Leaflet DEPOCYTE 50mg injection suspension

DepoCyte 50 mg suspension for injection

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.

Suspension for injection.

White to off-white suspension.

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

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

Safety and efficacy in children aged under 18 years have not been established. Currently available dataare described in section 5.1 but no recommendation on a posology can be made. DepoCyte is notrecommended 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) administeredintrathecally (lumbar puncture or intraventricularly via an Ommaya reservoir). The following regimenof 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 byan 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).

DepoCyte is to be administered by slow injection over a period of 1-5 minutes directly into thecerebrospinal fluid (CSF) via either an intraventricular reservoir or by direct injection into the lumbarsac. Following administration by lumbar puncture, it is recommended that the patient should beinstructed to lie flat for one hour. All patients should be started on dexamethasone 4 mg twice dailyeither 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 assupplied; it must not be diluted (see section 6.2). Patients should be observed by the physician forimmediate 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 listed in section 6.1. Patients withactive 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 leftuntreated, chemical arachnoiditis may be fatal.

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

Cytarabine, when administered intrathecally, has been associated with nausea, vomiting and seriouscentral 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 withcranial/spinal irradiation may increase the risk of neurotoxicity.

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

Blockage or reduction of CSF flow may result in increased free cytarabine concentrations in the CSFwith increased risk of neurotoxicity. Therefore, as with any intrathecal cytotoxic therapy, considerationshould 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 intrathecaltreatment, some effects on bone marrow function cannot be excluded. Systemic toxicity due tointravenous administration of cytarabine consists primarily of bone marrow suppression withleucopenia, thrombocytopenia and anaemia. Therefore monitoring of the haemopoietic system isadvised.

Anaphylactic reactions following intravenous administration of free cytarabine have been rarelyreported.

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

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

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

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

Despite the low apparent risk women of childbearing potential should not receive treatment untilpregnancy 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 thehuman spermatozoa, males undergoing DepoCyte treatment and their partner should be advised to usea reliable contraceptive method.

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

Cytarabine, the active ingredient in DepoCyte, can cause foetal harm when administered systemicallyduring 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 untilpregnancy is excluded and should be advised to use a reliable contraceptive method.

It is not known whether cytarabine is excreted in human milk following intrathecal administration. Thesystemic 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 reactionsin nursing infants, the use of DepoCyte is not recommended in breast-feeding women.

Fertility studies to assess the reproductive toxicity of DepoCyte have not been conducted. Because thesystemic exposure to free cytarabine following intrathecal treatment with DepoCyte is negligible, therisk 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 driveor use machines. However, on the basis of reported adverse reactions, patients should be advisedagainst driving or using machines during treatment.

In Phase 1-4 studies the most commonly reported adverse reactions associated with DepoCyte wereheadache (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 orcytarabine adverse reactions are listed by MedDRA body system organ class and by frequency (Verycommon (≥1/10); and Common (≥1/100 to < 1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000to <1/1,000); very rare (<1/10,000)) in Table 1 below. Within each frequency grouping, undesirableeffects are presented in order of decreasing seriousness.

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

DepoCyte Very common: Thrombocytopenia

Cytarabine Very common: Thrombocytopenia

DepoCyte Very common: arachnoiditis, confusion, headache

Cytarabine Very common: arachnoiditis, headache

Common: confusion

DepoCyte Very common: diarrhoea, vomiting, nausea

Cytarabine Very common: diarrhoea, vomiting, nausea

General disorders and administration siteconditions

DepoCyte Very common: weakness, pyrexia

Common: fatigue

Cytarabine Very common: weakness, pyrexia, fatigue

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

DepoCyte has the potential of producing serious neurological toxicity.

Intrathecal administration of cytarabine may cause myelopathy (3%) and other neurologic toxicitiessometimes leading to a permanent neurological deficit. Following intrathecal administration of

DepoCyte, serious central nervous system toxicity, including persistent convulsions (7%), extremesomnolence (3%), hemiplegia (1%), visual disturbances including blindness (1%), deafness (3%) andcranial nerve palsies (3%) have been reported. Symptoms and signs of peripheral neuropathy, such aspain (1%), numbness (3%), paresthesia (3%), hypoaesthesia (2%), weakness (13%), and impairedbowel (3%) and bladder control (incontinence) (1%), have also been observed and in some cases thiscombination 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 systemorgan 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 ofdecreasing seriousness.

