A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Depocyt Side Effects, and Drug Interactions - Cytarabine Liposome
Depocyt Side Effects, and Drug Interactions - Cytarabine Liposome
SIDE EFFECTS
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 DepoCyt at doses ranging from 12.5 mg
to 125 mg. In the randomized multi-arm study DepoCyt 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 DepoCyt, 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 DepoCyt 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 patients with lymphomatous meningitis in the controlled study are
shown in Figure 3.
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 DepoCyt should be treated concurrently with dexamethasone to mitigate
the symptoms of chemical arachnoiditis (see DOSAGE
AND ADMINISTRATION).
Table 2 shows the rate of all adverse events occurring in >10
% of patients, as a rate per cycle, in the lymphoma randomized study.
Table 2: 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
| |
All Adverse Events %
|
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
|
|
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.
DRUG INTERACTIONS
No formal drug interaction studies of DepoCyt and other drugs
were 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 co-administration of drugs.
Laboratory Test Interactions
Since DepoCyt particles are similar in size and appearance
to white blood cells, care must be taken in interpreting CSF examinations following
DepoCyt administration.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity, mutagenicity or impairment of fertility
studies have been conducted with DepoCyt. The active ingredient of 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 micronucleus assay). Cytarabine caused
the transformation of hamster embryo cells and rat H43 cells in vitro. Cytarabine
was clastogenic to meiotic cells; a dose-dependent increase in sperm-head abnormalities
and chromosomal aberrations occurred in mice given i.p. cytarabine. Impairment
of Fertility: No studies assessing the impact of cytarabine on fertility are
available in the literature. Because the systemic exposure to free cytarabine
following intrathecal treatment with DepoCyt was negligible, the risk of impaired
fertility after intrathecal DepoCyt is likely to be low.
Pregnancy
Pregnancy Category D (see WARNINGS).
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. Despite
the low apparent risk, because many drugs are excreted in human milk and because
of the potential for serious adverse reactions in nursing infants, the use of
DepoCyt is not recommended in nursing women.
Pediatric Use
The safety and efficacy of DepoCyt in pediatric patients has
not been established.
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