsia

Toothache

Gastrointestinal perforation

Pancreatitis acute

Hepatobiliary disorders

Increased alanine aminotransferase

Increased aspartate aminotransferase

Gamma-glutamyltransferase increased

Hyperbilirubinaemia

Hepatic failure

Cholestasis

Skin and subcutaneous tissue disorders

Rash

Pruritus

Erythema

Hyperhidrosis

Angioedema

Musculoskeletal and connective tissue disorders

Back pain

Arthralgia

Pain in extremity

Muscle spasms

Musculoskeletal pain

Musculoskeletal chest pain

Bone pain

Myalgia

Muscular weakness

Renal and urinary disorders

Increased blood creatinine

Acute kidney injury

Renal failure

Renal impairment

Decreased creatinine renal clearance

General disorders and administration site conditions

Pyrexia

Peripheral oedema

Asthenia

Fatigue

Chills

Chest pain

Pain

Infusion site reactions

Influenza like illness

Malaise

Multi-organ dysfunction syndrome

Investigations

Increased c-reactive protein

Increased blood uric acid

Injury, poisoning and procedural complications

Infusion related reaction

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

Description of selected adverse reactions

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 in approximately 1% of subjects (approximately 1% of subjects had grade ≥ 3 events) and myocardial ischaemia was reported in < 1% of subjects (< 1% of subjects had grade ≥ 3 events). These events typically occurred early in the course of Kyprolis therapy (< 5 cycles).

In study 20160275, the overall incidence of cardiac disorders (any and all grade events) in the subgroup of patients with baseline vascular disorders or baseline hypertension was 29.9% versus 19.8% (KdD versus Kd), and 30.6% versus 18.1%, respectively. For fatal cardiac events, the incidence was 1.9% versus 0.0% (KdD versus Kd) and 1.5% versus 0.0%, respectively. No single type of cardiac event accounted for the difference reported between the KdD versus Kd arms in the subgroup of patients with baseline vascular disorders or baseline hypertension.

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

Dyspnoea

Dyspnoea was reported in approximately 24% of subjects in clinical studies with Kyprolis. The majority of dyspnoea adverse reactions were non-serious (< 5% of subjects had grade ≥ 3 events), resolved, rarely resulted in treatment discontinuation, and had an onset early in the course of study (< 3 cycles). For clinical management of dyspnoea during Kyprolis treatment, see section 4.4.

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 21% of subjects and 8% of subjects had grade ≥ 3 hypertension events, but hypertensive crises occurred in < 0.5% of subjects. The incidence of hypertension adverse events was similar between those with or without a prior medical history of hypertension. For clinical management of hypertension during Kyprolis treatment, see section 4.4.

Thrombocytopenia

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

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 three phase 3 studies. In study PX-171-009 the incidence of venous thromboembolic events was 15.6% in the KRd arm and 9.0% in the Rd arm. Grade ≥ 3 venous thromboembolic events were reported in 5.6% of patients in the KRd arm and 3.9% of patients in the Rd arm. In study 2011-003 the incidence of venous thromboembolic events was 12.5% in the Kd arm and 3.3% in the bortezomib plus dexamethasone (Vd) arm. Grade ≥ 3 venous thromboembolic events were reported in 3.5% of patients in the Kd arm and 1.8% of patients in the Vd arm. In study 20160275 the incidence of venous thromboembolic events was 6.2% in the KdD arm and 11.1% in the Kd arm. Grade ≥ 3 venous thromboembolic events were reported in 1.9% of patients in the KdD arm and 6.5% of patients in the Kd arm.

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) versus bortezomib plus dexamethasone (Vd, n = 465), cases of grade 2 and higher peripheral neuropathy were reported in 7% of patients with relapsed multiple myeloma in the Kd arm, compared with 35% in the Vd arm at the time of the pre-planned OS analysis. In study 20160275, cases of grade 2 and higher peripheral neuropathy were reported in 10.1% of patients with relapsed multiple myeloma in the KdD arm compared with 3.9% in the Kd arm.

Infusion reaction

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

Respiratory tract infections

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

Secondary primary malignancies

In study 20160275, secondary primary malignancies in each treatment group (1.9% in KdD arm and 1.3% in Kd arm) have been reported.

Opportunistic infections

In study 20160275, opportunistic infections in each treatment group (9.4% in KdD arm and 3.9% in Kd arm) have been reported. Opportunistic infections occurring in ≥ 1% of subjects in the KdD arm included herpes zoster, oral candidiasis, oral herpes, and herpes simplex.

Hepatitis B reactivation

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

Other special populations

Elderly patients

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

In study 20160275, 47% of the 308 patients who received KdD 20/56 mg/m2 twice weekly were ≥ 65 years of age. In the KdD arm of the study, fatal treatment-emergent adverse events occurred in 6% of patients < 65 years of age and 14% of patients ≥ 65 years of age. In the Kd arm, these events occurred in 8% of patients < 65 years of age and 3% of patients ≥ 65 years of age.

Reporting 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.