Manufactured by: SkyePharma Inc. 10450 Science Center Dr. San Diego, CA 92121 USA Distributed by: Pharmacia & Upjohn Inc. 861 York Mills Road Don Mills, Ontario Canada, M3B 1Y6 Date of Preparation:
Control# 052637
November 1, 1999
PRODUCT MONOGRAPH
DepoCyt(tm) (cytarabine liposome injection)
10 mg/mL (50 mg/5 mL)
DEPOCYT (CYTARABINE LIPOSOME INJECTION) SHOULD BE ADMINISTERED ONLY UNDER THE SUPERVISION OF A QUALIFIED PHYSICIAN EXPERIENCED IN THE USE OF INTRATHECAL CANCER CHEMOTHERAPEUTIC AGENTS. APPROPRIATE MANAGEMENT OF COMPLICATIONS IS POSSIBLE ONLY WHEN ADEQUATE DIAGNOSTIC AND TREATMENT FACILITIES ARE READILY AVAILABLE. IN ALL CLINICAL STUDIES, CHEMICAL ARACHNOIDITIS, A SYNDROME MANIFESTED PRIMARILY BY NAUSEA, VOMITING, HEADACHE, AND FEVER WAS A COMMON ADVERSE EVENT. IF LEFT UNTREATED, CHEMICAL ARACHNOIDITIS MAY BE FATAL. THE INCIDENCE AND SEVERITY OF CHEMICAL ARACHNOIDITIS CAN BE REDUCED BY COADMINISTRATION OF DEXAMETHASONE (SEE WARNINGS). PATIENTS RECEIVING CYTARABINE LIPOSOME INJECTION SHOULD BE TREATED CONCURRENTLY WITH DEXAMETHASONE TO MITIGATE THE SYMPTOMS OF CHEMICAL ARACHNOIDITIS (SEE DOSAGE AND ADMINISTRATION).
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. Cytarabine is converted into cytarabine-5'-triphosphate (ara-CTP), which is the active metabolite in the cell. 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 a wide variety of proliferating mammalian cells in culture.
The pharmacokinetics of cytarabine liposome injection administered intrathecally to patients at a 50 mg dose every 2 weeks is currently under investigation. However, preliminary analysis of the pharmacokinetic data show that following cytarabine liposome injection intrathecal administration in patients, in either the lumbar sac or by intraventricular reservoir, peak levels of free cytarabine were observed within 5 hours in both the ventricle and lumbar sac. These peak levels were followed by a biphasic elimination profile 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 of free cytarabine showed a biphasic CSF concentration profile with a terminal phase half-life of 3.4 hours. Since the transfer rate of cytarabine from the CSF to plasma is slow and the conversion of cytarabine to ara-U in the plasma is fast, systemic exposure to cytarabine was negligible following intrathecal administration of cytarabine liposome injection, 50 mg or 75 mg.
The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U (1-$-D- arabinofuranosyluracil or uracil arabinoside), 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.
Cytarabine liposome injection is indicated for the intrathecal management of neoplastic meningitis due to solid tumours or lymphoma.
Cytarabine liposome injection is contraindicated in patients who are hypersensitive to cytarabine and in patients with active meningeal infection.
Cytarabine liposome injection should be administered only under the supervision of a qualified physician experienced in the use of intrathecal cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. In all clinical studies, chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache, and fever was a common adverse event. If left untreated, chemical arachnoiditis may be fatal. The incidence and severity of chemical arachnoiditis can be reduced by coadministration of dexamethasone. Patients receiving cytarabine liposome injection should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis (see DOSAGE AND ADMINISTRATION). During the clinical studies, 2 deaths related to cytarabine liposome injection were reported. One patient died after developing encephalopathy 36 hours after an intraventricular dose of cytarabine liposome injection, 125 mg. This patient was receiving concurrent whole-brain irradiation and had previously received systemic chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil, as well as intraventricular methotrexate. The other patient received cytarabine liposome injection, 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. The death of one additional patient was considered "possibly" related to cytarabine liposome injection. He was a 63 year old with extensive lymphoma involving the nasopharynx, brain, and meninges with multiple neurologic deficits who died of apparent disease progression 4 days after his second dose of cytarabine liposome injection. After intrathecal administration of free cytarabine the most frequently reported reactions are nausea, vomiting and fever. Intrathecal administration of free cytarabine may cause myelopathy and other neurologic toxicity sometimes leading to a permanent neurologic deficit. Administration of intrathecal cytarabine in combination with other chemotherapeutic agents or with cranial/spinal irradiation may increase the risk of neurotoxicity. When CSF flow is blocked, increased free cytarabine concentrations in the CSF and an increased risk of neurotoxicity may result.
