Water For Injections
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Water for Injections.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Water for Injections Ph. Eur 1.05 mL. The syringe is 5% overfilled.
3 PHARMACEUTICAL FORM
Water for Injections is presented as a single-use, prefilled syringe containing Water for Injections Ph. Eur.
Presentations
A single syringe, blister-packed with two needles, one 19G for reconstitution of an active lyophilisate in vial, and one 26G for injection after reconstitution.
1 pack 1 syringe/needle + 1 vial Granocyte-13 or Granocyte-34 1 pack 5 syringes/needles + 5 vials Granocyte-13 or Granocyte-34 1 pack 10 syringes/needles + 10 vials Granocyte-13 or Granocyte-34 1 pack 20 syringes/needles + 20 vials Granocyte-13 or Granocyte-34
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Solvent for injectable lyophilsate.
4.2 Posology and method of administration
For use in reconstitution of lyophilisate vials prior to administration by the subcutaneous or intravenous route.
4.3 Contraindications
Hypersensitivity to constituents of syringe.
4.4 Special warnings and precautions for use
Malignant Cell Growth
Granulocyte colony stimulating factor can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro.
The safety and efficacy of GRANOCYTE administration in patients with myelodysplasia or secondary AML or chronic myelogenous leukaemia have not been established. Therefore, it should not be used in these indications. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia.
Clinical trials have not established whether GRANOCYTE influences the progression of myelodysplastic syndrome to acute myeloid leukaemia. Caution should be exercised in using it in any pre-malignant myeloid condition. As some tumours with non-specific characteristics can exceptionally express a G-CSF receptor, caution should be exerted in the event of unexpected tumour regrowth concomitantly observed with rHuG-CSF therapy
• In children with ALL
An increased risk for secondary myeloid leukaemia or myelodysplastic syndrome associated with CSFs has been reported in children with ALL. A comparable risk has been established by a systematic review of 25 randomized controlled trials in 12.804 adult patients with solid tumors or lymphomas, a risk, however, without negative impact on long term outcome in the adults investigated. Therefore, GRANOCYTE 13 million IU/mL and GRANOCYTE 34 million IU/ml should be used in children, in particular with favorable long term prognosis, only after careful weighting of short term benefits versus long term risks.
• Leukocytosis
A leukocyte count greater than 50 x 109/L has not been observed in any of the 174 clinical trials patients treated with 5 pg/kg/day (0.64 million units/kg/day) following bone marrow transplantation. White blood cell counts of 70 x 109/L or greater have been observed in less than 5% of patients who received cytotoxic chemotherapy and were treated by GRANOCYTE at 5 pg/kg/day (0.64 million units/kg/day). No adverse events directly attributable to this degree of leukocytosis have been reported. In view of the potential risks associated with severe leukocytosis, a white blood cell count should, however, be performed at regular intervals during GRANOCYTE therapy.
If leukocyte counts exceed 50 x 109/L after the expected nadir,
GRANOCYTE should be discontinued immediately.
During PBPC mobilisation, GRANOCYTE should be discontinued if the leukocyte counts rise to > 70 x 109/L.
• Pulmonary adverse effects
Rare (>0.01% and <0.1%) pulmonary adverse effects, in particular interstitial pneumonia, have been reported after G-CSFs administration.
Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk.
The onset of pulmonary symptoms or signs, such as cough, fever and dyspnoea, in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of acute respiratory distress syndrome (ARDS).
GRANOCYTE should be immediately discontinued and appropriate treatment given.
• In Peripheral Stem Cells or Bone Marrow Transplantation
Special attention should be paid to platelet recovery since in double-blind placebo-controlled trials the mean platelet count was lower in patients treated with GRANOCYTE as compared with placebo.
The effect of GRANOCYTE on the incidence and severity of acute and chronic graft-versus-host disease has not been accurately determined.
• In Established Cytotoxic Chemotherapy
The use of GRANOCYTE is not recommended from 24 hours before, until 24 hours after chemotherapy ends (see section 4.5).
The safety of the use of GRANOCYTE with antineoplastic agents characterized by cumulative or predominant platelet lineage myelotoxicity (nitrosurea, mitomycin) has not been established. Administration of GRANOCYTE might enhance the toxicity of these agents, particularly to the platelets.
• Risks Associated with Increased Doses of Chemotherapy
The safety and efficacy of GRANOCYTE have yet to be established in the context of intensified chemotherapy. It should not be used to decrease, beyond the established limits, intervals between chemotherapy courses and/or to increase the doses of chemotherapy. Non-myeloid toxicities were limiting factors in a phase II chemotherapy intensification trial with GRANOCYTE.
• Special precautions in Peripheral Blood Progenitor Cells mobilisation.
Choice of the mobilisation method
Clinical trials carried out among the same patient population have shown that PBPC mobilisation, as assessed within the same laboratory, was higher when GRANOCYTE was used after chemotherapy than when used alone. Nevertheless the choice between the two mobilisation methods should be considered in relation to the overall objectives of treatment for an individual patient.
