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
Paraplatin Indications, Dosage, Storage, Stability - Carboplatin
Paraplatin Indications, Dosage, Storage, Stability - Carboplatin
INDICATIONS
Initial treatment
of advanced ovarian
carcinoma: PARAPLATIN is indicated for the initial
treatment of advanced
ovarian carcinoma
in established combination with other approved chemotherapeutic
agents. One established combination regimen
consists of PARAPLATIN and cyclophosphamide
(CYTOXAN ®). Two randomized controlled studies conducted by
the NCIC and SWOG with PARAPLATIN vs. cisplatin, both in combination
with cyclophosphamide, have demonstrated equivalent
overall survival between
the two groups (see CLINICAL PHARMACOLOGY: CLINICAL
STUDIES section).
There is limited statistical
power to demonstrate equivalence
in overall pathologic complete response
rates and long term survival
(³ 3 years) because of the small
number of patients with
these outcomes: the small number
of patients with residual
tumor < 2 cm
after initial surgery
also limits the statistical
power to demonstrate equivalence
in this subgroup.
Secondary treatment
of advanced ovarian
carcinoma: PARAPLATIN is indicated for the palliative
treatment of patients
with ovarian carcinoma
recurrent after prior chemotherapy,
including patients who have been previously treated with cisplatin.
Within the group of patients
previously treated with cisplatin, those who have developed progressive
disease while receiving
cisplatin therapy
may have a decreased response
rate.
DOSAGE AND ADMINISTRATION
NOTE: Aluminum reacts with carboplatin
causing precipitate
formation and loss of potency,
therefore, needles or intravenous
sets containing aluminum parts that may come in contact
with the drug must not
be used for the preparation
or administration
of PARAPLATIN.
Single agent therapy:
PARAPLATIN (carboplatin aqueous solution) INJECTION, as a single agent, has been shown to be effective
in patients with recurrent ovarian carcinoma at a dosage
of 360 mg/m2 I.V. on day 1 every 4 weeks (Alternatively
see Formula Dosing, below). In
general, however, single intermittent
courses of PARAPLATIN should not be repeated until the neutrophil
count is at least 2,000
and the platelet count
is at least 100,000.
Combination therapy
with cyclophosphamide: In
the chemotherapy of advanced ovarian
cancer, an effective
combination for previously untreated patients consists of:
PARAPLATIN: 300 mg/m2 I.V. on day 1 every 4 weeks
for six cycles (Alternatively see Formula Dosing, below).
Cyclophosphamide (CYTOXAN ®): 600 mg/m2 I.V.
on day 1 every 4 weeks for six cycles. For directions regarding
the use and administration of cyclophosphamide
(CYTOXAN ® ), please refer to its package insert. (See CLINICAL
PHARMACOLOGY: CLINICAL STUDIES
section).
Intermittent courses of PARAPLATIN in combination with cyclophosphamide
should not be repeated until the neutrophil
count is at least 2,000
and the platelet count
is at least 100,000.
Dose Adjustment Recommendations
Pretreatment platelet
count and performance
status are important
prognostic factors for severity of myelosuppression
in previously treated patients.
The suggested dose adjustments
for single agent or combination
therapy shown in the table
below are modified from controlled trials in previously treated
and untreated patients with ovarian
carcinoma. Blood counts were done weekly, and the recommendations
are based on the lowest post- treatment platelet or neutrophil
value.
|
Platelets
|
Neutrophils
|
Adjusted Dose* (From Prior Course)
|
|
> 100,000
|
> 2,000
|
125%
|
|
50,000- 100,000
|
500- 2,000
|
No Adjustment
|
|
< 50,000
|
< 500
|
75%
|
*Percentages apply to PARAPLATIN (carboplatin
for injection) as a single agent
or to both PARAPLATIN and cyclophosphamide
in combination. In the
controlled studies, dosages were also adjusted at a lower level
(50 to 60%) for severe myelosuppression. Escalations
above 125% were not recommended for these studies.
PARAPLATIN is usually administered by an infusion
lasting 15 minutes or longer. No
pre- or post- treatment
hydration or forced
diuresis is required.
Patients with impaired kidney
function: Patients with creatinine clearance values below 60
mL/min are at increased risk
of severe bone marrow suppression.
In renally impaired patients
who received single agent
PARAPLATIN therapy, the incidence
of severe leukopenia,
neutropenia, or
thrombocytopenia has been about 25% when the dosage
modifications in the table
below have been used.
|
Baseline Creatinine
Clearance
|
Recommended
Dose on Day 1
|
|
41- 59 mL/min
|
250 mg/m2
|
|
16- 40 mL/min
|
200 mg/m2
|
The data available for patients with severely impaired kidney
function (creatinine clearance
below 15 mL/min) are too limited to permit a recommendation for
treatment.1,2
These dosing recommendations apply to the initial
course of treatment. Subsequent dosages should be adjusted according
to the patient’s tolerance based on the degree
of bone marrow
suppression.
