Recognition and Treatment of Lymphomatous Meningitis

White PaPer

Recognition and Treatment of Lymphomatous Meningitis in Patients with Late-Stage Lymphoma

IndicationDepoCyt® (cytarabine liposome injection) is indicated for the intrathecal treatment of lym-phomatous meningitis.Important Safety InformationWARNING: CHEMICAL ARACHNOIDITIS ADVERSE REACTIONSChemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache and fever, was a common adverse event in all clinical studies. If left untreated, chemical arachnoiditis may be fatal. Patients receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis. [See Warnings and Precautions (5.1, 5.2) in full prescribing information]ContraindicationsDepoCyt® (cytarabine liposome injection) is contraindicated in patients who are hyper-sensitive to cytarabine or any component of the formulation, and in patients with active meningeal infection.

Warnings and PrecautionsDosingIn-line filters must not be used when administering DepoCyt. DepoCyt is administered di-rectly into the cerebrospinal fluid (CSF) via an intraventricular reservoir or by direct injec-tion into the lumbar sac. DepoCyt should be injected slowly over a period of 1-5 minutes. Following drug administration by lumbar puncture, the patient should be instructed to lie flat for 1 hour. Patients should be observed by the physician for immediate toxic reactions.

Chemical ArachnoiditisChemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache and fever, has been a common adverse event in all studies. If chemical arachnoiditis is sus-pected, exclude other inflammatory, infectious, or neoplastic conditions. If left untreated, chemical arachnoiditis may be fatal. The incidence and severity of chemical arachnoiditis can be reduced by coadministration of dexamethasone. Patients receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arach-noiditis.• Toxic effects may be related to a single dose or to cumulative administration. Because

toxic effects can occur at any time during therapy (although they are most likely to occur within 5 days of drug administration), patients receiving intrathecal therapy with Depo-Cyt should be monitored continuously for the development of neurotoxicity. If patients develop neurotoxicity, reduce subsequent doses of DepoCyt. If neurotoxicity persists, discontinue DepoCyt.

• Hydrocephalus has also been reported, possibly precipitated by arachnoiditis.• Arachnoiditis is an expected and well-documented side effect of both neoplastic men-

ingitis and of intrathecal chemotherapy. The incidence of severe and life-threatening arachnoiditis in patients receiving DepoCyt was 19% (48/257) in all patients and 30% (10/33) in patients with lymphomatous meningitis. In the early dose-finding study, chemi-cal arachnoiditis was observed in 100% of cycles without dexamethasone prophylaxis. When concurrent dexamethasone was administered, chemical arachnoiditis was observed in 33% of cycles.

(Continued on next page)

Distributed by Sigma-Tau Pharmaceuticals, Inc.

(Continued from previous page)Neurotoxicity• Intrathecal administration of cytarabine may cause myelopathy and other neurologic

toxicity and can rarely lead to a permanent neurologic deficit. Administration of intra-thecal cytarabine in combination with other chemotherapeutic agents or with cranial/spinal irradiation may increase this risk of neurotoxicity.

• Blockage to CSF flow may result in increased free cytarabine concentrations in the CSF and an 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.

• Following intrathecal administration of DepoCyt, central nervous system toxicity, including persistent extreme somnolence, hemiplegia, visual disturbances including blindness which may be total and permanent, deafness and cranial nerve palsies have been reported. Symptoms and signs of peripheral neuropathy, such as pain, numbness, paresthesia, weakness, and impaired bowel and bladder control have also been observed. In some cases, a combination of neurological signs and symptoms has been reported as Cauda Equina Syndrome.

• If patients develop neurotoxicity, reduce subsequent doses of DepoCyt or discontinue DepoCyt. Headache, nausea, and fever are expected in early signs of neurotoxicity.

Transient Elevations in CSF Protein and CSF White Blood CellsTransient elevations in CSF protein and white blood cell counts have been observed in patients following DepoCyt administration.

Embryo-Fetal ToxicityCytarabine, the active component of DepoCyt, can cause fetal harm if a pregnant woman is exposed to the drug systemically. The systemic exposure of cytarabine following intrathe-cal administration of DepoCyt is negligible. Cytarabine was teratogenic in mice and rats. Cytarabine was embryotoxic in mice when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to a fetus.

Adverse ReactionsAfter intrathecal administration of cytarabine the most frequently reported reactions (≥ 10%) are headache NOS, nausea, vomiting NOS, arachnoiditis, weakness, confusion, pyrexia, fatigue, constipation, back pain, gait abnormal NOS, convulsions NOS, dizziness NOS, lethargy, pain in limb, insomnia, urinary tract infection NOS, neck pain, death NOS, pain, memory impairment, dehydration, anemia NOS, diarrhea NOS, appetite decreased NOS, thrombocytopenia, edema peripheral, arthralgia, neck stiffness, vision blurred, muscle weakness, neutropenia, hypoesthesia, agitation, and dyspnea NOS.

Please see full prescribing information attached, including Boxed WARNINGS, or go to www.depocyt.com.

Manufactured by Pacira Pharmaceuticals, Inc.

4Recognition and Treatment of LM • April 2015

White PaPer

Recognition and Treatment of Lymphomatous Meningitis in Patients with Late-Stage Lymphoma

Lymphomatous meningitis (LM) oc-curs when malignant cells infiltrate the cerebrospinal fluid (CSF) and the leptomeninges. The brain and spinal cord are contained by the meninges,

a three-layered membrane consisting of the pia, the arachnoid, and the dura (see Figure 1). The pia is the most delicate and vascular of the three, lying directly on the brain’s surface. Be-tween it and the layer above, the arachnoid, is the subarachnoid space, where a large percent-age of the CSF flows and is held. Just above the arachnoid, is the dura, a thick, fibrous sheath that forms the outermost layer.3,4 When malig-nant cells penetrate the dura, the entire neuraxis is at risk and progressive deterioration in neu-rologic function occurs. Although the course may be variable, without treatment, prognosis is grave, with life expectancy approximately less than three months5. However, with early diagnosis and prompt treatment, survival may be extended to a few months.

Challenges with Diagnosis and Treatment

Patients with LM most commonly present with headache and cranial nerve dysfunction. Because these initial or early symptoms are typically subtle and their presentation similar to many other etiologies, proper diagnosis is challenging. Awareness of risk factors for LM

may help healthcare providers to be alert for this disease despite its vague early symptomatology (see Figure 2).

Achieving a diagnosis for LM involves elimi-nating other etiologies by implimenting a triad of methods4:

• A thorough neurologic examination, • Magnetic resonance imaging (MRI) with

and without gadolinium of the entire neuraxis, and

• Lumbar puncture for CSF sampling.The purposes of using these diagnostic tools

are to confirm lymphoma infiltration into the subarachnoid space, as well as the location of disease along the neuraxis and the extent of the blockage of CSF flow. Although any of the methods may stand alone as diagnostic criteri-on, most clinicians rely on a positive cytologic examination.4

In patients with an elevated risk profile, a thorough history and physical examination is essential because patients may not report subtle neurologic changes and other symptoms such as pain because they may not feel these are significant. Signs and symptoms by affected neural area are outlined in Table 1.

In addition to neurologic examination, MRI with and without gadolinium of the entire neur-axis and a lumbar puncture for CSF sampling and cytology completes the diagnostic triad for LM.4

MRI may detect spread of disease, as well as any bulky metastases that may be partially or

Lymphomatous meningitis (LM), a rare subset of neoplastic meningitis, is a devastat-ing complication of lymphoma that results in significant neurologic deficit, decreased Karnofsky performance status (KPS), and poor survival.1,2 Although this disease is progressive and treatment is palliative, early diagnosis and intervention may protect neurologic function and may improve KPS. This white paper presents the signs, symptoms, and risk factors of LM, as well as treatment with DepoCyt® (cytarabine liposome injection).

5Recognition and Treatment of LM • April 2015

Figure 1. Neuraxis Anatomy

6Recognition and Treatment of LM • April 2015

completely blocking the flow of CSF. Imaging of the entire neuraxis should be completed, be-cause leptomeningeal spread can occur at any area along this axis and is often present in more than one area or before symptoms are evident.

Lumbar puncture is typically performed to obtain CSF samples. CSF may be obtained from a ventricle if a patient has an Ommaya reser-voir.4 For diagnostic accuracy, at least 10 ml of CSF should be extracted for cytology and 3 to 5 ml for other evaluation.4 Two taps should yield an adequate amount of fluid for examination.

Once LM is properly identified, healthcare professionals may be reluctant to initiate treat-ment due to the patient’s status as late or end of life. However, with proper intervention, neuro-logic function may be preserved, and prognosis potentially extended from a few weeks to a few months. Oncology nurses are in an ideal posi-tion to recognize the subtle signs and prompt further investigation for LM and other neuro-logic conditions.

Once a positive diagnosis for LM is deter-mined, management includes palliation of symptoms and attempting to slow disease pro-gression. Radiation is used to shrink lesions that are causing symptoms or blocking CSF flow. Ideally, intrathecal chemotherapy is also employed to reach metastases along the CSF that may or may not be visible on MRI.4

Treatment with DepoCyt®

DepoCyt is a sustained-release cytarabine liposome suspension indicated for intrathecal treatment of LM. Although its mechanism of action is not completely understood, cytarabine is an antineoplastic agent that acts during the S-phase of cell division. Intrathecal administra-tion allows cytarabine to reach the metastatic lymphoma cells within the CSF to reduce tumor burden and slow progression of neurologic damage.9 The cytotoxic agent cytarabine is en-capsulated in a lipid so that it may be released over time into the CSF.

Table 1. Symptoms Related to the Part of the Neuraxis Affected1,8 Location Symptoms

Cranial nerves Diplopia, dysphagia, sensory changes (e.g., hearing loss, visual loss, altered taste and smell), facial numbness and weakness

Spinal cord and spinal nerves Lower extremity weakness, h e m i h y p e s -t h e s i a , paresthesias, pain (radicular or back or neck pain), bladder or bowel dys-function

Cerebral hemisphere involvement

Headache, mental status change, abnormal gait, nausea, vomiting, seizure

Secondary to obstruction of cerebrospinal fluid flow

Related to increased intracranial pressure (e.g., headache, nausea, vomiting, neurocogni-tive deficits, altered mental status, weakness)

Figure 2. Lymphomatous Meningitis Risk Factors6

High-grade lymphoma and advanced stage

Progressive recurrence

Refractory to treatment

Extensive extranodal disease

Younger age

Elevated serum lactate dehydrogenase (LDH) levels

Presence of immunocompromised and HIV-related lymphoma

Presence of primary central nervous system lymphoma

7Recognition and Treatment of LM • April 2015

Once DepoCyt is administered to a patient, the liposome membranes reorganize and dis-tribute throughout the CSF, releasing cytarabine molecules over two weeks. A sustained release formula allows for fewer treatments (one dose versus four doses) compared to unencapsulated cytarabine.

Intrathecal Administration for LMIntrathecal (IT) chemotherapy is used for pa-

tients with central nervous system malignancies and provide direct and consistent drug levels in the cerebrospinal fluid. IT administration should be administered only under the supervi-sion of a qualified physician experienced in the use of cancer chemotherapeutic agents. Only preservative-free solutions are used and labeled “For Intrathecal Administration Only.”

Table 2 shows the half-lives and dosage schedules of commonly used IT treatments for LM: methotrexate, unencapsulated cytarabine, and DepoCyt.

Intrathecal administration can be accom-plished in one of two ways: via lumbar puncture or injection into an intraventricular port, such as an Ommaya reservoir. Unlike unencapsulated

cytarabine, which tends to pool near the injec-tion site, the liposome encapsulation allows DepoCyt to distribute throughout the CSF with use of either injection site.10,11

Dosing ScheduleThe recommended dose of DepoCyt is 50

mg and includes induction, consolidation, and maintenance phases. During the induction phase, DepoCyt is administered every 14 days for 2 doses (weeks 1 and 3). The schedule for the consolidation phase is every 14 days for three doses (weeks 5, 7, and 9) followed by an additional dose at week 13. During mainte-nance the frequency is reduced to every 28 days for 4 doses (see Figure 3).

DepoCyt offers an effective dosing regimen for intrathecal treatment of lymphomatous meningitis—once every two weeks—compared to twice weekly unencapsulated cytarabine or methotrexate (see Figures 4 and 5).

Administration of DepoCyt®

DepoCyt must be slowly administered (over a period of one to five minutes), directly into the CSF via direct injection into the lumbar sac or an

Figure 3. DepoCyt® Dosing Schedule

Table 2. Intrathecal Treatments for Lymphomatous Meningitis5

Treatment Indications Intrathecal Dosing Regimen (Induction)

Half-Life in Cerebrospinal

FluidMethotrexate Prophylaxis and treatment

of meningeal leukemia12 mg every 2–5 days 7.2 hours

Unencapsulated cytarabine

Prophylaxis and treatment of meningeal leukemia

30 mg/m2 every 4 days 3.4 hours

DepoCyt® Treatment of lymphomatous meningitis

50 mg every 14 days Up to 82.4 hours

8Recognition and Treatment of LM • April 2015

Figure 4. Does Site of Administration Matter?10,11

Administration into the Lumbar Sac

Free Cytarabine DepoCyt®

Intraventricular Administration

Free Cytarabine DepoCyt®

Drawings courtesy of Dr. Michael Glantz.

1 dose versus 4 doses

Figure 5. DepoCyt® Versus Unencapsulated Cytarabine

intraventricular reservoir. Dexamethasone must be administered concurrently with each dose as prophylaxis for chemical arachnoiditis (inflam-mation of the arachnoid membrane). The pa-tient should be instructed to lie flat for one hour and observed for immediate toxic reactions. See the attached DepoCyt Prescribing Information for important precautions.

Efficacy Studies of DepoCyt®

Two clinical studies showed that this treat-ment resulted in higher complete cytologic responses in patients with LM treated with

DepoCyt compared to those patients treat-ed with unencapsultaed cytarabine. These two randomized, multicenter clinical trials of DepoCyt were in 57 patients with LM. Patients were treated with 50 mg of DepoCyt adminis-tered every two weeks or 50 mg of unencap-sulated intrathecal cytarabine administered twice weekly.9 Study 1 was a four-week trial and Study 2 involved six, two-week induction cycles followed by four maintenance cycles.

In both studies, the primary end point was complete cytologic response, which was de-fined as (a) conversion of positive to negative CSF cytology, and (b) the absence of progres-sive neurologic deficit. As Table 3 shows, both studies reported higher complete cytologic responses for DepoCyt when compared to un-encapsulated cytarabine. Study 2 results were not statistically significant.9

9Recognition and Treatment of LM • April 2015

Table 3. Complete Cytologic Response Rates in Patients with LM

in Studies 1 and 2*9

DepoCyt® Unencapsulated Cytarabine

Study 1Study 1

95% CI

7/17 (41%)

(18%, 67%)

1/16 (6%)

(0%, 30%)Study 2Study 2

95% CI

4/12 (33%)

(10%, 65%)

2/12 (17%)

(2%, 48%)*Complete cytologic response was prospectively defined as (a) conversion of positive to negative cerebrospinal fluid cytology, and (b) the absence of neurologic progression.

DepoCyt® Safety InformationDepoCyt is contraindicated in patients who

are hypersensitive to cytarabine or any com-ponent of the formulation, and in patients with active meningeal infection.

In controlled clinical trials, the most common severe adverse event was chemical arachnoidi-tis (inflammation of the arachnoid membrane). Dexamethasone should be concomitantly ad-ministered with DepoCyt to reduce the risk and severity of chemical arachnoiditis (see BOXED WARNING within the complete prescribing information attached to this white paper). Hy-drocephalus (abnormal buildup of CSF in and around the brain) has also been reported, pos-sibly precipitated by arachnoiditis.

Arachnoiditis is an expected and well-docu-mented side effect of both neoplastic meningitis and of intrathecal chemotherapy. The incidence of severe and life-threatening arachnoiditis in patients receiving DepoCyt was 19% (48/257) in all patients and 30% (10/33) in patients with lymphomatous meningitis. In the early dose-finding study, chemical arachnoiditis was observed in 100% of cycles without dexametha-sone prophylaxis. When concurrent dexametha-sone was administered, chemical arachnoiditis was observed in 33% of cycles.

After intrathecal administration of cytarabine the most frequently reported reactions (≥ 10%) are headache, nausea, vomiting, arachnoiditis, weakness, confusion, pyrexia, fatigue, consti-pation, back pain, abnormal gait, convulsions, dizziness, lethargy, pain in limb, insomnia, urinary tract infection, neck pain, death, pain, memory impairment, dehydration, anemia, di-arrhea, decreased appetite, thrombocytopenia,

peripheral edema, arthralgia, neck stiffness, blurred vission, muscle weakness, neutropenia, hypoesthesia, agitation, and dyspnea.

Cytarabine, the active component of Depo-Cyt, can cause fetal harm if a pregnant woman is exposed to the drug systemically. The sys-temic exposure of cytarabine following intra-thecal administration of DepoCyt is negligible. Cytarabine was teratogenic in mice and rats. Cytarabine was embryotoxic in mice when administered during the period of organogen-esis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to a fetus.

ConclusionsEarly diagnosis and prompt treatment of LM

is essential to preserve neurologic function and slow disease progression. In patients who have risk factors for LM, a thorough patient history that evaluates for changes in neurologic func-tion, MRI of the complete neuraxis, and CSF cytology and evaluation are considered ideal for accurate diagnosis.

Although LM occurs during late-stage dis-ease and treatment is palliative, proper diagno-sis and treatment may help patients with LM. DepoCyt features fewer doses, and in patients with LM, resulted in greater complete cytologic responses compared to unencapsulated cytara-bine alone. Nurses should be alert for the early signs of neurologic decline in patients who have risk factors for LM so that treatment may be considered for immediate initiation.

This white paper was developed by ONS:Edge in col-laboration with Sigma-Tau Pharmaceuticals, Inc. All content belongs to and is copyrighted by Sigma-Tau Pharmaceuticals, Inc. ONS:Edge assists with distribu-tion and promotion.ONS:Edge thanks reviewer Alixis Van Horn, RN, MSN, APRN-C(c), Director, Neurology Day Rehabilitation Pro-gram, Whittier Health Network, Boston, MA, and medical writer Laura J. Pinchot of ONS:Edge for their expertise.Alixis Van Horn is a paid speaker for Sigma-Tau Phar-maceuticals, Inc.

For more information about this paper or to download copies, visit www.onsedge.com. ONS:Edge can be con-tacted by email at [email protected] or by phone at 877-588-EDGE (3343) or 412-859-6108.

10Recognition and Treatment of LM • April 2015

References1. Demopoulos A. Leptomeningeal metastases.

Curr Neurol Neurosci Rep. 2004;4:196-204.2. Kesari S, Batchelor TT. Leptomeningeal

metastases. Neurol Clin. 2003;21:25-66.3. Garcia-Marco JA, Panizo, C, Garcia ES, et

al. Efficacy and safety of liposomal cytara-bine in lymphoma patients with central ner-vous system involvement from lymphoma. Cancer. 2009;115(9):1892-1898. doi: 10.1002/cncr.24204

4. Van Horn A. Lymphomatous meningitis: Early diagnosis and treatment. Clin J On-col Nurs. 2009;13(1):90-94. doi: 10.1188/09.CJON.90-94.

5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncol-ogy: Central nervous system cancer, version 2.2014. Accessed February 24, 2014. http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. .

6. Chamberlain MC, Nolan C, Abrey LE. Leukemic and lymphomatous meningitis incidence, prognosis and treatment. J Neu-rooncol. 2005;75:71-83.

7. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun M. Cancer Statistics, 2007. CA Cancer J Clin. 2007;57:43-66.

8. Kim L, Glantz MJ. Neoplastic meningitis. Curr Treat Options Oncol. 2001;2:517-527.

9. DepoCyt prescribing information. Sigma-Tau Pharmaceuticals, Inc.; 2014.

10. Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. JCO. 1999;17:3110-3116.

11. Kim S, Chatelut E, Kim JC, et al. Ex-tended CSF cytarabine exposure following intrathecal administration of DTC 101. JCO. 1993;11:2186-2193

Attach DepoCyt® Prescribing Information Here

This white paper was prepared by ONS Edge in collaboration with Sigma-Tau Pharmaceuticals,

Inc., Gaithersburg, MD.

Copyright © Sigma-Tau Pharmaceuticals, Inc., 2015. All rights reserved. 15-dep-162 3/15

125 Enterprise Drive, Suite 110

Pittsburgh, PA 15275-1214

ONSEDGE.com

Distributed by Sigma-Tau Pharmaceuticals, Inc. Manufactured by Pacira Pharmaceuticals, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

DEPOCYT® safely and effectively. See full prescribing information for

DEPOCYT.

DEPOCYT (cytarabine liposome injection)

For Intrathecal Use Only

Initial U.S. Approval: 1999

WARNING: CHEMICAL ARACHNOIDITIS ADVERSE REACTIONS

See full prescribing information for complete boxed warning

Chemical arachnoiditis, a syndrome manifested primarily by nausea,

vomiting, headache and fever, was a common adverse event in all clinical

studies. If left untreated, chemical arachnoiditis may be fatal. Patients

receiving DepoCyt should be treated concurrently with dexamethasone to

mitigate the symptoms of chemical arachnoiditis. (5.1, 5.2))

----------------------------INDICATIONS AND USAGE---------------------------

DepoCyt is indicated for the intrathecal treatment of lymphomatous meningitis. (1)

----------------------DOSAGE AND ADMINISTRATION-----------------------

DepoCyt is for intrathecal use only. (2.3)

Induction therapy: DepoCyt, 50 mg, administer intrathecally

(intraventricular or lumbar puncture) every 14 days for 2 doses (weeks 1 and 3) (2.4)

Consolidation therapy: DepoCyt, 50 mg, administer intrathecally

(intraventricular or lumbar puncture) every 14 days for 3 doses (weeks 5, 7 and 9) followed by 1 additional dose at week 13 (2.4)

Maintenance: DepoCyt, 50 mg, administer intrathecally (intraventricular or lumbar puncture) every 28 days for 4 doses

(weeks 17, 21, 25 and 29) (2.4)

Initiate dexamethasone 4 mg twice a day either by mouth or intravenously for 5 days beginning on the day of DepoCyt injection. If drug related

neurotoxicity develops, reduce DepoCyt to 25 mg. If neurotoxicity persists,

discontinue DepoCyt. (2.4)

---------------------DOSAGE FORMS AND STRENGTHS----------------------

Single-dose vial containing 50 mg/5 mL (10 mg/mL) of cytarabine

liposome injection (3)

-------------------------------CONTRAINDICATIONS------------------------------

Hypersensitive to cytarabine or any component of the formulation with active meningeal infection. (4)

-----------------------WARNINGS AND PRECAUTIONS------------------------

Neurotoxicity: Myelopathy and other neurologic toxicity may occur. Reduce the dose or discontinue DepoCyt. (5.2)

Embryo-fetal Toxicity: May cause fetal harm. Advise women of potential harm to a fetus and to avoid pregnancy if receiving DepoCyt. (5.4)

------------------------------ADVERSE REACTIONS-------------------------------

Most common adverse reactions (incidence ≥20%) are headache,

arachnoiditis, confusion, abnormal gait, convulsions, weakness, pyrexia,

fatigue, nausea, vomiting, constipation, and back pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau

Pharmaceuticals, Inc. at 1-888-393-4584 or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION

Revised: 12/2014

______________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: CHEMICAL ARACHNOIDITIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Preparation and Administration Precautions

2.2 Preparation and Administration

2.3 Dosing Precautions 2.4 Dosing Regimen

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Chemical Arachnoiditis

5.2 Neurotoxicity 5.3 Transient Elevations in CSF Protein and CSF White Blood Cells

5.4 Embryo-fetal Toxicity

6 ADVERSE REACTIONS

6.1 Most Frequently Reported Reactions

6.2 Clinical Trials Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Category D 8.3 Nursing Mothers

8.4 Pediatric Use

8.6 Hepatic and Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Study 1 - Solid Tumors, Lymphoma, or Leukemia 14.2 Study 2 – Lymphoma

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

____________________________________________________________________________________________________________________________________

2

FULL PRESCRIBING INFORMATION

WARNING: CHEMICAL ARACHNOIDITIS ADVERSE REACTIONS

Chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache and fever, was a

common adverse event in all clinical studies. If left untreated, chemical arachnoiditis may be fatal. Patients

receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of chemical

arachnoiditis. [see Warnings and Precautions (5.1, 5.2)]

1 INDICATIONS AND USAGE

DepoCyt® (cytarabine liposome injection) is indicated for the intrathecal treatment of lymphomatous

meningitis.

2 DOSAGE AND ADMINISTRATION

2.1 Preparation and Administration Precautions

DepoCyt is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be

used in handling DepoCyt. The use of gloves is recommended. If DepoCyt suspension contacts the skin,

wash immediately with soap and water. If it contacts mucous membranes, flush thoroughly with water.

2.2 Preparation and Administration

No further reconstitution or dilution is required. DepoCyt particles have a tendency to settle with time.

Vials of DepoCyt should be allowed to warm to room temperature and gently agitated or inverted to re-

suspend the particles immediately prior to withdrawal from the vial. Avoid aggressive agitation.

DepoCyt should be withdrawn from the vial immediately before administration. DepoCyt is a single dose

vial and does not contain any preservative. DepoCyt should be used within 4 hours of withdrawal from the

vial. Unused portions of each vial should be discarded properly [see How Supplied/ Storage and Handling

(16)]. Do not save any unused portions for later administration. Do not mix DepoCyt with any other

medications.

2.3 Dosing Precautions

In-line filters must not be used when administering DepoCyt. DepoCyt is administered directly into the

cerebrospinal fluid (CSF) via an intraventricular reservoir or by direct injection into the lumbar sac.

DepoCyt should be injected slowly over a period of 1-5 minutes. Following drug administration by lumbar

puncture, the patient should be instructed to lie flat for 1 hour. Patients should be observed by the physician

for immediate toxic reactions.

2.4 Dosing Regimen

For the treatment of lymphomatous meningitis, DepoCyt 50 mg (one vial of DepoCyt) is recommended to be

given according to the following schedule:

Induction therapy DepoCyt, 50 mg, administered intrathecally (intraventricular or lumbar

puncture) every 14 days for 2 doses (weeks 1 and 3).

Consolidation therapy DepoCyt, 50 mg, administered intrathecally (intraventricular or lumbar

puncture) every 14 days for 3 doses (weeks 5, 7 and 9) followed by 1

additional dose at week 13.

Maintenance DepoCyt, 50 mg, administered intrathecally (intraventricular or lumbar

puncture) every 28 days for 4 doses (weeks 17, 21, 25 and 29).

Patients should be started on dexamethasone 4 mg twice a day either by mouth or intravenously for 5 days

beginning on the day of DepoCyt injection.

If drug related neurotoxicity develops, the dose should be reduced to 25 mg. If it persists, treatment with

DepoCyt should be discontinued.

3

3 DOSAGE FORMS AND STRENGTHS

Ready-to-use, single dose vial containing 50 mg/5 mL (10 mg/mL) of cytarabine liposome injection.

4 CONTRAINDICATIONS

DepoCyt® (cytarabine liposome injection) is contraindicated in patients who are hypersensitive to cytarabine or

any component of the formulation, and in patients with active meningeal infection.

5 WARNINGS AND PRECAUTIONS

5.1 Chemical Arachnoiditis

Chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache and fever, has been

a common adverse event in all studies. If chemical arachnoiditis is suspected, exclude other inflammatory,

infectious, or neoplastic conditions. If left untreated, chemical arachnoiditis may be fatal. The incidence

and severity of chemical arachnoiditis can be reduced by coadministration of dexamethasone. Patients

receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of

chemical arachnoiditis [see Dosage and Administration (2)].

Toxic effects may be related to a single dose or to cumulative administration. Because toxic effects can

occur at any time during therapy (although they are most likely to occur within 5 days of drug

administration), patients receiving intrathecal therapy with DepoCyt should be monitored continuously for

the development of neurotoxicity. If patients develop neurotoxicity, reduce subsequent doses of DepoCyt.

If neurotoxicity persists, discontinue DepoCyt [see Warnings and Precautions (5.3)]

Hydrocephalus has also been reported, possibly precipitated by arachnoiditis.

Arachnoiditis is an expected and well-documented side effect of both neoplastic meningitis and of

intrathecal chemotherapy. The incidence of severe and life-threatening arachnoiditis in patients receiving

DepoCyt was 19% (48/257) in all patients and 30% (10/33) in patients with lymphomatous meningitis. In

the early dose-finding study, chemical arachnoiditis was observed in 100% of cycles without dexamethasone

prophylaxis. When concurrent dexamethasone was administered, chemical arachnoiditis was observed in

33% of cycles.

5.2 Neurotoxicity

Intrathecal administration of cytarabine may cause myelopathy and other neurologic toxicity and can rarely

lead to a permanent neurologic deficit. Administration of intrathecal cytarabine in combination with other

chemotherapeutic agents or with cranial/spinal irradiation may increase this risk of neurotoxicity.

Blockage to CSF flow may result in increased free cytarabine concentrations in the CSF and an 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.

Following intrathecal administration of DepoCyt, central nervous system toxicity, including persistent

extreme somnolence, hemiplegia, visual disturbances including blindness which may be total and

permanent, deafness and cranial nerve palsies have been reported. Symptoms and signs of peripheral

neuropathy, such as pain, numbness, paresthesia, weakness, and impaired bowel and bladder control have

also been observed. In some cases, a combination of neurological signs and symptoms has been reported as

Cauda Equina Syndrome.

If patients develop neurotoxicity, reduce subsequent doses of DepoCyt or discontinue DepoCyt Headache,

nausea, and fever are expected in early signs of neurotoxicity.

5.3 Transient Elevations in CSF Protein and CSF White Blood Cells

Transient elevations in CSF protein and white blood cell counts have been observed in patients following

DepoCyt administration.

5.4 Embryo-fetal Toxicity

Cytarabine, the active component of DepoCyt, can cause fetal harm if a pregnant woman is exposed to the

drug systemically. The systemic exposure of cytarabine following intrathecal administration of DepoCyt is

4

negligible. Cytarabine was teratogenic in mice and rats. Cytarabine was embryotoxic in mice when

administered during the period of organogenesis. If this drug is used during pregnancy or if the patient

becomes pregnant while taking this drug, the patient should be apprised of the potential harm to a fetus.

[See Use in Specific Populations, Sec. 8.1]

6 ADVERSE REACTIONS

The following serious adverse reactions are described in greater detail in other sections of the label:

Chemical Arachnoiditis [see Warnings and Precautions (5.1)]

Neurotoxicity [see Warnings and Precautions (5.2)]

Transient elevations in CSF protein and CSF white blood cells [see Warnings and Precautions (5.3)]

6.1 Most Frequently Reported Reactions

After intrathecal administration of cytarabine the most frequently reported reactions (≥ 10%) are headache

NOS, nausea, vomiting NOS, arachnoiditis, weakness, confusion, pyrexia, fatigue, constipation, back pain,

gait abnormal NOS, convulsions NOS, dizziness NOS, lethargy, pain in limb, insomnia, urinary tract

infection NOS, neck pain, death NOS, pain, memory impairment, dehydration, anemia NOS, diarrhea NOS,

appetite decreased NOS, thrombocytopenia, edema peripheral, arthralgia, neck stiffness, vision blurred,

muscle weakness, neutropenia, hypoesthesia, agitation, and dyspnea NOS.

6.2 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the

clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not

reflect the rates observed in practice. The toxicity database consists of the observations made during Phase

1-4 studies. The most common adverse reactions in all patients and in patients with lymphoma are shown in

Table 1. The incidences of symptoms possibly reflecting meningeal irritation are shown in Table 2.

Table 1. Incidence of adverse reactions occurring in > 10% of patients in all Phase 1-4 adult study patients

and in patients with lymphomatous meningitis receiving DepoCyt 50 mg or an active comparator

Lymphoma

System Organ Class / Preferred Term All DepoCyt

(N=257)

DepoCyt

(N=33)

Ara-C

(N=28)

Nervous System Disorders

Headache NOS 144 (56%) 17 (52%) 9 (32%)

Arachnoiditis 108 (42%) 14 (42%) 10 (36%)

Confusion 86 (33%) 12 (36%) 3 (11 %)

Gait abnormal NOS 60 (23%) 7 (21 %) 8 (29%)

Convulsions NOS 52 (20%) 7 (21%) 1 (4%)

Dizziness NOS 47 (18%) 7 (21%) 6 (21%)

Memory impairment 36 (14%) 4 (12%) 1 (4%)

Hypoesthesia 26 (10%) 4 (12%) 3 (11%)

Tremor 22 (9%) 5 (15%) 5 (18%)

Peripheral neuropathy NOS 9 (4%) 4 (12%) 1 (4%)

Syncope 8 (3%) 0 (0%) 3 (11 %)

Neuropathy NOS 7 (3%) 3 (9%) 3 (11 %)

Peripheral sensory neuropathy 7 (3%) 2 (6%) 3 (11 %)

Reflexes abnormal 7 (3%) 0 (0%) 3 (11 %)

General Disorders and Administration Site

Conditions

Weakness 103 (40%) 13 (39%) 15 (54%)

Pyrexia 81 (32%) 15 (45%) 12 (43%)

Fatigue 64 (25%) 9 (27%) 13 (46%)

Lethargy 41 (16%) 4 (12%) 4 (14%)

Death NOS 35 (14%) 9 (27%) 5 (18%)

5

Lymphoma

System Organ Class / Preferred Term All DepoCyt

(N=257)

DepoCyt

(N=33)

Ara-C

(N=28)

Pain NOS 35 (14%) 3 (9%) 5 (18%)

Edema peripheral 27 (11 %) 6 (18%) 7 (25%)

Fall 12 (5%) 0 (0%) 3 (11%)

Mucosal inflammation NOS 8 (3%) 4 (12%) 2 (7%)

Edema NOS 6 (2%) 1 (3%) 6 (21%)

Gastrointestinal Disorders

Nausea 117 (46%) 11 (33%) 15 (54%)

Vomiting NOS 112 (44%) 11 (33%) 9 (32%)

Constipation 64 (25%) 8 (24%) 7 (25%)

Diarrhea NOS 31 (12%) 9 (27%) 9 (32%)

Abdominal pain NOS 22 (9%) 5 (15%) 4 (14%)

Dysphagia 20 (8%) 3 (9%) 3 (11 %)

Hemorrhoids 8 (3%) 0 (0%) 3 (11 %)

Musculoskeletal and Connective Tissue

Disorders

Back pain 61 (24%) 7 (21%) 5 (18%)

Pain in limb 39 (15%) 4 (12%) 8 (29%)

Neck pain 36 (14%) 5 (15%) 3 (11%)

Arthralgia 29 (11%) 3 (9%) 4 (14%)

Neck stiffness 28 (11%) 2 (6%) 4 (14%)

Muscle weakness NOS 25 (10%) 5 (15%) 2 (7%)

Psychiatric Disorders

Insomnia 35 (14%) 6 (18%) 7 (25%)

Agitation 26 (10%) 5 (15%) 2 (7%)

Depression 21 (8%) 6 (18%) 4 (14%)

Anxiety 17 (7%) 1 (3%) 3 (11%)

Infections and Infestations

Urinary tract infection NOS 35 (14%) 6 (18%) 5 (18%)

Pneumonia NOS 16 (6%) 2 (6%) 3 (11%)

Metabolism and Nutrition Disorders

Dehydration 33 (13%) 6 (18%) 3 (11%)

Appetite decreased NOS 29 (11%) 4 (12%) 3 (11%)

Hyponatremia 18 (7%) 4 (12%) 1 (4%)

Hypokalemia 17 (7%) 5 (15%) 2 (7%)

Hyperglycemia 15 (6%) 4 (12%) 2 (7%)

Anorexia 14 (5%) 1 (3%) 5 (18%)

Investigations

Platelet count decreased 8 (3%) 0 (0%) 3 (11 %)

Renal and Urinary Disorders

Incontinence NOS 19 (7%) 3 (9%) 5 (18%)

Urinary retention 14 (5%) 0 (0%) 3 (11%)

Respiratory, Thoracic and Mediastinal

Disorders

Dyspnea NOS 25 (10%) 4 (12%) 6 (21%)

Cough 17 (7%) 3 (9%) 6 (21%)

Eye Disorders

Vision blurred 29 (11%) 4 (12%) 4 (14%)

Blood and Lymphatic Disorders

Anemia NOS 31 (12%) 6 (18%) 5 (18%)

Thrombocytopenia 27 (11%) 8 (24%) 9 (32%)

6

Lymphoma

System Organ Class / Preferred Term All DepoCyt

(N=257)

DepoCyt

(N=33)

Ara-C

(N=28)

Neutropenia 26 (10%) 12 (36%) 7 (25%)

Skin and Subcutaneous Tissue

Disorders

Contusion 6 (2%) 1 (3%) 3 (11 %)

Pruritus NOS 6 (2%) 0 (0%) 4 (14%)

Sweating increased 6 (2%) 1 (3%) 3 (11 %)

Vascular Disorders

Hypotension NOS 21 (8%) 6 (18%) 2 (7%)

Hypertension NOS 15 (6%) 5 (15%) 1 (4%)

Ear and Labyrinth Disorders

Hypacusis 15 (6%) 6 (18%) 3 (11%)

Cardiac Disorders

Tachycardia NOS 22 (9%) 0 (0%) 5 (18%)

Neoplasms Benign, Malignant and

Unspecified (Incl Cysts and Polyps)

Diffuse Large B-Cell Lymphoma NOS 1 (0%) 1 (3%) 3 (11%)

Table 2. Incidence of adverse reactions possibly reflecting meningeal irritation occurring in > 10% of all

studied adult patients receiving DepoCyt 50 mg or an active comparator*

System Organ Class / Preferred Term DepoCyt MTX Ara-C

(N=257) (N=78) (N=28)

Nervous System Disorders

Headache NOS 145 (56%) 33 (42%) 9 (32%)

Arachnoiditis 108 (42%) 15 (19%) 10 (36%)

Convulsions NOS 56 (22%) 11 (14%) 1 (4%)

Gastrointestinal Disorders

Nausea 117 (46%) 24 (31%) 15 (54%)

Vomiting NOS 112 (44%) 22 (28%) 9 (32%)

Musculoskeletal and Connective Tissue

Disorders

Back pain 61 (24%) 15 (19%) 5 (18%)

Neck pain 36 (14%) 6 (8%) 3 (11%)

Neck stiffness 28 (11%) 1 (1%) 4 (14%)

General Disorders and Administration

Site Conditions

Pyrexia 81 (32%) 15 (19%) 12 (43%)

* Hydrocephalus acquired, CSF pleocytosis and meningism occurred in ≤ 10% of all studied adult patients receiving

DepoCyt or an active comparator

During the clinical studies, 2 deaths related to DepoCyt were reported. One patient at the 125 mg dose level

died of encephalopathy 36 hours after receiving an intraventricular dose of DepoCyt. This patient, however,

was also receiving concomitant whole brain irradiation and had previously received intraventricular

methotrexate. The other patient received DepoCyt, 50 mg by the intraventricular route and developed focal

seizures progressing to status epilepticus. This patient died approximately 8 weeks after the last dose of study

medication. In the controlled lymphoma study, the patient incidence of seizures was higher in the DepoCyt

group (4/17, 23.5%) than in the cytarabine group (1/16, 6.3%). The death of 1 additional patient was

considered “possibly” related to DepoCyt. He was a 63-year-old with extensive lymphoma involving the

7

nasopharynx, brain, and meninges with multiple neurologic deficits who died of apparent disease progression 4

days after his second dose of DepoCyt.

7 DRUG INTERACTIONS

No formal assessments of pharmacokinetic drug-drug interactions between DepoCyt and other agents have been

conducted. Concomitant administration of DepoCyt with other antineoplastic agents administered by the

intrathecal route has not been studied. With intrathecal cytarabine and other cytotoxic agents administered

intrathecally, enhanced neurotoxicity has been associated with coadministration of drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Category D [see Warnings and Precautions (5.8)]

Risk Summary

There are no studies assessing the reproductive toxicity of DepoCyt. The systemic exposure of cytarabine

following intrathecal administration of DepoCyt is negligible. Cytarabine can cause fetal harm if a pregnant

woman is exposed to the drug systemically. Three anecdotal cases of major limb malformations have been

reported in infants after their mothers received intravenous cytarabine, alone or in combination with other

agents, during the first trimester. Advise women of childbearing potential to avoid becoming pregnant while

receiving DepoCyt. If this drug is used during pregnancy or if the patient becomes pregnant while taking

this drug, the patient should be apprised of the potential harm to a fetus.

Animal Data

Cytarabine was teratogenic in mice (cleft palate, phocomelia, deformed appendages, skeletal abnormalities)

when doses ≥2 mg/kg/day were administered IP during the period of organogenesis (about 0.2 times the

recommended human dose on a mg/m2 basis), and in rats (deformed appendages) when 20 mg/kg was

administered as a single IP dose on day 12 of gestation (about 4 times the recommended human dose on a

mg/m2 basis). Single IP doses of 50 mg/kg in rats (about 10 times the recommended human dose on a

mg/m2 basis) on day 14 of gestation reduced prenatal and postnatal brain size and permanent impairment of

learning ability.

Cytarabine was embryotoxic in mice when administered during the period of organogenesis.

Embryotoxicity was characterized by decreased fetal weight at 0.5 mg/kg/day (about 0.05 times the

recommended human dose on mg/m2 basis), and increased early and late resorptions and decreased live litter

sizes at 8 mg/kg/day (approximately equal to the recommended human dose on mg/m2 basis).

8.3 Nursing Mothers

It is not known whether cytarabine is excreted in human milk following intrathecal DepoCyt administration.

The systemic exposure to free cytarabine following intrathecal treatment with DepoCyt was negligible.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in

nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking

into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and efficacy of DepoCyt in pediatric patients has not been established.

8.6 Hepatic and Renal Impairment

The effects of hepatic or renal impairment on the pharmacokinetics of DepoCyt have not been studied.

10 OVERDOSAGE

No overdosages with DepoCyt® (cytarabine liposome injection) have been reported. An overdose with

DepoCyt may be associated with severe chemical arachnoiditis including encephalopathy. In an early

uncontrolled study without dexamethasone prophylaxis, single doses up to 125 mg were administered.

There is no antidote for overdose of intrathecal DepoCyt or unencapsulated cytarabine released from DepoCyt.

Exchange of CSF with isotonic saline has been carried out in a case of intrathecal overdose of free cytarabine,

and such a procedure may be considered in the case of DepoCyt overdose. Management of overdose should be

directed at maintaining vital functions.

8

11 DESCRIPTION

DepoCyt® (cytarabine liposome injection) is a sterile, injectable suspension of the antimetabolite cytarabine for

intrathecal administration. The chemical name of cytarabine is 4-amino-1-β-D-arabinofuranosyl-2(1H)-

pyrimidinone and is also known as cytosine arabinoside. It has a molecular formula of C9H13N3O5 and a

molecular weight 243.22 g/mol. Cytarabine has the following structural formula:

DepoCyt is available as a single-dose vial containing 50 mg/5 mL (10 mg/mL) of cytarabine. DepoCyt is

formulated as a sterile, non-pyrogenic, white to off-white suspension of cytarabine liposomes in 0.9% w/v

sodium chloride in water for injection. Each mL contains 10 mg cytarabine, 4.4 mg cholesterol, 1.2 mg triolein,

5.7 mg dioleoylphosphatidylcholine (DOPC), and 1.0 mg dipalmitoylphosphatidylglycerol (DPPG). DepoCyt

is preservative-free. The pH of the product falls within the range from 5.5 to 8.5.