Teratology studies in animals have not been conducted with cytarabine liposome injection. There are no adequate and well-controlled studies in pregnant women. Cytarabine is known to be teratogenic in some species and can cause fetal harm when administered to a pregnant female. Cytarabine liposome injection should not be used in women who are pregnant (particularly during the first trimester) or who may become pregnant unless the possible benefits outweigh the potential risks. If cytarabine liposome injection is used during pregnancy, or if the patient becomes pregnant while taking cytarabine liposome injection, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant.
It is not known whether cytarabine liposome injection is excreted in human milk. 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 cytarabine liposome injection therapy taking into account the importance of the drug to the mother.
The safety and efficacy of cytarabine liposome injection have not been established for pediatric use.
The effects of gender or race on the pharmacokinetics of cytarabine liposome injection have not been studied, nor has the effect of renal or hepatic impairment.
Cytarabine liposome injection has the potential of producing serious toxicity (see WARNING). All patients receiving cytarabine liposome injection should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis (see DOSAGE AND ADMINISTRATION). 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 within 5 days of drug administration), patients receiving intrathecal therapy with cytarabine liposome injection should be monitored continuously for the development of neurotoxicity. If patients develop neurotoxicity, subsequent doses of cytarabine liposome injection should be reduced, and cytarabine liposome injection should be discontinued if toxicity persists. Some patients with neoplastic meningitis receiving treatment with cytarabine liposome injection may require concurrent radiation or systemic therapy with other chemotherapeutic agents; this may increase the rate of adverse events. Anaphylactic reactions following intravenous administration of free cytarabine have been reported. Although significant systemic exposure to free cytarabine following intrathecal treatment is not expected, some effect on bone marrow function cannot be excluded. Systemic toxicity due to intravenous administration of cytarabine consists primarily of bone marrow suppression with leukopenia, thrombocytopenia, and anemia. Accordingly, careful monitoring of the hematopoietic system is advised. Transient elevations in CSF protein and white blood cells have been observed in patients following cytarabine liposome injection administration and have also been noted after intrathecal treatment with methotrexate or cytarabine.
No formal drug interaction studies of cytarabine liposome injection and other drugs were conducted. Concomitant administration of cytarabine liposome injection 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 co-administration of drugs.
Since cytarabine liposome injection particles are similar in size and appearance to white blood cells, care must be taken in interpreting CSF examinations following cytarabine liposome injection administration.
Patients should be informed about the expected adverse events of headache, nausea, vomiting, and fever, and about the early signs and symptoms of neurotoxicity. The importance of concurrent dexamethasone administration should be emphasized at the initiation of each cycle of cytarabine liposome injection treatment. Patients should be instructed to seek medical attention if signs or symptoms of neurotoxicity develop, or if oral dexamethasone is not well tolerated (see DOSAGE AND ADMINISTRATION).
