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Kymriah cells dispersion for infusion
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Clinical particulars - Fertility, pregnancy and lactation
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Interaction with other medicinal products and other forms of interaction
No pharmacokinetic or pharmacodynamic drug interaction studies with tisagenlecleucel have been performed. The co-administration of agents known to inhibit T-cell function has not been formally studied. Administration of low-dose steroids as per the cytokine release syndrome treatment algorithm does not impact the expansion and persistence of CAR-T cells. The co-administration of agents known to stimulate T-cell function has not been investigated and the effects are unknown.
Live vaccines
The safety of immunisation with live vaccines during or following Kymriah treatment has not been studied. Vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and until immune recovery following treatment with Kymriah.
4.6
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Kymriah cells dispersion for infusion
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Clinical particulars - Effects on ability to drive and use machines
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Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Pregnancy status for females of child-bearing age should be verified prior to starting treatment with Kymriah.
See the prescribing information for lymphodepleting chemotherapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Kymriah.
Pregnancy
There are no data from the use of Kymriah in pregnant women. No animal studies have been conducted with Kymriah to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3). It is not known whether Kymriah has the potential to be transferred to the foetus via the placenta and could cause foetal toxicity, including B-cell lymphocytopenia. Kymriah is not recommended during pregnancy and in women of childbearing potential not using contraception.
Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Kymriah therapy should be discussed with the treating physician. Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with Kymriah.
Breast-feeding
It is unknown whether Kymriah cells are excreted in human milk. A risk to the breast-fed infant cannot be excluded. Women who are breast-feeding should be advised of the potential risk to the breast-fed infant.
Following administration of Kymriah, breast-feeding should be discussed with the treating physician.
Fertility
There are no data on the effect of Kymriah on fertility. Effects of Kymriah on male and female fertility have not been evaluated in animal studies.
4.7
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Kymriah cells dispersion for infusion
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Clinical particulars - Undesirable effects
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Effects on ability to drive and use machines
Kymriah has major influence on the ability to drive and use machines.
Due to the potential for neurological events, including altered mental status or seizures, patients receiving Kymriah are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion.
4.8
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Kymriah cells dispersion for infusion
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Clinical particulars - Overdose
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Undesirable effects
Summary of the safety profile
Safety assessment was based on a total of 424 patients (with paediatric and young adult B-cell ALL, DLBCL and FL) who received Kymriah in three multicentre pivotal clinical studies.
B-cell ALL
The adverse reactions described in this section were characterised in 212 patients infused with Kymriah in the pivotal clinical study CCTL019B2202 and in the supportive studies CCTL019B2205J and CCTL019B2001X.
The most common non-haematological adverse reactions were cytokine release syndrome (75%), infections (70%), hypogammaglobulinaemia (49%), pyrexia (43%) and decreased appetite (28%).
The most common haematological laboratory abnormalities were decreased white blood cells (100%), decreased haemoglobin (99%), decreased neutrophils (98%), decreased lymphocytes (98%) and decreased platelets (95%).
Grade 3 and 4 adverse reactions were reported in 86% of patients. The most common Grade 3 and 4 non-haematological adverse reaction was cytokine release syndrome (37%).
The most common Grade 3 and 4 haematological laboratory abnormalities were white blood cells decreased (97%), lymphocytes decreased (94%), neutrophils decreased (96%), platelets decreased (70%) and haemoglobin decreased (46%).
Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post-infusion (78% of patients) compared to after 8 weeks post-infusion (49% of patients).
DLBCL
The adverse reactions described in this section were characterised in 115 patients infused with Kymriah in one global multicentre international study, i.e. the ongoing pivotal clinical study CCTL019C2201.
The most common non-haematological adverse reactions were cytokine release syndrome (57%), infections (58%), pyrexia (35%), diarrhoea (31%), nausea (29%), fatigue (27%) and hypotension (25%).
The most common haematological laboratory abnormalities were decreased lymphocytes (100%), decreased white blood cells (99%), decreased haemoglobin (99%), decreased neutrophils (97%), and decreased platelets (95%).
Grade 3 and 4 adverse reactions were reported in 88% of patients. The most common Grade 3 and 4 non-haematological adverse reactions were infections (34%) and cytokine release syndrome (23%).
The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocyte count decreased (95%), neutrophil count decreased (82%), white blood cell count decreased (78%), haemoglobin decreased (59%) and platelet count decreased (56%).
Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post-infusion (82%) compared to after 8 weeks post-infusion (48%).
FL
The adverse reactions described in this section were characterised in 97 patients infused with Kymriah in one global multicentre international study, i.e. the ongoing pivotal clinical study CCTL019E2202.
The most common non-haematological adverse reactions (>25%) were cytokine release syndrome (50%), infections (50%) and headache (26%).
The most common haematological laboratory abnormalities were decreased haemoglobin (94%), decreased lymphocytes (92%), decreased white blood cells (91%), decreased neutrophils (89%) and decreased platelets (89%).
Grade 3 and 4 adverse reactions were reported in 75% of patients. The most common Grade 3 and 4 non-haematological adverse reactions were infections (16%).
The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocyte count decreased (87%), white blood cell count decreased (74%), neutrophil count decreased (71%), platelet count decreased (26%) and haemoglobin decreased (25%).
Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post-infusion (70%) compared to after 8 weeks post-infusion (40%).
Tabulated list of adverse drug reactions
The adverse reactions described in this section were identified in 79, 115 and 97 patients in the ongoing multicentre pivotal clinical studies (CCTL019B2202, CCTL019C2201 and CCTL019E2202), as well as 64 and 69 patients in the supportive studies (CCTL019B2205J and CCTL019B2001X). Adverse drug reactions from these clinical studies (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first, using the following convention: 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); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.
Table 2 Adverse drug reactions observed in clinical studies
Infections and infestations1)
Very common:
Infections pathogen unspecified, viral infections, bacterial infections
Common:
Fungal infections
Blood and lymphatic system disorders
Very common:
Anaemia, febrile neutropenia, neutropenia, thrombocytopenia
Common:
Leukopenia, pancytopenia, coagulopathy, lymphopenia
Uncommon:
B-cell aplasia
Immune system disorders
Very common:
Cytokine release syndrome, hypogammaglobulinaemia2)
Common:
Infusion-related reaction, graft-versus-host disease3), haemophagocytic lymphohistiocytosis
Metabolism and nutrition disorders
Very common:
Decreased appetite, hypokalaemia, hypophosphataemia
Common:
Hypomagnesaemia, hypoalbuminaemia4), hyperglycaemia, hyponatraemia, hyperuricaemia5), hypercalcaemia, tumour lysis syndrome, hyperkalaemia, hyperphosphataemia6), hypernatraemia, hyperferritinaemia7), hypocalcaemia
Uncommon:
Hypermagnesaemia
Psychiatric disorders
Common:
Anxiety, delirium8), sleep disorder9)
Nervous system disorders
Very common
Headache10), encephalopathy11)
Common:
Dizziness12), peripheral neuropathy13), tremor14), motor dysfunction15), seizure16), speech disorders17), neuralgia18)
Uncommon:
Ischaemic cerebral infarction, ataxia19), immune effector cell-associated neurotoxicity syndrome**
Eye disorders
Common:
Visual impairment20)
Cardiac disorders
Very common:
Tachycardia21)
Common:
Cardiac failure22), cardiac arrest, atrial fibrillation
Uncommon:
Ventricular extrasystoles
Vascular disorders
Very common:
Haemorrhage23), hypotension24), hypertension
Common:
Thrombosis25), capillary leak syndrome
Uncommon:
Flushing
Respiratory, thoracic and mediastinal disorders
Very common:
Cough26), dyspnoea27), hypoxia
Common:
Oropharyngeal pain28), pulmonary oedema29), nasal congestion, pleural effusion, tachypnoea
Uncommon:
Acute respiratory distress syndrome, lung infiltration
Gastrointestinal disorders
Very common:
Diarrhoea, nausea, vomiting, constipation, abdominal pain30)
Common:
Stomatitis, abdominal distension, dry mouth, ascites
Hepatobiliary disorders
Common:
Hyperbilirubinaemia
Skin and subcutaneous tissue disorders
Very common:
Rash31)
Common
Pruritus, erythema, hyperhidrosis, night sweats
Musculoskeletal and connective tissue disorders
Very common:
Arthralgia, musculoskeletal pain32)
Common:
Myalgia
Renal and urinary disorders
Very common
Acute kidney injury33)
General disorders and administration site conditions
Very common:
Pyrexia, fatigue34), oedema35), pain36)
Common:
Influenza-like illness, asthenia, multiple organ dysfunction syndrome, chills
Investigations
Very common:
Lymphocyte count decreased*, white blood cell count decreased*, haemoglobin decreased*, neutrophil count decreased*, platelet count decreased*, hepatic enzyme increased37)
Common:
Blood bilirubin increased, weight decreased, blood fibrinogen decreased, international normalised ratio increased, fibrin D dimer increased, activated partial thromboplastin time prolonged, prothrombin time prolonged
1) Infections and infestations presented reflect high-level group terms.
2) Hypogammaglobulinaemia includes blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, hypogammaglobulinaemia, immunodeficiency, immunodeficiency common variable and immunoglobulins decreased.
3) Graft-versus-host disease (GvHD) includes GvHD, GvHD in gastrointestinal tract, GvHD in skin
4) Hypoalbuminaemia includes blood albumin decreased, hypoalbuminaemia
5) Hyperuricaemia includes blood uric acid increased, hyperuricaemia.
6) Hyperphosphataemia includes blood phosphorus increased, hyperphosphataemia.
7) Hyperferritinaemia includes hyperferritinaemia, serum ferritin increased
8) Delirium includes agitation, delirium, hallucination, hallucination visual, irritability and restlessness.
9) Sleep disorder includes insomnia, nightmare and sleep disorder.
10) Headache includes headache and migraine.
11) Encephalopathy includes automatism, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, encephalopathy, lethargy, memory impairment, mental status changes, metabolic encephalopathy, somnolence and thinking abnormal. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms.
12) Dizziness includes dizziness, presyncope and syncope.