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

DepoCyte Common: somnolence

Cytarabine Common: somnolence

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

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

DepoCyte Common: visual disturbances, blindness

Cytarabine Common: visual disturbances, blindness

Ear and labyrinth disorders

DepoCyte Common: deafness

Cytarabine Common: deafness

DepoCyte Common: impaired bowel control

Cytarabine Common: impaired bowel control

DepoCyte Common: urinary incontinence

Cytarabine Common: urinary incontinence

General disorders and administration siteconditions

DepoCyte Very Common: weakness

Common: pain

Cytarabine Very Common: weakness

Common: pain

All patients receiving DepoCyte should be treated concurrently with dexamethasone to mitigate thesymptoms 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 daysof administration), patients receiving DepoCyte therapy should be monitored continuously for thedevelopment of neurotoxicity. If patients develop neurotoxicity, subsequent doses of DepoCyteshould be reduced, and treatment should be discontinued if toxicity persists.

Arachnoiditis, a very common adverse reaction associated with DepoCyte, is a syndrome manifestedby several adverse reactions. The incidence of these adverse reactions, possibly reflecting meningealirritation, 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 CSFpleocytosis with or without altered state of consciousness (1%). Table 3 below lists these reactions forpatients 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 frequencygrouping, undesirable effects are presented in order of decreasing seriousness.

Table 3: Adverse reactions possibly reflecting meningeal irritation in Phase II, III, and IVpatients

DepoCyte (n = 929 cycles) Very common: headache

Common: convulsions, hydrocephalus acquired,

CSF pleocytosis

Uncommon: meningism

Methotrexate (n = 258 cycles) Very common: headache

Common: convulsions, hydrocephalus acquired,meningism

Cytarabine (n = 99 cycles) Very common: headache

Common: convulsions, meningism

DepoCyte (n = 929 cycles) Very common: vomiting, nausea

Methotrexate (n = 258 cycles) Very common: vomiting, nausea

Cytarabine (n = 99 cycles) Very common: vomiting, nausea

Musculoskeletal and connective tissuedisorders

DepoCyte (n = 929 cycles) Common: back pain, neck pain, neck stiffness

Methotrexate (n = 258 cycles) Common: back pain, neck pain

Uncommon: neck stiffness

Cytarabine (n = 99 cycles) Common: back pain, neck pain, neck stiffness

General disorders and administration siteconditions

DepoCyte (n = 929 cycles) Very common: pyrexia

Methotrexate (n = 258 cycles) Common: pyrexia

Cytarabine (n = 99 cycles) Very common: pyrexia

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

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 orcytarabine. These reactions have been reported mainly from post-marketing experience with

DepoCyte as spontaneous case reports. Because these reactions are reported from a population ofuncertain size, it is not possible to reliably estimate their frequency.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No overdoses with DepoCyte have been reported. An overdose with DepoCyte may be associatedwith severe arachnoiditis including encephalopathy.

In an early uncontrolled study without dexamethasone prophylaxis, single doses up to 125 mg wereadministered. 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 brainirradiation 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 caseof 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 thecerebrospinal fluid (CSF).

Cytarabine is a cell-cycle phase specific antineoplastic agent, affecting cells only during the S-phase ofcell division. Intracellularly, cytarabine is converted into cytarabine-5’-triphosphate (ara-CTP), whichis 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 alsocontribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to a wide variety of proliferatingmammalian cells in culture.

For cell-cycle phase specific antimetabolites the duration of exposure of neoplastic cells to cytotoxicconcentrations is an important determination of efficacy.

In vitro studies, examining more than 60 cell lines, demonstrated that the median cytarabineconcentration resulting in 50% growth inhibition (IC50) was approximately 10 µM (2.4 µg/ml) for twodays of exposure and 0.1 µM (0.024 µg/ml) for 6 days of exposure. The studies also demonstratedsusceptibility of many solid tumour cell lines to cytarabine, particularly after longer periods ofexposure to cytarabine.

In an open-label, active-controlled, multicentre clinical study, 35 patients with lymphomatousmeningitis (with malignant cells found on CSF cytology) were randomised to intrathecal therapy witheither DepoCyte (n=18) or unencapsulated cytarabine (n=17). During the 1 month Induction phase oftreatment, DepoCyte was administered intrathecally as 50 mg every 2 weeks, and unencapsulatedcytarabine as 50 mg twice a week. Patients who did not respond discontinued protocol treatment after4 weeks. Patients who achieved a response (defined as clearing of the CSF of malignant cells in theabsence of progression of neurological symptoms) went on to receive Consolidation and Maintenancetherapy for up to 29 weeks.

Responses were observed in 13/18 (72%, 95% confidence intervals: 47, 90) of DepoCyte patientsversus 3/17 (18% patients, 95% confidence intervals: 4, 43) in the unencapsulated cytarabine arm. Astatistically significant association between treatment and response was observed (Fisher’s exact testp-value = 0.002). The majority of DepoCyte patients went on beyond Induction to receive additionaltherapy. DepoCyte patients received a median of 5 cycles (doses) per patient (range 1 to 10 doses) witha 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 oflife and overall survival. Median progression-free survival (defined as time to neurologicalprogression or death) for all treated patients was 77 versus 48 days for DepoCyte versusunencapsulated 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) withleukaemic meningitis or neoplastic meningitis due to primary brain tumour, an intrathecal dose of35 mg was identified as the maximum tolerated dose.

Analysis of the available pharmacokinetic data shows that following intrathecal DepoCyteadministration in patients, either via the lumbar sac or by intraventricular reservoir, peaks of freecytarabine were observed within 5 hours in both the ventricle and lumbar sac. These peaks werefollowed by a biphasic elimination profile consisting of an initial sharp decline and subsequent slowdecline with a terminal phase half-life of 100 to 263 hours over a dose-range of 12.5 mg to 75 mg. Incontrast, intrathecal administration of 30 mg free cytarabine has shown a biphasic CSF concentrationprofile with a terminal phase half-life of about 3.4 hours.

Pharmacokinetic parameters of DepoCyte (75 mg) in neoplastic meningitis patients in whom themedicinal product was administered either intraventricularly or by lumbar puncture suggest thatexposure to the active substance in the ventricular or lumbar spaces is similar regardless of the route ofadministration. In addition, compared with free cytarabine, the formulation increases the biologicalhalf-life by a factor of 27 to 71 depending upon the route of administration and the compartmentsampled. Encapsulated cytarabine concentrations and the counts of the lipid particles in which thecytarabine is encapsulated in followed a similar distribution pattern. AUCs of free and encapsulatedcytarabine 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 arelinear 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 determinedto be negligible following intrathecal administration of 50 mg and 75 mg of DepoCyte.

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 withsystemically 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 deaminaseactivity in the CNS tissues and CSF. The CSF clearance rate of cytarabine is similar to the CSF bulkflow rate of 0.24 ml/min.

The distribution and clearance of cytarabine and of the predominant phospholipid component of thelipid particle (DOPC) following intrathecal administration of DepoCyte was evaluated in rodents.

Radiolabels for cytarabine and DOPC were distributed rapidly throughout the neuraxis. More than90% of cytarabine was excreted by day 4 and an additional 2.7% by 21 days. The results suggest thatthe lipid components undergo hydrolysis and are largely incorporated in the tissues followingbreakdown in the intrathecal space.

A review of the toxicological data available for the constituent lipids (DOPC and DPPG) or similarphospholipids to those in DepoCyte indicates that such lipids are well tolerated in various animalspecies 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 tomoderate inflammation of the meninges in the spinal cord and brain and/or astrocytic activation wereobserved in animals receiving intrathecal DepoCyte. These changes were believed to be consistentwith 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 DepoFoamalone (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 haemopoieticsystem.

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 clastogenicin vitro (chromosome aberrations and sister chromatid exchange in human leukocytes) and in vivo(chromosome aberrations and sister chromatid exchange assay in rodent bone marrow, mousemicronucleus assay). Cytarabine caused the transformation of hamster embryo cells and rat H43 cellsin vitro. Cytarabine was clastogenic to meiotic cells; a dose-dependent increase in sperm-headabnormalities 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 thesystemic 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 agentshave been conducted. DepoCyte should not be diluted or mixed with any other medicinal products, asany 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. Ifnot used immediately, in-use storage times and conditions prior to use are the responsibility of the userand 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 aluminiumflip-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 forthe 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 andbe gently inverted to resuspend the particles immediately prior to withdrawal from the vial. Vigorousshaking 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 singleuse vial and does not contain any preservative, the medicinal product should be used within 4 hours ofwithdrawal from the vial. Unused medicinal product must not be used subsequently. DepoCyte mustnot 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 intothe CSF via an intraventricular reservoir or by direct injection into the lumbar sac. DepoCyte shouldbe injected slowly over a period of 1-5 minutes. Following administration by lumbar puncture, thepatient should be instructed to lie flat for one hour. Patients should be observed by the physician forimmediate toxic reactions.

All patients should be started on dexamethasone 4 mg twice daily either orally or intravenously for 5days 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 beexcluded 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-disposalbags for high temperature incineration;

* in the event of accidental contact with the skin, exposed areas should be washed immediatelywith soap and water;

* in the event of accidental contact with the mucous membranes, exposed areas should be treatedimmediately by copious lavage with water; medical attention should be sought.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pacira Limited

Wessex House

Marlow Road

Bourne End

Buckinghamshire

SL8 5SP

United Kingdom

EU/1/01/187/001

Date of first authorisation: 11 July 2001

Date of latest renewal: 11 July 2011

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