The toxicity database consists of the observations made during an early uncontrolled study and the controlled multi-arm study described above. In the early study, patients received cytarabine liposome injection at doses ranging from 12.5 mg to 125 mg. In the randomized multi-arm study cytarabine liposome injection was administered at a dose of 50 mg every two weeks and was compared to standard intrathecal chemotherapy (cytarabine or methotrexate) in patients with lymphoma, leukemia and solid tumors; twenty-eight lymphoma patients, 5 leukemia patients and 59 solid tumor patients received study drug. Arachnoiditis is an expected and well-documented side effect of both neoplastic meningitis and of intrathecal chemotherapy. For clinical studies of cytarabine liposome injection, chemical arachnoiditis was defined as the occurrence of any one of the symptoms of neck rigidity, neck pain, meningism, or any two of the symptoms of nausea, vomiting, headache, fever, back pain, or CSF pleocytosis; the grade assigned to an episode of chemical arachnoiditis was the highest severity grade of its component symptoms. Since most of the adverse events reported in the trials were transient episodes associated with drug exposure, the incidence of these events is best expressed by drug cycle. A cycle of treatment for all treatment groups was defined as the 14-day period between cytarabine liposome injection doses. The duration of reported symptoms was from 1 to 5 days. Although it was sometimes difficult to distinguish between drug-related chemical arachnoiditis, infectious meningitis, or disease progression, >90% of the chemical arachnoiditis cases reported occurred within 48 hours of the administration of intrathecal drug, indicating a drug etiology. The incidence and severity of chemical arachnoiditis by cycle in the randomized study are shown in Figure 1a (in patients with solid tumour neoplastic meningitis) and Figure 1b (in patients with lymphomatous meningitis). In the early study, chemical arachnoiditis was observed in 100% of cycles without dexamethasone prophylaxis; with concurrent administration of dexamethasone, chemical arachnoiditis was observed in 33% of cycles. Patients receiving cytarabine liposome injection should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis (see DOSAGE AND ADMINISTRATION).
Figure 1a: Incidence and Severity of Chemical Arachnoiditis by Cycle
in Patients with Solid Tumour Neoplastic Meningitis in the Randomized Study
Figure 1b: Incidence and Severity of Chemical Arachnoiditis by Cycle in Patients with Lymphomatous Meningitis in the Randomized Study
The rate of all adverse events occurring in >10 % of patients, as a rate per cycle, in the randomized study is shown in Table 1a (in patients with meningitis solid tumour neoplastic meningitis) and Tale 1b (in patients with lymphomatous).
Table 1a: Comparison of Adverse Events Occurring in >10% of Patients, by Cycle
Patients with Solid Tumour Neoplastic Meningitis Receiving DepoCyt or Methotrexate (MTX) in the Randomized Study
Grade 3 or 4 Adverse Events
%
| Number of Cycles | n = 102 | n = 69.5 | n = 102 | n = 69.5 |
| Body System/Adverse Event | DepoCyt | MTX | DepoCyt | MTX |
| Body as a Whole | 69 | 71 | 23 | 30 |
| Headache * | 25 | 22 | 5 | 3 |
| Asthenia | 18 | 35 | 5 | 13 |
| Fever * | 18 | 12 | 0 | 1 |
| Back Pain * | 15 | 14 | 4 | 1 |
| Pain | 14 | 23 | 1 | 1 |
| Nervous System | 46 | 73 | 18 | 14 |
| Confusion | 10 | 20 | 5 | 1 |
| Somnolence | 8 | 9 | 1 | 1 |
| Abnormal Gait | 5 | 6 | 1 | 0 |
| Hypesthesia | 4 | 14 | 0 | 3 |
| Digestive System | 34 | 47 | 5 | 6 |
| Nausea * | 16 | 17 | 3 | 3 |
| Vomiting * | 13 | 24 | 3 | 1 |
| Constipation | 5 | 17 | 0 | 1 |
| Metabolic and Nutritional Disorders | 17 | 14 | 2 | 3 |
| Peripheral Edema | 7 | 1 | 0 | 0 |
| Hemic and Lymphatic System | 11 | 14 | 7 | 13 |
| Neutropenia | 4 | 4 | 4 | 4 |
| Number of Cycles | n = 102 | n = 69.5 | n = 102 | n = 69.5 |
| Body System/Adverse Event | DepoCyt | MTX | DepoCyt | MTX |
| Thrombocytopenia | 2 | 9 | 2 | 7 |
| Anemia | 2 | 0 | 0 | 0 |
| Urogenital System | 13 | 23 | 3 | 3 |
| Urinary Incontinence | 6 | 4 | 1 | 0 |
| Special Senses | 11 | 24 | 1 | 6 |
| Vision Abnormalities | 2 | 10 | 0 | 3 |
*Components of Chemical Arachnoiditis.
