PARAPLATIN® (carboplatin aqueous solution) INJECTION is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of carboplatin. Carboplatin is a platinum coordination compound. The chemical name for carboplatin is platinum, diammine [1, 1-cyclobutane-dicarboxylato (2-)-0, 0´]-, (SP-4-2), and carboplatin has the following structural formula:

Carboplatin is a crystalline powder with the molecular formula of C₆H₁₂N₂O₄Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide.

Initial Treatment of Advanced Ovarian Carcinoma: PARAPLATIN (carbo-platin aqueous solution) INJECTION 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. Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin vs cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see Clinical Studies).

There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival ( ≥ 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.

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/mm²I. V. on day 1 every 4 weeks (alternatively see Formula Dosing). 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/mm² I. V. on day 1 every four weeks for six cycles (alternatively see Formula Dosing).

Cyclophosphamide-600 mg/mm² I. V. on day 1 every four weeks for six cycles. For directions regarding the use and administration of cyclophos-phamide please refer to its package insert. (See Clinical Studies.)

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 myelo-suppression 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

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 carbo-platin therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.

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.

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 function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin. (See CLINICAL PHARMACOLOGY.) 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. In these studies, GFR was measured by ⁵¹Cr-EDTA clearance.

CALVERT FORMULA FOR CARBOPLATIN DOSING

Total Dose (mg) = (target AUC) x (GFR + 25)

Note: With the Calvert formula, the total dose of PARAPLATIN is calculatedin mg, not mg/mm².

The target AUC of 4-6 mg/mL•min using single-agent carboplatinappears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single-agent carboplatin administered to previously treated patients and the likelihood of developing toxicity.

Geriatric Dosing: Because renal function is often decreased in elderly patients, formula dosing of PARAPLATIN based on estimates of GFR should be used in elderly patients to provide predictable plasma PARAPLATIN AUCs and thereby minimize the risk of toxicity.

PREPARATION OF INTRAVENOUS SOLUTIONS

PARAPLATIN (carboplatin 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 (D₅ W) or 0. 9% Sodium Chloride Injection, USP.

When prepared as directed, PARAPLATIN aqueous solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that PARAPLATIN aqueous solutions be discarded 8 hours after dilution.

PARAPLATIN®
(carboplatin aqueous solution) Injection

NDC 0015-3210-30 50 mg/5 mL aqueous solution in multidose vials (with white flip-off 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 25º 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.

Handling and Disposal

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published. ^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

REFERENCES

1. 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.

2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA1985;253(11):1590-1592.

3. National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983;1:426-428.

5. 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.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.

7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996;53:1669-1685.

Bristol Myers Squibb Company, Princeton, NJ 08543. USA. Revised: January, 2004. FDA revision date: 1/9/2004

For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see Clinical Studies: Comparative Toxicity.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER

*Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer: Data are based on the experience of 393 patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC (see Clinical Studies).

Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences that can be noted in the adverse experience table.

**Single Agent Use for the Secondary Treatment of Ovarian Cancer: Data are based on the experience of 553 patients with previously treated ovarian carcinoma (regardless of baseline status) who received single-agent carbo-platin.

In the narrative section that follows, the incidences of adverse events are based on data from 1893 patients with various types of tumors who received carboplatin as single-agent therapy.

Hematologic Toxicity: Bone marrow suppression is the dose-limiting toxicity of PARAPLATIN (carboplatin lyophilized powder) for INJECTION. Thrombocytopenia with platelet counts below 50, 000/mmm³occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1000/mmm³occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2000/mmm³occurs in 15% of the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in patients receiving single-agent therapy. By day 28, 90% of patients have platelet counts above 100, 000/mmm³; 74% have neutrophil counts above 2000/mmm³; 67% have leukocyte counts above 4000/mmm³.

Marrow suppression is usually more severe in patients with impaired kidney function. Patients with poor performance status have also experienced a higher incidence of severe leukopenia and thrombocytopenia.

The hematologic effects, although usually reversible, have resulted in infectious or hemorrhagic complications in 5% of the patients treated with carboplatin, with drug related death occurring in less than 1% of the patients. Fever has also been reported in patients with neutropenia.

Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients who started therapy with a baseline above that value. The incidence of anemia increases with increasing exposure to PARAPLATIN. Transfusions have been administered to 26% of the patients treated with carboplatin (44% of previously treated ovarian cancer patients).

Bone marrow depression may be more severe when PARAPLATIN is combined with other bone marrow suppressing drugs or with radiotherapy.

Gastrointestinal Toxicity: Vomiting occurs in 65% of the patients (81% of previously treated ovarian cancer patients) and in about one-third of these patients it is severe. Carboplatin, as a single agent or in combination, is significantly less emetogenic than cisplatin; however, patients previously treated with emetogenic agents, especially cisplatin, appear to be more prone to vomiting. Nausea alone occurs in an additional 10% to 15% of patients. Both nausea and vomiting usually cease within 24 hours of treatment and are often responsive to antiemetic measures. Although no conclusive efficacy data exist with the following schedules, prolonged administration of carbo-platin, either by continuous 24-hour infusion or by daily pulse doses given for 5 consecutive days, was associated with less severe vomiting than the singledose intermittent schedule. Emesis was increased when carboplatin was used in combination with other emetogenic compounds. Other gastrointestinal effects observed frequently were pain, in 17% of the patients; diarrhea, in 6%; and constipation, also in 6%.

Neurologic Toxicity: Peripheral neuropathies have been observed in 4% of the patients receiving carboplatin (6% of pretreated ovarian cancer patients) with mild paresthesias occurring most frequently. Carboplatin therapy produces significantly fewer and less severe neurologic side effects than does therapy with cisplatin. However, patients older than 65 years and/or previously treated with cisplatin appear to have an increased risk (10%) for peripheral neuropathies.

In 70% of the patients with pre-existing cisplatin-induced peripheral neurotoxicity, there was no worsening of symptoms during therapy with carbo-platin. Clinical ototoxicity and other sensory abnormalities such as visual disturbances and change in taste have been reported in only 1% of the patients. Central nervous system symptoms have been reported in 5% of the patients and appear to be most often related to the use of antiemetics.

Although the overall incidence of peripheral neurologic side effects induced by carboplatin is low, prolonged treatment, particularly in cisplatin pretreated patients, may result in cumulative neurotoxicity.

Nephrotoxicity: Development of abnormal renal function test results is uncommon, despite the fact that carboplatin, unlike cisplatin, has usually been administered without high-volume fluid hydration and/or forced diuresis. The incidences of abnormal renal function tests reported are 6% for serum creatinine and 14% for blood urea nitrogen (10% and 22%, respectively, in pretreated ovarian cancer patients). Most of these reported abnormalities have been mild and about one-half of them were reversible.

Creatinine clearance has proven to be the most sensitive measure of kidney function in patients receiving carboplatin, and it appears to be the most useful test for correlating drug clearance and bone marrow suppression. Twenty-seven percent of the patients who had a baseline value of 60 mL/min or more demonstrated a reduction below this value during carboplatintherapy.

Hepatic Toxicity: The incidences of abnormal liver function tests in patients with normal baseline values were reported as follows:total bilirubin, 5%; SGOT, 15%; and alkaline phosphatase, 24%; (5%, 19%, and 37%, respectively, in pretreated ovarian cancer patients). These abnormalities have generally been mild and reversible in about one-half of the cases, although the role of metastatic tumor in the liver may complicate the assessment in many patients. In a limited series of patients receiving very high dosages of carboplatin and autologous bone marrow transplantation, severe abnormalities of liver function tests were reported.

Electrolyte Changes: The incidences of abnormally decreased serum electrolyte values reported were as follows:sodium, 29%; potassium, 20%; calcium, 22%; and magnesium, 29%; (47%, 28%, 31%, and 43%, respec-tively, in pretreated ovarian cancer patients). Electrolyte supplementation was not routinely administered concomitantly with carboplatin, and these electrolyte abnormalities were rarely associated with symptoms.

Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of the patients. These allergic reactions have been similar in nature and severity to those reported with other platinum-containing compounds, ie, rash, urticaria, erythema, pruritus, and rarely bronchospasm and hypoten-sion. Anaphylactic reactions have been reported as part of postmarketing surveillance (see WARNINGS). These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy.

Injection Site Reactions: Injection site reactions, including redness, swelling, and pain, have been reported during postmarketing surveillance. Necrosis associated with extravasation has also been reported.

Other Events: Pain and asthenia were the most frequently reported miscellaneous adverse effects; their relationship to the tumor and to anemia was likely. Alopecia was reported (3%). Cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred in 6% or less of the patients. Cardiovascular events (cardiac failure, embolism, cerebrovascular accidents) were fatal in less than 1% of the patients and did not appear to be related to chemotherapy. Cancer-associated hemolytic uremic syndrome has been reported rarely.

Malaise, anorexia, and hypertension have been reported as part of post-marketing surveillance.

The renal effects of nephrotoxic compounds may be potentiated by PARAPLATIN.

Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during PARAPLATIN treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in patients receiving single-agent carboplatin. In general, single intermittent courses of PARAPLATIN should not be repeated until leukocyte, neutrophil, and platelet counts have recovered.

