DepoCyte

1  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX 1 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
DepoCyte 50 mg suspension for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One ml of suspension contains 10 mg cytarabine.  
Each 5 ml vial contains 50 mg cytarabine. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Suspension for injection. 
White to off-white suspension. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Intrathecal treatment of lymphomatous meningitis. In the majority of patients such treatment will be 
part of symptomatic palliation of the disease. 
 
4.2 Posology and method of administration 
 
DepoCyte should be administered only under the supervision of a physician experienced in the use of 
cancer chemotherapeutic agents. 
 
Posology 
 
Paediatric population 
 
Safety and efficacy in children aged under 18 years have not been established. Currently available data 
are described in section 5.1 but no recommendation on a posology can be made. DepoCyte is not 
recommended for use in children and adolescents until further data become available. 
 
Adults and the elderly 
 
For the treatment of lymphomatous meningitis, the dose for adults is 50 mg (one vial) administered 
intrathecally (lumbar puncture or intraventricularly via an Ommaya reservoir). The following regimen 
of induction, consolidation and maintenance therapy is recommended: 
 
Induction therapy: 50 mg administered every 14 days for 2 doses (weeks 1 and 3). 
 
Consolidation therapy: 50 mg administered every 14 days for 3 doses (weeks 5, 7 and 9) followed by 
an additional dose of 50 mg at week 13. 
 
Maintenance therapy:  50 mg administered every 28 days for 4 doses (weeks 17, 21, 25 and 29). 
 
Method of administration 
 
DepoCyte is to be administered by slow injection over a period of 1-5 minutes directly into the 
cerebrospinal fluid (CSF) via either an intraventricular reservoir or by direct injection into the lumbar 

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sac.  Following administration by lumbar puncture, it is recommended that the patient should be 
instructed to lie flat for one hour.  All patients should be started on dexamethasone 4 mg twice daily 
either orally or intravenously for 5 days beginning on the day of injection of DepoCyte. 
 
DepoCyte must not be administered by any other route of administration. DepoCyte must be used as 
supplied; it must not be diluted (see section 6.2). Patients should be observed by the physician for 
immediate toxic reactions. 
 
If neurotoxicity develops, the dose should be reduced to 25 mg.  If it persists, treatment with 
DepoCyte should be discontinued. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with 
active meningeal infection. 
 
4.4 Special warnings and precautions for use 
 
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. 
 

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4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 
4.6 Fertility, pregnancy and lactation 
 
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). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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%). 

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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) 
 
Blood and lymphatic system disorders 
DepoCyte 
Cytarabine 

 
Very common: Thrombocytopenia 
Very common: Thrombocytopenia 

Nervous system disorders 
DepoCyte 
Cytarabine 

 
Very common: arachnoiditis, confusion, headache 
Very common: arachnoiditis, headache 
Common: confusion 

Gastrointestinal disorders 
DepoCyte 
Cytarabine 

 
Very common: diarrhoea, vomiting, nausea 
Very common: diarrhoea, vomiting, nausea 

General disorders and administration site 
conditions 
DepoCyte 
 
Cytarabine 

 

Very common: weakness, pyrexia 
Common: fatigue 
Very common: weakness, pyrexia, fatigue 

*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. 
 

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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) 
 
Psychiatric disorders 
DepoCyte 
Cytarabine 

 
Common: somnolence 
Common: somnolence 

Nervous system disorders 
DepoCyte 
 
 
Cytarabine 

 
Common: cauda equina syndrome, convulsions, 
cranial nerve palsies, hypoesthesia, myelopathy, 
paresthesia, hemiplegia, numbness 
Common: cauda equina syndrome, convulsions, 
cranial nerve palsies, hypoesthesia, myelopathy, 
paresthesia, hemiplegia, numbness 

Eye disorders 
DepoCyte 
Cytarabine 

 
Common: visual disturbances, blindness 
Common: visual disturbances, blindness 

Ear and labyrinth disorders 
DepoCyte 
Cytarabine 

 
Common: deafness 
Common: deafness 

Gastrointestinal disorders  
DepoCyte Common: impaired bowel control 
Cytarabine Common: impaired bowel control 
Renal and urinary disorders 
DepoCyte 
Cytarabine 

 
Common: urinary incontinence 
Common: urinary incontinence 

General disorders and administration site 
conditions 
DepoCyte 
 
Cytarabine 

 

Very Common: weakness 
Common: pain 
Very Common: weakness 
Common: pain 

 
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. 
 

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Table 3: Adverse reactions possibly reflecting meningeal irritation in Phase II, III, and IV 
patients 
Nervous system disorders 
DepoCyte (n = 929 cycles) 
 
 
 
Methotrexate (n = 258 cycles)  
 
 
Cytarabine (n = 99 cycles) 

 
Very common: headache 
Common: convulsions, hydrocephalus acquired, 
CSF pleocytosis 
Uncommon: meningism 
Very common: headache 
Common: convulsions, hydrocephalus acquired, 
meningism 
Very common: headache 
Common: convulsions, meningism 

Gastrointestinal disorders 
DepoCyte (n = 929 cycles) 
Methotrexate (n = 258 cycles)  
Cytarabine (n = 99 cycles) 

 
Very common: vomiting, nausea 
Very common: vomiting, nausea 
Very common: vomiting, nausea 

Musculoskeletal and connective tissue 
disorders 
DepoCyte (n = 929 cycles) 
Methotrexate (n = 258 cycles) 
 
Cytarabine (n = 99 cycles) 

 

Common: back pain, neck pain, neck stiffness 
Common: back pain, neck pain 
Uncommon: neck stiffness 
Common: back pain, neck pain, neck stiffness 

General disorders and administration site 
conditions 
DepoCyte (n = 929 cycles)  
Methotrexate (n = 258 cycles) 
Cytarabine (n = 99 cycles) 

 

Very common: pyrexia 
Common: pyrexia 
Very common: pyrexia 

*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. 
 
4.9 Overdose 
 
No overdoses with DepoCyte have been reported.  An overdose with DepoCyte may be associated 
with severe arachnoiditis including encephalopathy. 
 
In an early uncontrolled study without dexamethasone prophylaxis, single doses up to 125 mg were 
administered.  One patient at the 125 mg dose level died of encephalopathy 36 hours after receiving 
DepoCyte intraventricularly.  This patient, however, was also receiving concomitant whole brain 
irradiation and had previously received intraventricular methotrexate. 
 

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There is no antidote for intrathecal DepoCyte or unencapsulated cytarabine released from DepoCyte. 
Exchange of cerebrospinal fluid with isotonic sodium chloride solution has been carried out in a case 
of intrathecal overdose of free cytarabine and such a procedure may be considered in the case of 
DepoCyte overdose. Management of overdose should be directed at maintaining vital functions. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antimetabolites, pyrimidine analogues, ATC code: L01BC01 
 
Mechanism of action 
 
DepoCyte is a sustained-release formulation of cytarabine, designed for direct administration into the 
cerebrospinal fluid (CSF). 
 
Cytarabine is a cell-cycle phase specific antineoplastic agent, affecting cells only during the S-phase of 
cell division. Intracellularly, cytarabine is converted into cytarabine-5’-triphosphate (ara-CTP), which 
is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-
CTP acts primarily through inhibition of DNA synthesis. Incorporation into DNA and RNA may also 
contribute to cytarabine cytotoxicity.  Cytarabine is cytotoxic to a wide variety of proliferating 
mammalian cells in culture. 
 
For cell-cycle phase specific antimetabolites the duration of exposure of neoplastic cells to cytotoxic 
concentrations is an important determination of efficacy. 
 