Table 1b: Comparison of Adverse Events Occurring in >10% of Patients, by Cycle
Patients with Lymphomatous Meningitis Receiving DepoCyt or Cytarabine (ara-C) in the Randomized Study
Grade 3 or 4 Adverse Events
%
| Number of Cycles | n = 74 | n = 45 | n = 74 | n = 45 |
| Body System/Adverse Event | DepoCyt | ara-C | DepoCyt | ara-C |
| Body as a Whole | 53 | 60 | 18 | 22 |
| Headache * | 28 | 9 | 5 | 2 |
| Asthenia | 19 | 33 | 5 | 9 |
| Fever * | 11 | 24 | 4 | 0 |
| Back Pain * | 7 | 11 | 0 | 2 |
| Pain | 11 | 20 | 3 | 0 |
| Nervous System | 45 | 53 | 18 | 18 |
| Confusion | 14 | 7 | 4 | 2 |
| Somnolence | 12 | 11 | 4 | 2 |
| Abnormal Gait | 4 | 11 | 1 | 2 |
| Digestive System | 27 | 44 | 7 | 9 |
| Nausea * | 11 | 16 | 0 | 4 |
| Vomiting * | 12 | 18 | 3 | 2 |
| Constipation | 7 | 11 | 0 | 0 |
| Metabolic and Nutritional Disorders | 16 | 24 | 0 | 0 |
| Peripheral Edema | 7 | 11 | 0 | 0 |
| Hematologic | 19 | 22 | 11 | 13 |
| Neutropenia | 9 | 11 | 8 | 11 |
| Thrombocytopenia | 8 | 16 | 5 | 11 |
| Number of Cycles | n = 74 | n = 45 | n = 74 | n = 45 |
| Body System/Adverse Event | DepoCyt | ara-C | DepoCyt | ara-C |
| Anemia | 1 | 13 | 1 | 4 |
| Urogenital System | 11 | 20 | 3 | 2 |
| Urinary Incontinence | 3 | 11 | 0 | 0 |
| Special Senses | 16 | 18 | 1 | 2 |
*Components of Chemical Arachnoiditis.
No overdosages with cytarabine liposome injection have been reported. An overdose with cytarabine liposome injection 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. One patient at the 125 mg dose level died of encephalopathy 36 hours after receiving an intraventricular dose of cytarabine liposome injection (see WARNINGS). This patient, however, was also receiving concomitant whole brain irradiation and had previously received intraventricular methotrexate. There is no antidote for overdose of intrathecal cytarabine liposome injection or unencapsulated cytarabine released from cytarabine liposome injection. 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 cytarabine liposome injection overdose. Management of overdose should be directed at maintaining vital functions.
For the treatment of solid tumor neoplastic meningitis
Cytarabine liposome injection 50 mg (one vial of cytarabine liposome injection) is recommended to be given according to the following schedule:
Induction therapy
: Cytarabine liposome injection, 50 mg, administered intrathecally (intraventricular or lumbar puncture) every 14 days for 2 doses (weeks 1 and 3).
Consolidation therapy
: Cytarabine liposome injection, 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.
For the treatment of lymphomatous meningitis
Cytarabine liposome injection 50 mg (one vial of cytarabine liposome injection) is recommended to be given according to the following schedule:
Induction therapy
: Cytarabine liposome injection, 50 mg, administered intrathecally (intraventricular or lumbar puncture) every 14 days for 2 doses (weeks 1 and 3).
Consolidation therapy
: Cytarabine liposome injection, 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
: Cytarabine liposome injection, 50 mg, administered intrathecally (intraventricular or lumbar puncture) every 28 days for 4 doses (weeks 17, 21, 25 and 29).
If drug related neurotoxicity develops, the dose should be reduced to 25 mg. If it persists, treatment with cytarabine liposome injection should be discontinued.
