Carboplatin - Carboplatin injection, Solution

(Carboplatin)

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Carboplatin - Carboplatin injection, Solution Prescribing Information

Carboplatin injection 10 mg/mL should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available.

Bone marrow suppression is dose related and may be severe, resulting in infection and/or bleeding. Anemia may be cumulative and may require transfusion support. Vomiting is another frequent drug-related side effect.

Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of carboplatin injection administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

Initial Treatment of Advanced Ovarian Carcinoma

Carboplatin 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 carboplatin and cyclophosphamide. Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see

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 6 courses before surgical reevaluation. The following results were obtained from both studies:

Comparative Efficacy

Overview of Pivotal Trials
	NCIC	SWOG
Number of patients randomized	447	342
Median age (years)	60	62
Dose of cisplatin	75 mg/m²	100 mg/m²
Dose of carboplatin	300 mg/m²	300 mg/m²
Dose of cyclophosphamide	600 mg/m²	600 mg/m²
Residual tumor <2 cm (number of patients)	39% (174/447)	14% (49/342)

Clinical Response in Measurable Disease Patients
	NCIC	SWOG
Carboplatin (number of patients)	60% (48/80)	58% (48/83)
Cisplatin (number of patients)	58% (49/85)	43% (33/76)
95% CI of difference (Carboplatin-Cisplatin)	(-13.9%, 18.6%)	(-2.3%, 31.1%)

Pathologic Complete Response*
* 114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study. 90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study.
	NCIC	SWOG
Carboplatin (number of patients)	11% (24/224)	10% (17/171)
Cisplatin (number of patients)	15% (33/223)	10% (17/171)
95% CI of difference (Carboplatin -Cisplatin)	(-10.7%, 2.5%)	(-6.9%, 6.9%)

Progression-Free Survival (PFS)
* Kaplan-Meier Estimates Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis. ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
	NCIC	SWOG
Median
Carboplatin	59 weeks	49 weeks
Cisplatin	61 weeks	47 weeks
2-year PFS*
Carboplatin	31%	21%
Cisplatin	31%	21%
95% CI of difference (Carboplatin-Cisplatin)	(-9.3, 8.7)	(-9, 9.4)
3-year PFS*
Carboplatin	19%	8%
Cisplatin	23%	14%
95% CI of difference (Carboplatin-Cisplatin)	(-11.5, 4.5)	(-14.1, 0.3)
Hazard Ratio ^†	1.10	1.02
95% CI (Carboplatin-Cisplatin)	(0.89, 1.35)	(0.81, 1.29)

Survival
* Kaplan-Meier Estimates ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median	NCIC	SWOG
Carboplatin	110 weeks	86 weeks
Cisplatin	99 weeks	79 weeks
2-year Survival*
Carboplatin	51.9%	40.2%
Cisplatin	48.4%	39%
95% CI of difference (Carboplatin-Cisplatin)	(-6.2, 13.2)	(-9.8, 12.2)
3-year Survival*
Carboplatin	34.6%	18.3%
Cisplatin	33.1%	24.9%
95% CI of difference (Carboplatin-Cisplatin)	(-7.7, 10.7)	(-15.9, 2.7)
Hazard Ratio ^†	0.98	1.01
95% CI (Carboplatin-Cisplatin)	(0.78, 1.23)	(0.78, 1.30)

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 thrombocytopenia 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 toxicity, hypomagnesemia, and alopecia) were significantly more frequent in the cisplatin-containing arms.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	70	29	<0.001
Thrombocytopenia	<50,000/mm³	41	6	<0.001
Neutropenia	<2,000 cells/mm³	97	96	ns
Neutropenia	<1,000 cells/mm³	81	79	ns
Leukopenia	<4,000 cells/mm³	98	97	ns
Leukopenia	<2,000 cells/mm³	68	52	0.001
Anemia	<11 g/dL	91	91	ns
Anemia	<8 g/dL	18	12	ns
Infections		14	12	ns
Bleeding		10	4	ns
Transfusions		42	31	0.018
Gastrointestinal
Nausea and vomiting		93	98	0.010
Vomiting		84	97	<0.001
Other GI side effects		50	62	0.013
Neurologic
Peripheral neuropathies		16	42	<0.001
Ototoxicity		13	33	<0.001
Other sensory side effects		6	10	ns
Central neurotoxicity		28	40	0.009
Renal
Serum creatinine elevations		5	13	0.006
Blood urea elevations		17	31	<0.001
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		17	13	ns
Alkaline phosphatase elevations		-	-	-
Electrolytes loss
Sodium		10	20	0.005
Potassium		16	22	ns
Calcium		16	19	ns
Magnesium		63	88	<0.001
Other side effects
Pain		36	37	ns
Asthenia		40	33	ns
Cardiovascular		15	19	ns
Respiratory		8	9	ns
Allergic		12	9	ns
Genitourinary		10	10	ns
Alopecia^‡		50	62	0.017
Mucositis		10	9	ns

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	59	35	<0.001
Thrombocytopenia	<50,000/mm³	22	11	0.006
Neutropenia	<2,000 cells/mm³	95	97	ns
Neutropenia	<1,000 cells/mm³	84	78	ns
Leukopenia	<4,000 cells/mm³	97	97	ns
Leukopenia	<2,000 cells/mm³	76	67	ns
Anemia	<11 g/dL	88	87	ns
Anemia	<8 g/dL	8	24	<0.001
Infections		18	21	ns
Bleeding		6	4	ns
Transfusions		25	33	ns
Gastrointestinal
Nausea and vomiting		94	96	ns
Vomiting		82	91	0.007
Other GI side effects		40	48	ns
Neurologic
Peripheral neuropathies		13	28	0.001
Ototoxicity		12	30	<0.001
Other sensory side effects		4	6	ns
Central neurotoxicity		23	29	ns
Renal
Serum creatinine elevations		7	38	<0.001
Blood urea elevations		-	-	-
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		23	16	ns
Alkaline phosphatase elevations		29	20	ns
Electrolytes loss
Sodium		-	-	-
Potassium		-	-	-
Calcium		-	-	-
Magnesium		58	77	<0.001
Other side effects
Pain		54	52	ns
Asthenia		43	46	ns
Cardiovascular		23	30	ns
Respiratory		12	11	ns
Allergic		10	11	ns
Genitourinary		11	13	ns
Alopecia^‡		43	57	0.009
Mucositis		6	11	ns

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 6 clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71+ weeks.

).

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

Carboplatin injection 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 carboplatin injection.

Single-Agent Therapy

Carboplatin injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m² intravenous on day 1 every 4 weeks (alternatively see

Formula Dosing

). In general, however, single intermittent courses of carboplatin injection 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:

Carboplatin injection - 300 mg/m² intravenous on day 1 every 4 weeks for 6 cycles (alternatively see

Formula Dosing

Another approach for determining the initial dose of carboplatin injection 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 carboplatin injection target area under the concentration versus time curve (AUC in mg/mL.min), has been proposed by Calvert. In these studies, GFR was measured by⁵¹Cr-EDTA clearance.

CALVERT FORMULA FOR CARBOPLATIN DOSING

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

Note: With the Calvert formula, the total dose of carboplatin is calculated in mg,

not

mg/m².

The target AUC of 4 mg/mL·min to 6 mg/mL·min using single-agent carboplatin appears 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.

% Actual Toxicity in Previously Treated Patients
AU C (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 carboplatin injection based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin injection AUCs and thereby minimize the risk of toxicity.

).

Cyclophosphamide - 600 mg/m² intravenous on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert (see

CLINICAL STUDIES

Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer

Comparative Efficacy

Overview of Pivotal Trials
	NCIC	SWOG
Number of patients randomized	447	342
Median age (years)	60	62
Dose of cisplatin	75 mg/m²	100 mg/m²
Dose of carboplatin	300 mg/m²	300 mg/m²
Dose of cyclophosphamide	600 mg/m²	600 mg/m²
Residual tumor <2 cm (number of patients)	39% (174/447)	14% (49/342)

Clinical Response in Measurable Disease Patients
	NCIC	SWOG
Carboplatin (number of patients)	60% (48/80)	58% (48/83)
Cisplatin (number of patients)	58% (49/85)	43% (33/76)
95% CI of difference (Carboplatin-Cisplatin)	(-13.9%, 18.6%)	(-2.3%, 31.1%)

Pathologic Complete Response*
* 114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study. 90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study.
	NCIC	SWOG
Carboplatin (number of patients)	11% (24/224)	10% (17/171)
Cisplatin (number of patients)	15% (33/223)	10% (17/171)
95% CI of difference (Carboplatin -Cisplatin)	(-10.7%, 2.5%)	(-6.9%, 6.9%)

