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Section 4.8 - Undesirable effects
1. NAME OF THE MEDICINAL PRODUCT
Atriance 5 mg/ml solution for infusion
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4. CLINICAL PARTICULARS
4.2 Posology and method of administration
Nelarabine is for intravenous use only and must only be administered under the supervision of a physician experienced in the use of cytotoxic agents.
Posology
Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricemia, the use of allopurinol should be considered (see section 4.4). Nelarabine is not diluted prior to administration. The appropriate dose of nelarabine is transferred into polyvinylchloride (PVC) or ethyl vinyl acetate (EVA) infusion bags or glass containers and administered as a two-hour infusion in adult patients and as a one-hour infusion in paediatric patients. Complete blood counts including platelets must be monitored regularly (see sections 4.4 and 4.8). Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricemia, the use of allopurinol should be considered (see section 4.4). Adults and adolescents (aged 16 years and older) The recommended dose of nelarabine for adults is 1,500 mg/m2 administered intravenously over two hours on days 1, 3 and 5 and repeated every 21 days. Paediatric population Children and adolescents (aged 21 years and younger) The recommended dose of nelarabine for children is 650 mg/m2 administered intravenously over one hour daily for 5 consecutive days, repeated every 21 days. In clinical studies, the 650 mg/m2 and 1,500 mg/m2 dose have both been used in patients in the age range 16 to 21 years. Efficacy and safety were similar for both regimens. The prescribing physician should consider which regimen is appropriate when treating patients in this age range. Limited clinical pharmacology data are available for patients below the age of 4 years (see section 5.2). Dose modification Nelarabine must be discontinued at the first sign of neurological events of National Cancer Institute Common Terminology Criteria Adverse Event (NCI CTCAE) grade 2 or greater. Delaying subsequent dosing is an option for other toxicities, including haematological toxicity. Elderly Insufficient numbers of patients aged 65 years of age and older have been treated with nelarabine to determine whether they respond differently than younger patients (see sections 4.4 and 5.2). Renal Impairment Nelarabine has not been studied in individuals with renal impairment. Nelarabine and 9-β-D-arabinofuranosylguanine (ara-G) are partially renally excreted (see section 5.2 — Renal impairment). There are insufficient data to support a dose adjustment recommendation for patients with a renal clearance of creatinin Clcr less than 50 ml/min. Patients with renal impairment must be closely monitored for toxicities when treated with nelarabine. Hepatic Impairment Nelarabine has not been studied in patients with hepatic impairment. These patients should be treated with caution. Method of administration Nelarabine is not diluted prior to administration. The appropriate dose of nelarabine is transferred into polyvinylchloride (PVC) or ethyl vinyl acetate (EVA) infusion bags or glass containers and administered as a two-hour infusion in adult patients and as a one-hour infusion in paediatric patients. Complete blood counts including platelets must be monitored regularly (see sections 4.4 and 4.8). ********************************************************* 4.4 Special warnings and precautions for use Sodium warning This medicinal product contains 1.725 mg/ml (75 micromols) of sodium. To be taken into consideration by patients on a controlled sodium diet. ********************************************************* 4.6 Fertility, Ppregnancy and lactation Contraception in males and females Both sexually active men and women should use effective methods of contraception during treatment and for at least three months following cessation of treatment. Pregnancy There are no adequate data from the use of nelarabine in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). The potential risk in humans is unknown, however, exposure during pregnancy will likely lead to anomalies and malformations of the foetus. Nelarabine should not be used during pregnancy unless clearly necessary. If a patient becomes pregnant during treatment with nelarabine, they should be informed of the possible risk to the foetus. Breastfeeding It is unknown whether nelarabine or its metabolites are excreted in human breast milk. The excretion of nelarabine in milk has not been studied in animals. However, because of the potential for serious adverse reactions in infants, breastfeeding should be discontinued. Fertility Both sexually active men and women should use effective methods of contraception during treatment and for at least three months following cessation of treatment. The effect of nelarabine on fertility in humans is unknown. Based on the pharmacological action of the compound, undesirable effects on fertility are possible. Family planning should be discussed with patients as appropriate. It is unknown whether nelarabine or its metabolites are excreted in human breast milk. The excretion of nelarabine in milk has not been studied in animals. However, because of the potential for serious adverse reactions in infants, breastfeeding should be discontinued. ********************************************************* 4.8 Undesirable effects Clinical trial data MedDRA Preferred Term(s)Adverse event(s) Adults (1,500 mg/m2) N=103(%) Children (650 mg/m2) N=84(%) Infections and infestations Infection (including but not limited to; sepsis, bacteraemia, pneumonia, fungal infection) Very common: 40 (39) Very common: 13 (15) Respiratory, thoracic, and mediastinal disorders Pleural effusion Common: 10 (10) N/A Wheezing Common: 5 (5) N/A Dyspnoea Very common: 21 (20) N/A Cough Very common: 26 (25) N/A ********************************************************* 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Adult studies In an open-label study carried out by the Cancer and Leukaemia Group B and the Southwest Oncology Group, the safety and efficacy of nelarabine were evaluated in 39 adults with T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL). Twenty–eight of the 39 adults had relapsed or were refractory to at least two prior induction regimens and aged between 16 to 65 years of age (mean 34 years). Nelarabine at a dose of 1500 mg/m2/day was administered intravenously over two hours on days 1, 3 and 5 of a 21 day cycle. Five of the 28 patients (18%) [95% CI:6%-37%] treated with nelarabine achieved a complete response (bone marrow blast counts ≤ 5%,no other evidence of disease, and full recovery of peripheral blood counts). A total of 6 patients (21%) [95% CI: 8%–41%] achieved a complete response with or without haematological recovery. Time to complete response in both classifications of response ranged from 2.9 to 11.7 weeks. Duration of response (in both classifications of response (n=5) ranged between 15 and 195+ weeks. Median overall survival was 20.6 weeks [95% CI: 10.4–36.4]. Survival at one year was 29% [95% CI: 12%–45%]. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary. ********************************************************* 10. DATE OF REVISION OF THE TEXT 19 November 200829 November 2010 Detailed information on this medicinal product is available on the website of the European Medicine Agency (EMEA) http://www.emea.europa.eu/
Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricemia, the use of allopurinol should be considered (see section 4.4).
Nelarabine is not diluted prior to administration. The appropriate dose of nelarabine is transferred into polyvinylchloride (PVC) or ethyl vinyl acetate (EVA) infusion bags or glass containers and administered as a two-hour infusion in adult patients and as a one-hour infusion in paediatric patients.
Complete blood counts including platelets must be monitored regularly (see sections 4.4 and 4.8). Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricemia, the use of allopurinol should be considered (see section 4.4).
Adults and adolescents (aged 16 years and older)
The recommended dose of nelarabine for adults is 1,500 mg/m2 administered intravenously over two hours on days 1, 3 and 5 and repeated every 21 days.
Paediatric population
Children and adolescents (aged 21 years and younger)
The recommended dose of nelarabine for children is 650 mg/m2 administered intravenously over one hour daily for 5 consecutive days, repeated every 21 days.
In clinical studies, the 650 mg/m2 and 1,500 mg/m2 dose have both been used in patients in the age range 16 to 21 years. Efficacy and safety were similar for both regimens. The prescribing physician should consider which regimen is appropriate when treating patients in this age range. Limited clinical pharmacology data are available for patients below the age of 4 years (see section 5.2).
Dose modification
Nelarabine must be discontinued at the first sign of neurological events of National Cancer Institute Common Terminology Criteria Adverse Event (NCI CTCAE) grade 2 or greater. Delaying subsequent dosing is an option for other toxicities, including haematological toxicity.
Elderly
Insufficient numbers of patients aged 65 years of age and older have been treated with nelarabine to determine whether they respond differently than younger patients (see sections 4.4 and 5.2).
