DEPOCYTE Suspension for injection Ref.[2692] Active ingredients: Cytarabine

Patients receiving DepoCyte should be concurrently treated with corticosteroids (e.g. dexamethasone) to mitigate the symptoms of arachnoiditis (see section 4.8), which is a very common adverse reaction.

Arachnoiditis is a syndrome manifested primarily by nausea, vomiting, headache and fever. If left untreated, chemical arachnoiditis may be fatal.

Patients should be informed about the expected adverse reactions of headache, nausea, vomiting and fever, and about the early signs and symptoms of neurotoxicity. The importance of concurrent dexamethasone administration should be emphasised at the initiation of each cycle of DepoCyte treatment. Patients should be instructed to seek medical attention if signs or symptoms of neurotoxicity develop, or if oral dexamethasone is not well tolerated.

Cytarabine, when administered intrathecally, has been associated with nausea, vomiting and serious central nervous system toxicity which can lead to a permanent deficit, this includes blindness, myelopathy and other neurological toxicity.

Administration of DepoCyte in combination with other neurotoxic chemotherapeutic agents or with cranial/spinal irradiation may increase the risk of neurotoxicity.

Infectious meningitis may be associated with intrathecal administration. Hydrocephalus has also been reported, possibly precipitated by arachnoiditis.

Blockage or reduction of CSF flow may result in increased free cytarabine concentrations in the CSF with increased risk of neurotoxicity. Therefore, as with any intrathecal cytotoxic therapy, consideration should be given to the need for assessment of CSF flow before treatment is started.

Although significant systemic exposure to free cytarabine is not expected following intrathecal treatment, some effects on bone marrow function cannot be excluded. Systemic toxicity due to intravenous administration of cytarabine consists primarily of bone marrow suppression with leucopenia, thrombocytopenia and anaemia. Therefore monitoring of the haemopoietic system is advised.

Anaphylactic reactions following intravenous administration of free cytarabine have been rarely reported.

Since DepoCyte’s particles are similar in size and appearance to white blood cells, care must be taken in interpreting CSF examination following administration.

No definite interactions between DepoCyte delivered intrathecally and other medicinal products have been established.

Concomitant administration of DepoCyte with other antineoplastic agents administered by the intrathecal route has not been studied.

Intrathecal co-administration of cytarabine with other cytotoxic agents may increase the risk of neurotoxicity.

Women of childbearing potential/Contraception in males and females

Despite the low apparent risk women of childbearing potential should not receive treatment until pregnancy is excluded and should be advised to use a reliable contraceptive method.

Given that cytarabine has a mutagenic potential which could induce chromosomal damage in the human spermatozoa, males undergoing DepoCyte treatment and their partner should be advised to use a reliable contraceptive method.

Pregnancy

Teratology studies in animals have not been conducted with DepoCyte and there are no adequate and well controlled studies in pregnant women.

Cytarabine, the active ingredient in DepoCyte, can cause foetal harm when administered systemically during pregnancy, mainly during the first trimester. Concern for foetal harm following intrathecal DepoCyte administration however, is low because systemic exposure to cytarabine is negligible. Despite the low apparent risk women of childbearing potential should not receive treatment until pregnancy is excluded and should be advised to use a reliable contraceptive method.

Breast-feeding

It is not known whether cytarabine is excreted in human milk following intrathecal administration. The systemic exposure to free cytarabine following intrathecal treatment with DepoCyte was negligible. Because of possible excretion in human milk and because of the potential for serious adverse reactions in nursing infants, the use of DepoCyte is not recommended in breast-feeding women.

Fertility

Fertility studies to assess the reproductive toxicity of DepoCyte have not been conducted. Because the systemic exposure to free cytarabine following intrathecal treatment with DepoCyte is negligible, the risk of impaired fertility is likely to be low (see section 5.3).

There have been no reports explicitly relating to effects of DepoCyte treatment on the ability to drive or use machines. However, on the basis of reported adverse reactions, patients should be advised against driving or using machines during treatment.

In Phase 1-4 studies the most commonly reported adverse reactions associated with DepoCyte were headache (23%), arachnoiditis (16%), pyrexia (14%), weakness (13%), nausea (13%), vomiting (12%), confusion (11%), diarrhoea (11%), thrombocytopenia (10%), and fatigue (6%).