Prior exposure to radiotherapy and/or cytotoxic agents
Patients, who have undergone extensive prior myelosuppressive therapy and/or radiotherapy, may not show sufficient PBPC mobilisation to achieve the acceptable minimum yield (> 2 x106 CD34+ /kg) and therefore adequate haematological reconstitution.
A PBPC transplantation program should be defined early in the treatment course of the patient and particular attention should be paid to the number of PBPC mobilised before the administration of high-dose chemotherapy. If yields are low, other forms of treatment should replace the PBPC transplantation program.
Assessment of progenitor cell yields
Particular attention should be paid to the method of quantification of progenitor cell yields as the results of flow cytometric analysis of CD34+ cell number vary among laboratories.
The minimum yield of CD34+ cells is not well defined. The recommendation of a minimum yield of > 2.0 x 106 CD34+ cells/kg is based on published experience in order to achieve adequate haematological reconstitution. Yields higher than > 2.0 x 106 CD34+ cells/kg are associated with more rapid recovery, including platelets, while lower yields result in slower recovery.
• In healthy donors
The PBPC mobilisation, which is a procedure without direct benefit for healthy people, should only be considered through a clear regular delimitation in accordance with local regulations as for bone marrow donation when applicable.
The efficacy and safety of GRANOCYTE has not been assessed in donors aged over 60 years, therefore the procedure cannot be recommended. Based on some local regulations and lack of studies, minor donors should not be considered.
PBPC mobilisation procedure should be considered for donors who fit usual clinical and laboratory eligibility criteria for bone marrow donation especially normal haematological values.
Marked leukocytosis (WBC > 50 x 109/L) was observed in 24% of subjects studied.
Apheresis-related thrombocytopenia (platelets < 100 x 109/L) was observed in 42% of subjects studied and values < 50 x 109/L were occasionally noted following leukapheresis without related clinical adverse events, all recovered. Therefore leukapheresis should not be performed in donors who are anticoagulated or who have known defects in haemostasis. If more than one leukapheresis is required particular attention should be paid to donors with platelets < 100 x 109/L prior to apheresis ; in general apheresis should not be performed if platelets < 75 x 109/L.
Insertion of a central venous catheter should be avoided if possible with consideration given to venous access in selection of donors.
Transient cytogenetic modifications have been observed in normal donors following G-CSF use. The significance of these changes is unknown.
Long-term safety follow up of donors is ongoing. Nevertheless, a risk of promotion of a malignant myeloid clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety.
In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates, dyspnoea and hypoxia) have been reported in post marketing experience. In case of suspected or confirmed pulmonary adverse events, discontinuation of treatment with GRANOCYTE should be considered and appropriate medical care given.
• In recipients of allogeneic peripheral stem-cells mobilised with GRANOCYTE
Allogeneic stem-cell grafting may be associated with an increased risk for chronic GVH (Graft Versus Host Disease), and long-term data of graft functioning are sparse.
• Other Special Precautions
In patients with severe impairment of hepatic or renal function, the safety and efficacy of GRANOCYTE have not been established.
In patients with substantially reduced myeloid progenitor cells (e.g. due to prior intensive radiotherapy/chemotherapy), neutrophil response is sometimes diminished and the safety of GRANOCYTE has not been established.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture have been reported in either healthy donors or patients following administration of Granulocyte-colony stimulating factors (G-CSFs). Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered when left upper abdominal pain or shoulder tip pain is reported.
Capillary leak syndrome has been reported after G-CSF administration, and is characterised by hypotension, hypoalbuminaemia, oedema and hemoconcentration. Lenograstim should be discontinued if patients develop symptoms of capillary leak syndrome, and appropriate symptomatic treatment, which may include a need for intensive care, should be given (see section 4.8).
GRANOCYTE contains phenylalanine, which may be harmful for people with phenylketonuria.
The tip cap composition of the pre-filled syringe contains latex rubber which may cause severe allergic reactions in predisposed subjects.
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
None stated.
4.7 Effects on ability to drive and use machines
None stated.
4.8 Undesirable effects
The safety profile in children, adolescents, and adults is comparable.
■ In Peripheral Stem Cells or Bone Marrow Transplantation
In double-blind placebo-controlled trials the mean platelet count was lower in patients treated with GRANOCYTE as compared with placebo without an increase in incidence of adverse events related to blood loss and the median number of days following BMT to last platelet infusion was similar in both groups (see section 4.4).
■ In Peripheral Stem Cells or Bone Marrow Transplantation and Chemotherapy-Induced Neutropenia
In clinical trials, the most frequently reported adverse events (15%) were the same in patients treated with either GRANOCYTE or placebo. These adverse events were those usually encountered with conditioning regimens and those observed in cancer patients treated with chemotherapy. The most commonly reported adverse events were infection/inflammatory disorder of the buccal cavity, sepsis and infection, fever, diarrhoea, abdominal pain, vomiting, nausea, rash, alopecia, and headache.