Since anemia is cumulative, transfusions may be needed during treatment with PARAPLATIN, particularly in patients receiving prolonged therapy.

Bone marrow suppression is increased in patients who have received prior therapy, especially regimens including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial PARA-PLATIN dosages in these patients should be appropriately reduced (see DOSAGE AND ADMINISTRATION) and blood counts should be carefully monitored between courses. The use of PARAPLATIN in combination with other bone marrow suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize additive effects.

Carboplatin has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when carboplatin was administered at higher than recommended doses in combination with other ototoxic agents.

PARAPLATIN can induce emesis, which can be more severe in patients previously receiving emetogenic therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. Although no conclusive efficacy data exist with the following schedules of PARAPLATIN, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over five consecutive daily pulse doses has resulted in reduced emesis.

Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving carboplatin as secondary treatment.

Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin with doses higher than those recommended in the package insert. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses.

As in the case of other platinum-coordination compounds, allergic reactions to carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy. (See CONTRAINDICATIONS and ADVERSE REACTIONS: Allergic Reactions.)

High dosages of carboplatin (more than four times the recommended dose) have resulted in severe abnormalities of liver function tests.

PARAPLATIN (carboplatin aqueous solution) INJECTION may cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

General

Needles or intravenous administration sets containing aluminum parts that may come in contact with PARAPLATIN INJECTION should not be used for the preparation or administration of the drug. Aluminum can react with carboplatin causing precipitate formation and loss of potency.

Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy.

Pregnancy: Pregnancy Category D (see WARNINGS).

Nursing Mothers: It is not known whether carboplatin is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to PARAPLATIN treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with PARAPLATIN INJECTION.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established (see WARNINGS; “audiologic toxicity”).

Geriatric Use: Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 395 patients were treated with carboplatin in combination with cyclophosphamide. Of these, 141 were over 65 years of age and 22 were 75 years or older. In these trials, age was not a prognostic factor for survival. In terms of safety, elderly patients treated with carbo-platin were more likely to develop severe thrombocytopenia than younger patients. In a combined database of 1942 patients (414 were ≥ 65 years of age) that received single-agent carboplatin for different tumor types, a similar incidence of adverse events was seen in patients 65 years and older and in patients less than 65. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because renal function is often decreased in the elderly, renal function should be considered in the selection of PARAPLATIN dosage (see DOSAGE AND ADMINISTRATION).

There is no known antidote for PARAPLATIN (carboplatin aqueous solution) INJECTION overdosage. The anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity.

PARAPLATIN INJECTION is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum-containing compounds.

PARAPLATIN should not be employed in patients with severe bone marrow depression or significant bleeding.

Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, which is thought to produce the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the difference in aquation rates.

In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 to 500 mg/mm²of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n = 6), and the post-distribution plasma half-life (beta) was found to be 2.6 to 5. 9 hours (n = 6). The total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4. 4 L/hour, 16 L and 3. 5 hours, respectively. The Cmax values and areas under the plasma concentration vs time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300-500 mg/mm²).

Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carbo-platin are present in plasma. However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days.

The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as carboplatin. Only 3 to 5% of the administered platinum is excreted in the urine between 24 and 96 hours. There are insufficient data to determine whether biliary excretion occurs.

In patients with creatinine clearances below 60 mL/min the total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. PARAPLATIN dosages should therefore be reduced in these patients (see DOSAGE AND ADMINISTRATION).

The primary determinant of PARAPLATIN clearance is glomerular filtration rate (GFR) and this parameter of renal function is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR (see DOSAGE AND ADMINISTRATION) to provide predictable PARAPLATIN plasma AUCs should be used in elderly patients to minimize the risk of toxicity.

Clinical Studies

Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer: In two prospectively randomized, controlled studies conducted by the National Cancer Institute of Canada, Clinical Trials Group (NCIC) and the Southwest Oncology Group (SWOG), 789 chemotherapy naive patients with advanced ovarian cancer were treated with carboplatin or cisplatin, both in combination with cyclophosphamide every 28 days for six courses before surgical reevaluation. The following results were obtained from both studies:

Comparative Efficacy:

Overview of Pivotal Trials

Clinical Response in Measurable Disease Patients

Pathologic Complete Response*

Progression-Free Survival (PFS)

Survival

Comparative Toxicity: The pattern of toxicity exerted by the carboplatin-containing regimen was significantly different from that of the cisplatin-containing combinations. Differences between the two studies may be explained by different cisplatin dosages and by different supportive care.

The carboplatin-containing regimen induced significantly more throm-bocytopenia and, in one study, significantly more leukopenia and more need for transfusional support. The cisplatin-containing regimen produced significantly more anemia in one study. However, no significant differences occurred in incidences of infections and hemorrhagic episodes.

Non-hematologic toxicities (emesis, neurotoxicity, ototoxicity, renal toxi-city, hypomagnesemia, and alopecia) were significantly more frequent in the cisplatin-containing arms.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY

Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer: In two prospective, randomized controlled studies in patients with advanced ovarian cancer previously treated with chemotherapy, carboplatin achieved six clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71+ weeks.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CARBOPLATIN - INJECTION

(CAR-bow-plah-tin)

COMMON BRAND NAME(S): Paraplatin

WARNING: Carboplatin can cause severe blood disorders (e.g., anemia, bone marrow suppression) that can result in infection and bleeding problems. Your risk of developing these problems increases with higher doses or longer treatment with carboplatin. Also, an unlikely but very serious allergic reaction to this drug may occur within minutes of receiving a dose. Tell your doctor immediately if you develop any of the following symptoms: easy bruising/bleeding, signs of infection (e.g., persistent sore throat, fever), unusual tiredness, rash, itching, swelling, severe dizziness, or trouble breathing.

Vomiting is a common side effect of this medication. See the Side Effects section for more information.

USES: Carboplatin is used to treat various types of cancer. It is a chemotherapy drug that contains platinum. It is used alone or in combination with other medications to slow or stop cancer cell growth.

HOW TO USE: Carboplatin is usually given by infusion into a vein (intravenously-IV) over at least 15 minutes by a healthcare professional. This medication should be mixed in the proper solution. Before using, check this medication visually for particles or discoloration. If either is present, do not use the liquid. Do not use needles or IV tubing that contain aluminum because this medication reacts with aluminum. If you have questions regarding the use of this medication, consult your pharmacist.

The dosage is based on your medical condition, body size, and response to therapy. In general, courses of carboplatin treatment should not be given more often than once every 4 weeks. Consult your doctor or pharmacist for more details.

SIDE EFFECTS: Stomach pain, body aches/pain, diarrhea, constipation, weakness, nausea, and vomiting may occur. Nausea and vomiting can be severe in some patients but usually go away within 24 hours of treatment. Drug therapy may be needed to prevent or relieve nausea and vomiting. Not eating before your treatment may help relieve vomiting. Changes in diet such as eating several small meals or limiting activity may help lessen some of these effects. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: numbness or tingling in the hands/feet, mouth sores, yellowing eyes/skin, dark urine, unusual tiredness, change in the amount of urine, pain/swelling/redness at the injection site.

Tell your doctor immediately if any of these rare but very serious side effects occur: hearing problems (e.g., ringing in the ears, hearing loss), easy bruising/bleeding, blood in the urine, black/bloody stools, fast/irregular heartbeat.

Rarely, temporary vision loss may occur with high doses of carboplatin. Normal vision usually returns within several weeks after the end of treatment. Consult your doctor or pharmacist for more details and report this side effect immediately if it occurs.

This medication can lower your body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills or persistent sore throat.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking carboplatin, tell your doctor or pharmacist if you are allergic to it, or to cisplatin; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: decreased bone marrow function/blood cell disorders (e.g., anemia, leukopenia, thrombocytopenia).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, mineral imbalance (low blood levels of sodium, potassium, magnesium, calcium).

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine.

Use caution with sharp objects like safety razors or nail cutters and avoid activities such as contact sports to lower the chance of getting cut, bruised or injured.

Wash your hands well to prevent the spread of infections.

The elderly may be more sensitive to the side effects of this drug, especially to bleeding problems and numbness/tingling of the hands/feet.

Children may be at greater risk for hearing loss when carboplatin is used at higher-than-recommended doses in combination with other medications that may affect hearing.

This medication is not recommended for use during pregnancy. It may cause harm to an unborn baby. Women of childbearing age should use reliable form(s) of birth control during treatment and for some time afterwards. Consult your doctor for more details.

It is not known whether this drug passes into breast milk. Because of the potential risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because very serious interactions may occur: nalidixic acid.

If you are currently using the medication listed above, tell your doctor or pharmacist before starting carboplatin.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: aminoglycoside antibiotics (e.g., gentamicin, neomycin), amphotericin B, certain anti-seizure medications (hydantoins such as phenytoin), certain "water pills" (loop diuretics such as furosemide, bumetanide, ethacrynic acid).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood counts, kidney function tests, blood mineral levels) should be performed to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For optimal benefits, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule.

STORAGE: Store the US vials at room temperature (77 degrees F or 25 degrees C) away from light. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted.

Store the Canadian vials at room temperature between 59 to 77 degrees F (15 to 25 degrees C) away from light.

Once prepared, this medication should be used within 8 hours.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.