Progression-Free Survival (PFS)
* Kaplan-Meier Estimates Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis. ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
	NCIC	SWOG
Median
Carboplatin	59 weeks	49 weeks
Cisplatin	61 weeks	47 weeks
2-year PFS*
Carboplatin	31%	21%
Cisplatin	31%	21%
95% CI of difference (Carboplatin-Cisplatin)	(-9.3, 8.7)	(-9, 9.4)
3-year PFS*
Carboplatin	19%	8%
Cisplatin	23%	14%
95% CI of difference (Carboplatin-Cisplatin)	(-11.5, 4.5)	(-14.1, 0.3)
Hazard Ratio ^†	1.10	1.02
95% CI (Carboplatin-Cisplatin)	(0.89, 1.35)	(0.81, 1.29)

Survival
* Kaplan-Meier Estimates ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median	NCIC	SWOG
Carboplatin	110 weeks	86 weeks
Cisplatin	99 weeks	79 weeks
2-year Survival*
Carboplatin	51.9%	40.2%
Cisplatin	48.4%	39%
95% CI of difference (Carboplatin-Cisplatin)	(-6.2, 13.2)	(-9.8, 12.2)
3-year Survival*
Carboplatin	34.6%	18.3%
Cisplatin	33.1%	24.9%
95% CI of difference (Carboplatin-Cisplatin)	(-7.7, 10.7)	(-15.9, 2.7)
Hazard Ratio ^†	0.98	1.01
95% CI (Carboplatin-Cisplatin)	(0.78, 1.23)	(0.78, 1.30)

Comparative Toxicity

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	70	29	<0.001
Thrombocytopenia	<50,000/mm³	41	6	<0.001
Neutropenia	<2,000 cells/mm³	97	96	ns
Neutropenia	<1,000 cells/mm³	81	79	ns
Leukopenia	<4,000 cells/mm³	98	97	ns
Leukopenia	<2,000 cells/mm³	68	52	0.001
Anemia	<11 g/dL	91	91	ns
Anemia	<8 g/dL	18	12	ns
Infections		14	12	ns
Bleeding		10	4	ns
Transfusions		42	31	0.018
Gastrointestinal
Nausea and vomiting		93	98	0.010
Vomiting		84	97	<0.001
Other GI side effects		50	62	0.013
Neurologic
Peripheral neuropathies		16	42	<0.001
Ototoxicity		13	33	<0.001
Other sensory side effects		6	10	ns
Central neurotoxicity		28	40	0.009
Renal
Serum creatinine elevations		5	13	0.006
Blood urea elevations		17	31	<0.001
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		17	13	ns
Alkaline phosphatase elevations		-	-	-
Electrolytes loss
Sodium		10	20	0.005
Potassium		16	22	ns
Calcium		16	19	ns
Magnesium		63	88	<0.001
Other side effects
Pain		36	37	ns
Asthenia		40	33	ns
Cardiovascular		15	19	ns
Respiratory		8	9	ns
Allergic		12	9	ns
Genitourinary		10	10	ns
Alopecia^‡		50	62	0.017
Mucositis		10	9	ns

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	59	35	<0.001
Thrombocytopenia	<50,000/mm³	22	11	0.006
Neutropenia	<2,000 cells/mm³	95	97	ns
Neutropenia	<1,000 cells/mm³	84	78	ns
Leukopenia	<4,000 cells/mm³	97	97	ns
Leukopenia	<2,000 cells/mm³	76	67	ns
Anemia	<11 g/dL	88	87	ns
Anemia	<8 g/dL	8	24	<0.001
Infections		18	21	ns
Bleeding		6	4	ns
Transfusions		25	33	ns
Gastrointestinal
Nausea and vomiting		94	96	ns
Vomiting		82	91	0.007
Other GI side effects		40	48	ns
Neurologic
Peripheral neuropathies		13	28	0.001
Ototoxicity		12	30	<0.001
Other sensory side effects		4	6	ns
Central neurotoxicity		23	29	ns
Renal
Serum creatinine elevations		7	38	<0.001
Blood urea elevations		-	-	-
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		23	16	ns
Alkaline phosphatase elevations		29	20	ns
Electrolytes loss
Sodium		-	-	-
Potassium		-	-	-
Calcium		-	-	-
Magnesium		58	77	<0.001
Other side effects
Pain		54	52	ns
Asthenia		43	46	ns
Cardiovascular		23	30	ns
Respiratory		12	11	ns
Allergic		10	11	ns
Genitourinary		11	13	ns
Alopecia^‡		43	57	0.009
Mucositis		6	11	ns

Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer

Intermittent courses of carboplatin injection 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.

