Paraplatin

carboplatin

Dosage Form: injection

Warning

Paraplatin (carboplatin aqueous solution) INJECTION 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 Paraplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

Paraplatin Description

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-cyclobutanedicarboxylato(2-)-O,O′]-, (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 to 7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide.

Paraplatin - Clinical Pharmacology

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 mg/m2 to 500 mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n=6), and the postdistribution 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 versus 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 mg/m2 to 500 mg/m2).

Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin 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 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*

	NCIC	SWOG
* 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.
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)

	NCIC	SWOG
*  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.
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)	(−9.0, 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

	NCIC	SWOG
*  Kaplan-Meier Estimates
** Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median
Carboplatin	110 weeks	86 weeks
Cisplatin	99 weeks	79 weeks
2-year Survival*
Carboplatin	51.9%	40.2%
Cisplatin	48.4%	39.0%
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
	<50,000/mm3	41	6	<0.001
Neutropenia	<2000 cells/mm3	97	96	ns
	<1000 cells/mm3	81	79	ns
Leukopenia	<4000 cells/mm3	98	97	ns
	<2000 cells/mm3	68	52	0.001
Anemia	<11 g/dL	91	91	ns
	<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
	<50,000/mm3	22	11	0.006
Neutropenia	<2000 cells/mm3	95	97	ns
	<1000 cells/mm3	84	78	ns
Leukopenia	<4000 cells/mm3	97	97	ns
	<2000 cells/mm3	76	67	ns
Anemia	<11 g/dL	88	87	ns
	<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.

INDICATIONS

Initial Treatment of Advanced Ovarian Carcinoma

Paraplatin (carboplatin 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 versus 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.

Contraindications

Paraplatin (carboplatin aqueous solution) 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.

Warnings

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 Paraplatin 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 5 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 4 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.

Precautions

General

Needles or intravenous administration sets containing aluminum parts that may come in contact with Paraplatin (carboplatin aqueous solution) 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.

Drug Interactions

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

Carcinogensis, 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 (carboplatin aqueous solution) 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 carboplatin were more likely to develop severe thrombocytopenia than younger patients. In a combined database of 1,942 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).

Adverse Reactions

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 Toxicity.

ADVERSE EXPERIENCES IN PATIENTS WITH 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). 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	<2000 cells/mm3	96	67
	<1000 cells/mm3	82	21
Leukopenia	<4000 cells/mm3	97	85
	<2000 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 as single-agent therapy.

Hematologic Toxicity

Bone marrow suppression is the dose-limiting toxicity of Paraplatin. Thrombocytopenia with platelet counts below 50,000/mm3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm3 occurs in 15% of the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in patients receiving single-