Formula Dosing
Another approach for
determining the initial
dose of PARAPLATIN is the
use of mathematical formulae, which are based on a patient’s
pre-existing renal function3-5 or renal
function and desired
platelet nadir.6
Renal excretion is
the major route of elimination
for carboplatin. (see CLINICAL
PHARMACOLOGY section). The use of dosing formulae, as compared
to empirical dose
calculation based on body
surface area, allows
compensation for
patient variations in
pretreatment renal function
that might otherwise result in either underdosing (in patients with
above average renal
function) or overdosing (in patients with impaired renal function).
A simple formula
for calculating dosage,
based upon a patient’s glomerular filtration rate
(GFR in mL/min) and PARAPLATIN target
area under the concentration
versus time curve
(AUC in mg/mL•min), has been proposed by Calvert 3-5.
In these studies, GFR was
measured by 51Cr- EDTA, which has a good correlation
with creatinine clearance7.
|
CALVERT
FORMULA FOR PARAPLATIN DOSING
|
|
Total
Dose (mg) = (target A.C.
X (GFR + 25)
|
|
Note:
With the Calvert formula, the total dose
of PARAPLATIN is calculated in mg, not mg/m2.
|
The target AUC
of 4-6 mg/ mL•min using single agent
PARAPLATIN appears to provide the most appropriate
dose range
in previously treated patients4. This study also showed
a trend between the AUC
of single agent PARAPLATIN
administered to previously treated patients and the likelihood of
developing toxicity1.
|
% Actual
Toxicity in Previously Treated Patients
|
|
AUC
(mg/mL•min)
|
Gr 3
or Gr 4
Thrombocytopenia
|
Gr 3
or Gr 4
Leukopenia
|
|
4 to 5
|
16%
|
13%
|
|
6 to 7
|
33%
|
34%
|
Geriatric Dosing
Because renal function is often decreased in elderly patients, formula dosing of PATAPLATIN based on estimates of GFR should be used in elderly patients to provide predictable plasma PARAPLATIN AUC's and thereby minimize the risk of toxicity.
Preparation of Intravenous Solutions
PARAPLATIN (carboplatic aqueous solution) INJECTION is a premixed aqueous solution of 10 mg/mL carboplatin.
PARAPLATIN aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP
When prepared as directed, PARAPLATIN aqueous solutions are stable for 8 hours at room temperature (25C). Since no antibacterial preservative is contained in the formulation, it is recommended that PARAPLATIN aqueous solution be discarded 8 hours after dilution.
|
Vial
Strength
|
Diluent
Volume
|
|
50 mg
|
5 mL
|
|
150 mg
|
15 mL
|
|
450 mg
|
45 mL
|
These dilutions all produce a carboplatin
concentration of 10 mg/mL. PARAPLATIN can be further diluted to
concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W)
or 0.9% Sodium Chloride Injection, USP.
HOW SUPPLIED
PARAPLATIN. (carboplatin aqueous solution) INJECTION
NDC 0015-3210-30 50 mg/5 mL aqueous solution in multidose vials (with white flipoff
seals), individually cartoned.
NDC 0015-3211-30 150 mg/15 mL aqueous solution in multidose vials (with white
flip-off seals), individually cartoned.
NDC 0015-3212-30 450 mg/45 mL aqueous solution in multidose vials (with white
flip-off seals), individually cartoned.
NDC 0015-3216-30 600 mg/60 mL aqueous solution in multidose vials (with white
flip-off seals), individually cartoned.
Storage
Unopened vials of PARAPLATIN (carboplatin aqueous solution) INJECTION are stable
to the date indicated on the package when stored at 25° C (77° F); excursions permitted
from 15°-30° C (59°-86° F) [see USP Controlled Room Temperature]. Protect from light.
PARAPLATIN (carboplatin aqueous solution) INJECTION multidose vials
maintain microbial, chemical, and physical stability for up to 14 days at 25° C following
multiple needle entries.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration. Solutions for infusion should be discarded 8 hours
after preparation.
REFERENCES
- Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH
Publication. No. 83-2621 For sale by the Superintendent of Documents, US
Government Printing Office, Washington, DC 20402.
- AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA
1985; 253(11):1590-1592.
- National Study Commission on Cytotoxic Exposure - Recommendations for Handling
Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study
Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied
Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
- Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe
Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428.
- Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report From the
Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians 1983; (Sept/Oct)
258-263.
- American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling
Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.
- Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE
GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685.
US Patent No. 4,657,927
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