* Percentages apply to carboplatin injection as a single agent or to both carboplatin 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.
Platelets	Neutrophils	Adjusted Dose* (From Prior Course)
>100,000	>2,000	125%
50 to 100,000	500 to 2,000	No Adjustment
<50,000	<500	75%

Carboplatin injection 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 carboplatin 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 to 59 mL/min	250 mg/m²
16 to 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.

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.

For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see

CLINICAL STUDIES

Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer

Comparative Efficacy

Overview of Pivotal Trials
	NCIC	SWOG
Number of patients randomized	447	342
Median age (years)	60	62
Dose of cisplatin	75 mg/m²	100 mg/m²
Dose of carboplatin	300 mg/m²	300 mg/m²
Dose of cyclophosphamide	600 mg/m²	600 mg/m²
Residual tumor <2 cm (number of patients)	39% (174/447)	14% (49/342)

Clinical Response in Measurable Disease Patients
	NCIC	SWOG
Carboplatin (number of patients)	60% (48/80)	58% (48/83)
Cisplatin (number of patients)	58% (49/85)	43% (33/76)
95% CI of difference (Carboplatin-Cisplatin)	(-13.9%, 18.6%)	(-2.3%, 31.1%)

Pathologic Complete Response*
* 114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study. 90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study.
	NCIC	SWOG
Carboplatin (number of patients)	11% (24/224)	10% (17/171)
Cisplatin (number of patients)	15% (33/223)	10% (17/171)
95% CI of difference (Carboplatin -Cisplatin)	(-10.7%, 2.5%)	(-6.9%, 6.9%)

Progression-Free Survival (PFS)
* Kaplan-Meier Estimates Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis. ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
	NCIC	SWOG
Median
Carboplatin	59 weeks	49 weeks
Cisplatin	61 weeks	47 weeks
2-year PFS*
Carboplatin	31%	21%
Cisplatin	31%	21%
95% CI of difference (Carboplatin-Cisplatin)	(-9.3, 8.7)	(-9, 9.4)
3-year PFS*
Carboplatin	19%	8%
Cisplatin	23%	14%
95% CI of difference (Carboplatin-Cisplatin)	(-11.5, 4.5)	(-14.1, 0.3)
Hazard Ratio ^†	1.10	1.02
95% CI (Carboplatin-Cisplatin)	(0.89, 1.35)	(0.81, 1.29)

Survival
* Kaplan-Meier Estimates ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median	NCIC	SWOG
Carboplatin	110 weeks	86 weeks
Cisplatin	99 weeks	79 weeks
2-year Survival*
Carboplatin	51.9%	40.2%
Cisplatin	48.4%	39%
95% CI of difference (Carboplatin-Cisplatin)	(-6.2, 13.2)	(-9.8, 12.2)
3-year Survival*
Carboplatin	34.6%	18.3%
Cisplatin	33.1%	24.9%
95% CI of difference (Carboplatin-Cisplatin)	(-7.7, 10.7)	(-15.9, 2.7)
Hazard Ratio ^†	0.98	1.01
95% CI (Carboplatin-Cisplatin)	(0.78, 1.23)	(0.78, 1.30)

Comparative Toxicity

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	70	29	<0.001
Thrombocytopenia	<50,000/mm³	41	6	<0.001
Neutropenia	<2,000 cells/mm³	97	96	ns
Neutropenia	<1,000 cells/mm³	81	79	ns
Leukopenia	<4,000 cells/mm³	98	97	ns
Leukopenia	<2,000 cells/mm³	68	52	0.001
Anemia	<11 g/dL	91	91	ns
Anemia	<8 g/dL	18	12	ns
Infections		14	12	ns
Bleeding		10	4	ns
Transfusions		42	31	0.018
Gastrointestinal
Nausea and vomiting		93	98	0.010
Vomiting		84	97	<0.001
Other GI side effects		50	62	0.013
Neurologic
Peripheral neuropathies		16	42	<0.001
Ototoxicity		13	33	<0.001
Other sensory side effects		6	10	ns
Central neurotoxicity		28	40	0.009
Renal
Serum creatinine elevations		5	13	0.006
Blood urea elevations		17	31	<0.001
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		17	13	ns
Alkaline phosphatase elevations		-	-	-
Electrolytes loss
Sodium		10	20	0.005
Potassium		16	22	ns
Calcium		16	19	ns
Magnesium		63	88	<0.001
Other side effects
Pain		36	37	ns
Asthenia		40	33	ns
Cardiovascular		15	19	ns
Respiratory		8	9	ns
Allergic		12	9	ns
Genitourinary		10	10	ns
Alopecia^‡		50	62	0.017
Mucositis		10	9	ns

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	59	35	<0.001
Thrombocytopenia	<50,000/mm³	22	11	0.006
Neutropenia	<2,000 cells/mm³	95	97	ns
Neutropenia	<1,000 cells/mm³	84	78	ns
Leukopenia	<4,000 cells/mm³	97	97	ns
Leukopenia	<2,000 cells/mm³	76	67	ns
Anemia	<11 g/dL	88	87	ns
Anemia	<8 g/dL	8	24	<0.001
Infections		18	21	ns
Bleeding		6	4	ns
Transfusions		25	33	ns
Gastrointestinal
Nausea and vomiting		94	96	ns
Vomiting		82	91	0.007
Other GI side effects		40	48	ns
Neurologic
Peripheral neuropathies		13	28	0.001
Ototoxicity		12	30	<0.001
Other sensory side effects		4	6	ns
Central neurotoxicity		23	29	ns
Renal
Serum creatinine elevations		7	38	<0.001
Blood urea elevations		-	-	-
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		23	16	ns
Alkaline phosphatase elevations		29	20	ns
Electrolytes loss
Sodium		-	-	-
Potassium		-	-	-
Calcium		-	-	-
Magnesium		58	77	<0.001
Other side effects
Pain		54	52	ns
Asthenia		43	46	ns
Cardiovascular		23	30	ns
Respiratory		12	11	ns
Allergic		10	11	ns
Genitourinary		11	13	ns
Alopecia^‡		43	57	0.009
Mucositis		6	11	ns

Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer

CLINICAL STUDIES

Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer

Comparative Efficacy

Overview of Pivotal Trials
	NCIC	SWOG
Number of patients randomized	447	342
Median age (years)	60	62
Dose of cisplatin	75 mg/m²	100 mg/m²
Dose of carboplatin	300 mg/m²	300 mg/m²
Dose of cyclophosphamide	600 mg/m²	600 mg/m²
Residual tumor <2 cm (number of patients)	39% (174/447)	14% (49/342)

Clinical Response in Measurable Disease Patients
	NCIC	SWOG
Carboplatin (number of patients)	60% (48/80)	58% (48/83)
Cisplatin (number of patients)	58% (49/85)	43% (33/76)
95% CI of difference (Carboplatin-Cisplatin)	(-13.9%, 18.6%)	(-2.3%, 31.1%)

Pathologic Complete Response*
* 114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study. 90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study.
	NCIC	SWOG
Carboplatin (number of patients)	11% (24/224)	10% (17/171)
Cisplatin (number of patients)	15% (33/223)	10% (17/171)
95% CI of difference (Carboplatin -Cisplatin)	(-10.7%, 2.5%)	(-6.9%, 6.9%)

Progression-Free Survival (PFS)
* Kaplan-Meier Estimates Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis. ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
	NCIC	SWOG
Median
Carboplatin	59 weeks	49 weeks
Cisplatin	61 weeks	47 weeks
2-year PFS*
Carboplatin	31%	21%
Cisplatin	31%	21%
95% CI of difference (Carboplatin-Cisplatin)	(-9.3, 8.7)	(-9, 9.4)
3-year PFS*
Carboplatin	19%	8%
Cisplatin	23%	14%
95% CI of difference (Carboplatin-Cisplatin)	(-11.5, 4.5)	(-14.1, 0.3)
Hazard Ratio ^†	1.10	1.02
95% CI (Carboplatin-Cisplatin)	(0.89, 1.35)	(0.81, 1.29)

Survival
* Kaplan-Meier Estimates ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median	NCIC	SWOG
Carboplatin	110 weeks	86 weeks
Cisplatin	99 weeks	79 weeks
2-year Survival*
Carboplatin	51.9%	40.2%
Cisplatin	48.4%	39%
95% CI of difference (Carboplatin-Cisplatin)	(-6.2, 13.2)	(-9.8, 12.2)
3-year Survival*
Carboplatin	34.6%	18.3%
Cisplatin	33.1%	24.9%
95% CI of difference (Carboplatin-Cisplatin)	(-7.7, 10.7)	(-15.9, 2.7)
Hazard Ratio ^†	0.98	1.01
95% CI (Carboplatin-Cisplatin)	(0.78, 1.23)	(0.78, 1.30)

Comparative Toxicity

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	70	29	<0.001
Thrombocytopenia	<50,000/mm³	41	6	<0.001
Neutropenia	<2,000 cells/mm³	97	96	ns
Neutropenia	<1,000 cells/mm³	81	79	ns
Leukopenia	<4,000 cells/mm³	98	97	ns
Leukopenia	<2,000 cells/mm³	68	52	0.001
Anemia	<11 g/dL	91	91	ns
Anemia	<8 g/dL	18	12	ns
Infections		14	12	ns
Bleeding		10	4	ns
Transfusions		42	31	0.018
Gastrointestinal
Nausea and vomiting		93	98	0.010
Vomiting		84	97	<0.001
Other GI side effects		50	62	0.013
Neurologic
Peripheral neuropathies		16	42	<0.001
Ototoxicity		13	33	<0.001
Other sensory side effects		6	10	ns
Central neurotoxicity		28	40	0.009
Renal
Serum creatinine elevations		5	13	0.006
Blood urea elevations		17	31	<0.001
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		17	13	ns
Alkaline phosphatase elevations		-	-	-
Electrolytes loss
Sodium		10	20	0.005
Potassium		16	22	ns
Calcium		16	19	ns
Magnesium		63	88	<0.001
Other side effects
Pain		36	37	ns
Asthenia		40	33	ns
Cardiovascular		15	19	ns
Respiratory		8	9	ns
Allergic		12	9	ns
Genitourinary		10	10	ns
Alopecia^‡		50	62	0.017
Mucositis		10	9	ns

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	59	35	<0.001
Thrombocytopenia	<50,000/mm³	22	11	0.006
Neutropenia	<2,000 cells/mm³	95	97	ns
Neutropenia	<1,000 cells/mm³	84	78	ns
Leukopenia	<4,000 cells/mm³	97	97	ns
Leukopenia	<2,000 cells/mm³	76	67	ns
Anemia	<11 g/dL	88	87	ns
Anemia	<8 g/dL	8	24	<0.001
Infections		18	21	ns
Bleeding		6	4	ns
Transfusions		25	33	ns
Gastrointestinal
Nausea and vomiting		94	96	ns
Vomiting		82	91	0.007
Other GI side effects		40	48	ns
Neurologic
Peripheral neuropathies		13	28	0.001
Ototoxicity		12	30	<0.001
Other sensory side effects		4	6	ns
Central neurotoxicity		23	29	ns
Renal
Serum creatinine elevations		7	38	<0.001
Blood urea elevations		-	-	-
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		23	16	ns
Alkaline phosphatase elevations		29	20	ns
Electrolytes loss
Sodium		-	-	-
Potassium		-	-	-
Calcium		-	-	-
Magnesium		58	77	<0.001
Other side effects
Pain		54	52	ns
Asthenia		43	46	ns
Cardiovascular		23	30	ns
Respiratory		12	11	ns
Allergic		10	11	ns
Genitourinary		11	13	ns
Alopecia^‡		43	57	0.009
Mucositis		6	11	ns

Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer

Comparative Toxicity

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	70	29	<0.001
Thrombocytopenia	<50,000/mm³	41	6	<0.001
Neutropenia	<2,000 cells/mm³	97	96	ns
Neutropenia	<1,000 cells/mm³	81	79	ns
Leukopenia	<4,000 cells/mm³	98	97	ns
Leukopenia	<2,000 cells/mm³	68	52	0.001
Anemia	<11 g/dL	91	91	ns
Anemia	<8 g/dL	18	12	ns
Infections		14	12	ns
Bleeding		10	4	ns
Transfusions		42	31	0.018
Gastrointestinal
Nausea and vomiting		93	98	0.010
Vomiting		84	97	<0.001
Other GI side effects		50	62	0.013
Neurologic
Peripheral neuropathies		16	42	<0.001
Ototoxicity		13	33	<0.001
Other sensory side effects		6	10	ns
Central neurotoxicity		28	40	0.009
Renal
Serum creatinine elevations		5	13	0.006
Blood urea elevations		17	31	<0.001
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		17	13	ns
Alkaline phosphatase elevations		-	-	-
Electrolytes loss
Sodium		10	20	0.005
Potassium		16	22	ns
Calcium		16	19	ns
Magnesium		63	88	<0.001
Other side effects
Pain		36	37	ns
Asthenia		40	33	ns
Cardiovascular		15	19	ns
Respiratory		8	9	ns
Allergic		12	9	ns
Genitourinary		10	10	ns
Alopecia^‡		50	62	0.017
Mucositis		10	9	ns