Cytarabine liposome injection is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be used in handling cytarabine liposome injection. The use of gloves is recommended. If cytarabine liposome injection suspension contacts the skin, wash immediately with soap and water. If it contacts mucous membranes, flush thoroughly with water (see SPECIAL INSTRUCTIONS). Cytarabine liposome injection particles are more dense than the diluent and have a tendency to settle with time. Vials of cytarabine liposome injection 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. No further reconstitution or dilution is required. Cytarabine liposome injection should be withdrawn from the vial immediately before administration. Cytarabine liposome injection is a single-use vial and does not contain any preservative; cytarabine liposome injection should be used within 4 hours of withdrawal from the vial. Unused portions of each vial should be discarded properly (see STABILITY AND STORAGE RECOMMENDATIONS and SPECIAL INSTRUCTIONS). Do not save any unused portions for later administration. Do not mix cytarabine liposome injection with any other medications.
In-line filters must not be used when administering cytarabine liposome injection.
Cytarabine liposome injection is administered directly into the CSF via either an intraventricular reservoir or by direct injection into the lumbar sac. Cytarabine liposome injection 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 one hour. Patients should be observed by the physician for immediate toxic reactions.
Patients should be started on dexamethasone 4 mg bid either PO or IV for 5 days beginning on the day of injection of cytarabine liposome injection. Cytarabine liposome injection must only be administered by the intrathecal route. Further dilution of cytarabine liposome injection is not recommended.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. Cytarabine liposome injection is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be used in handling cytarabine liposome injection. The use of gloves is recommended. If cytarabine liposome injection suspension contacts the skin, wash immediately with soap and water. If it contacts mucous membranes, flush thoroughly with water. All vials, syringes, needles and other materials which have come in contact with cytarabine liposome injection should be segregated and destroyed by incineration (sealed containers may explode). If incineration in unavailable, neutralization using 5% sodium hypochlorite or 5% sodium thiosulfate should be carried out instead.
USAN Name: cytarabine Common Name: cytosine arabinoside Chemical Name: 4-amino-1-$-D-arabinofuranosyl-2-(1H)-pyrimidone Molecular Formula: C9H13N3O5 Molecular Weight: 243.22. Structural Formula: Physical Characteristics:
| Physical Form: | White to off-white, odorless, crystalline powder |
| Solubility: | One gram of cytarabine dissolves in 5 mL of water, 300 mL of methyl alcohol, 500 mL of ethyl alcohol, or 1000 mL of chloroform. |
| Pk a : | 4.1 |
| pH: | 1% solution of cytarabine in water has a pH of 4 to 8. |
| Partition Coefficient: | log p = -0.79 (water/octanol) |
| Melting Point: | Between 210 and 222 o C |
The following is an artist's rendition of a cytarabine liposome injection particle:
Nonconcentric vesicles, each with an internal, aqueous chamber containing encapsulated cytarabine solution, surrounded by a bilayer lipid membrane.
Non-medicinal ingredients in cytarabine liposome injection are present in the following concentrations:
| Ingredient | Concentration |
| Cholesterol | 4.1 mg/mL |
| Triolein | 1.2 mg/mL |
| Dioleoylphosphatidylcholine (DOPC) | 5.7 mg/mL |
| Dipalmitoylphosphatidylglycerol (DPPG) | 1.0 mg/mL |
| Glucose | LT 15 mg/mL |
| L-Lysine | LT 20 :mol/mL |
| Residual chloroform | LT 50 ppm |
| LT = Less than | |
Cytarabine liposome injection is formulated as a sterile, non-pyrogenic, white to off-white suspension of cytarabine in Sodium Chloride 0.9% w/v in Water for Injection. Cytarabine liposome injection is preservative-free.
Refrigerate at 2-8degC. Protect from freezing and avoid aggressive agitation. For single use only. Discard unused portion.
Cytarabine liposome injection is supplied as a sterile, white to off-white suspension in 5 mL glass vials. Available as individual carton containing one ready to use vial.
Cytarabine liposome injection is a sustained release formulation of the active ingredient cytarabine designed for direct administration into the cerebral spinal fluid (CSF). Cytarabine is a cell cycle phase- specific antineoplastic agent, affecting cells only during the S-phase of cell division. The drug is taken up intracellularly by a facilitated diffusion mechanism shared by naturally occurring nucleosides. Intracellularly, it is activated by metabolic conversion into cytarabine-5'-triphosphate (ara-CTP), which is the active intracellular metabolite. For cell cycle phase-specific antimetabolites, such as cytarabine, the duration of exposure of neoplastic cells to cytotoxic concentrations is an important determination of drug efficacy. In in vitro studies examining more than 60 cell lines, the median cytarabine concentration resulting in 50% growth inhibition (IC50) was approximately 10 uM (2.4 ug/mL) for two days of exposure, and 0.1 uM (0.024 ug/mL) for 6 days of exposure. The studies also demonstrated susceptibility of solid tumor cell lines, as well as hematological malignancies, to cytarabine, particularly after longer periods of exposure to drug. Cytarabine liposome injection consists of microscopic, spherical particles composed of numerous non- concentric internal aqueous chambers containing the encapsulated drug. Each chamber is separated from adjacent chambers by a lipid bilayer. The lipid bilayer is composed of synthetic analogs of common, naturally occurring lipids. Cytarabine is released over time by erosion and/or reorganization of the lipid membranes (See PHARMACEUTICAL INFORMATION). By achieving drug release over time, cytarabine liposome injection increases the duration of exposure of cells to dividing cytotoxic concentrations of cytarabine.
Clinical
Following cytarabine liposome injection intrathecal administration in patients in the Phase I study, in either the lumbar sac or by intraventricular reservoir, peaks of free cytarabine were observed within 5 hours in both the ventricular and lumbar spaces. The peaks were followed by a biphasic 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. Tumoricidal concentrations of cytarabine (>0.02 ug/mL) were maintained in ventricular and lumbar CSF up to 2 weeks after intraventricular and lumbar puncture administration of cytarabine liposome injection, 50 mg or 75 mg. In contrast, intrathecal administration of free cytarabine, 30 mg, showed a biphasic CSF concentration profile with a terminal phase half-life of 3.4 hours. Table 2 shows the pharmacokinetic parameter values of cytarabine liposome injection, 75 mg, in patients with neoplastic meningitis. Administration was by either intraventricular or lumbar puncture, with samples obtained from both the ventricle and lumbar sac.
Table 2: Pharmacokinetic Parameters of Intrathecal Administration of DepoCyt, 75 mg,
in Neoplastic Meningitis Patients by Administration and Sampling Routes
| Dose Route | Sampling Route | n (patients) | T ma x (hr) | C ma x ug/mL | C mi n ug/mL (at 336 hrs) | T 1/ 2 (hr) |
| IVT | VENT | 9 | 0.3 | 257.8 | 0.5 | 218 |
| IVT | LUMB | 6 | 3.0 | 7.4 | 0.5 | 100 |
| LP | VENT | 7 | 3.3 | 6.1 | 0.4 | 263 |
| LP | LUMB | 8 | 0.3 | 225.4 | 0.7 | 238 |
IVT - Intraventricular LP - Lumbar puncture VENT - Ventricle LUMB - Lumbar sac
These data suggest that exposure to drug in the ventricular and lumbar spaces is similar regardless of the route of administration. In addition, compared to free cytarabine, the DepoFoam formulation increases the biological t1/2 by a factor of 27 to 71 depending upon the route of administration and the compartment sampled. Encapsulated cytarabine concentrations and DepoFoam particle counts followed a similar distribution pattern. Area Under the Curves (AUCs) of free and encapsulated cytarabine after ventricular injection of cytarabine liposome injection appeared to increase linearly with increasing dose, indicating that the release of encapsulated cytarabine from cytarabine liposome injection and the pharmacokinetics of cytarabine are linear in human CSF. The transfer rate of cytarabine from the CSF to plasma is slow and the conversion to ara-U in the plasma is fast, therefore, cytarabine has not previously been detected in patient plasma samples following intrathecal administration. Systemic exposure to cytarabine was determined to be negligible following intrathecal administration of cytarabine liposome injection, 50 mg or 75 mg.
Clinical
The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U (1-$-D- arabinofuranosyluracil or uracilarabininoside), 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.