Pharmacodynamic effects 
 
In vitro studies, examining more than 60 cell lines, demonstrated that the median cytarabine 
concentration resulting in 50% growth inhibition (IC50) was approximately 10 µM (2.4 µg/ml) for two 
days of exposure and 0.1 µM (0.024 µg/ml) for 6 days of exposure. The studies also demonstrated 
susceptibility of many solid tumour cell lines to cytarabine, particularly after longer periods of 
exposure to cytarabine. 
 
Clinical efficacy and safety 
 
In an open-label, active-controlled, multicentre clinical study, 35 patients with lymphomatous 
meningitis (with malignant cells found on CSF cytology) were randomised to intrathecal therapy with 
either DepoCyte (n=18) or unencapsulated cytarabine (n=17). During the 1 month Induction phase of 
treatment, DepoCyte was administered intrathecally as 50 mg every 2 weeks, and unencapsulated 
cytarabine as 50 mg twice a week. Patients who did not respond discontinued protocol treatment after 
4 weeks. Patients who achieved a response (defined as clearing of the CSF of malignant cells in the 
absence of progression of neurological symptoms) went on to receive Consolidation and Maintenance 
therapy for up to 29 weeks. 
 
Responses were observed in 13/18 (72%, 95% confidence intervals: 47, 90) of DepoCyte patients 
versus 3/17 (18% patients, 95% confidence intervals: 4, 43) in the unencapsulated cytarabine arm.  A 
statistically significant association between treatment and response was observed (Fisher’s exact test 
p-value = 0.002). The majority of DepoCyte patients went on beyond Induction to receive additional 
therapy. DepoCyte patients received a median of 5 cycles (doses) per patient (range 1 to 10 doses) with 
a median time on therapy of 90 days (range 1 to 207 days). 
 
No statistically significant differences were noted in secondary endpoints such as duration of response, 
progression-free survival, neurological signs and symptoms, Karnofsky performance status, quality of 
life and overall survival. Median progression-free survival (defined as time to neurological 
progression or death) for all treated patients was 77 versus 48 days for DepoCyte versus 

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unencapsulated cytarabine, respectively. The proportion of patients alive at 12 months was 24% for 
DepoCyte versus 19% for unencapsulated cytarabine. 
 
Paediatric population 
 
In an open-label non-comparative dose escalation study in 18 paediatric patients (4 to 19 years) with 
leukaemic meningitis or neoplastic meningitis due to primary brain tumour, an intrathecal dose of 
35 mg was identified as the maximum tolerated dose. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Analysis of the available pharmacokinetic data shows that following intrathecal DepoCyte 
administration in patients, either via the lumbar sac or by intraventricular reservoir, peaks of free 
cytarabine were observed within 5 hours in both the ventricle and lumbar sac. These peaks were 
followed by a biphasic elimination profile consisting of an initial sharp decline and subsequent slow 
decline with a terminal phase half-life of 100 to 263 hours over a dose-range of 12.5 mg to 75 mg.  In 
contrast, intrathecal administration of 30 mg free cytarabine has shown a biphasic CSF concentration 
profile with a terminal phase half-life of about 3.4 hours. 
 
Pharmacokinetic parameters of DepoCyte (75 mg) in neoplastic meningitis patients in whom the 
medicinal product was administered either intraventricularly or by lumbar puncture suggest that 
exposure to the active substance in the ventricular or lumbar spaces is similar regardless of the route of 
administration. In addition, compared with free cytarabine, the formulation increases the biological 
half-life by a factor of 27 to 71 depending upon the route of administration and the compartment 
sampled.  Encapsulated cytarabine concentrations and the counts of the lipid particles in which the 
cytarabine is encapsulated in followed a similar distribution pattern.  AUCs of free and encapsulated 
cytarabine after ventricular injection of DepoCyte appeared to increase linearly with increasing dose, 
indicating that the release of cytarabine from DepoCyte and the pharmacokinetics of cytarabine are 
linear in human CSF. 
 
Distribution 
 
The transfer rate of cytarabine from CSF to plasma is slow and the conversion to uracil arabinoside 
(ara-U), the inactive metabolite, in the plasma is fast. Systemic exposure to cytarabine was determined 
to be negligible following intrathecal administration of 50 mg and 75 mg of DepoCyte. 
 
Biotransformation 
 
The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, (1-β-D- 
arabinofuranosyluracil or uracil arabinoside) followed by urinary excretion of ara-U. In contrast with 
systemically administered cytarabine which is rapidly metabolised to ara-U, conversion to ara-U in the 
CSF is negligible after intrathecal administration because of the significantly lower cytidine deaminase 
activity in the CNS tissues and CSF. The CSF clearance rate of cytarabine is similar to the CSF bulk 
flow rate of 0.24 ml/min. 
 
Elimination 
 
The distribution and clearance of cytarabine and of the predominant phospholipid component of the 
lipid particle (DOPC) following intrathecal administration of DepoCyte was evaluated in rodents. 
Radiolabels for cytarabine and DOPC were distributed rapidly throughout the neuraxis. More than 
90% of cytarabine was excreted by day 4 and an additional 2.7% by 21 days.  The results suggest that 
the lipid components undergo hydrolysis and are largely incorporated in the tissues following 
breakdown in the intrathecal space. 

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5.3 Preclinical safety data 
 
A review of the toxicological data available for the constituent lipids (DOPC and DPPG) or similar 
phospholipids to those in DepoCyte indicates that such lipids are well tolerated in various animal 
species even when administered for prolonged periods at doses in the g/kg range. 
 
The results of acute and subacute toxicity studies performed in monkeys suggested that intrathecal 
DepoCyte was tolerated up to a dose of 10 mg (comparable to a human dose of 100 mg).  Slight to 
moderate inflammation of the meninges in the spinal cord and brain and/or astrocytic activation were 
observed in animals receiving intrathecal DepoCyte. These changes were believed to be consistent 
with the toxic effects of other intrathecal agents such as unencapsulated cytarabine. Similar changes 
(generally described as minimal to slight) were also observed in some animals receiving DepoFoam 
alone (DepoCyte vesicles without cytarabine) but not in sodium chloride solution control animals. 
Mouse, rat and dog studies have shown that free cytarabine is highly toxic for the haemopoietic 
system. 
 
No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with 
DepoCyte. The active ingredient, cytarabine, was mutagenic in in vitro tests and was clastogenic 
in vitro (chromosome aberrations and sister chromatid exchange in human leukocytes) and in vivo 
(chromosome aberrations and sister chromatid exchange assay in rodent bone marrow, mouse 
micronucleus assay).  Cytarabine caused the transformation of hamster embryo cells and rat H43 cells 
in vitro.  Cytarabine was clastogenic to meiotic cells; a dose-dependent increase in sperm-head 
abnormalities and chromosomal aberrations occurred in mice given intraperitoneal (i.p.) cytarabine. 
No studies assessing the impact of cytarabine on fertility are available in the literature.  Because the 
systemic exposure to free cytarabine following intrathecal treatment with DepoCyte was negligible, 
the risk of impaired fertility is likely to be low. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Cholesterol 
Triolein 
Dioleoylphosphatidylcholine (DOPC)  
Dipalmitoylphosphatidylglycerol (DPPG) 
Sodium chloride 
Water for injections 
 
6.2 Incompatibilities 
 
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. 
 
6.3 Shelf life 
 
18 months. 
 
After first opening: from a microbiological point of view, the product should be used immediately. If 
not used immediately, in-use storage times and conditions prior to use are the responsibility of the user 
and would normally not be longer than 4 hours at 18 to 22°C. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C).  
Do not freeze. 

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6.5 Nature and contents of container 
 
Type I glass vial closed with a fluororesin faced butyl rubber stopper and sealed with an aluminium 
flip-off seal containing 50 mg cytarabine in 5 ml suspension. 
 