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	59	35	<0.001
Thrombocytopenia	<50,000/mm³	22	11	0.006
Neutropenia	<2,000 cells/mm³	95	97	ns
Neutropenia	<1,000 cells/mm³	84	78	ns
Leukopenia	<4,000 cells/mm³	97	97	ns
Leukopenia	<2,000 cells/mm³	76	67	ns
Anemia	<11 g/dL	88	87	ns
Anemia	<8 g/dL	8	24	<0.001
Infections		18	21	ns
Bleeding		6	4	ns
Transfusions		25	33	ns
Gastrointestinal
Nausea and vomiting		94	96	ns
Vomiting		82	91	0.007
Other GI side effects		40	48	ns
Neurologic
Peripheral neuropathies		13	28	0.001
Ototoxicity		12	30	<0.001
Other sensory side effects		4	6	ns
Central neurotoxicity		23	29	ns
Renal
Serum creatinine elevations		7	38	<0.001
Blood urea elevations		-	-	-
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		23	16	ns
Alkaline phosphatase elevations		29	20	ns
Electrolytes loss
Sodium		-	-	-
Potassium		-	-	-
Calcium		-	-	-
Magnesium		58	77	<0.001
Other side effects
Pain		54	52	ns
Asthenia		43	46	ns
Cardiovascular		23	30	ns
Respiratory		12	11	ns
Allergic		10	11	ns
Genitourinary		11	13	ns
Alopecia^‡		43	57	0.009
Mucositis		6	11	ns

Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer

First Line

Combination Therapy*

Percent

Second Line

Single-Agent Therapy

^†

Percent

* 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

Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer

Comparative Efficacy

Overview of Pivotal Trials
	NCIC	SWOG
Number of patients randomized	447	342
Median age (years)	60	62
Dose of cisplatin	75 mg/m²	100 mg/m²
Dose of carboplatin	300 mg/m²	300 mg/m²
Dose of cyclophosphamide	600 mg/m²	600 mg/m²
Residual tumor <2 cm (number of patients)	39% (174/447)	14% (49/342)

Clinical Response in Measurable Disease Patients
	NCIC	SWOG
Carboplatin (number of patients)	60% (48/80)	58% (48/83)
Cisplatin (number of patients)	58% (49/85)	43% (33/76)
95% CI of difference (Carboplatin-Cisplatin)	(-13.9%, 18.6%)	(-2.3%, 31.1%)

Pathologic Complete Response*
* 114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study. 90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study.
	NCIC	SWOG
Carboplatin (number of patients)	11% (24/224)	10% (17/171)
Cisplatin (number of patients)	15% (33/223)	10% (17/171)
95% CI of difference (Carboplatin -Cisplatin)	(-10.7%, 2.5%)	(-6.9%, 6.9%)

Progression-Free Survival (PFS)
* Kaplan-Meier Estimates Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis. ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
	NCIC	SWOG
Median
Carboplatin	59 weeks	49 weeks
Cisplatin	61 weeks	47 weeks
2-year PFS*
Carboplatin	31%	21%
Cisplatin	31%	21%
95% CI of difference (Carboplatin-Cisplatin)	(-9.3, 8.7)	(-9, 9.4)
3-year PFS*
Carboplatin	19%	8%
Cisplatin	23%	14%
95% CI of difference (Carboplatin-Cisplatin)	(-11.5, 4.5)	(-14.1, 0.3)
Hazard Ratio ^†	1.10	1.02
95% CI (Carboplatin-Cisplatin)	(0.89, 1.35)	(0.81, 1.29)

Survival
* Kaplan-Meier Estimates ^† Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median	NCIC	SWOG
Carboplatin	110 weeks	86 weeks
Cisplatin	99 weeks	79 weeks
2-year Survival*
Carboplatin	51.9%	40.2%
Cisplatin	48.4%	39%
95% CI of difference (Carboplatin-Cisplatin)	(-6.2, 13.2)	(-9.8, 12.2)
3-year Survival*
Carboplatin	34.6%	18.3%
Cisplatin	33.1%	24.9%
95% CI of difference (Carboplatin-Cisplatin)	(-7.7, 10.7)	(-15.9, 2.7)
Hazard Ratio ^†	0.98	1.01
95% CI (Carboplatin-Cisplatin)	(0.78, 1.23)	(0.78, 1.30)

Comparative Toxicity

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	70	29	<0.001
Thrombocytopenia	<50,000/mm³	41	6	<0.001
Neutropenia	<2,000 cells/mm³	97	96	ns
Neutropenia	<1,000 cells/mm³	81	79	ns
Leukopenia	<4,000 cells/mm³	98	97	ns
Leukopenia	<2,000 cells/mm³	68	52	0.001
Anemia	<11 g/dL	91	91	ns
Anemia	<8 g/dL	18	12	ns
Infections		14	12	ns
Bleeding		10	4	ns
Transfusions		42	31	0.018
Gastrointestinal
Nausea and vomiting		93	98	0.010
Vomiting		84	97	<0.001
Other GI side effects		50	62	0.013
Neurologic
Peripheral neuropathies		16	42	<0.001
Ototoxicity		13	33	<0.001
Other sensory side effects		6	10	ns
Central neurotoxicity		28	40	0.009
Renal
Serum creatinine elevations		5	13	0.006
Blood urea elevations		17	31	<0.001
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		17	13	ns
Alkaline phosphatase elevations		-	-	-
Electrolytes loss
Sodium		10	20	0.005
Potassium		16	22	ns
Calcium		16	19	ns
Magnesium		63	88	<0.001
Other side effects
Pain		36	37	ns
Asthenia		40	33	ns
Cardiovascular		15	19	ns
Respiratory		8	9	ns
Allergic		12	9	ns
Genitourinary		10	10	ns
Alopecia^‡		50	62	0.017
Mucositis		10	9	ns

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY
		Carboplatin Arm Percent^*	Cisplatin Arm Percent*	P-Values ^†
* Values are in percent of evaluable patients. ^† ns = not significant, p>0.05. ^‡May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm³	59	35	<0.001
Thrombocytopenia	<50,000/mm³	22	11	0.006
Neutropenia	<2,000 cells/mm³	95	97	ns
Neutropenia	<1,000 cells/mm³	84	78	ns
Leukopenia	<4,000 cells/mm³	97	97	ns
Leukopenia	<2,000 cells/mm³	76	67	ns
Anemia	<11 g/dL	88	87	ns
Anemia	<8 g/dL	8	24	<0.001
Infections		18	21	ns
Bleeding		6	4	ns
Transfusions		25	33	ns
Gastrointestinal
Nausea and vomiting		94	96	ns
Vomiting		82	91	0.007
Other GI side effects		40	48	ns
Neurologic
Peripheral neuropathies		13	28	0.001
Ototoxicity		12	30	<0.001
Other sensory side effects		4	6	ns
Central neurotoxicity		23	29	ns
Renal
Serum creatinine elevations		7	38	<0.001
Blood urea elevations		-	-	-
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		23	16	ns
Alkaline phosphatase elevations		29	20	ns
Electrolytes loss
Sodium		-	-	-
Potassium		-	-	-
Calcium		-	-	-
Magnesium		58	77	<0.001
Other side effects
Pain		54	52	ns
Asthenia		43	46	ns
Cardiovascular		23	30	ns
Respiratory		12	11	ns
Allergic		10	11	ns
Genitourinary		11	13	ns
Alopecia^‡		43	57	0.009
Mucositis		6	11	ns

Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer

).

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 carboplatin.

Bone Marrow

Thrombocytopenia <100,000/mm³ 66 62

<50,000/mm³ 33 35

Neutropenia <2,000 cells/mm³ 96 67

<1,000 cells/mm³ 82 21

Leukopenia <4,000 cells/mm³ 97 85

<2,000 cells/mm³ 71 26

Anemia <11 g/dL 90 90

<8 g/dL 14 21

Infections 16 5

Bleeding 8 5

Transfusions 35 44

Gastrointestinal

Nausea and vomiting 93 92

Vomiting 83 81

Other GI side effects 46 21

Neurologic

Peripheral neuropathies 15 6

Ototoxicity 12 1

Other sensory side effects 5 1

Central neurotoxicity 26 5

Renal

Serum creatinine elevations 6 10

Blood urea elevations 17 22

Hepatic

Bilirubin elevations 5 5

SGOT elevations 20 19

Alkaline phosphatase elevations 29 37

Electrolytes loss

Sodium 10 47

Potassium 16 28

Calcium 16 31

Magnesium 61 43

Other side effects

Pain 44 23

Asthenia 41 11

Cardiovascular 19 6

Respiratory 10 6

Allergic 11 2

Genitourinary 10 2

Alopecia 49 2

Mucositis 8 1

In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin, USP as single-agent therapy.

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