13) Peripheral neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, neuropathy peripheral, paraesthesia and peripheral sensory neuropathy.
14) Tremor includes dyskinesia and tremor.
15) Motor dysfunction includes muscle spasms, muscle twitching, myoclonus and myopathy.
16) Seizure includes generalised tonic-clonic seizures, seizure and status epilepticus.
17) Speech disorders includes aphasia, dysarthria and speech disorders.
18) Neuralgia includes neuralgia and sciatica.
19) Ataxia includes ataxia and dysmetria.
20) Visual impairment includes vision blurred and visual impairment.
21) Tachycardia includes sinus tachycardia, supraventricular tachycardia, tachycardia
22) Cardiac failure includes cardiac failure, cardiac failure congestive, left ventricular dysfunction and right ventricular dysfunction.
23) Haemorrhage includes anal haemorrhage, blood blister, blood urine present, catheter site haemorrhage, cerebral haemorrhage, conjunctival haemorrhage, contusion, cystitis haemorrhagic, disseminated intravascular coagulation, duodenal ulcer haemorrhage, ecchymosis, epistaxis, eye contusion, gastrointestinal haemorrhage, gingival bleeding, haemarthrosis, haematemesis, haematochezia, haematoma, haematuria, haemoptysis, heavy menstrual bleeding, injection site haematoma, intermenstrual bleeding, large intestinal haemorrhage, lip haemorrhage, melaena, mouth haemorrhage, mucosal haemorrhage, oral blood blister, periorbital haematoma, peritoneal haematoma, petechiae, pharyngeal haemorrhage, postprocedural haemorrhage, pulmonary haemorrhage, purpura, rectal haemorrhage, retinal haemorrhage, stoma site haemorrhage, subcutaneous haematoma, subdural haematoma, subdural haemorrhage, tooth socket haemorrhage, tracheal haemorrhage, traumatic haematoma, tumour haemorrhage, upper gastrointestinal haemorrhage and vaginal haemorrhage.
24) Hypotension includes hypotension and orthostatic hypotension.
25) Thrombosis includes deep vein thrombosis, embolism, pulmonary embolism, thrombosis, vena cava thrombosis and venous thrombosis.
26) Cough includes cough, productive cough and upper-airway cough syndrome.
27) Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory distress and respiratory failure.
28) Oropharyngeal pain includes oral pain and oropharyngeal pain.
29) Pulmonary oedema includes acute pulmonary oedema and pulmonary oedema.
30) Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper and gastrointestinal pain.
31) Rash includes dermatitis, dermatitis acneiform, dermatitis contact, rash, rash maculo papular, rash papular and rash pruritic.
32) Musculoskeletal pain includes back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, neck pain, non-cardiac chest pain.
33) Acute kidney injury includes acute kidney injury, anuria, azotaemia, blood creatinine abnormal, blood creatinine increased, blood urea increased, renal failure, renal tubular dysfunction and renal tubular necrosis.
34) Fatigue includes fatigue and malaise.
35) Oedema includes face oedema, fluid retention, generalised oedema, hypervolaemia, localised oedema, oedema peripheral, periorbital oedema and peripheral swelling.
36) Pain includes pain and pain in extremity.
37) Hepatic enzyme increased includes alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, hepatic enzyme increased, transaminases increased.
* Frequency is based on laboratory values. Patients are counted only for the worst grade observed post baseline.
** Abbreviated as ICANS. Symptoms or signs can be progressive and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral oedema.
Description of selected adverse drug reactions
Cytokine release syndrome
In the clinical studies in paediatric and young adult B cell ALL (N=212), cytokine release syndrome was reported in 75% of patients (37% with Grade 3 or 4; 0.5% [1 patient] with fatal outcome).
In the ongoing clinical study in DLBCL (N=115), cytokine release syndrome was reported in 57% of patients (23% with Grade 3 or 4).
In the ongoing clinical study in FL (N=97), cytokine release syndrome was reported in 50% of patients. No Grade 3 or 4 events were reported.
Cytokine release syndrome was graded per Penn criteria in the paediatric and young adult B-cell ALL and DLBCL studies as follows: Grade 1: mild reactions, reactions requiring supportive care; Grade 2: moderate reactions, reactions requiring intravenous therapies; Grade 3: severe reactions, reactions requiring low-dose vasopressors or supplemental oxygen; Grade 4: life-threatening reactions, those requiring high-dose vasopressors or intubation; Grade 5: death.
Cytokine release syndrome was graded per the Lee criteria in the FL study as follows: Grade 1: mild general symptoms requiring symptomatic treatment; Grade 2: symptoms requiring moderate intervention such as low-flow oxygen supplementation or low-dose vasopressor; Grade 3: symptoms requiring aggressive intervention, such as high-flow oxygen supplementation and high-dose vasopressor; Grade 4: life-threatening symptoms requiring intubation; Grade 5: death.
For clinical management of cytokine release syndrome, see section 4.4 and Table 1.
Infections and febrile neutropenia
In B-cell ALL patients severe infections (Grade 3 and higher), which can be life-threatening or fatal, occurred in 36% of patients after Kymriah infusion. The overall incidence (all grades) was 70% (unspecified 55%, viral 31%, bacterial 24% and fungal 12%) (see section 4.4). 41% of the patients experienced an infection of any type within 8 weeks after Kymriah infusion.
In DLBCL patients severe infections (Grade 3 and higher), which can be life-threatening or fatal, occurred in 34% of patients. The overall incidence (all grades) was 58% (unspecified 48%, bacterial 15%, fungal 11% and viral 11%) (see section 4.4). 37% of the patients experienced an infection of any type within 8 weeks.
In FL patients severe infections (Grade 3 or 4), occurred in 16% of patients. The overall incidence (all grades) was 50% (unspecified 36%, viral 17%, bacterial 6%, and fungal 2%) (see section 4.4). 19% of the patients experienced an infection of any type within 8 weeks.
Severe febrile neutropenia (Grade 3 or 4) was observed in 26% of paediatric and young adult B-cell ALL patients, 17% of DLBCL patients and 12% of FL patients. See section 4.4 for the management of febrile neutropenia before and after Kymriah infusion.
Prolonged cytopenias
Cytopenias are very common based on prior chemotherapies and Kymriah therapy.
All paediatric and young adult B-cell ALL patients had a Grade 3 or 4 cytopenia at some time after Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 after Kymriah infusion based on laboratory findings included decreased count of white blood cells (50%), neutrophils (56%), lymphocytes (43%), and thrombocytes (32%) and decreased haemoglobin (11%).
All adult DLBCL patients had Grade 3 and 4 cytopenias at some time after Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 based on laboratory findings included decreased count of thrombocytes (39%), lymphocytes (29%), neutrophils (25%), and white blood cells (21%) and decreased haemoglobin (14%).
In adult patients with FL, 99% had Grade 3 and 4 cytopenias at any time post Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 after Kymriah infusion based on laboratory findings included a decreased count of lymphocytes (23%), thrombocytes (17%), neutrophils (16%), white blood cells (13%) and decreased haemoglobin (3%).
Neurological adverse reactions
The majority of neurotoxic events occurred within 8 weeks following infusion and were transient.
In paediatric and young adult B-cell ALL patients, serious neurological adverse reactions including manifestations of encephalopathy and/or delirium occurred in 32% of patients (10% were Grade 3 or 4) within 8 weeks after Kymriah infusion. In DLBCL patients, manifestations of encephalopathy and/or delirium occurred in 20% of patients (11% were Grade 3 or 4) within 8 weeks after Kymriah infusion. In FL patients, these occurred in 9% of patients (1% Grade 3 or 4) within 8 weeks after Kymriah infusion. Among the neurotoxic events in FL patients, immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4% of patients (1% Grade 3 or 4), all within 8 weeks of Kymriah infusion.
Hypogammaglobulinaemia
Hypogammaglobulinaemia was reported in 49% of patients treated with Kymriah for r/r ALL, 17% of patients with r/r DLBCL and 17% of patients with r/r FL.
Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Immunoglobulin levels should be assessed in newborns of mothers treated with Kymriah.
Immunogenicity
In clinical studies, humoral immunogenicity of tisagenlecleucel was measured by determination of anti-murine CAR19 antibodies (anti-mCAR19) in serum pre- and post-administration. The majority of patients tested positive for pre-dose anti-mCAR19 antibodies in paediatric and young adult ALL (B2202, B2205J, B2001X, 84.0%), adult DLBCL (C2201, 93.9%) and adult FL (E2202, 66.0%) patients.
Treatment-induced anti-mCAR19 antibodies were found in 40.5% of paediatric and young adult ALL (B2202), 8.7% of adult DLBCL and 28.7% of adult FL patients. Pre-existing and treatment-induced antibodies were not associated with an impact on clinical response nor did they have an impact on the expansion and persistence of tisagenlecleucel. There is no evidence that the presence of pre-existing and treatment-induced anti-mCAR19 antibodies impacts the safety or effectiveness of Kymriah.
T-cell immunogenicity responses were not observed in paediatric and young adult B-cell ALL, adult r/r DLBCL and adult FL patients.
Paediatric population
The safety of tisagenlecleucel in r/r B-cell ALL paediatric patients from 3 years of age and older was assessed in 212 patients in the pivotal study B2202 and the supportive studies B2205J and B2001X in which the majority of patients (81%) were under 18 years old (65/79 in B2202, 54/64 in B2205J and 52/69 in B2001X). The frequency, type and severity of adverse reactions in paediatric patients are reflected in “Summary of the safety profile” and in Table 2 above.
The safety of tisagenlecleucel in r/r B-cell ALL paediatric patients below 3 years of age was assessed in the observational study B2401 (n=43) where the overall safety experience was generally consistent with the known safety profile of tisagenlecleucel.
Post-marketing experience
The following adverse drug reactions have been derived from post-marketing experience with Kymriah via spontaneous case reports, literature cases, expanded access programs, and clinical studies other than the global registration studies. 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 tisagenlecleucel exposure.