DepoCyte is supplied in individual cartons each containing one single-dose vial. 
 
6.6 Special precautions for disposal and other handling 
 
Preparation of DepoCyte 
 
Given its toxic nature, special precautions should be taken in handling DepoCyte.  See ‘Precautions for 
the handling and disposal of DepoCyte’ below. 
 
Vials should be allowed to warm to room temperature (18°C -22°C) for a minimum of 30 minutes and 
be gently inverted to resuspend the particles immediately prior to withdrawal from the vial. Vigorous 
shaking should be avoided. No further reconstitution or dilution is required. 
 
DepoCyte administration 
 
DepoCyte must only be administered by the intrathecal route. 
 
DepoCyte should be withdrawn from the vial immediately before administration. Since it is a single 
use vial and does not contain any preservative, the medicinal product should be used within 4 hours of 
withdrawal from the vial. Unused medicinal product must not be used subsequently. DepoCyte must 
not be mixed with any other medicinal products (see section 6.2). The suspension must not be diluted. 
 
In-line filters must not be used when administering DepoCyte.  DepoCyte is administered directly into 
the CSF via an intraventricular reservoir or by direct injection into the lumbar sac.  DepoCyte should 
be injected slowly over a period of 1-5 minutes.  Following administration by lumbar puncture, the 
patient should be instructed to lie flat for one hour.  Patients should be observed by the physician for 
immediate toxic reactions. 
 
All patients should be started on dexamethasone 4 mg twice daily either orally or intravenously for 5 
days beginning on the day of DepoCyte injection. 
 
Precautions for the handling and disposal of DepoCyte 
 
The following protective recommendations are given due to the toxic nature of this substance: 
• personnel should be trained in good technique for handling anticancer agents; 
• male and female staff who are trying to conceive and female staff who are pregnant should be 

excluded from working with the substance; 
• personnel must wear protective clothing: goggles, gowns, disposable gloves and masks; 
• a designated area should be defined for preparation (preferably under a laminar flow system). 

The work surface should be protected by disposable, plastic backed, absorbent paper; 
• all items used during administration or cleaning should be placed in high risk, waste-disposal 

bags for high temperature incineration; 
• in the event of accidental contact with the skin, exposed areas should be washed immediately 

with soap and water; 
• in the event of accidental contact with the mucous membranes, exposed areas should be treated 

immediately by copious lavage with water; medical attention should be sought. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 

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7. MARKETING AUTHORISATION HOLDER 
 
Pacira Limited 
Wessex House  
Marlow Road  
Bourne End  
Buckinghamshire  
SL8 5SP 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/01/187/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 11 July 2001 
Date of latest renewal: 11 July 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu. 

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ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

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14  

 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Almac Pharma Services Limited 
20 Seagoe Industrial Estate  
Craigavon, Co Armagh  
BT63 5QD 
United Kingdom 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided 
for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web- 
portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
Not applicable. 

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15  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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16  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

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17  

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DepoCyte 50 mg suspension for injection 
Cytarabine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 50 mg cytarabine (10 mg/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains:  cholesterol, triolein, dioleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, 
sodium chloride, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Suspension for injection. One 5 ml vial. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intrathecal use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2ºC - 8ºC).  
 
Do not freeze. 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pacira Limited  
Wessex House  
Marlow Road  
Bourne End  
Buckinghamshire  
SL8 5SP 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/187/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 
 
 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

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19  

 
VIAL LABEL 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
DepoCyte 50 mg suspension for injection 
Cytarabine 
 
Intrathecal use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml. 
 
 
6. OTHER 
 

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20  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

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21  

 
Package leaflet: Information for the user 

 
DepoCyte 50 mg suspension for injection 

Cytarabine 
 
Read all of this leaflet carefully before you receive this medicine because it contains important 
information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have further questions, ask your doctor. 
− If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4.. 
 
