Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

DepoCyte 50 mg suspension for injection

One ml of suspension contains 10 mg cytarabine.

Each 5 ml vial contains 50 mg cytarabine.

For a full list of excipients, see section 6.1.

Suspension for injection.

White to off-white suspension.

Intrathecal treatment of lymphomatous meningitis. In the majority of patients such treatment will be part of symptomatic palliation of the disease.

DepoCyte should be administered only under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

Posology

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).

Paediatric population

Safety and efficacy in children have not been adequately demonstrated (see section 5.1). DepoCyte is not recommended for use in children and adolescents until further data become available.

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 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.

Hypersensitivity to the active substance or to any of the excipients.

Patients with active meningeal infection.

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.

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.

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.

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.

*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.

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.

*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.

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.

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.

Pharmacotherapeutic group: Antimetabolites, pyrimidine analogues, ATC code L01BC01

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.

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.

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 unencapsulated cytarabine, respectively. The proportion of patients alive at 12 months was 24% for DepoCyte versus 19% for unencapsulated cytarabine.

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.

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.

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 and elimination

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.

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.

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.

Cholesterol

Triolein

Dioleoylphosphatidylcholine (DOPC)

Dipalmitoylphosphatidylglycerol (DPPG)

Sodium chloride

Water for injections

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.

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.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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.

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 be discarded and not 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.

Pacira Limited

3 Glory Park Avenue

Wooburn Green

High Wycombe

Buckinghamshire

HP10 0DF

United Kingdom

EU/1/01/187/001

Date of first authorisation: 11 July 2001

Date of latest renewal:

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu.