1. Name Of The Medicinal Product
SYNAGIS
2. Qualitative And Quantitative Composition
Each vial contains 50 mg or 100 mg palivizumab*, providing 100 mg/ml of palivizumab when reconstituted as recommended.
*recombinant humanised monoclonal antibody produced by DNA technology in mouse myeloma host cells.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder and solvent for solution for injection.
The powder is a white to off-white cake.
4. Clinical Particulars
4.1 Therapeutic Indications
SYNAGIS is indicated for the prevention of serious lower respiratory tract disease requiring hospitalisation caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease:
• Children born at 35 weeks of gestation or less and less than 6 months of age at the onset of the RSV season.
• Children less than 2 years of age and requiring treatment for bronchopulmonary dysplasia within the last 6 months.
• Children less than 2 years of age and with haemodynamically significant congenital heart disease.
4.2 Posology And Method Of Administration
Recommended dose
The recommended dose of palivizumab is 15 mg/kg of body weight, given once a month during anticipated periods of RSV risk in the community. Where possible, the first dose should be administered prior to commencement of the RSV season. Subsequent doses should be administered monthly throughout the RSV season.
The majority of experience including the pivotal phase III clinical trials with palivizumab has been gained with 5 injections during one season (see section 5.1). Data, although limited, are available on greater than 5 doses (see sections 4.8 and 5.1), therefore the benefit in terms of protection beyond 5 doses has not been established.
To reduce risk of rehospitalisation, it is recommended that children receiving palivizumab who are hospitalised with RSV continue to receive monthly doses of palivizumab for the duration of the RSV season.
For children undergoing cardiac bypass, it is recommended that a 15 mg/kg of body weight injection of palivizumab be administered as soon as stable after surgery to ensure adequate palivizumab serum levels. Subsequent doses should resume monthly through the remainder of the RSV season for children that continue to be at high risk of RSV disease (see section 5.2).
Method of administration
Palivizumab is administered in a dose of 15 mg/kg of body weight once a month intramuscularly, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection site because of the risk of damage to the sciatic nerve. The injection should be given using standard aseptic technique. Injection volumes over 1 ml should be given as a divided dose.
For information on reconstituting SYNAGIS, see section 6.6.
4.3 Contraindications
Known hypersensitivity to the active substance or to any of the excipients (see section 6.1), or other humanised monoclonal antibodies.
4.4 Special Warnings And Precautions For Use
Allergic reactions including very rare cases of anaphylaxis have been reported following palivizumab administration (see section 4.8).
Medicinal products for the treatment of severe hypersensitivity reactions, including anaphylaxis, should be available for immediate use following administration of palivizumab.
A moderate to severe acute infection or febrile illness may warrant delaying the use of palivizumab, unless, in the opinion of the physician, withholding palivizumab entails a greater risk. A mild febrile illness, such as mild upper respiratory infection, is not usually reason to defer administration of palivizumab.
As with any intramuscular injection, palivizumab should be given with caution to patients with thrombocytopaenia or any coagulation disorder.
The efficacy of palivizumab when administered to patients as a second course of treatment during an ensuing RSV season has not been formally investigated in a study performed with this objective. The possible risk of enhanced RSV infection in the season following the season in which the patients were treated with palivizumab has not been conclusively ruled out by studies performed aiming at this particular point.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No formal interactions studies with other medicinal products were conducted, however no interactions have been described to date. In the phase III IMpact-RSV study in the premature and bronchopulmonary dysplasia paediatric populations, the proportions of patients in the placebo and palivizumab groups who received routine childhood vaccines, influenza vaccine, bronchodilators or corticosteroids were similar and no incremental increase in adverse reactions was observed among patients receiving these agents.
Since the monoclonal antibody is specific for RSV, palivizumab is not expected to interfere with the immune response to vaccines.
4.6 Pregnancy And Lactation
Not relevant. SYNAGIS is not indicated for use in adults. Data on pregnancy and lactation are not available.
4.7 Effects On Ability To Drive And Use Machines
Not relevant.
4.8 Undesirable Effects
Adverse drug reactions (ADRs) reported in the prophylactic paediatric studies were similar in the placebo and palivizumab groups. The majority of ADRs were transient and mild to moderate in severity.