What is in this leaflet: 
 
1. What DepoCyte is and what it is given for 
2. What you need to know before you are given DepoCyte 
3. How DepoCyte is given 
4. Possible side effects 
5. How to store DepoCyte 
6. Contents of the pack and other information 
 
 
1. What DepoCyte is and what it is given for 
 
DepoCyte is used to treat lymphomatous meningitis. 
 
Lymphomatous meningitis is a condition in which tumour cells have invaded the fluid or membranes 
that surround the brain and spinal cord. 
 
DepoCyte is used in adults to kill lymphoma tumour cells. 
 
 
2. What you need to know before you are given DepoCyte 
 
DepoCyte should not be given 
− if you are allergic to cytarabine or any of the other ingredients of this medicine (listed in 

section 6). 
− if you have a meningeal infection. 
 
Warnings and precautions 
Severe neurological side effects have been reported with the use of DepoCyte.  Symptoms have 
included effects on the nervous system (e.g. convulsions, pain, numbness or tingling, blindness or 
visual disturbances). Your doctor will check for these symptoms regularly. 
 
Make sure you take as directed any dexamethasone tablets that you may have been prescribed, as they 
reduce the risk of unwanted effects caused by DepoCyte. 
 
If your side effects get worse or you notice any new side effects, tell your doctor. 
 
Other medicines and DepoCyte 
Please tell your doctor if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription. 
 

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22  

Pregnancy, breast-feeding and fertility 
DepoCyte should not be given to pregnant women as it may harm an unborn child.  Women of 
childbearing potential should use a reliable contraceptive method to avoid pregnancy whilst being 
treated with DepoCyte. 
 
Male patients undergoing DepoCyte treatment should use a reliable contraceptive method.  
 
Women should not breast-feed during treatment as DepoCyte may enter breast milk. 
 
Driving and using machines 
Do not drive during treatment. 
Do not operate any tools or machines during treatment. 
 
 
3. How DepoCyte is given 
 
A qualified and experienced doctor or physician in the treatment of cancer will inject DepoCyte in the 
spinal fluid or lumber sac. DepoCyte must not be administered by any other way. Injections are given 
slowly over 1-5 minutes and you may be asked to lie flat for one hour afterwards. 
 
You will also be given dexamethasone, usually as tablets but possibly by intravenous injection for 
5 days after you receive each DepoCyte dose to help reduce any side effects which might occur. 
 
Before DepoCyte is used the vial should be warmed to room temperature (18°C – 22°C) for at least 
30 minutes. Just before withdrawing DepoCyte, the vial should be gently inverted to mix the particles 
evenly. It should not be shaken vigorously. 
 
Proper precautions should be taken for the handling and administration of a cytotoxic drug (proper 
handling technique, use of a suitable designated area, protective clothing, procedures to address risk of 
contamination). Staff who are pregnant or trying to conceive (male and female) should not work with 
DepoCyte. In the event of accidental contact with the mucous membranes, treat immediately by 
copious washing with water; medical attention should be sought. 
 
DepoCyte should be withdrawn from the vial immediately before administration; the medicinal 
product should be used within 4 hours of withdrawal from the vial.  Unused medicinal product must be 
discarded and not used subsequently.  DepoCyte must not be mixed with any other medicinal 
products. In-line filters must not be used when administering DepoCyte. 
 
DepoCyte must be used as supplied without further dilution. The dose for adults is 50 mg (one vial of 
DepoCyte). 
 
For the treatment of lymphomatous meningitis, DepoCyte is given according to the following 
schedules: 
 
Start-up treatment: one vial of DepoCyte (50 mg) administered every 14 days for 2 doses (weeks 1 
and 3). 
 
Follow-up treatment: one vial of DepoCyte (50 mg) administered every 14 days for 3 doses (weeks 
5, 7 and 9) followed by an additional dose at week 13. 
 
Maintenance treatment: one vial of DepoCyte (50 mg) administered every 28 days for 4 doses 
(weeks 17, 21, 25 and 29). 
 