Frequency unknown: Anaphylactic reaction/infusion related reaction, neurotoxicity.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9
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Kymriah cells dispersion for infusion
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Clinical particulars - Subsection 10
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Overdose
Not applicable.
5. Pharmacological properties
5.1
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Kymriah cells dispersion for infusion
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Pharmacodynamic properties - Pharmacodynamic properties
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Pharmacokinetic properties
Following infusion of Kymriah into paediatric and young adult r/r B-cell ALL, r/r DLBCL and r/r FL patients, tisagenlecleucel typically exhibited an initial rapid expansion followed by a slower bi-exponential decline. High inter-subject variability was associated with the in vivo exposure metrics (AUC0-28d and Cmax) across all indications.
Cellular kinetics in paediatric and young adult B-cell ALL patients
A summary of cellular kinetic parameters of tisagenlecleucel in paediatric and young adult B-cell ALL patients is provided in Table 9 below. The maximal expansion (Cmax) was approximately 1.6-fold higher in CR/CRi patients (n=103) compared with non-responding (NR) patients (n=10) as measured by qPCR. Delayed and lower expansion was observed in NR patients compared to CR/CRi patients.
Table 9 Cellular kinetic parameters of tisagenlecleucel in paediatric and young adult r/r B-cell ALL (Studies B2202 and B2205J)
Parameter
Summary statistics
Responding patients (CR/CRi)
N=105
Non-responding patients (NR)
N=12
Cmax (copies/μg)
Geometric mean (CV%), n
35,300 (154.0), 103
21,900 (80.7), 10
Tmax‡ (day)
Median [min;max], n
9.83 [5.70; 27.8], 103
20.1 [12.6; 62.7], 10
AUC0-28d (copies/μg*day)
Geometric mean (CV%), n
309,000 (178.1), 103
232,000 (104.5), 8
T½ (day)
Geometric mean (CV%), n
25.2 (307.8), 71
3.80 (182.4), 4
Tlast
Median [min;max], n
166 [20.9; 916], 103
28.8 [26.7; 742], 9
Cellular kinetics in adult DLBCL patients
A summary of cellular kinetic parameters of tisagenlecleucel in DLBCL patients is provided in Table 10 below.
Table 10 Cellular kinetic parameters of tisagenlecleucel in r/r DLBCL patients
Parameter
Summary statistics
Responding patients
(CR and PR)
N=43
Non-responding patients
(SD/PD/Unknown)
N=72
Cmax (copies/μg)
Geometric mean (CV%), n
5,840 (254.3), 43
5,460 (326.89), 65
Tmax (day)
Median [min;max], n
9.00 [5.78; 19.8], 35
8.84 [3.04; 27.7], 65
AUC0-28d (copies/μg*day)
Geometric mean (CV%), n
61,200 (177.7), 40
67,000 (275.2), 56
T½ (day)
Geometric mean (CV%), n
129 (199.2), 33
14.7 (147.1), 44
Tlast
Median [min;max], n
551 [17.1; 1030], 43
61.4 [19.8; 685], 56
Cellular kinetics in FL patients
A summary of cellular kinetic parameters of tisagenlecleucel in FL patients by BOR is provided in Table 11 below.
The geometric mean AUC0-28d value of responders was 2.9 fold higher compared to non-responders, while the geometric mean Cmax value was 2.1 fold higher in responders compared to non-responders.
Table 11 Cellular kinetic parameters of tisagenlecleucel in r/r FL patients
Parameter
Summary statistics
Responding patients
(CR and PR)
N=81
Non-responding patients
(SD/PD)
N=12
Cmax (copies/micrograms)
Geometric mean (CV%), n
6280 (331), 67
3000 (1190), 8
Tmax (day)
Median [min;max], n
9.92 [2.62; 28.0], 67
13.0 [7.73; 16.0], 8
AUC0-28d (copies/micrograms*day)
Geometric mean (CV%), n
57500 (261), 66
20100 (18100), 7
T½ (day)
Geometric mean (CV%), n
43.8 (287), 43
24.4 (180), 6
Tlast (day)
Median [min;max], n
191 [19.9; 558], 73
107 [18.7; 366], 10
Distribution
In paediatric and young adult B-cell ALL patients, tisagenlecleucel has been shown to be present in the blood and bone marrow beyond 2 years. The blood to bone marrow partitioning of tisagenlecleucel in bone marrow was 47.2% of that present in blood at day 28 while at months 3 and 6 it distributes at 68.3% and 69%, respectively (Studies B2202 and B2205J). Tisagenlecleucel also traffics and persists in cerebrospinal fluid in paediatric and young adult B-cell ALL patients (Study B2101J) for up to 1 year.
In adult DLBCL patients (Study C2201), tisagenlecleucel has been detected for up to 3 years in peripheral blood and up to month 9 in bone marrow for complete responder patients. The blood to bone marrow partitioning in bone marrow was nearly 70% of that present in blood at day 28 and 50% at month 3 in both responder and non-responder patients.
In adult FL patients (Study E2202), tisagenlecleucel has been detected for up to 18 months in peripheral blood and up to month 3 in bone marrow for complete responder patients. The blood to bone marrow partitioning in bone marrow was nearly 54% of that present in blood at month 3 in both responder and non-responder patients.
Elimination
The elimination profile of Kymriah includes a bi-exponential decline in peripheral blood and bone marrow.
Linearity/non-linearity
There is no apparent relationship between dose and AUC0-28d or Cmax.
Special populations
Elderly
The scatter plots of cellular kinetic parameters versus age (22 to 76 years in DLBCL patients and 29 to 73 years in FL patients) revealed no relevant relationship between cellular kinetic parameters (AUC0-28d and Cmax) with age.
Gender
Gender has not been identified as a significant characteristic influencing tisagenlecleucel expansion in B-cell ALL, DLBCL and FL patients. In Study B2202, there were 43% female and 57% male patients, in Study C2201 38% female and 62% male patients and in Study E2202 34% female and 66% male patients who received Kymriah. Further, in Study E2202, the geometric means of the exposure parameters (Cmax and AUC0-28d) were shown to be 111% and 106% higher, respectively, in female patients compared to male patients. Although the interpretation of expansion in relation to gender is difficult due to overlapping ranges and high inter-subject variability.
Race/ethnicity
There is limited evidence that race/ethnicity impact the expansion of Kymriah in paediatric and young adult ALL, DLBCL and FL patients. In Study B2202 there were 73.4% Caucasian, 12.7% Asian and 13.9% other ethnic patients. In Study C2201 there were 85% Caucasian, 9% Asian, 4% Black or African American patients, and 3 patients (3%) of unknown race. In Study E2202, there were 75% Caucasian, 13% Asian, 1% Black or African American patients, and 10% of unknown race.
Body weight
In ALL, DLBCL and FL patients, across the weight ranges (ALL; 14.4 to 137 kg; DLBCL: 38.4 to 186.7 kg; FL: 44.3 to 127.7 kg), the scatter plots of qPCR cellular kinetic parameters versus weight revealed no apparent relationship between cellular kinetic parameters with weight.
Prior transplantation
Prior transplantation did not impact the expansion/persistence of Kymriah in paediatric and young adult B-cell ALL patients, adult DLBCL or adult FL patients.
5.3
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Kymriah cells dispersion for infusion
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Pharmacodynamic properties - Pharmacokinetic properties
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Preclinical safety data
Non-clinical safety assessment of Kymriah addressed the safety concerns of potential uncontrolled cell growth of transduced T cells in vitro and in vivo as well as dose-related toxicity, biodistribution and persistence. No such risks were identified based on these studies.
Carcinogenicity and mutagenicity
Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically-modified cell therapy products. No alternative adequate animal models are available.
In vitro expansion studies with CAR-positive T cells (Kymriah) from healthy donors and patients showed no evidence for transformation and/or immortalisation of T cells. In vivo studies in immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell expansion for up to 7 months, which represents the longest meaningful observation period for immunocompromised mouse models. A genomic insertion site analysis of the lentiviral vector was performed on Kymriah products from 14 individual donors (12 patients and 2 healthy volunteers). There was no evidence for preferential integration near genes of concern or preferential outgrowth of cells harbouring integration sites of concern.
Reproductive toxicity
No non-clinical reproductive safety studies were conducted as no adequate animal model is available.
Juvenile animal studies
Juvenile toxicity studies were not conducted.
6.
|
Kymriah cells dispersion for infusion
|
Pharmaceutical particulars - List of excipients
|
List of excipients
Glucose
Sodium chloride
Human albumin solution
Dextran 40 for injection
Dimethylsulfoxide
Sodium gluconate
Sodium acetate
Potassium chloride
Magnesium chloride
Sodium-N-acetyltryptophanate
Sodium caprylate
Aluminium
Water for injections
6.2
|
Kymriah cells dispersion for infusion
|
Pharmaceutical particulars - Incompatibilities
|
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3
|
Kymriah cells dispersion for infusion
|
Pharmaceutical particulars - Shelf life
|
Shelf life
9 months.
The product should be administered immediately after thawing. After thawing, the product should be kept at room temperature (20°C-25°C) and infused within 30 minutes to maintain maximum product viability, including any interruption during the infusion.
6.4
|
Kymriah cells dispersion for infusion
|
Pharmaceutical particulars - Special precautions for storage
|
Special precautions for storage
Store and transport below -120°C, e.g. in a container for cryogenic storage in the vapour phase of liquid nitrogen.
For storage conditions after thawing of the medicinal product, see section 6.3.
6.5
|
Kymriah cells dispersion for infusion
|
Pharmaceutical particulars - Nature and contents of container
|
Nature and contents of container
Ethylene vinyl acetate (EVA) infusion bag with polyvinyl chloride (PVC) tubing and a luer spike interconnector closed by a luer-lock cap containing either 10–30 mL (50 mL bags) or 30–50 mL (250 mL bags) cell dispersion.
Each infusion bag is placed into a secondary packaging layer.
One individual treatment dose comprises 1 or more infusion bags.
6.6
|
Kymriah cells dispersion for infusion
|
Pharmaceutical particulars - Special precautions for disposal and other handling
|
Special precautions for disposal and other handling
Inspection and thawing of the infusion bag(s)
Do not thaw the product until it is ready to be used.