Adverse events at least possibly causally-related to palivizumab, both clinical and laboratory, are displayed by system organ class and frequency (common
Within each frequency grouping, adverse reactions have been presented in order of decreasing seriousness.
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No medically important differences were observed during the prophylactic studies carried out in the premature and bronchopulmonary dysplasia paediatric populations in ADRs by body system or when evaluated in subgroups of children by clinical category, gender, age, gestational age, country, race/ethnicity or quartile serum palivizumab concentration. No significant difference in safety profile was observed between children without active RSV infection and those hospitalised for RSV. Permanent discontinuation of palivizumab due to ADRs was rare (0.2%). Deaths were balanced between the integrated placebo and palivizumab groups and were not drug-related.
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In the congenital heart disease study no medically important differences were observed in ADRs by body system or when evaluated in subgroups of children by clinical category. The incidence of serious adverse events was significantly lower in the palivizumab group compared to the placebo group. No serious adverse events related to palivizumab were reported. The incidences of cardiac surgeries classified as planned, earlier than planned or urgent were balanced between the groups. Deaths associated with RSV infection occurred in 2 patients in the palivizumab group and 4 patients in the placebo group and were not drug-related.
Post-marketing experience:
The following events were reported during post-marketing experience of palivizumab. Because these events 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 palivizumab exposure.
Blood and lymphatic system disorders: thrombocytopenia
Immune system disorders: anaphylaxis
Nervous system disorders: convulsion
Respiratory, thoracic and mediastinal disorders: apnoea
Skin and subcutaneous tissue disorders: urticaria
Post-marketing serious spontaneous adverse events reported during palivizumab treatment between 1998 and 2002 covering four RSV seasons were evaluated. A total of 1,291 serious reports were received where palivizumab had been administered as indicated and the duration of therapy was within one season. The onset of the adverse event occurred after the sixth or greater dose in only 22 of these reports (15 after the sixth dose, 6 after the seventh doses and 1 after the eight dose). These events are similar in character to those after the initial five doses.
Palivizumab treatment schedule and adverse events were monitored in a group of nearly 20,000 infants tracked through a patient compliance registry between 1998 and 2000. Of this group 1,250 enrolled infants had 6 injections, 183 infants had 7 injections, and 27 infants had either 8 or 9 injections. Adverse events observed in patients after a sixth or greater dose were similar in character and frequency to those after the initial 5 doses.
Human anti-human antibody (HAHA) response:
Antibody to palivizumab was observed in approximately 1% of patients in the IMpact-RSV during the first course of therapy. This was transient, low titre, resolved despite continued use (first and second season), and could not be detected in 55/56 infants during the second season (including 2 with titres during the first season). Therefore, HAHA responses appear to be of no clinical relevance.
Immunogenicity was not studied in the congenital heart disease study.
4.9 Overdose
In clinical studies, three children received an overdose of more than 15 mg/kg. These doses were 20.25 mg/kg, 21.1 mg/kg and 22.27 mg/kg. No medical consequences were identified in these instances.
From the post-marketing experience, overdoses as high as 60 mg/kg have been reported without any untoward medical events.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: specific immunoglobulins; ATC Code: J06BB16
Palivizumab is a humanised IgG1κ monoclonal antibody directed to an epitope in the A antigenic site of the fusion protein of respiratory syncytial virus (RSV). This humanised monoclonal antibody is composed of human (95%) and murine (5%) antibody sequences. It has potent neutralising and fusion-inhibitory activity against both RSV subtype A and B strains.
Palivizumab serum concentrations of approximately 30 μg/ml have been shown to produce a 99% reduction in pulmonary RSV replication in the cotton rat model.
Clinical studies
In a placebo-controlled trial of RSV disease prophylaxis in (IMpact-RSV trial) 1502 high-risk children (1002 SYNAGIS; 500 placebo), 5 monthly doses of 15 mg/kg reduced the incidence of RSV related hospitalisation by 55% (p = < 0.001). The RSV hospitalisation rate was 10.6% in the placebo group. On this basis, the absolute risk reduction is 5.8% which means the number needed to treat is 17 to prevent one hospitalisation. The severity of RSV disease in children hospitalised despite prophylaxis with palivizumab in terms of days in ICU stay per 100 children and days of mechanical ventilation per 100 children was not affected.