If you are given more DepoCyte than you should 
The recommended dose will be given to you by the doctor or physician as necessary. There is no 
antidote for DepoCyte. Management of overdose should be directed at maintaining vital functions. 
 

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23  

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. Side 
effects may occur after each injection, usually within the first five days. 
 
Your doctor will discuss these with you and will explain the potential risks and benefits of your 
treatment. 
 
The frequency of possible side effects listed below is defined using the following convention: very 
common (affects more than 1 user in 10); common (affects 1 to 10 users in 100); uncommon (affects 1 
to 10 users in 1,000); rare (affects 1 to 10 users in 10,000); very rare (affects less than 1 user in 
10,000); not known (frequency cannot be estimated from the available data). 
 
The severity of adverse events of DepoCyte may be increased when DepoCyte is given in combination 
with other chemotherapeutic agents. 
 
Tell the medical staff monitoring you during this time, if you suffer from: 
 
Very common (experienced in more than 1 in 10 patients) 
 
• Nausea and/or vomiting 
• Weakness 
• Confusion 
• Fever 
• Headaches 
• Dizziness 
• Shaking 
 
Common (experienced in less than 1 in 10 but more than 1 in 100 patients) 
 
• Back pain 
• Convulsion 
• Neck pain 
• A stiff or rigid neck 
• Infection of the meninges 
• Fatigue 
• Pain, numbness or tingling (feeling of sensation of pins and needles) 
• Blindness and other visual disturbances 
• Hearing loss 
• Persistent or extreme sleepiness 
• Partial paralysis 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
inform the medical staff looking after you. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store DepoCyte 
 
Keep this medicine out of the sight and reach of children. 
 
 

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24  

Do not use this medicine after the expiry date which is stated on the carton and on the vial after EXP. 
The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not freeze. 
 
DepoCyte should be used as soon as possible after first opening, and should normally be used within 4 
hours (stored at 18-22ºC). 
 
DepoCyte is a sterile white to off-white-suspension. Do not use this medicine if you notice severe 
discolouration, a changed appearance or a defective container. 
 
Do not throw away any medicines via wastewater. DepoCyte contains cytarabine, and should be 
disposed of in a manner consistent with local requirements. 
 
 
6. Contents of the pack and other information 
 
What DepoCyte contains 
 
− The active substance is cytarabine. One ml of suspension contains 10 mg cytarabine. Each 5 ml 

vial contains 50 mg cytarabine 
− The other ingredients are cholesterol, triolein, dioleoylphosphatidylcholine, 

dipalmitoylphosphatidylglycerol, sodium chloride, and water for injections. 
 
What DepoCyte looks like and contents of the pack 
 
DepoCyte is a white to off-white-suspension for injection supplied in a glass vial.  
Each vial contains 5 ml of suspension for a single injection. 
Each pack contains a single vial. 
 
Marketing Authorisation Holder 
 
Pacira Limited, Wessex House, Marlow Road, Bourne End, Buckinghamshire, SL8 5SP, United 
Kingdom. 
 
Manufacturer 
Almac Pharma Services Limited, 20 Seagoe Industrial Estate, Craigavon, Co Armagh, BT63 5QD, 
United Kingdom. 

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25  

 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 

België/Belgique/Belgien  
Mundipharma Comm VA.  
Tél/Tel: +32 (0) 15 45 11 80 
info@mundipharma.be 

Lietuva 
KBM Pharma OÜ 
Tel. +372 733 8080 
kbmpharma@kbmpharma.eu 

 
България 
ТП Мундифарма Медикъл ООД 
Тел. +359 2 962 13 56/54 
mundipharma@mundipharma.bg 

 
Luxembourg/Luxemburg  
Mundipharma Comm VA.  
Tél: +32 (0) 15 45 11 80 
info@mundipharma.be 