The infusion bag should be placed inside a second sterile bag during thawing to protect ports from contamination and avoid spills in the unlikely event of the bag leaking. Kymriah should be thawed at 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. The bag should be removed immediately from the thawing device and kept at room temperature (20°C-25°C) until infusion. If more than one infusion bag has been received for the treatment dose, the next bag should only be thawed after the contents of the preceding bag have been infused.
Kymriah should not be manipulated. For example, Kymriah should not be washed (spun down and resuspended in new media) prior to infusion.
The infusion bag(s) should be examined for any breaks or cracks prior to thawing. If the infusion bag appears to have been damaged or to be leaking, it should not be infused and should be disposed of according to local procedures on handling of biological waste (see section 4.2.).
Precautions to be taken for transport and disposal of the medicinal product
Kymriah should be transported within the facility in closed, break-proof, leak-proof containers.
Kymriah contains genetically-modified human blood cells. Local guidelines on handling of biological waste should be followed for unused medicinal product or waste material. All material that has been in contact with Kymriah (solid and liquid waste) should be handled and disposed in accordance with local guidelines on handling of biological waste.
7.
|
Kymriah cells dispersion for infusion
|
Marketing authorisation holder
|
Novartis Pharmaceuticals UK Limited
2nd Floor, The WestWorks Building
White City Place
195 Wood Lane
London W12 7FQ
8. Marketing authorisation number(s)
PLGB 00101/1101
9.
|
Kymriah cells dispersion for infusion
|
Date of first authorisation/renewal of the authorisation
|
01 January 2021
10.
|
Kymriah cells dispersion for infusion
|
Date of revision of the text
|
11 July 2023
LEGAL CATEGORY
POM
|
Kyntheum 210 mg Solution for Injection
|
Name of the medicinal product
|
Kyntheum 210 mg solution for injection in pre-filled syringe
2.
|
Kyntheum 210 mg Solution for Injection
|
Qualitative and quantitative composition
|
Each pre-filled syringe contains 210 mg brodalumab in 1.5 ml solution.
1 ml solution contains 140 mg brodalumab.
Brodalumab is a human monoclonal antibody produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3.
|
Kyntheum 210 mg Solution for Injection
|
Pharmaceutical form
|
Solution for injection (injection)
The solution is clear to slightly opalescent, colourless to slightly yellow and free from particles.
4.
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Therapeutic indications
|
Therapeutic indications
Kyntheum is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy.
4.2
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Posology and method of administration
|
Posology and method of administration
Kyntheum is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of psoriasis.
Posology
The recommended dose is 210 mg administered by subcutaneous injection at weeks 0, 1, and 2 followed by 210 mg every 2 weeks.
Consideration should be given to discontinuing treatment in patients who have shown no response after 12-16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.
Elderly (aged 65 years and over)
No dose adjustment is recommended in elderly patients (see section 5.2).
Renal and hepatic impairment
Kyntheum has not been studied in these patient populations. No dose recommendations can be made.
Paediatric population
The safety and efficacy of Kyntheum in children and adolescents below the age of 18 years have not yet been established. No data are available.
Method of administration
Kyntheum is administered by subcutaneous injection. Each pre-filled syringe is for single use only. Kyntheum should not be injected into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis. The pre-filled syringe must not be shaken.
After proper training in subcutaneous injection technique, patients may self-inject Kyntheum when deemed appropriate by a physician. Patients should be instructed to inject the full amount of Kyntheum according to the instructions provided in the package leaflet. Detailed instructions for use are included at the end of the package leaflet.
4.3
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Contraindications
|
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active Crohn's disease.
Clinically important active infections (e.g. active tuberculosis, see section 4.4).
4.4
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Special warnings and precautions for use
|
Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Inflammatory bowel disease (including Crohn's disease and ulcerative colitis)
Cases of new or exacerbations of inflammatory bowel disease have been reported with IL-17 inhibitors. Therefore, brodalumab is not recommended in patients with inflammatory bowel disease (see section 4.8). If a patient develops signs and symptoms of inflammatory bowel disease, or experiences an exacerbation of pre-existing inflammatory bowel disease, treatment should be discontinued and appropriate medical management should be initiated.
Suicidal ideation and behaviour
Suicidal ideation and behaviour, including completed suicide, have been reported in patients treated with brodalumab. The majority of patients with suicidal behaviour had a history of depression and/or suicidal ideation or behaviour. A causal association between treatment with brodalumab and increased risk of suicidal ideation and behaviour has not been established.
The risk and benefit of treatment with brodalumab should be carefully weighed for patients with a history of depression and/or suicidal ideation or behaviour, or for patients who develop such symptoms. Patients, caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal ideation, anxiety, or other mood changes, and they should contact their healthcare provider if such events occur. If a patient suffers from new or worsening symptoms of depression and/or suicidal ideation or behaviour is identified, it is recommended to discontinue treatment.
Hypersensitivity reactions
Rare cases of anaphylactic reactions have been reported in the post-marketing setting. In the event of an anaphylactic reaction, or any other serious allergic reaction, administration of brodalumab should be discontinued and appropriate therapy initiated.
Infections
Brodalumab may increase the risk of infections.
During the 12-week placebo-controlled clinical trial period in patients with psoriasis, serious infections were observed in 0.5% of patients receiving brodalumab (see section 4.8).
Caution should be exercised when considering the use of brodalumab in patients with a chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, the patient should be closely monitored and brodalumab should not be administered until the infection resolves.
Brodalumab should not be given to patients with active tuberculosis. Anti-tuberculosis therapy should be considered prior to initiation of treatment in patients with latent tuberculosis.
Vaccinations
It is recommended that patients be brought up-to-date with all immunisations in accordance with local immunisation guidelines prior to initiation of treatment. Live vaccines should not be given concurrently with brodalumab (see section 4.5). No data are available on the response to live vaccines or the risk of infection, or transmission of infection after the administration of live vaccines in patients receiving brodalumab.
Vaccination of infants
Vaccination of infants with live vaccines following third trimester exposure to brodalumab should be discussed with a physician (see also section 4.6).
Concomitant immunosuppressive therapy
The safety and efficacy of brodalumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated.
4.5
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Interaction with other medicinal products and other forms of interaction
|
Interaction with other medicinal products and other forms of interaction
Live vaccines should not be given concurrently with brodalumab (see section 4.4).
The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g. IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Although a role for interleukin (IL)-17A and IL-17RA in the regulation of CYP450 enzymes has not been reported, the effect of brodalumab on CYP3A4/3A5 activity was evaluated in a disease-drug-drug interaction study.
In patients with moderate to severe plaque psoriasis, a single subcutaneous dose of 210 mg brodalumab increased the exposure of midazolam, a CYP3A4/3A5 substrate by 24%. Based on the magnitude of change in exposure of midazolam, no dose adjustment of CYP3A4/3A5 substrates is necessary when administered concomitantly with brodalumab.
4.6
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Fertility, pregnancy and lactation
|
Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should use an effective method of contraception during treatment and for at least 12 weeks after treatment.
Pregnancy
There are no or limited amount of data from the use of brodalumab in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Human IgG2 is known to cross the placental barrier and brodalumab is a human IgG2, therefore, brodalumab has the potential to be transmitted from the mother to the developing foetus. As a precautionary measure, it is preferable to avoid the use of Kyntheum in pregnancy.
As the metabolism of brodalumab is unknown in infants, benefit risk for exposure of the infant to live vaccines following third trimester exposure to Kyntheum should be discussed with a physician.
Breast-feeding
It is unknown whether brodalumab is excreted in human milk. Brodalumab is a monoclonal antibody and is expected to be present in the first milk and at low levels afterwards.
A risk to the newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Kyntheum therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
No data are available on the effect of brodalumab on human fertility. Animal studies did not show any effects on male and female reproductive organs and on sperm count, motility and morphology (see section 5.3).
4.7
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Effects on ability to drive and use machines
|
Effects on ability to drive and use machines
Kyntheum has no or negligible influence on the ability to drive and use machines.
4.8
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Undesirable effects
|
Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions are arthralgia (4.6%), headache (4.3%), fatigue (2.6%), diarrhoea (2.2%), and oropharyngeal pain (2.1%).
Tabulated list of adverse reactions
Adverse reactions from clinical trials and post-marketing experience (Table 1) are listed by MedDRA system organ class (SOC). Within each SOC, the adverse reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse reaction is based on the following convention: 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) and very rare (<1/10,000). Within each frequency grouping adverse reactions are presented in order of decreasing seriousness.
Table
1: List of adverse reactions in clinical trials and post-marketing experience
System Organ Class
Frequency
Adverse reaction
Infections and infestations
Common
Influenza
Tinea infections (including tinea pedis, tinea versicolor, tinea cruris)
Uncommon
Candida infections (including oral, genital, and oesophageal infections)
Blood and lymphatic system disorders
Uncommon
Neutropenia
Immune system disorders
Rare
Anaphylactic reaction*
Nervous system disorders
Common
Headache
Eye disorders
Uncommon
Conjunctivitis
Respiratory, thoracic and mediastinal disorders
Common
Oropharyngeal pain
Gastrointestinal disorders
Common
Diarrhoea
Nausea
Musculoskeletal and connective tissue disorders
Common
Arthralgia
Myalgia
General disorders and administration site conditions
Common
Fatigue
Injection site reactions (including injection site erythema, pain, pruritus, bruising, haemorrhage)
* from post-marketing experience
Description of selected adverse reactions
Inflammatory bowel disease
Cases of new or exacerbations of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) have been reported with IL-17 inhibitors (see section 4.4).
Infections
During the 12-week placebo-controlled trial period in plaque psoriasis, infections were reported in 28.2% of patients treated with brodalumab compared with 23.4% of patients treated with placebo. The majority of infections consisted of nasopharyngitis, upper respiratory tract infection, pharyngitis, urinary tract infections, bronchitis, influenza and sinusitis, which did not necessitate treatment discontinuation. Serious infections occurred in 0.5% of patients treated with brodalumab and in 0.1% of patients treated with placebo. Higher rates of fungal infections, primarily non-serious skin and mucosal candida infections, were observed in brodalumab patients compared to placebo patients, 2.5% vs 1.0%, respectively.