Liposome drug products may behave differently from nonliposome drug products. DepoCyt (cytarabine

liposome injection) is not equivalent to, and cannot be substituted for, other drug products containing

cytarabine.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

DepoCyt® (cytarabine liposome injection) is a sustained-release formulation of the active ingredient

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 polymerase. Incorporation into DNA and RNA may also contribute to cytarabine

cytotoxicity. Cytarabine is cytotoxic to proliferating mammalian cells in culture.

12.3 Pharmacokinetics

Following intrathecal administration of DepoCyt 50 mg, peak levels of free CSF cytarabine were observed

within 1 hour of dosing and ranged from 30 to 50 mcg/mL. The terminal half-life for the free CSF

cytarabine ranged from of 5.9 to 82.4 hours. Systemic exposure to cytarabine was negligible following

intrathecal administration of DepoCyt 50 mg.

Metabolism and Elimination

The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by

urinary excretion of ara-U. In contrast to systemically administered cytarabine, which is rapidly

metabolized 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with DepoCyt.

Cytarabine was mutagenic in in vitro tests and was clastogenic in vitro (chromosome aberrations and SCE

in human leukocytes) and in vivo (chromosome aberrations and SCE assay in rodent bone marrow, mouse

9

micronucleus assay). Cytarabine caused the transformation of hamster embryo cells and rat H43 cells in

vitro.

No studies assessing the impact of cytarabine on fertility are available in the literature. Cytarabine was

clastogenic to meiotic cells; a dose-dependent increase in sperm-head abnormalities and chromosomal

aberrations occurred in mice given IP cytarabine. Because the systemic exposure to free cytarabine

following intrathecal treatment with DepoCyt was negligible, the risk of impaired fertility after intrathecal

DepoCyt is likely to be low.

14 CLINICAL STUDIES

DepoCyt® (cytarabine liposome injection) was studied in 2 controlled clinical studies that enrolled patients with

neoplastic meningitis.

14.1 Study 1 – Solid Tumors, Lymphoma, or Leukemia

The first study, which was a randomized, multi-center, multi-arm study involving a total of 99 treated

patients, compared 50 mg of DepoCyt administered every 2 weeks to standard intrathecal chemotherapy

administered twice a week to patients with solid tumors, lymphoma, or leukemia. For patients with

lymphoma, standard therapy consisted of 50 mg of unencapsulated cytarabine given twice a week. Thirty-

three lymphoma patients (17 DepoCyt, 16 cytarabine) were treated. Patients went off study if they had not

achieved a complete response defined as clearing of the CSF from all previously positive sites in the

absence of progression of neurological symptoms, after 4 weeks of treatment with study drug.

In the first study, complete response was prospectively defined as (1) conversion, confirmed by a blinded

central pathologist, from a positive examination of the CSF for malignant cells to a negative examination

on two separate occasions (at least 3 days apart, on day 29 and later) at all initially positive sites, together

with (2) an absence of neurological progression during the treatment period.

The complete response rates in the first study of lymphoma are shown in Table 3. Although there was a

plan for central pathology review of the data, in 4 of the 7 responding patients on the DepoCyt arm this was

not accomplished and these cases were considered to have had a complete response based on the reading of

an unblinded pathologist. The median overall survival of all treated patients was 99.5 days in the DepoCyt

group and 63 days in the cytarabine group. In both groups the majority of patients died from progressive

systemic disease, not neoplastic meningitis.

14.2 Study 2 – Lymphoma

The second study was a randomized, multi-center, multi-arm study involving a total of 124 treated patients

with either solid tumors or lymphomas. In this study, 24 patients with lymphoma were randomized and

treated with DepoCyt or cytarabine. Patients received 6 two-week induction cycles of DepoCyt 50 mg

every 2 weeks or cytarabine 50 mg twice weekly. Patients then received four maintenance cycles of

DepoCyt 50 mg every 4 weeks, or cytarabine 50 mg weekly for 4 weeks. In both studies, patients received

concurrent treatment with dexamethasone to minimize symptoms associated with chemical arachnoiditis

[see Warnings and Precautions (5) and Dosage and Administration (2)]. In this study, cytological response

was assessed in a blinded fashion utilizing a similar definition as in the first study. The results in patients

with lymphomatous meningitis are shown in Table 3.

Table 3: Complete Cytological Responses in

Patients with Lymphomatous Meningitis

DepoCyt®

Cytarabine

Study 1 7/17 (41%) 1/16 (6%)

95% CI (18%, 67%) (0%, 30%)

Study 2 4/12 (33%) 2/12 (17%)

95% CI (10%, 65%) (2%, 48%)

10

15 REFERENCES

OSHA Hazardous Drugs. OSHA. [Accessed on November 4, 2014, from

http://www.osha.gov/SLTC/hazardousdrugs/index.html].

16 HOW SUPPLIED/STORAGE AND HANDLING

DepoCyt® (cytarabine liposome injection) is supplied as a sterile, white to off-white suspension in 5 mL glass,

single dose vials.

Store refrigerated at 2° to 8°C (36° to 46°F). Protect from freezing and avoid aggressive agitation.

Available in individual carton containing one ready to use vial. NDC 57665-331-01.

Do not use beyond expiration date printed on the label.

DepoCyt is a genotoxic drug. Follow special handling and disposal procedures [see References (15)].

17 PATIENT COUNSELING INFORMATION

Advise patients of the following expected adverse events: headache, nausea, vomiting, and fever, and

about the early signs and symptoms of neurotoxicity.

Advise patients of the importance of concurrent dexamethasone administration should be emphasized at the

initiation of each cycle of DepoCyt® treatment.

Instruct patients to seek medical attention if signs or symptoms of neurotoxicity develop, or if oral

dexamethasone is not well tolerated.

For additional information, contact Sigma-Tau Pharmaceuticals, Inc. at: 1-888-393-4584.

Manufactured by:

Pacira Pharmaceuticals, Inc., San Diego, CA 92121

Distributed by: Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878

I-070-21-US-F

U.S. patent Nos.

5,807,572

5,723,147

5,455,044

5,891,467