Renal Impairment
Nelarabine has not been studied in individuals with renal impairment. Nelarabine and 9-β-D-arabinofuranosylguanine (ara-G) are partially renally excreted (see section 5.2 — Renal impairment). There are insufficient data to support a dose adjustment recommendation for patients with a renal clearance of creatinin Clcr less than 50 ml/min. Patients with renal impairment must be closely monitored for toxicities when treated with nelarabine.
Hepatic Impairment
Nelarabine has not been studied in patients with hepatic impairment. These patients should be treated with caution.
Method of administration
Nelarabine is not diluted prior to administration. The appropriate dose of nelarabine is transferred into polyvinylchloride (PVC) or ethyl vinyl acetate (EVA) infusion bags or glass containers and administered as a two-hour infusion in adult patients and as a one-hour infusion in paediatric patients. Complete blood counts including platelets must be monitored regularly (see sections 4.4 and 4.8). ********************************************************* 4.4 Special warnings and precautions for use Sodium warning This medicinal product contains 1.725 mg/ml (75 micromols) of sodium. To be taken into consideration by patients on a controlled sodium diet. ********************************************************* 4.6 Fertility, Ppregnancy and lactation Contraception in males and females Both sexually active men and women should use effective methods of contraception during treatment and for at least three months following cessation of treatment. Pregnancy There are no adequate data from the use of nelarabine in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). The potential risk in humans is unknown, however, exposure during pregnancy will likely lead to anomalies and malformations of the foetus. Nelarabine should not be used during pregnancy unless clearly necessary. If a patient becomes pregnant during treatment with nelarabine, they should be informed of the possible risk to the foetus. Breastfeeding It is unknown whether nelarabine or its metabolites are excreted in human breast milk. The excretion of nelarabine in milk has not been studied in animals. However, because of the potential for serious adverse reactions in infants, breastfeeding should be discontinued. Fertility Both sexually active men and women should use effective methods of contraception during treatment and for at least three months following cessation of treatment. The effect of nelarabine on fertility in humans is unknown. Based on the pharmacological action of the compound, undesirable effects on fertility are possible. Family planning should be discussed with patients as appropriate. It is unknown whether nelarabine or its metabolites are excreted in human breast milk. The excretion of nelarabine in milk has not been studied in animals. However, because of the potential for serious adverse reactions in infants, breastfeeding should be discontinued. ********************************************************* 4.8 Undesirable effects Clinical trial data MedDRA Preferred Term(s)Adverse event(s) Adults (1,500 mg/m2) N=103(%) Children (650 mg/m2) N=84(%) Infections and infestations Infection (including but not limited to; sepsis, bacteraemia, pneumonia, fungal infection) Very common: 40 (39) Very common: 13 (15) Respiratory, thoracic, and mediastinal disorders Pleural effusion Common: 10 (10) N/A Wheezing Common: 5 (5) N/A Dyspnoea Very common: 21 (20) N/A Cough Very common: 26 (25) N/A ********************************************************* 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Adult studies In an open-label study carried out by the Cancer and Leukaemia Group B and the Southwest Oncology Group, the safety and efficacy of nelarabine were evaluated in 39 adults with T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL). Twenty–eight of the 39 adults had relapsed or were refractory to at least two prior induction regimens and aged between 16 to 65 years of age (mean 34 years). Nelarabine at a dose of 1500 mg/m2/day was administered intravenously over two hours on days 1, 3 and 5 of a 21 day cycle. Five of the 28 patients (18%) [95% CI:6%-37%] treated with nelarabine achieved a complete response (bone marrow blast counts ≤ 5%,no other evidence of disease, and full recovery of peripheral blood counts). A total of 6 patients (21%) [95% CI: 8%–41%] achieved a complete response with or without haematological recovery. Time to complete response in both classifications of response ranged from 2.9 to 11.7 weeks. Duration of response (in both classifications of response (n=5) ranged between 15 and 195+ weeks. Median overall survival was 20.6 weeks [95% CI: 10.4–36.4]. Survival at one year was 29% [95% CI: 12%–45%]. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary. ********************************************************* 10. DATE OF REVISION OF THE TEXT 19 November 200829 November 2010 Detailed information on this medicinal product is available on the website of the European Medicine Agency (EMEA) http://www.emea.europa.eu/
Complete blood counts including platelets must be monitored regularly (see sections 4.4 and 4.8).
4.4 Special warnings and precautions for use
Sodium warning
This medicinal product contains 1.725 mg/ml (75 micromols) of sodium. To be taken into consideration by patients on a controlled sodium diet.
4.6 Fertility, Ppregnancy and lactation
Contraception in males and females
Both sexually active men and women should use effective methods of contraception during treatment and for at least three months following cessation of treatment.
Pregnancy
There are no adequate data from the use of nelarabine in pregnant women.
Studies in animals have shown reproductive toxicity including malformations (see section 5.3). The potential risk in humans is unknown, however, exposure during pregnancy will likely lead to anomalies and malformations of the foetus.
Nelarabine should not be used during pregnancy unless clearly necessary. If a patient becomes pregnant during treatment with nelarabine, they should be informed of the possible risk to the foetus.
Breastfeeding
It is unknown whether nelarabine or its metabolites are excreted in human breast milk. The excretion of nelarabine in milk has not been studied in animals. However, because of the potential for serious adverse reactions in infants, breastfeeding should be discontinued.
Fertility
The effect of nelarabine on fertility in humans is unknown. Based on the pharmacological action of the compound, undesirable effects on fertility are possible. Family planning should be discussed with patients as appropriate.
4.8 Undesirable effects
Clinical trial data
MedDRA Preferred Term(s)Adverse event(s)
Adults (1,500 mg/m2) N=103(%)
Children (650 mg/m2) N=84(%)
Infections and infestations
Infection (including but not limited to; sepsis, bacteraemia, pneumonia, fungal infection)
Very common: 40 (39)
Very common: 13 (15)
Respiratory, thoracic, and mediastinal disorders
Pleural effusion
Common: 10 (10)
N/A
Wheezing
Common: 5 (5)
Dyspnoea
Very common: 21 (20)
Cough
Very common: 26 (25)
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Adult studies
In an open-label study carried out by the Cancer and Leukaemia Group B and the Southwest Oncology Group, the safety and efficacy of nelarabine were evaluated in 39 adults with T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL). Twenty–eight of the 39 adults had relapsed or were refractory to at least two prior induction regimens and aged between 16 to 65 years of age (mean 34 years). Nelarabine at a dose of 1500 mg/m2/day was administered intravenously over two hours on days 1, 3 and 5 of a 21 day cycle. Five of the 28 patients (18%) [95% CI:6%-37%] treated with nelarabine achieved a complete response (bone marrow blast counts ≤ 5%,no other evidence of disease, and full recovery of peripheral blood counts). A total of 6 patients (21%) [95% CI: 8%–41%] achieved a complete response with or without haematological recovery. Time to complete response in both classifications of response ranged from 2.9 to 11.7 weeks. Duration of response (in both classifications of response (n=5) ranged between 15 and 195+ weeks. Median overall survival was 20.6 weeks [95% CI: 10.4–36.4]. Survival at one year was 29% [95% CI: 12%–45%].
The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.
10. DATE OF REVISION OF THE TEXT
19 November 200829 November 2010
Detailed information on this medicinal product is available on the website of the European Medicine Agency (EMEA) http://www.emea.europa.eu/
The following text has been added:
Nelaarbine is not diluted prior to administration. The appropriate dose of nelarabine is transferred into polyvinylchloride (PVC) or ethyl vinyl acetate (EVA) infusion bags or glass containers and administered as a two-hour infusion in adult patients and as a one-hour infusion in paediatric patients.
Section 6.3