Nonclinical
In rodents, a study was carried out to assess the distribution and clearance of cytarabine and the predominant phospholipid component (DOPC) of the DepoFoam particle following intrathecal administration of cytarabine liposome injection. Radiolabels for cytarabine and DOPC were distributed rapidly throughout the neuraxis. Greater than 90% of cytarabine was accounted for in urine by 4 days and an additional 2.7% by 21 days. A small percentage (<10%) of DOPC label remained incorporated in CNS tissue at 21 days. There was minimal accumulation of DOPC label in peripheral tissues (<2%) or excretion in urine (~6%). The majority of DOPC label was probably expired as CO2 after metabolism of the phospholipid by standard catabolic pathways. No formal assessments of pharmacokinetic drug-drug interactions between cytarabine liposome injection and other agents have been conducted and no studies have been conducted in special patient populations.
Overview
Cytarabine liposome injection was studied in a Phase I trial and two controlled trials, one in patients with lymphomatous meningitis and the other in patients with solid tumor neoplastic meningitis. In the Phase I trial, 19 patients received cytarabine liposome injection at doses ranging from 12.5 to 125 mg, with 8 of 19 patients receiving one or more doses at either 50 or 75 mg for up to 7 cycles of therapy. The two controlled trials were randomized, open-label, parallel-group multicenter trials designed to determine the efficacy and safety of cytarabine liposome injection relative to that of standard intrathecal chemotherapy for the treatment of patients with either lymphomatous or solid tumor neoplastic meningitis with a positive cerebrospinal fluid cytology. In both trials cytarabine liposome injection 50 mg was administered intrathecally once every two weeks, whereas the standard therapy was administered intrathecally twice a week. In patients with lymphomatous meningitis, standard therapy consisted of cytarabine 50 mg twice a week; in patients with solid tumor neoplastic meningitis standard therapy consisted of methotrexate 10 mg twice a week plus leucovorin 10 mg PO every 6 hours for 8 doses starting 24 hours after the administration of methotrexate. All patients were to receive concurrent treatment with oral dexamethasone to minimize symptoms of meningitis irritation, a known toxicity of intrathecal cytarabine and methotrexate (see WARNINGS and DOSAGE AND ADMINISTRATION). In both controlled trials, response was defined prospectively as conversion from a positive to a negative cerebrospinal fluid cytology at all sites known to be positive prior to the start of treatment, and absence of progression of neurologic signs and symptoms at the time the cytologic conversion was documented. Scoring of response was based on the interpretation of a blinded central cytopathologist who reviewed all of the slides that could be recovered from the treating institution; the interpretation of the local cytopathologist was relied upon when slides could not be recovered. All patients were to receive a 1 month course of Induction therapy consisting of 2 doses of cytarabine liposome injection or 8 doses of standard therapy. Patient attaining a response were candidates to receive 3 months of Consolidation therapy, and patients with lymphomatous meningitis still in response at the end of Consolidation were candidates to receive 4 months of Maintenance.
Solid tumor neoplastic meningitis
Sixty-one patients were enrolled, 31 on the cytarabine liposome injection arm and 30 on the methotrexate arm. The response rates are shown in Table 3. Median time to progression of neurologic signs and symptoms for all treated patients was 58 days on the cytarabine liposome injection arm and 30 days on the methotrexate arm. Median survival of all treated patients was 105 days on the cytarabine liposome injection arm and 78 days on the methotrexate arm.
Table 3: Complete Responses in Patients with Solid Tumor Neoplastic Meningitis in the Controlled Study
Intent-to-treat
| DepoCyt | Methotrexate |
| 8/31 (26%) | 6/30 (20%) |
Lymphomatous meningitis
Thirty-three patients were enrolled, 17 on the cytarabine liposome injection arm and 16 on the cytarabine arm. The response rates are shown in Table 4. Median time to progression of neurologic signs and symptoms for all treated patients was 78.5 days on the cytarabine liposome injection arm and 42 days on the cytarabine arm. The median survival of all treated patients was 99.5 days on the cytarabine liposome injection arm and 63 days on the cytarabine arm. In both arms the majority of patients died from progressive systemic disease, not the lymphomatous meningitis. There has been no demonstration of an improved clinical outcome as a result of the higher response rate for cytarabine liposome injection.
Table 4: Complete Responses in Patients with Lymphomatous Meningitis in the Controlled Study
Intent-to-treat
| DepoCyt | Cytarabine |
| 7/17 (41%) | 1/16 (6%) |
The toxicity of cytarabine liposome injection was evaluated in one multi-dose study in the Rhesus monkey. This study focused on characterizing the duration and extent of exposure of the subjects to cytarabine after an intrathecal injection of cytarabine liposome injection and on the neurobehavioral and neuropathological consequences of intrathecal administration. The same formulation as used in clinical trials was evaluated in the multi-dose toxicity study.
Title:
DTC 101 (DepoFoam(tm) Encapsulated Cytarabine) 4-Cycle Intrathecal Subchronic Toxicity Study in the Rhesus Monkey with a Subsequent Treatment-Free Period (HE Study No. 1363-002)
Objective:
To evaluate the potential toxicity of DTC 101 and DepoFoam placebo (vehicle) administered repeatedly via intrathecal injection, determine the reversibility of adverse effects in a subsequent treatment-free period, and detect any delayed effect of DTC 101 and/or DepoFoam placebo administration. The results of this study are summarized below.
Species:
Rhesus Monkey
Group Size:
9M, 9F
1/sex/group saline control 3/sex/group vehicle & 10 mg DTC 101 2/sex/group 5 mg DTC 101
Animal Weights:
Males: 3.9 - 9.2 kg Females: 4.0 - 5.7 kg
Route of Administration:
Intrathecal (IT) administration via port catheter system at L3-L6 by infusion (approximately 15 min. ).
4 cycles of treatment (1 dose/cycle, 14 day cycle), 8 weeks total.
Animals necropsied 14 days after 4th dose except 1/sex in the vehicle and 10 mg DTC 101 groups held for recovery phase (1 from each group sacrificed 3 or 6 months later).
Treatment Groups:
4 Groups: Saline control, vehicle control, 5 mg & 10 mg cytarabine liposome injection. All groups received dexamethasone during first half of each treatment cycle
Observations:
Saline control No findings
Vehicle control All animals inflammatory foci in spinal cord & 3/4 astrocytic activation (absent in recovery animals). 5 mg 9 body weight & food consumption; 4/4 inflammatory foci in brain & spinal cord, & astrocytic
activation; CSF findings: 8 phosphorus, total protein, potassium.
10 mg 1/6 recumbency, back stiffness & slow movements; 9 body weight & food consumption (also in recovery); 1/4 inflammatory foci in brain; 4/4 astrocytic activation; 3/4 inflammatory foci in spinal cord; CSF findings: 8 phosphorus, total protein, potassium; 1/6 9 neurological status, resolved with 8 dexamethasone therapy; recovery of histopathology findings
In this study, dosing volume was independent of body weight. Animals received either 0.5 mL of DTC 101 delivering 5 mg of cytarabine or 1.0 mL of DTC 101 delivering 10 mg of active drug. For comparative purposes, the doses administered in this study may be expressed either on a mg/kg or a mg/m2 basis. In this respect, male animals (3.9 - 9.2 kg) administered 0.5 mL DTC 101 received 0.5 - 1.3 mg/kg (6.2 - 16.0 mg/m2) DTC 101. Female animals (4.0 - 5.7 kg) in this dosing group received 0.9 - 1.3 mg/kg (11.1 - 16.0 mg/m2) DTC 101. For the 1.0 mL dosing group, male animals received 1.1 - 2.6 mg/kg (13.5 - 32.0 mg/m2) DTC 101; females received 1.8 - 2.5 mg/kg (22.1 - 30.1 mg/m2) DTC 101. Using standard interspecies dosing conversion factors, the doses of DTC 101 administered to monkeys in this multiple-dosing toxicology study are comparable to approximate human doses of 0.2 - 0.9 mg/kg (7.4 - 33.3 mg/m2). The results of this study demonstrated that repeated intrathecal administration of DTC 101 to monkeys is well tolerated. No clinically meaningful systemic findings were noted in animals administered either 5 or 10 mg of DTC 101 per 14 day dosing cycle (4 cycles total). Neurohistopathological findings (meningeal inflammation and/or astrocytic activation in brain and/or spinal cord) were reversible and considered to be the result of nonspecific irritation.
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