Through week 52, the event rates per 100 patient-years for infections were 134.7 for patients treated with brodalumab and 124.1 for patients treated with ustekinumab. The event rates per 100 patient-years for serious infections were 2.4 for patients treated with brodalumab and 1.2 for patients treated with ustekinumab. One serious case of cryptococcal meningitis and one serious case of coccidioidies infection were observed in clinical trials (see section 4.4).
Neutropenia
During the 12-week placebo-controlled period of clinical trials, neutropenia was reported in 0.9% of patients treated with brodalumab compared with 0.5% of patients treated with placebo. Most of the brodalumab-associated neutropenias were mild, transient and reversible.
Neutropenia Grade 3 (<1.0 × 109/L to 0.5 × 109/L) was reported in 0.5% of patients receiving brodalumab compared to none of the patients who received ustekinumab or placebo. No Neutropenia Grade 4 (<0.5 × 109/L) was reported in patients who received either brodalumab or placebo, but in 0.2% of patients who received ustekinumab. No serious infections were associated with neutropenia.
Immunogenicity
Antibodies to brodalumab developed in 2.2% (88/3935) of patients treated with brodalumab for up to 52 weeks in psoriasis clinical trials (0.3% of the patients had anti-brodalumab antibodies at baseline). Of these patients, none had neutralising antibodies.
No evidence of altered pharmacokinetic profile, clinical response, or safety profile was associated with anti-brodalumab antibody development.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9
|
Kyntheum 210 mg Solution for Injection
|
Clinical particulars - Overdose
|
Overdose
Doses up to 700 mg intravenously have been administered in clinical trials with no evidence of dose limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.
5. Pharmacological properties
5.1
|
Kyntheum 210 mg Solution for Injection
|
Pharmacodynamic properties - Pharmacodynamic properties
|
Pharmacokinetic properties
Absorption
Based on population pharmacokinetic modelling, the estimated accumulation ratio after 20 weeks of dosing is 2.5-fold. In moderate to severe plaque psoriasis patients following a single subcutaneous administration of brodalumab at 210 mg, the mean maximum serum concentration (Cmax) was 13.4 mcg/ml (standard deviation [SD] = 7.29 mcg/ml). The median time to maximum concentration (Tmax) was 3.0 days (range: 2.0 to 4.0 days) and the mean area under the concentration time curve to the last measurable concentration (AUClast) was 111 mcg*day/ml (SD = 64.4 mcg*day/ml). The subcutaneous bioavailability of brodalumab estimated by population pharmacokinetic modelling was 55%.
The observed pharmacokinetic parameters during steady-state (weeks 10-12) were: mean steady-state area under the concentration time curve over the dosing interval (AUCtau) was 227.4 mcg*day/ml (SD = 191.7 mcg*day/ml) corresponding to average concentration (Cav,ss) of 16.2 mcg/ml, mean Cmax was 20.9 mcg/ml (SD = 17.0 mcg/ml) and Week 12 mean minimum serum concentration (Ctrough) was 9.8 mcg/ml (SD = 11.2 mcg/ml).
Distribution
Based on population pharmacokinetic modelling, the estimated mean steady-state volume of distribution of brodalumab was approximately 7.24 L.
Biotransformation
As an IgG2 human monoclonal antibody brodalumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Elimination
Following subcutaneous administrations of 210 mg, brodalumab exhibits non-linear pharmacokinetics typical for a monoclonal antibody that undergoes target-mediated drug disposition.
Brodalumab clearance decreases with increasing dose and exposure increases in a greater than dose-proportional manner. For a 3-fold increase in SC brodalumab dose from 70 to 210 mg, the steady-state serum brodalumab Cmax and AUC0-t increased approximately 18- and 25-fold, respectively.
Following a single subcutaneous administration of brodalumab 210 mg in plaque psoriasis patients, the apparent clearance (CL/F) is 2.95 L/day.
Population pharmacokinetic modelling predicted that serum brodalumab concentrations dropped below the quantification limit (0.05 mcg/ml) 63 days after discontinuation of steady-state dosing of brodalumab 210 mg administered every 2 weeks in 95% of the patients. However, brodalumab concentrations below LLOQ (Lower Limit of Quantification) were associated with IL-17 receptor occupancy up to 81%.
Based on population pharmacokinetic modelling the estimated half-life of brodalumab was 10.9 days at steady-state after every other week subcutaneous dose of 210 mg.
Impact of weight on pharmacokinetics
Population pharmacokinetic modelling indicated that exposure decreased as body weight increased. No dose adjustment is recommended.
Elderly patients
Population pharmacokinetic modelling indicated that age did not have an effect on brodalumab pharmacokinetics, which was co-based on 259 (6%) patients being 65-74 years old and on 14 (0.3%) patients being ≥75 years old, within a total PK population of 4271 plaque psoriasis patients.
Renal or hepatic impairment
No pharmacokinetic data are available in patients with impaired renal or hepatic function. Renal elimination of intact brodalumab, an IgG monoclonal antibody, is expected to be low and of minor consequence. Brodalumab is expected to be mainly eliminated via catabolism and hepatic impairment is not expected to influence clearance.
Other populations
The pharmacokinetics of brodalumab was similar between Japanese and non-Japanese patients with psoriasis.
Population pharmacokinetic analysis indicated that gender did not have an effect on brodalumab pharmacokinetics.
Pharmacokinetic/pharmacodynamic relationship(s)
A population pharmacokinetic/pharmacodynamic model, developed using all available data indicated that at a dose of 210 mg every 2 weeks, 90% of all patients would be predicted to maintain a trough concentration greater than the estimated IC90 value of 1.51 mcg/ml. Based on an exploratory descriptive analysis, no relationship was observed between exposure and incidence of serious infections and infestations, candida infections, viral infections, and suicidal ideation and behaviour events. Exposure-response analysis indicates that higher brodalumab concentrations are related to better PASI and sPGA response.
5.3
|
Kyntheum 210 mg Solution for Injection
|
Pharmacodynamic properties - Pharmacokinetic properties
|
Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints and assessment of fertility-related endpoints), and toxicity to reproduction and development.
Carcinogenicity studies with brodalumab have not been conducted. However, there were no proliferative changes in cynomolgus monkeys administered weekly subcutaneous doses of brodalumab at 90 mg/kg for 6 months (AUC exposure 47-fold higher than in human patients receiving brodalumab 210 mg every 2 weeks). The mutagenic potential of brodalumab was not evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
In cynomolgus monkeys there were no effects on male and female reproductive organs and on sperm count, motility and morphology following administration of brodalumab at dose levels up to 90 mg/kg once weekly for 6 months, (AUC exposure up to 47-fold higher than in human patients receiving brodalumab 210 mg every 2 weeks).
In cynomolgus monkeys, no effects on embryo-foetal or postnatal (up to 6 months of age) development were observed when brodalumab was dosed subcutaneously throughout pregnancy at exposure levels up to 27-fold higher than those achieved in human patients receiving brodalumab 210 mg every 2 weeks based on the area under the concentration curve (AUC). Serum concentrations in monkey infants and in foetal rabbits indicated considerable passage of brodalumab from the mother to the foetus at the end of pregnancy.
In cynomolgus monkeys, after weekly subcutaneous dosing of brodalumab at dose levels up to 90 mg/kg for 6 months, brodalumab-related effects were limited to injection site reactions and mucocutaneous inflammation that was consistent with pharmacologic modulation of host surveillance to commensal microflora. There were no effects on peripheral blood immunophenotyping and the T-cell dependent antibody response assay. In a local tolerance test in rabbits, moderate to severe edema was observed after subcutaneous injection of a formulation containing brodalumab at the clinical concentration of 140 mg/ml.
6.
|
Kyntheum 210 mg Solution for Injection
|
Pharmaceutical particulars - List of excipients
|
List of excipients
Proline
Glutamate
Polysorbate 20
Water for injections
6.2
|
Kyntheum 210 mg Solution for Injection
|
Pharmaceutical particulars - Incompatibilities
|
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3
|
Kyntheum 210 mg Solution for Injection
|
Pharmaceutical particulars - Shelf life
|
Shelf life
4 years
6.4
|
Kyntheum 210 mg Solution for Injection
|
Pharmaceutical particulars - Special precautions for storage
|
Special precautions for storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
Kyntheum may be stored at room temperature (up to 25°C) once, in the outer carton, for a maximum single period of 14 days. Once Kyntheum has been removed from the refrigerator and has reached room temperature (up to 25°C) it must either be used within 14 days or discarded.
6.5
|
Kyntheum 210 mg Solution for Injection
|
Pharmaceutical particulars - Nature and contents of container
|
Nature and contents of container
1.5 ml solution in a type I glass pre-filled syringe with stainless steel 27G x ½” needle, covered with an elastomeric needle cap.
Kyntheum is available in unit packs containing 2 pre-filled syringes and in multipacks containing 6 (3 packs of 2) pre-filled syringes.
Not all pack sizes may be marketed.
6.6
|
Kyntheum 210 mg Solution for Injection
|
Pharmaceutical particulars - Special precautions for disposal and other handling
|
Special precautions for disposal and other handling
To avoid discomfort at the site of injection, at least 30 minutes should be allowed for the pre-filled syringe to reach room temperature before injecting. The pre-filled syringe should not be warmed in any other way. The pre-filled syringe should not be shaken. The needle cap on the pre-filled syringe should not be removed while allowing to reach room temperature.
Kyntheum should be visually inspected for particles and discoloration prior to administration.. This medicinal product should not be used if the solution is cloudy or discoloured or contains lumps, flakes, or particles.