For Phase 1-4 studies in patients with lymphomatous meningitis receiving either DepoCyte or cytarabine adverse reactions are listed by MedDRA body system organ class and by frequency (Very common (≥1/10); and 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)) in Table 1 below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Adverse reactions occurring in >10% of cycles in either treatment group in Phase 1-4 study patients with lymphomatous meningitis receiving DepoCyte 50 mg (n=151 cycles) or cytarabine (n=99 cycles):

* Induction and Maintenance cycle lengths were 2 and 4 weeks, respectively, during which the patient received either 1 dose of DepoCyte or 4 doses of cytarabine. Cytarabine patients not completing all 4 doses within a cycle are counted as a complete cycle.

Nervous system disorders

DepoCyte has the potential of producing serious neurological toxicity.

Intrathecal administration of cytarabine may cause myelopathy (3%) and other neurologic toxicities sometimes leading to a permanent neurological deficit. Following intrathecal administration of DepoCyte, serious central nervous system toxicity, including persistent convulsions (7%), extreme somnolence (3%), hemiplegia (1%), visual disturbances including blindness (1%), deafness (3%) and cranial nerve palsies (3%) have been reported. Symptoms and signs of peripheral neuropathy, such as pain (1%), numbness (3%), paresthesia (3%), hypoaesthesia (2%), weakness (13%), and impaired bowel (3%) and bladder control (incontinence) (1%), have also been observed and in some cases this combination of neurological signs and symptoms has been reported as Cauda equina syndrome (3%).

Adverse reactions possibly reflecting neurotoxicity are listed in Table 2 by MedDRA body system organ class and by frequency: Very common (≥1/10); Common (≥1/100 to <1/10); and Uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2. Adverse reactions possibly reflecting neurotoxicities in Phase II, III, and IV patients receiving DepoCyte 50 mg (n=99 cycles) or cytarabine (n=84 cycles):

All patients receiving DepoCyte should be treated concurrently with dexamethasone to mitigate the symptoms of arachnoiditis. Toxic effects may be related to a single dose or to cumulative doses. Because toxic effects can occur at any time during therapy (although they are most likely within 5 days of administration), patients receiving DepoCyte therapy should be monitored continuously for the development of neurotoxicity. If patients develop neurotoxicity, subsequent doses of DepoCyte should be reduced, and treatment should be discontinued if toxicity persists.

Arachnoiditis, a very common adverse reaction associated with DepoCyte, is a syndrome manifested by several adverse reactions. The incidence of these adverse reactions, possibly reflecting meningeal irritation, are headache (24%), nausea (18%), vomiting (17%), pyrexia (12%), neck stiffness (3%), neck pain (4%), back pain (7%), meningism (<1%), convulsions (6%), hydrocephalus (2%), and CSF pleocytosis with or without altered state of consciousness (1%). Table 3 below lists these reactions for patients treated DepoCyte, and for patients treated with methotrexate and cytarabine as well.

Adverse reactions are listed by MedDRA body system organ class and by frequency: Very common (≥1/10); Common (≥1/100 to <1/10); and Uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3. Adverse reactions possibly reflecting meningeal irritation in Phase II, III, and IV patients:

* Cycle length was 2 weeks during which the patient received either 1 dose of DepoCyte or 4 doses of cytarabine or methotrexate. Cytarabine and methotrexate patients not completing all 4 doses are counted as a fraction of a cycle.

Investigations

Transient elevations in CSF protein and white blood cells have been observed in patients following DepoCyte administration, and have also been noted after intrathecal treatment with methotrexate or cytarabine. These reactions have been reported mainly from post-marketing experience with DepoCyte as spontaneous case reports. Because these reactions are reported from a population of uncertain size, it is not possible to reliably estimate their frequency.

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 national reporting system listed in Appendix V.

No formal assessments of pharmacokinetic drug-drug interactions between DepoCyte and other agents have been conducted. DepoCyte should not be diluted or mixed with any other medicinal products, as any change in concentration or pH may affect the stability of the microparticles.