■ In PBPC mobilisation in healthy donors
The most frequently reported undesirable effects were transient and mild to moderate: pain, bone pain, back pain, asthenia, fever, headache and nausea, increased ALAT, ASAT, blood alkaline phosphatise and LDH.
Apheresis-related thrombocytopenia and leukocytosis were observed in 42% and 24% respectively in study subjects.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture have been reported.
Rare pulmonary adverse reactions have been reported like dyspnoea, hypoxia or haemoptysis, including very rarely Acute Respiratory Distress Syndrome (ARDS) (see section 4.4).
Allergic reactions including anaphylaxis have been reported very rarely after the first subcutaneous administration of lenograstim.
• Post-marketing life-threatening Adverse Drug Reaction (ADR)
Capillary leak syndrome which can be life-threatening if treatment is delayed has been reported uncommonly (> 1/1000 to < 1/100) in the postmarketing setting following administration of granulocyte-colony-stimulating factors, mostly in cancer patients undergoing chemotherapy (see section 4.4).
Frequency of adverse reactions issued from clinical trials and post-marketing surveillance data. Very common (> 10%); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from the available data).
|
Medra System Organ Class |
Very common |
Common |
Uncommon |
Rare |
Very rare |
|
Investigations |
Elevated LDH | ||||
|
Blood and lymphatic system disorders |
Leucocytosis Thrombocytopenia |
Enlarged spleen size |
Splenic rupture (5) | ||
|
Nervous system disorders |
Headache Asthenia | ||||
|
Vascular Disorders |
Capillary leak syndrome6 | ||||
|
Respiratory, thoracic and madiastinal disorders |
Pulmonary edema Interstitial pneumonia (3) Pulmonary infiltrates Pulmonary fibrosis | ||||
|
Gastrointestinal disorders |
Abdominal pain | ||||
|
Skin and subcutaneous tissue disorders |
Cutaneous vasculitis Sweet’s syndrome (4) Erythema nodosum Pyoderma gangrenosum Lyell’s syndrome | ||||
|
Musculoskeletal and connective tissue disorders |
Bone pain Back pain |
Pain (1) | |||
|
General disorders and administration site condition |
Injection site reaction | ||||
|
Immune system disorders |
Allergic reaction Anaphylactic shock |
|
Hepatobiliary disorders |
Elevated ASAT/ALAT (2) Elevated Alkaline-phosphatase |
1 / The risk of occurrence of pain is increased in subjects with high peak WBC values, especially when WBC > 50
9
x 10/L
2 / Transient increase of ASAT and/or ALAT was observed. In most cases, liver function abnormalities improved after lenograstim discontinuation.
3 / Some of the respiratory reported cases have resulted in respiratory failure or acute respiratory distress syndrome (ADRS) which may be fatal.
4 / Sweet’s syndrome, erythema nodosum and pyoderma gangrenosum were mainly described in patients with hematological malignancies, a condition known to be associated with neutrophilic dermatosis, but also in nonmalignant related neutropenia.
5 / Splenic ruptures have been reported in either healthy donors or patients receiving G-CSFs (see section 4.4)
6 / There have been post-marketing reports of life-threatening capillary leak syndrome (see section 4.4)
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 Overdose
None stated.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
None stated.
5.2 Pharmacokinetic properties
None stated.
5.3 Preclinical safety data
None stated.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
None stated.
6.2 Incompatibilities
6.3 Shelf life 30 months
6.4 Special precautions for storage
Store under refrigeration between 2°C to 8°C
Short exposure of the vials to elevated temperatures (up to two weeks at 30°C) does not affect the product stability.
The water for injections syringes may be temporarily stored at ambient temperatures (25°C) for a period up to six months.
6.5 Nature and contents of container
Type 1 Borosilicate Glass Syringe with grey rubber stopper of 4023/50 bromotyl basic polymer, capped with a grey W-1883 chlorobutyl natural rubber stopper. Supplied blister-packed with two needles (1 x 19G, 1 x 26G).
6.6 Special precautions for disposal and other handling
Refer to the prescribing information of the lyophilisate before use.
Aseptically add the contents of the syringe to the vial of lyophilisate using the 19G needle.
Allow to dissolve completely.
Withdraw the vial contents into the syringe.
Replace the 19G needle with the 26G needle and administer immediately.
7 MARKETING AUTHORISATION HOLDER
Chugai Pharma UK Ltd.
Mulliner House,
Flanders Road,
Turnham Green,
London W4 1NN
8 MARKETING AUTHORISATION NUMBER
PL 12185/0005
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10/11/2005
10 DATE OF REVISION OF THE TEXT
29/10/2014