The pre-filled syringe should not be used if it has been dropped on a hard surface.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.
|
Kyntheum 210 mg Solution for Injection
|
Marketing authorisation holder
|
LEO Pharma A/S
Industriparken 55
DK-2750 Ballerup
Denmark
8. Marketing authorisation number(s)
PLGB 05293/0171
9.
|
Kyntheum 210 mg Solution for Injection
|
Date of first authorisation/renewal of the authorisation
|
19/07/2022
10.
|
Kyntheum 210 mg Solution for Injection
|
Date of revision of the text
|
19/07/2022
|
Kyprolis powder for solution for infusion
|
Name of the medicinal product
|
Kyprolis 10 mg powder for solution for infusion
Kyprolis 30 mg powder for solution for infusion
Kyprolis 60 mg powder for solution for infusion
2.
|
Kyprolis powder for solution for infusion
|
Qualitative and quantitative composition
|
Kyprolis 10 mg powder for solution for infusion
Each vial contains 10 mg of carfilzomib.
Excipient with known effect
Each vial contains 37 mg sodium.
Each vial contains 500 mg of cyclodextrin (betadex sulfobutyl ether sodium).
Kyprolis 30 mg powder for solution for infusion
Each vial contains 30 mg of carfilzomib.
Excipient with known effect
Each vial contains 109 mg sodium.
Each vial contains 1,500 mg of cyclodextrin (betadex sulfobutyl ether sodium).
Kyprolis 60 mg powder for solution for infusion
Each vial contains 60 mg of carfilzomib.
Excipient with known effect
Each vial contains 216 mg sodium.
Each vial contains 3,000 mg of cyclodextrin (betadex sulfobutyl ether sodium).
After reconstitution, 1 mL of solution contains 2 mg of carfilzomib.
For the full list of excipients, see section 6.1.
3.
|
Kyprolis powder for solution for infusion
|
Pharmaceutical form
|
Powder for solution for infusion.
White to off-white lyophilised powder.
4.
|
Kyprolis powder for solution for infusion
|
Clinical particulars - Therapeutic indications
|
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
|
Kyprolis powder for solution for infusion
|
Clinical particulars - Posology and method of administration
|
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
|
Kyprolis powder for solution for infusion
|
Clinical particulars - Contraindications
|
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
|
Kyprolis powder for solution for infusion
|
Clinical particulars - Special warnings and precautions for use
|
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
|
Kyprolis powder for solution for infusion
|
Clinical particulars - Interaction with other medicinal products and other forms of interaction
|
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
|
Kyprolis powder for solution for infusion
|
Clinical particulars - Fertility, pregnancy and lactation
|
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
|
Kyprolis powder for solution for infusion
|
Clinical particulars - Effects on ability to drive and use machines
|
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
|
Kyprolis powder for solution for infusion
|
Clinical particulars - Undesirable effects
|
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
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Kyprolis powder for solution for infusion
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Clinical particulars - Overdose
|
Overdose
There is currently insufficient information to draw conclusions about the safety of doses higher than those evaluated in clinical studies. Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error.
There is no known specific antidote for carfilzomib overdose. In the event of an overdose, the patient should be monitored, specifically for the adverse reactions to Kyprolis listed in section 4.8.
5. Pharmacological properties
5.1
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Kyprolis powder for solution for infusion
|
Pharmacodynamic properties - Pharmacodynamic properties
|
Pharmacokinetic properties
Absorption
The Cmax and AUC following a 2 to 10 minute intravenous infusion of 27 mg/m2 was 4,232 ng/mL and 379 ng•hr/mL, respectively. Following repeated doses of Kyprolis at 15 and 20 mg/m2, systemic exposure (AUC) and half-life were similar on days 1 and 15 or 16 of cycle 1, suggesting there was no systemic carfilzomib accumulation. At doses between 20 and 56 mg/m2, there was a dose-dependent increase in exposure.
A 30 minute infusion resulted in a similar half-life and AUC, but 2- to 3-fold lower Cmax compared to that observed with a 2 to 10 minute infusion of the same dose. Following a 30 minute infusion of the 56 mg/m2 dose, the AUC (948 ng•hr/mL) was approximately 2.5-fold that observed at the 27 mg/m2 level, and Cmax (2,079 ng/mL) was lower compared to that of 27 mg/m2 over the 2 to 10 minute infusion.
Distribution
The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the concentration range of 0.4 to 4 micromolar.
Biotransformation
Carfilzomib was rapidly and extensively metabolised. The predominant metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450 mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity.
Elimination
Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on day 1 of cycle 1. The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. Carfilzomib is eliminated primarily via metabolism with subsequent excretion of its metabolites in urine.
Special populations
Population pharmacokinetic analyses indicate there are no effects of age, gender or race on the pharmacokinetics of carfilzomib.
Hepatic impairment
A pharmacokinetic study evaluated 33 patients with relapsed or progressive advanced malignancies (solid tumours; n = 31 or haematologic malignancies; n = 2) who had normal hepatic function (bilirubin ≤ upper limit of normal [ULN]; aspartate aminotransferase [AST] ≤ ULN, n = 10), mild hepatic impairment (bilirubin > 1-1.5 × ULN or AST > ULN, but bilirubin ≤ ULN, n = 14), or moderate hepatic impairment (bilirubin > 1.5-3 × ULN; any AST, n = 9). The pharmacokinetics of carfilzomib has not been studied in patients with severe hepatic impairment (bilirubin > 3 × ULN and any AST). Kyprolis, as a single agent, was administered intravenously over 30 minutes at 20 mg/m2 on days 1 and 2 and at 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1. If tolerated, patients received 56 mg/m2 starting in cycle 2. Baseline hepatic function status had no marked effect on the total systemic exposure (AUClast) of carfilzomib following single or repeat-dose administration (geometric mean ratio in AUClast at the 27 mg/m2 dose in cycle 1, day 16 for mild and moderate impairment versus normal hepatic function were 144.4% and 126.1%, respectively; and at the 56 mg/m2 dose in cycle 2, day 1 were 144.7% and 121.1%). However, in patients with mild or moderate baseline hepatic impairment, all of whom had solid tumours, there was a higher subject incidence of hepatic function abnormalities, ≥ grade 3 adverse events and serious adverse events compared with subjects with normal hepatic function (see section 4.2).
Renal impairment
The pharmacokinetics of carfilzomib was studied in two dedicated renal impairment studies.
The first study was conducted in 50 multiple myeloma patients with normal renal function (CrCL > 80 mL/min, n = 12), mild (CrCL 50-80 mL/min, n = 12), moderate (CrCL 30-49 mL/min, n = 10), and severe (CrCL < 30 mL/min, n = 8) renal impairment, and patients on chronic dialysis (n = 8). Kyprolis, as a single agent, was administered intravenously over 2 to 10 minutes at doses up to 20 mg/m2. Pharmacokinetic data were collected from patients following the 15 mg/m2 dose in cycle 1 and the 20 mg/m2 dose in cycle 2. The second study was conducted in 23 relapsed multiple myeloma patients with creatinine clearance ≥ 75 mL/min (n = 13) and patients with end stage renal disease (ESRD) requiring dialysis (n = 10). Pharmacokinetic data were collected from patients following administration of a 27 mg/m2 dose as a 30 minute infusion on cycle 1, day 16 and the 56 mg/m2 dose on cycle 2, day 1.
Results from both studies show that renal function status had no marked effect on the exposure of carfilzomib following single or repeat-dose administration. The geometric mean ratio in AUClast at the 15 mg/m2 dose cycle 1, day 1 for mild, moderate, severe renal impairment and chronic dialysis versus normal renal function were 124.36%, 111.07%, 84.73% and 121.72%, respectively. The geometric mean ratios in AUClast at the 27 mg/m2 dose cycle 1, day 16 and at the 56 mg/m2 dose cycle 2, day 1 for ESRD versus normal renal function were 139.72% and 132.75%, respectively. In the first study the M14 metabolite, a peptide fragment and the most abundant circulating metabolite, increased 2- and 3-fold in patients with moderate and severe renal impairment, respectively, and 7-fold in patients requiring dialysis (based on AUClast). In the second study, the exposures for M14 were greater (approximately 4-fold) in subjects with ESRD than in subjects with normal renal function. This metabolite has no known biological activities. Serious adverse events related to worsening renal function were more common in subjects with baseline renal dysfunction (see section 4.2).
5.3
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Kyprolis powder for solution for infusion
|
Pharmacodynamic properties - Pharmacokinetic properties
|
Preclinical safety data
Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.
Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (which corresponds to 36 mg/m2 and is similar to the recommended dose in humans of 27 mg/m2 based on BSA) experienced hypotension, increased heart rate, and increased serum levels of troponin T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac haemorrhage/degeneration), gastrointestinal (necrosis/haemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (haemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on BSA. The highest non-severely toxic dose of 0.5 mg/kg in monkeys resulted in interstitial inflammation in the kidney along with slight glomerulopathy and slight heart inflammation. Those findings were reported at 6 mg/m2 which are below the recommended dose in humans of 27 mg/m2.
Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies. Carfilzomib caused embryo-foetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Carfilzomib administered to pregnant rats during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day, which is approximately half the recommended dose in humans of 27 mg/m2 based on BSA.
6.
|
Kyprolis powder for solution for infusion
|
Pharmaceutical particulars - List of excipients
|
List of excipients
Betadex sulfobutyl ether sodium
Anhydrous citric acid (E330)
Sodium hydroxide (for pH adjustment)
6.2
|
Kyprolis powder for solution for infusion
|
Pharmaceutical particulars - Incompatibilities
|
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Kyprolis powder for solution for infusion must not be mixed with sodium chloride 9 mg/mL (0.9%) solution for injection.
6.3
|
Kyprolis powder for solution for infusion
|
Pharmaceutical particulars - Shelf life
|
Shelf life
Powder vial (unopened)
3 years.
Reconstituted solution
Chemical and physical in-use stability of reconstituted solutions in the vial, syringe or intravenous bag has been demonstrated for 24 hours at 2°C - 8°C or for 4 hours at 25°C. The elapsed time from reconstitution to administration should not exceed 24 hours.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should not be longer than 24 hours at 2°C – 8°C.
6.4
|
Kyprolis powder for solution for infusion
|
Pharmaceutical particulars - Special precautions for storage
|
Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5
|
Kyprolis powder for solution for infusion
|
Pharmaceutical particulars - Nature and contents of container
|
Nature and contents of container
Kyprolis 10 mg powder for solution for infusion
10 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with a light blue plastic flip off cap.
Kyprolis 30 mg powder for solution for infusion
30 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with an orange plastic flip off cap.
Kyprolis 60 mg powder for solution for infusion
50 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with a purple plastic flip off cap.
Pack size of one vial.
6.6
|
Kyprolis powder for solution for infusion
|
Pharmaceutical particulars - Special precautions for disposal and other handling
|
Special precautions for disposal and other handling
General precautions
Carfilzomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of Kyprolis. Use of gloves and other protective equipment is recommended.
Reconstitution and preparation for intravenous administration
Kyprolis vials contain no antimicrobial preservatives and are intended for single use only. Proper aseptic technique must be observed.
The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution:
1. Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patient's BSA at baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of ≤ 20%.
2. Remove vial from refrigerator just prior to use.
3. Use only a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to aseptically reconstitute each vial by slowly injecting 5 mL (for 10 mg vial), 15 mL (for 30 mg vial) or 29 mL (for 60 mg vial) sterile water for injections through the stopper and directing the solution onto the INSIDE WALL OF THE VIAL to minimise foaming.
4. Gently swirl and/or invert the vial slowly for approximately 1 minute, or until complete dissolution. DO NOT SHAKE. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately 5 minutes) and the solution is clear.
5. Visually inspect for particulate matter and discolouration prior to administration. The reconstituted product should be a clear, colourless to slightly yellow solution and should not be administered if any discolouration or particulate matter is observed.
6. Discard any unused portion left in the vial.
7. Kyprolis can be administered directly by intravenous infusion or optionally administered in an intravenous bag. Do not administer as an intravenous push or bolus.
8. When administering in an intravenous bag, use only a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose from the vial and dilute into a 50 or 100 mL intravenous bag containing 5% glucose solution for injection.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.
|
Kyprolis powder for solution for infusion
|
Marketing authorisation holder
|
Amgen Limited
216 Cambridge Science Park
Milton Road
Cambridge
CB4 0WA
United Kingdom
8. Marketing authorisation number(s)
PLGB 13832/0023
PLGB 13832/0024
PLGB 13832/0025
9.
|
Kyprolis powder for solution for infusion
|
Date of first authorisation/renewal of the authorisation
|
01/01/2021
10.
|
Kyprolis powder for solution for infusion
|
Date of revision of the text
|
21/04/2022
|
Kytril 1 mg film-coated tablets
|
Name of the medicinal product
|
Kytril 1 mg film-coated tablets
2.
|
Kytril 1 mg film-coated tablets
|
Qualitative and quantitative composition
|
2.1 General description
2.2
|
Kytril 1 mg film-coated tablets
|
Qualitative and quantitative composition
|
Each film-coated tablet contains 1 mg granisetron (as the hydrochloride).
Excipients with known effect:
Each tablet contains 69.38 mg of lactose monohydrate.
Sodium starch glycolate
For the full list of excipients, see section 6.1.
3.
|
Kytril 1 mg film-coated tablets
|
Pharmaceutical form
|
Film-coated tablet.
The tablets are white to almost white triangular biconvex tablets imprinted with K1 on one side.
4.
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Therapeutic indications
|
Therapeutic indications
Kytril film-coated tablets are indicated in adults for the prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapy.
Kytril film-coated tablets are indicated in adults for prevention of delayed nausea and vomiting associated with chemotherapy and radiotherapy.
4.2
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Posology and method of administration
|
Posology and method of administration
Posology
1 mg twice a day or 2 mg once a day for up to one week following radiotherapy or chemotherapy. The first dose of Kytril should be administered within 1 hour before the start of therapy. Dexamethasone has been used concomitantly at doses up to 20 mg once a day orally.
Paediatric population
The safety and efficacy of granisetron tablets in children have not yet been established.
No data are available.
Older people and renal impairment
There are no special precautions required for its use in either elderly patients or those patients with renal impairment.
Hepatic impairment
There is no evidence to date for an increased incidence of adverse events in patients with hepatic disorders. On the basis of its kinetics, whilst no dosage adjustment is necessary, granisetron should be used with a certain amount of caution in this patient group (see section 5.2).
Method of administration
The tablets should be swallowed whole with water.
4.3
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Contraindications
|
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Special warnings and precautions for use
|
Special warnings and precautions for use
As granisetron may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following its administration.
As for other 5-HT3 antagonists, ECG changes including QT interval prolongation have been reported with granisetron. In patients with pre-existing arrhythmias or cardiac conduction disorders this might lead to clinical consequences. Therefore caution should be exercised in patients with cardiac co-morbidities, on cardiotoxic chemotherapy and/or with concomitant electrolyte abnormalities (see section 4.5).
Cross-sensitivity between 5-HT3 antagonists (e.g. dolasteron, ondansetron) has been reported.
Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone, but mostly in combination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRIs), and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like symptoms is advised.
Kytril is essentially 'sodium free' as it contains less than 1 mmol sodium (23 mg) per dose (2 mg).
Paediatric population
There is insufficient clinical evidence to recommend administration of these tablets to children.
4.5
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Interaction with other medicinal products and other forms of interaction
|
Interaction with other medicinal products and other forms of interaction
As for other 5-HT3 antagonists, cases of ECG modifications including QT prolongation have been reported with granisetron. In patients concurrently treated with medicinal products known to prolong QT interval and/or which are arrhythmogenic, this may lead to clinical consequences (see section 4.4).
In studies in healthy subjects, no evidence of any interaction has been indicated between granisetron and benzodiazepines (lorazepam), neuroleptics (haloperidol) or anti-ulcer medicinal products (cimetidine). Additionally, granisetron has not shown any apparent medicinal product interaction with emetogenic cancer chemotherapies.
No specific interaction studies have been conducted in anaesthetised patients.
Serotonergic medicinal products (e.g. SSRIs and SNRIs): there have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists and other serotonergic medicinal products (including SSRIs and SNRIs) (see section 4.4).
4.6
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Fertility, pregnancy and lactation
|
Fertility, pregnancy and lactation
Pregnancy
There is limited amount of data from the use of granisetron in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of granisetron during pregnancy.
Breastfeeding
It is unknown whether granisetron or its metabolites are excreted in human milk. As a precautionary measure, breast-feeding should not be advised during treatment with Kytril.
Fertility
In rats, granisetron had no harmful effects on reproductive performance or fertility.
4.7
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Effects on ability to drive and use machines
|
Effects on ability to drive and use machines
Kytril has no or negligible influence on the ability to drive and use machines.
4.8
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Undesirable effects
|
Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions for Kytril are headache and constipation, which may be transient. ECG changes including QT prolongation have been reported with Kytril (see sections 4.4 and 4.5).
Tabulated list of adverse reactions
The following table of listed adverse reactions is derived from clinical trials and post-marketing data associated with Kytril and other 5-HT3 antagonists.
Frequency categories are as follows:
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)
Very rare (<1/10,000)
Immune system disorders
Uncommon
Hypersensitivity reactions e.g. anaphylaxis, urticaria
Psychiatric disorders
Common
Insomnia
Nervous system disorders
Very common
Headache
Uncommon
Extrapyramidal Reactions
Uncommon
Serotonin Syndrome (see also sections 4.4 and 4.5)
Cardiac disorders
Uncommon
QT prolongation
Gastrointestinal disorders
Very common
Constipation
Common
Diarrhoea
Hepatobiliary disorders
Common
Elevated hepatic transaminases*
Skin and subcutaneous tissue disorders
Uncommon
Rash
*Occurred at a similar frequency in patients receiving comparator therapy
Description of selected adverse reactions
As for other 5-HT3 antagonists, ECG changes including QT prolongation have been reported with granisetron (see sections 4.4 and 4.5).
As with other 5-HT3 antagonists, cases of serotonin syndrome (including altered mental status, autonomic dysfunction and neuromuscular abnormalities) have been reported following the concomitant use of Kytril and other serotonergic drugs (see sections 4.4 and 4.5).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.
4.9
|
Kytril 1 mg film-coated tablets
|
Clinical particulars - Overdose
|
Overdose
There is no specific antidote for Kytril. In the case of overdose with the tablets, symptomatic treatment should be given. Doses of up to 38.5 mg of Kytril as a single injection have been reported, with symptoms of mild headache but no other reported sequelae.
5. Pharmacological properties
5.1
|
Kytril 1 mg film-coated tablets
|
Pharmacodynamic properties - Pharmacodynamic properties
|
Pharmacokinetic properties
Pharmacokinetics of the oral administration is linear up to 2.5-fold of the recommended dose in adults. It is clear from the extensive dose-finding programme that the antiemetic efficacy is not unequivocally correlated with either administered doses or plasma concentrations of granisetron.
A fourfold increase in the initial prophylactic dose of granisetron made no difference in terms of either the proportion of patient responding to treatment or in the duration of symptoms control.
Absorption
Absorption of granisetron is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism. Oral bioavailability is generally not influenced by food.
Distribution
Granisetron is extensively distributed, with a mean volume of distribution of approximately 3 l/kg. Plasma protein binding is approximately 65%.
Biotransformation
Granisetron is metabolized primarily in the liver by oxidation followed by conjugation. The major compounds are 7-OH-granisetron and its sulphate and glycuronide conjugates. Although antiemetic properties have been observed for 7-OH-granisetron and indazoline N-desmethyl granisetron, it is unlikely that these contribute significantly to the pharmacological activity of granisetron in man.
In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily (see section 4.5).
Elimination
Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged granisetron averages 12% of dose while that of metabolites amounts to about 47% of dose. The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients by the oral and intravenous route is approximately 9 hours, with a wide inter-subject variability.
Pharmacokinetics in special populations
Renal failure
In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects.
Hepatic impairment
In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary (see section 4.2).
Paediatric population
These tablets are not recommended in children.
Older people
In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.
5.3
|
Kytril 1 mg film-coated tablets
|
Pharmacodynamic properties - Pharmacokinetic properties
|
Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproductive toxicity and genotoxicity. Carcinogenicity studies revealed no special hazard for humans when used in the recommended human dose. However, when administered in higher doses and over a prolonged period of time the risk of carcinogenicity cannot be ruled out.
A study in cloned human cardiac ion channels has shown that granisetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. Granisetron has been shown to block both sodium and potassium channels, which potentially affects both depolarization and repolarization through prolongation of PR, QRS, and QT intervals. This data helps to clarify the molecular mechanisms by which some of the ECG changes (particularly QT and QRS prolongation) associated with this class of agents occur. However, there is no modification of the cardiac frequency, blood pressure or the ECG trace. If changes do occur, they are generally without clinical significance.
6.
|
Kytril 1 mg film-coated tablets
|
Pharmaceutical particulars - List of excipients
|
List of excipients
Lactose monohydrate
Hypromellose
Sodium starch glycolate
Cellulose, microcrystalline
Magnesium stearate
Film-coat:
Hypromellose
Titanium dioxide (E171)
Macrogol 400
Polysorbate 80
6.2
|
Kytril 1 mg film-coated tablets
|
Pharmaceutical particulars - Incompatibilities
|
Incompatibilities
Not applicable.
6.3
|
Kytril 1 mg film-coated tablets
|
Pharmaceutical particulars - Shelf life
|
Shelf life
5 years
6.4
|
Kytril 1 mg film-coated tablets
|
Pharmaceutical particulars - Special precautions for storage
|
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
|
Kytril 1 mg film-coated tablets
|
Pharmaceutical particulars - Nature and contents of container
|
Nature and contents of container
Opaque PVC blisters sealed with an aluminium foil containing 2 or 10 tablets (1mg) or 1, 5 or 10 tablets (2mg). Not all pack sizes may be marketed.
6.6
|
Kytril 1 mg film-coated tablets
|
Pharmaceutical particulars - Special precautions for disposal and other handling
|
Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.
|
Kytril 1 mg film-coated tablets
|
Marketing authorisation holder
|
Atnahs Pharma UK Limited
Sovereign House
Miles Gray Road
Basildon
Essex
SS14 3FR
United Kingdom
8. Marketing authorisation number(s)
PL 43252/0016
9.
|
Kytril 1 mg film-coated tablets
|
Date of first authorisation/renewal of the authorisation
|
Date of first authorisation: 15 September 2001
Date of latest renewal: 05 November 2004
10.
|
Kytril 1 mg film-coated tablets
|
Date of revision of the text
|
17-July-2017
Detailed information on this medicinal product is available on the Medicines and Healthcare Products Regulatory Agency (MHRA) website : http://www.mhra.gov.uk
|
Kytril 2 mg film-coated tablets
|
Name of the medicinal product
|
Kytril 2 mg film-coated tablets
2.
|
Kytril 2 mg film-coated tablets
|
Qualitative and quantitative composition
|
2.1 General description
2.2
|
Kytril 2 mg film-coated tablets
|
Qualitative and quantitative composition
|
Each film-coated tablet contains 2 mg granisetron (as the hydrochloride).
Excipients with known effect:
Each tablet contains 138.76 mg of lactose monohydrate.
Sodium starch glycolate
For the full list of excipients, see section 6.1.
3.
|
Kytril 2 mg film-coated tablets
|
Pharmaceutical form
|
Film-coated tablet.
The tablets are white to almost white triangular biconvex tablets imprinted with K2 on one side.
4.
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Therapeutic indications
|
Therapeutic indications
Kytril film-coated tablets are indicated in adults for the prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapy.
Kytril film-coated tablets are indicated in adults for prevention of delayed nausea and vomiting associated with chemotherapy and radiotherapy.
4.2
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Posology and method of administration
|
Posology and method of administration
Posology
1 mg twice a day or 2 mg once a day for up to one week following radiotherapy or chemotherapy. The first dose of Kytril should be administered within 1 hour before the start of therapy. Dexamethasone has been used concomitantly at doses up to 20 mg once a day orally.
Paediatric population
The safety and efficacy of granisetron tablets in children have not yet been established.
No data are available.
Older people and renal impairment
There are no special precautions required for its use in either elderly patients or those patients with renal impairment.
Hepatic impairment
There is no evidence to date for an increased incidence of adverse events in patients with hepatic disorders. On the basis of its kinetics, whilst no dosage adjustment is necessary, granisetron should be used with a certain amount of caution in this patient group (see section 5.2).
Method of administration
The tablets should be swallowed whole with water.
4.3
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Contraindications
|
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Special warnings and precautions for use
|
Special warnings and precautions for use
As granisetron may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following its administration.
As for other 5-HT3 antagonists, ECG changes including QT interval prolongation have been reported with granisetron. In patients with pre-existing arrhythmias or cardiac conduction disorders this might lead to clinical consequences. Therefore caution should be exercised in patients with cardiac co-morbidities, on cardiotoxic chemotherapy and/or with concomitant electrolyte abnormalities (see section 4.5).
Cross-sensitivity between 5-HT3 antagonists (e.g. dolasteron, ondansetron) has been reported.
Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone, but mostly in combination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRIs), and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like symptoms is advised.
Kytril is essentially 'sodium free' as it contains less than 1 mmol sodium (23 mg) per dose (2 mg).
Paediatric population
There is insufficient clinical evidence to recommend administration of these tablets to children.
4.5
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Interaction with other medicinal products and other forms of interaction
|
Interaction with other medicinal products and other forms of interaction
As for other 5-HT3 antagonists, cases of ECG modifications including QT prolongation have been reported with granisetron. In patients concurrently treated with medicinal products known to prolong QT interval and/or which are arrhythmogenic, this may lead to clinical consequences (see section 4.4).
In studies in healthy subjects, no evidence of any interaction has been indicated between granisetron and benzodiazepines (lorazepam), neuroleptics (haloperidol) or anti-ulcer medicinal products (cimetidine). Additionally, granisetron has not shown any apparent medicinal product interaction with emetogenic cancer chemotherapies.
No specific interaction studies have been conducted in anaesthetised patients.
Serotonergic medicinal products (e.g. SSRIs and SNRIs): there have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists and other serotonergic medicinal products (including SSRIs and SNRIs) (see section 4.4).
4.6
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Fertility, pregnancy and lactation
|
Fertility, pregnancy and lactation
Pregnancy
There is limited amount of data from the use of granisetron in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of granisetron during pregnancy.
Breastfeeding
It is unknown whether granisetron or its metabolites are excreted in human milk. As a precautionary measure, breast-feeding should not be advised during treatment with Kytril.
Fertility
In rats, granisetron had no harmful effects on reproductive performance or fertility.
4.7
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Effects on ability to drive and use machines
|
Effects on ability to drive and use machines
Kytril has no or negligible influence on the ability to drive and use machines.
4.8
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Undesirable effects
|
Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions for Kytril are headache and constipation, which may be transient. ECG changes including QT prolongation have been reported with Kytril (see sections 4.4 and 4.5).
Tabulated list of adverse reactions
The following table of listed adverse reactions is derived from clinical trials and post-marketing data associated with Kytril and other 5-HT3 antagonists.
Frequency categories are as follows:
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)
Very rare (<1/10,000)
Immune system disorders
Uncommon
Hypersensitivity reactions e.g. anaphylaxis, urticaria
Psychiatric disorders
Common
Insomnia
Nervous system disorders
Very common
Headache
Uncommon
Extrapyramidal Reactions
Uncommon
Serotonin Syndrome (see also sections 4.4 and 4.5)
Cardiac disorders
Uncommon
QT prolongation
Gastrointestinal disorders
Very common
Constipation
Common
Diarrhoea
Hepatobiliary disorders
Common
Elevated hepatic transaminases*
Skin and subcutaneous tissue disorders
Uncommon
Rash
*Occurred at a similar frequency in patients receiving comparator therapy
Description of selected adverse reactions
As for other 5-HT3 antagonists, ECG changes including QT prolongation have been reported with granisetron (see sections 4.4 and 4.5).
As with other 5-HT3 antagonists, cases of serotonin syndrome (including altered mental status, autonomic dysfunction and neuromuscular abnormalities) have been reported following the concomitant use of Kytril and other serotonergic drugs (see sections 4.4 and 4.5).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.
4.9
|
Kytril 2 mg film-coated tablets
|
Clinical particulars - Overdose
|
Overdose
There is no specific antidote for Kytril. In the case of overdose with the tablets, symptomatic treatment should be given. Doses of up to 38.5 mg of Kytril as a single injection have been reported, with symptoms of mild headache but no other reported sequelae.
5. Pharmacological properties
5.1
|
Kytril 2 mg film-coated tablets
|
Pharmacodynamic properties - Pharmacodynamic properties
|
Pharmacokinetic properties
Pharmacokinetics of the oral administration is linear up to 2.5-fold of the recommended dose in adults. It is clear from the extensive dose-finding programme that the antiemetic efficacy is not unequivocally correlated with either administered doses or plasma concentrations of granisetron.
A fourfold increase in the initial prophylactic dose of granisetron made no difference in terms of either the proportion of patient responding to treatment or in the duration of symptoms control.
Absorption
Absorption of granisetron is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism. Oral bioavailability is generally not influenced by food.
Distribution
Granisetron is extensively distributed, with a mean volume of distribution of approximately 3 l/kg. Plasma protein binding is approximately 65%.
Biotransformation
Granisetron is metabolized primarily in the liver by oxidation followed by conjugation. The major compounds are 7-OH-granisetron and its sulphate and glycuronide conjugates. Although antiemetic properties have been observed for 7-OH-granisetron and indazoline N-desmethyl granisetron, it is unlikely that these contribute significantly to the pharmacological activity of granisetron in man.
In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily (see section 4.5).
Elimination
Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged granisetron averages 12% of dose while that of metabolites amounts to about 47% of dose. The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients by the oral and intravenous route is approximately 9 hours, with a wide inter-subject variability.
Pharmacokinetics in special populations
Renal failure
In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects.
Hepatic impairment
In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary (see section 4.2).
Paediatric population
These tablets are not recommended in children.
Older people
In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.
5.3
|
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