28.04.2015 :‫תאריך‬
Name of the product:
Kyprolis :‫שם תכשיר באנגלית‬
Registration No's:
151-21-33948-00 :‫מספר רישום‬
Name of the registration owner:
Amgen Europe B.V. ‫שם בעל הרישום‬
Current
------WARNINGS AND PRECAUTIONS----- Cardiac Adverse Reactions including heart failure and ischemia: Monitor
for cardiac complications. Treat promptly and withhold KYPROLIS.
(2.4, 5.1)
 Pulmonary Hypertension: Withhold dosing if suspected. (2.4, 5.2)
 Pulmonary Complications: Monitor for and manage dyspnea
immediately; interrupt KYPROLIS until symptoms have resolved or
returned to baseline. (2.4, 5.3)
 Infusion Reactions: Pre-medicate with dexamethasone to prevent. (2.3)
Advise patients to seek immediate medical attention if symptoms
develop. (5.4)
 Tumor Lysis Syndrome (TLS): Hydrate patients to prevent. (2.2)
Monitor for TLS and treat promptly. (5.5)
 Thrombocytopenia: Monitor platelet counts; reduce or interrupt dosing
as clinically indicated. (2.4, 5.6)
 Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes and
withhold dosing if suspected. (2.4, 5.7)
 Embryo-fetal Toxicity: KYPROLIS can cause fetal harm. Females of
reproductive potential should avoid becoming pregnant while being
treated. (5.8, 8.1)
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Guidelines
2.2 Hydration and Fluid Monitoring
Proposed
-------------WARNINGS AND PRECAUTIONS------------ Cardiac Adverse Reactions including heart failure and ischemia: Monitor for
cardiac complications. Treat promptly and withhold KYPROLIS. (2.4, 5.1)
 Pulmonary Hypertension: Withhold dosing if suspected. (2.4, 5.2)
 Pulmonary Complications: Monitor for and manage dyspnea immediately;
interrupt KYPROLIS until symptoms have resolved or returned to baseline.
(2.4, 5.3)
 Infusion Reactions: Pre-medicate with dexamethasone to prevent. (2.3)
Advise patients to seek immediate medical attention if symptoms
develop. (5.4)
 Tumor Lysis Syndrome (TLS): Hydrate patients to prevent. (2.2) Monitor
for TLS and treat promptly. (5.5)
 Thrombocytopenia: Monitor platelet counts; reduce or interrupt dosing as
clinically indicated. (2.4, 5.6)
 Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes and withhold
dosing if suspected. (2.4, 5.7)
 Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
(TTP/HUS). Monitor for signs and symptoms of TTP/HUS. Discontinue
KYPROLIS if suspected. (5.8).
 Posterior reversible encephalopathy syndrome (PRES): Consider neuroradiological imaging (MRI) for onset of visual or neurological symptoms;
discontinue KYPROLIS if suspected. (5.9)
 Embryo-fetal Toxicity: KYPROLIS can cause fetal harm. Females of
reproductive potential should avoid becoming pregnant while being treated.
(5.10, 8.1)
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Guidelines
2.2 Hydration and Fluid Monitoring
3
4
5
6
7
2.3 Dexamethasone Premedication
2.4 Dose Modifications based on Toxicities
2.5 Administration Precautions
2.6 Reconstitution and Preparation for Intravenous Administration
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
5.1 Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia
5.2 Pulmonary Hypertension
5.3 Pulmonary Complications
5.4 Infusion Reactions
5.5 Tumor Lysis Syndrome
5.6 Thrombocytopenia
5.7 Hepatic Toxicity and Hepatic Failure
5.8 Embryo-fetal Toxicity
ADVERSE REACTIONS
6.1 Clinical Trials Safety Experience
DRUG INTERACTIONS
3
4
5
6
[…]
7
2.3 Dexamethasone Premedication
2.4 Dose Modifications based on Toxicities
2.5 Administration Precautions
2.6 Reconstitution and Preparation for Intravenous Administration
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
5.1 Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia
5.2 Pulmonary Hypertension
5.3 Pulmonary Complications
5.4 Infusion Reactions
5.5 Tumor Lysis Syndrome
5.6 Thrombocytopenia
5.7 Hepatic Toxicity and Hepatic Failure
5.8 Thrombocytopenic Thrombotic Purpura/Hemolytic Uremic Syndrome
5.9 Posterior Reversible Encephalopathy Syndrome (PRES)
5.10 Embryo-fetal Toxicity
ADVERSE REACTIONS
6.1 Clinical Trials Safety Experience
6.2 Post-marketing Experience
DRUG INTERACTIONS
[…]
5
WARNINGS AND PRECAUTIONS
5
[…]
[…]
5.8 Embryo-fetal Toxicity
5.8
WARNINGS AND PRECAUTIONS
Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic
Syndrome
Cases of thrombotic thrombocytopenic purpura/hemolytic uremic
syndrome (TTP/HUS) including fatal outcome have been reported in
patients who received KYPROLIS. Monitor for signs and symptoms of
TTP/HUS. If the diagnosis is suspected, stop KYPROLIS and evaluate.
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.
5.9
Posterior Reversible Encephalopathy Syndrome (PRES)
PRES, formerly termed Reversible Posterior Leukoencephalopathy
Syndrome (RPLS), is a 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 (MRI).
Cases of PRES have been reported in patients receiving KYPROLIS.
Discontinue KYPROLIS if PRES is suspected and evaluate. The safety
of reinitiating KYPROLIS therapy in patients previously experiencing
PRES is not known.
5.8 5.10
Embryo-fetal Toxicity
KYPROLIS can cause fetal harm when administered to a pregnant
KYPROLIS can cause fetal harm when administered to a pregnant
woman based on its mechanism of action and findings in animals.
woman based on its mechanism of action and findings in animals.There
There are no adequate and well-controlled studies in pregnant
are no adequate and well-controlled studies in pregnant women using
women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity
KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant
in pregnant rabbits at doses that were lower than in patients receiving
rabbits at doses that were lower than in patients receiving the
the recommended dose.
recommended dose.
Females of reproductive potential should be advised to avoid
Females of reproductive potential should be advised to avoid becoming
becoming pregnant while being treated with KYPROLIS. If this
pregnant while being treated with KYPROLIS. If this drug is used
drug is used during pregnancy, or if the patient becomes pregnant
during pregnancy, or if the patient becomes pregnant while taking this
while taking this drug, the patient should be apprised of the potential
drug, the patient should be apprised of the potential hazard to the fetus
hazard to the fetus [see Use in Specific Populations (8.1)].
[see Use in Specific Populations (8.1)].
6
ADVERSE REACTIONS
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in
The following adverse reactions are discussed in greater detail in other
other sections of the labeling:
sections of the labeling:

Cardiac Arrest, Congestive Heart Failure, Myocardial
Ischemia [see Warnings and Precautions (5.1)]

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia
[see Warnings and Precautions (5.1)]

Pulmonary Hypertension [see Warnings and Precautions
(5.2)]

Pulmonary Hypertension [see Warnings and Precautions (5.2)]


Pulmonary Complications [see Warnings and Precautions (5.3)]
Pulmonary Complications [see Warnings and Precautions
(5.3)]

Infusion Reactions [see Warnings and Precautions (5.4)]

Infusion Reactions [see Warnings and Precautions (5.4)]

Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]

Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]

Thrombocytopenia [see Warnings and Precautions (5.6)]

Thrombocytopenia [see Warnings and Precautions (5.6)]


Hepatic Toxicity and Hepatic Failure [see Warnings and
Precautions (5.7)]
Hepatic Toxicity and Hepatic Failure [see Warnings and
Precautions (5.7)]

Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic
Syndrome [see Warnings and Precautions (5.8)]

Posterior Reversible Encephalopathy Syndrome (PRES) [see
Warnings and Precautions (5.9)]
The most common adverse reactions (incidence of 30% or greater) to
KYPROLIS observed in clinical trials of patients with multiple
myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea,
The most common adverse reactions (incidence of 30% or greater) to
diarrhea, and pyrexia.
KYPROLIS observed in clinical trials of patients with multiple myeloma
were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and
pyrexia.
6
ADVERSE REACTIONS
6
[…]
ADVERSE REACTIONS
[…]
6.2 Post-marketing Experience
The following adverse reactions were reported in the post-marketing
experience: dehydration, peripheral neuropathy, rash, thrombotic
thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS),
tumor lysis syndrome including fatal outcomes, and posterior reversible
encephalopathy syndrome (PRES). Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible
to reliably estimate their frequency or establish a causal relationship to
drug exposure.
8
USE IN SPECIFIC POPULATIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.1
Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.8)].
Pregnancy Category D [see Warnings and Precautions (5.8 5.10)].
.‫ שבו מסומנות ההחמרות המבוקשות על רקע צהוב‬,‫מצ"ב העלון‬
The leaflet, in which the changes requested are yellow highlighted, was sent by e -mail on 29/04/15
‫שינויים שאינם בגדר החמרות סומנו (בעלון) בצבע שונה‪ .‬יש לסמן רק תוכן מהותי ולא שינויים במיקום הטקסט‪.‬‬