A total of 222 children were enrolled in two separate studies to examine the safety of palivizumab when it is administered for a second RSV season. One hundred and three (103) children received monthly palivizumab injections for the first time, and 119 children received palivizumab for two consecutive seasons. No difference between groups regarding immunogenicity was observed in either study. However, as the efficacy of palivizumab when administered to patients as a second course of treatment during an ensuing RSV season has not been formally investigated in a study performed with this objective, the relevance of these data in terms of efficacy is unknown.
In an open label prospective trial designed to evaluate pharmacokinetics, safety and immunogenicity after administration of 7 doses of palivizumab within a single RSV season, pharmacokinetic data indicated that adequate mean palivizumab levels were achieved in all 18 children enrolled. Transient, low levels of antipalivizumab antibody were observed in one child after the second dose of palivizumab that dropped to undetectable levels at the fifth and seventh dose.
In a placebo-controlled trial in 1,287 patients
5.2 Pharmacokinetic Properties
In studies in adult volunteers, palivizumab had a pharmacokinetic profile similar to a human IgG1 antibody with regard to volume of distribution (mean 57 ml/kg) and half-life (mean 18 days). In prophylactic studies in premature and bronchopulmonary dysplasia paediatric populations, the mean half-life of palivizumab was 20 days and monthly intramuscular doses of 15 mg/kg achieved mean 30 day trough serum active substance concentrations of approximately 40 μg/ml after the first injection, approximately 60 μg/ml after the second injection, approximately 70 μg/ml after the third injection and fourth injection. In the congenital heart disease study, monthly intramuscular doses of 15 mg/kg achieved mean 30 day trough serum active substance concentrations of approximately 55 µg/ml after the first injection and approximately 90 µg/ml after the fourth injection.
Among 139 children in the congenital heart disease study receiving palivizumab who had cardio
5.3 Preclinical Safety Data
Single dose toxicology studies have been conducted in cynomolgus monkeys (maximum dose 30 mg/kg), rabbits (maximum dose 50 mg/kg) and rats (maximum dose 840 mg/kg). No significant findings were observed.
Studies carried out in rodents gave no indication of enhancement of RSV replication, or RSV-induced pathology or generation of virus escape mutants in the presence of palivizumab under the chosen experimental conditions.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Powder:
Histidine
Glycine
Mannitol (E421)
Solvent:
Water for injections
6.2 Incompatibilities
Palivizumab should not be mixed with any medicinal products or diluents other than water for injections.
6.3 Shelf Life
3 years.
After reconstitution, the product should be used immediately. However in-use stability has been demonstrated for 3 hours at 20 - 24oC.
6.4 Special Precautions For Storage
Store in a refrigerator (2ºC to 8ºC).
Do not freeze.
Store in the original container.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
50 mg of powder in a 4 ml vial (Type I glass) with a stopper (bromobutyl rubber) and a flip-off seal (aluminium).
100 mg of powder in a 10 ml vial (Type I glass) with a stopper (bromobutyl rubber) and a flip-off seal (aluminium).
1ml of water for injections in an ampoule (type I glass).
Pack size of 1.
6.6 Special Precautions For Disposal And Other Handling
SLOWLY add 0.6 ml of water for injections for the 50 mg vial or 1.0 ml of water for injections for the 100 mg vial along the inside wall of the vial to minimise foaming. After the water is added, tilt the vial slightly and gently rotate the vial for 30 seconds. DO NOT SHAKE THE VIAL. Palivizumab solution should stand at room temperature for a minimum of 20 minutes until the solution clarifies. Palivizumab solution does not contain a preservative and should be administered within 3 hours of preparation.
When reconstituted as recommended, the final concentration is 100 mg/ml.
The appearance of the reconstituted solution is clear to slightly opalescent.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Abbott Laboratories Limited
Abbott House,
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
United Kingdom
8. Marketing Authorisation Number(S)
50 mg vial: EU/1/99/117/001
100 mg vial: EU/1/99/117/002
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 13 August 1999
Date of latest renewal: 13 August 2009
10. Date Of Revision Of The Text
23 December 2009
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