 
Česká republika 
Mundipharma Ges.m.b.H. Austria 
Organizační složka ČR  
Tel : +420 222 318 221 
office@mundipharma.cz 

 
Magyarország 
Medis Hungary Kft 
Információsvonal: +36 2 380 1028 
info@medis.hu 

 
Danmark 
Mundipharma A/S 
Tlf: +45 45 17 48 00 
mundipharma@mundipharma.dk 

 
Malta 
Pacira Limited 
Wessex House, Marlow Road 
Bourne End, Buckinghamshire 
SL8 5SP - Renju Unit 
Τel: +44 (0) 1628 530554 

 
Deutschland 
Mundipharma GmbH 
Tel: + 49 (0) 64 31 701-0 
mundipharma@mundipharma.de 

 
Nederland 
Mundipharma Pharmaceuticals B.V.  
Tel: +31 (0) 33 450 8270  
info@mundipharma.nl 

 
Eesti 
KBM Pharma OÜ  
Tel: +372 733 8080 
kbmpharma@kbmpharma.eu 

 
Norge  
Mundipharma AS  
Tlf: +47 67 51 89 00 
post@mundipharma.no 

 
Eλλάδα 
Pacira Limited 
Wessex House, Marlow Road 
Bourne End, Buckinghamshire 
SL8 5SP 
Ηνωμένο Βασίλειο 
Τηλ: +44 (0) 1628 530554 

 
Österreich 
Mundipharma Gesellschaft.m.b.H.  
Tel: + 43 (0) 1 523 25 05 
office@mundipharma.at 

 
España 
Mundipharma Pharmaceuticals, S.L. 
Tel: +34 91 3821870 
infomed@mundipharma.es 

 
Polska 
Mundipharma Polska Sp.z o.o. 
Tel: +48(0) 22 866 87 12 
office@mundipharma.pl 

 

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26  

France 
Mundipharma 
Tel: +33 (0) 1 40 65 29 29 
infomed@mundipharma.fr 

Portugal 
Companhia Portuguesa Higiene Pharma – 
Produtos Farmacêuticos, S.A.  
Tel: +351 214 449 600 
geral@ferrergrupo.com.pt 

 
Hrvatska 
Medis Adria d.o.o.  
Kolarova 7, 
10000 Zagreb 
Tel.: +385 1 2303 446 

 
România 
Mundipharma Gesellschaft m.b.H., Austria  
Tel: +40 751 121 222 
office@mundipharma.ro 

 
Ireland 
Mundipharma Pharmaceuticals Limited 
Tel: +353 1 2063800 
oncologymedinfo@napp.co.uk 

 
Slovenija 
Medis, d.o.o. 
Tel: +386 158969 00 
info@medis.si 

 
Ísland 
Mundipharma A/S 
Tel: +45 45 17 48 00 
mundipharma@ mundipharma.dk 

 
Slovenská republika  
Mundipharma Ges.m.b.H. - o.z  
Tel: +421 2 63811611 
mundipharma@mundipharma.sk 

 
Italia 
Mundipharma Pharmaceuticals Srl 
Tel: + 39.02.318288216 
Italy.InfoMedica@mundipharma.it 

 
Suomi/Finland 
Mundipharma Oy 
Puh/Tel: +358 (0)9 8520 2065 
info@mundipharma.fi 

 
Κύπρος 
Mundipharma Pharmaceuticals Ltd 
Τηλ: +357 22 81 56 56  
info@mundipharma.com.cy 

 
Sverige 
Mundipharma AB 
Tel: + 46 (0)31 773 75 30 
info@mundipharma.se 

 
Latvija 
Institute of Innovative Biomedical Technology 
Tel: +371 7 800810 
info@ibti.lvoffice 

 
United Kingdom 
Napp Pharmaceuticals Limited 
Tel: +44 (0) 1223 424444 
oncologymedinfo@napp.co.uk 

 
 
This leaflet was last revised in MM/YYYY 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. Me

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET