Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Carboplatin is an analog of cisplatin. Like cisplatin, it contains a platinum atom surrounded in a plane by two ammonia groups and two other ligands in the cis position. The other two ligands in carboplatin are present in a ring structure rather than as two chloride atoms in cisplatin. This difference makes carboplatin more stable and has less nephrotoxicity, neurotoxicity, ototoxicity and emetogenesis.1,2 The exact mechanism of action of carboplatin is not known. Carboplatin undergoes intracellular activation to form reactive platinum complexes which are believed to inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules. Carboplatin is a radiation-sensitizing agent.3,4 It is cell cycle-phase nonspecific.2

PHARMACOKINETICS:

Ultrafilterable platinum consists of carboplatin and free carboplatin metabolites; total platinum consists of protein bound and free platinum. Pharmacokinetics of ultrafilterable platinum is clinically more useful as only free platinum species are cytotoxic.

SPECIAL PRECAUTIONS:

Contraindication: Manufacturer states that carboplatin is contraindicated in patients with known hypersensitivity to carboplatin, other platinum agents (eg, cisplatin) or mannitol.12 However, with appropriate precautions, rechallenging with carboplatin or switching to cisplatin has been tolerated by some patients with hypersensitivity reactions to carboplatin.

Incidence of peripheral neuropathy is increased and myelosuppression may be more severe in patients older than 65 years of age. In addition, elderly patients are more likely to have age-related renal function impairment, which may require dosage reduction and careful monitoring of blood counts.

increases the risk and severity of toxicities (eg, myelosuppression, nausea, vomiting, peripheral neuropathy, ototoxicity).

has not been fully studied, but drugs with similar mechanisms of action and mutagenicity have been reported to be carcinogenic.

may cause gonadal suppression (amenorrhea, azoospermia) which is generally related to dose and length of therapy and may be irreversible.

Pregnancy: FDA Pregnancy Category D.11 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

SIDE EFFECTS:

ORGAN SITE	SIDE EFFECT	ONSET
Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
allergy/immunology	hypersensitivity (2-30%) 18-20	I	E
auditory/hearing	ototoxicity (tinnitus, visual and taste disturbances) (1%)		E
blood/bone marrow febrile neutropenia	anemia (71%)		E
	leukopenia (severe 14%) nadir 21 days; recovery 30 days 11		E
	neutropenia (severe 18%) nadir 21-28 days; recovery 35 days 11		E
	thrombocytopenia (severe 25%) nadir 21 days; recovery 30 days 11		E
constitutional symptoms	asthenia (8%)		E
dermatology/skin	extravasation hazard: nonvesicant	I
dermatology/skin	alopecia (3%)			D
gastrointestinal	emetogenic potential: high moderate
	constipation (6%)		E
	diarrhea (6%)		E
	nausea (15%)	I
	vomiting (64%)	I
hepatic	elevated alkaline phosphatase (24%)		E
	elevated AST (15%)		E
	elevated bilirubin (5%)		E
infection	infections (4%)		E
metabolic/laboratory	hypocalcemia (22%)		E
	hypomagnesemia (29%)		E
	hypokalemia (20%)		E
	hyponatremia (29%)		E
	increased BUN (14%)		E
	increased uric acid (5%)		E
neurology	CNS symptoms (5%) 2		E
neurology	peripheral neuropathy (4%)		E
ocular/visual	visual disturbances (rare) 2		E	D
pain	abdominal pain (17%)	I	E
renal/genitourinary	acute renal failure (rare) 2		E
	decreased creatinine clearance (27%)		E
	increased serum creatinine (6%)		E
syndromes	hemolytic-uremic syndrome (rare)		E

Adapted from reference 12 unless specified otherwise.

Myelosuppression

is the dose-limiting toxicity, usually manifested as thrombocytopenia and less commonly as leukopenia, neutropenia and anemia. Risk factors include prior cytotoxic therapy (especially cisplatin), poor

performance status, old age, impaired renal function and concurrent myelosuppressive therapy.2,12 Myelosuppression is dose dependent, closely related to the renal clearance of carboplatin, and minimized by using the Calvert AUC-based dosing formula.7,12 Anemia is more common with increased carboplatin exposure and blood transfusions may be needed during prolonged carboplatin therapy (eg, more than 6 cycles).2 Hypersensitivity has been reported in 2% of patients receiving carboplatin alone and in 9-30% patients receiving carboplatin with other cytotoxic drugs.18-20 Reactions are similar to those seen with other platinum agents (eg, cisplatin) and include anaphylaxis and anaphylactoid reactions.2 Symptoms may vary in severity and include pruritus, rash, palmar erythema, fever, chills, rigors, swelling (face, tongue, infusion arm), GI upset, dyspnea, wheezing, tachycardia, and hypertension or hypotension.16,19 Reactions can develop during or several hours to days after carboplatin administration. The risk of reactions increases with repeated exposure to platinum agents,18,19 particularly after 7 courses of carboplatin or receiving the second course of carboplatin after prior platinum therapy.16,19 The hypersensitivity appears to be mainly an IgE-mediated type I immediate reaction but may also involve direct histamine release. Some reactions may also be due to the mannitol present in some carboplatin formulations.2 Management includes prompt treatment of anaphylaxis (see BCCA Hypersensitivity Guidelines) and oral diphenhydramine 25-50 mg every 4-6 hours for minor delayed reactions.19 In some cases, carboplatin therapy may be continued with prophylactic corticosteroid and antihistamine and/or desensitization.17,19

Nausea and vomiting

usually begin within 6-12 hours after administration and may persist up to 24 hours or longer. Acute vomiting appears to be mediated by local GI and central serotonin mechanisms and is most common in patients with prior emetogenic cytotoxic therapy or receiving concurrent emetogenic agents. The incidence and severity of vomiting may be reduced by prophylactic antiemetics. There is some evidence that the incidence of nausea and vomiting is reduced when carboplatin is given as a 24-hour continuous IV infusion or in divided doses

over 5 consecutive days.2

Neurotoxicity

such as peripheral sensory neuropathy (eg, paresthesia) is less frequent or severe than with cisplatin. Peripheral neuropathy is more common in patients over 65, receiving prolonged carboplatin therapy or with prior cisplatin therapy. Patients with pre-existing cisplatin-induced peripheral neurotoxicity generally do not worsen during

carboplatin therapy.2 Neurologic evaluations should be performed regularly.21 Nephrotoxicity: is less common or severe than with cisplatin; concomitant IV hydration and diuresis generally are not needed with carboplatin.1,2 The risk and severity of nephrotoxicity are increased with high dose carboplatin regimen, especially when given concurrently with other nephrotoxic chemotherapy.22,23

INTERACTIONS:

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

: 50 mg, 150 mg and 450 mg vials; each mL contains 10 mg of carboplatin; preservative-free. Store at room temperature. Protect from light.

Diluted solution for infusion: PARAPLATIN-AQ(r) and Novopharm brand injections: must be further diluted prior to infusion with D5W or NS; the final concentrations should be no less than 0.5 mg/mL; diluted solution is stable for 8 hours at room temperature or 24 hours under refrigeration.12,27 Faulding brand injection: must be further diluted with D5W or NS to final concentrations of 0.3-2 mg/mL; diluted solution is stable for 24 hours at room temperature or 48 hours under refrigeration.21 Although NS is compatible with carboplatin, D5W is the preferred IV solution for dilution as carboplatin decomposition is less in D5W than in NS.28 Compatibility: The following are compatible via Y-site injection: amifostine, cladribine, filgrastim, fludarabine, granisetron, melphalan, ondansetron, paclitaxel, teniposide, thiotepa, vinorelbine.28 The following are compatible in the same infusion solution: carboplatin (1 mg/mL) and cisplatin (0.2 mg/mL), carboplatin (1 mg/mL) and etoposide (0.2 mg/mL), carboplatin (1 mg/mL) and ifosfamide (1 mg/mL).28 Incompatibility: The following are incompatible in the same infusion solution: carboplatin (10 mg/mL) and fluorouracil (1 mg/mL), carboplatin (1 mg/L) and mesna (1 mg/mL).28 Aluminum-containing IV needles, syringes or sets should not be used to prepare or administer carboplatin; aluminum reacts with platinum from carboplatin to form a black precipitate, resulting in loss of potency.12

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

2-4 weeks: AUC-based carboplatin dose IV for one dose on day 1 Calculate carboplatin dose with Calvert formula: Dose (mg) = AUC x (GFR + 25)

where AUC = 4-7, GFR obtained from nuclear renogram (preferred) or approximated by CrCl calculated from serum creatinine using the Cockcroft-Gault formula31: GFR (mL/min) = N x (140 - Age) x weight (kg) serum creatinine (umol/L) where N = 1.04 for females and 1.23 for males Note that the Cockcroft-Gault formula overpredicts CrCl in certain conditions (eg, muscle wasting, obesity, ascites). Lean or ideal body weight may be used to correct for excess fat or fluid.32 Repeat renogram to modify dose if > 20% increase in serum creatinine during treatment.33,34 Calvert AUC-based dosing formula is not recommended with GFR or CrCl < 20 mL/min.

eg, 266-666 mg/m2/day IV for 3 days 200-500 mg/m2/day IV for 4 days 175-400 mg/m2/day IV for 5 days22,35,36 Concurrent with radiation: investigational, 30 mg/m2 IV once daily on days 1-5 in weeks 1-4 has been used as radiosensitizer3

guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression".

CrCl (mL/min) = N x (140 - Age) x weight (kg) serum creatinine (umol/L) where N = 1.04 for females and 1.23 for males adjust subsequent dose according to hematological toxicity to previous

Dosage in dialysis: Hemodialysis: Supplement with 50% of the dose after dialysis.37 In dialysis-dependent chronic renal failure, a fixed dose of 100 mg (previous platinum treatment) or 150 mg (no previous platinum treatment) may be used, with dialysis performed 24 h after carboplatin administration.38

Children: Cycle length: Intravenous: 3-4 weeks: 400 mg/m2 IV once daily for 2 consecutive days starting on day 1 (total dose per cycle 800 mg/m2)39 4 weeks5: 560 mg/m2 IV for one dose on day 1 4 weeks: 80-216 mg/m2 IV once daily for 5 consecutive days starting on day 1 (total dose per cycle 400-1080 mg/m2)5,40 Some investigators calculate carboplatin dose with modified Calvert formula: (GFR is obtained from nuclear renogram.39,41) Dose (mg) = AUC x [(GFR x BSA)/1.73 + (15 x BSA)] where GFR in mL/min/1.73 and AUC39,41 = 6-7 or Dose (mg) = AUC x {GFR + [0.36 x weight (kg)]} where AUC6,42 = 2-7 Cycle length:

transplant, eg, 100-800 mg/m2/day IV for 3 days 250-300 mg/m2/day IV for 4 days 250-350 mg/m2/day IV for 5 days5

REFERENCES:

de Lemos ML. Application of the area under the curve of carboplatin in predicting toxicity and efficacy. Cancer Treatment Reviews 1998; 24(6):407-14.

B.C. Cancer Agency Head and Neck Tumour Group. BCCA protocol summary for in-house phase II pilot study using carboplatin with 24-hr 5-fluorouracil infusion (HNCARFU). Vancouver, British Columbia: BC Cancer Agency; 6 January 1998.

Cockcroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41.

B.C. Cancer Agency Gynecology Tumour Group. BCCA protocol summary for primary treatment of invasive epithelial ovarian, fallopian tube and primary peritoneal cancer, with no visible residual tumour (moderate-high risk) (GOOVCATM). Vancouver, British Columbia: BC Cancer Agency; 1 October 1999.

Tonda ME, Heideman RL, Petros WP, et al. Carboplatin pharmacokinetics in young children with brain tumors. Cancer Chemotherapy and Pharmacology 1996; 38(5):395-400.

Wandt H, Birkmann J, Denzel T, et al. Sequential cycles of high-dose chemotherapy with dose escalation of carboplatin with or without paclitaxel supported by G-CSF mobilized peripheral blood progenitor cells: a phase I/II study in advanced ovarian cancer. Bone Marrow Transplantation 1999; 23(8):763-70.

Leukemia/Bone Marrow Transplantation Program of British Columbia. Bone marrow transplant protocol for high-dose chemotherapy with autologous HSCT for high-risk nonseminomatous germ cell tumour (BMT 88-02). Vancouver, British Columbia: BC Cancer Agency; 22 February 2000.

Aronoff GR, Bennet WM, Bernes JS. Drug prescribing in renal failure: dosing guidelines for adults. 4th ed. Philadelphia, Pennsylvania: American College of Physicians; 1999.

Chatelut E, Rostaing L, V G, et al. Pharmacokinetics of carboplatin in a patient suffering from advanced ovarian carcinoma with hemodialysis-dependent renal insufficiency. Nephron 1994; 66(2):157-61.

B.C. Children's Hospital. Children's Cancer Group (CCG) protocol. Vancouver, British Columbia: BC Children's Hospital; 16 June 2001.

Frappaz D, Michon J, Hartmann O, et al. Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study. Journal of Clinical Oncology 1992; 10(10):1592-601.

Mann JR, Raafat F, Robinson K, et al. The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. Journal of Clinical Oncology 2000; 18(22):3809-18.

Bin P, Boddy AV, English MW, et al. The comparative pharmacokinetics and pharmacodynamics of cisplatin and carboplatin in paediatric patients: a review. Anticancer Research 1994; 14(6A):2279-83.

Interpatient variability	2- to 3-fold variability in AUC with BSA-based dosing. 5,6 Variability can be reduced with Calvert AUC-based dosing formula. 6,7
Oral Absorption	poorly absorbed; oral route not used clinically 8
Intraperitoneal Absorption	peak plasma level within 2-4 h after intraperitoneal instillation with 65% of dose absorbed over 4 h of dwelling 2,9
Distribution	widely distributed, mostly in kidney, liver, skin, tumour tissue; also in erythrocytes
	cross blood brain barrier?	yes
	volume of distribution 10	ultrafilterable platinum * : 17 +- 2 L/1.73 m 2
	plasma protein binding	carboplatin: minimal 2,11 platinum: 87%, 2,12
Metabolism	undergoes intracellular hydrolysis to form reactive platinum complexes
	active metabolite(s)	platinum complexes
	inactive metabolite(s)	no information found
Excretion	renal excretion via glomerular filtration; extensively removed by hemodialysis.
	urine	71% within 24 h
	terminal half life	5.8 +- 1.6 days (total platinum *) 1,10 platinum elimination from erythrocytes: 12 days
	clearance	1.38 +- 0.36 L/h/1.73 m 2 (total platinum *) 10
Gender	no information found
Elderly	clearance may be reduced due to age-related renal function impairment 2,11
Children	similar to adults 6,13
Ethnicity	no information found

Primary uses:	Other uses:
Brain tumours 11	Bladder cancer 11
Endometrial cancer 11	Breast cancer 2
Germ cell tumours 11	Cervical cancer 2
Head and neck cancer 2,11	Ewing's sarcoma 5
* Ovarian cancer 1,11	Leukemia, acute lymphocytic 5
Lung cancer, non-small cell 2,11
Lung cancer, small cell 2,11
Lymphoma, non-Hodgkin's 14
Melanoma 11
Neuroblastoma 2,5
Osteosarcoma 5,15
Rhabdomyosarcoma 5
Retinoblastoma 2,5
Testicular cancer 2,11
Wilms' tumour 2

AGENT	EFFECT	MECHANISM	MANAGEMENT
aminoglycosides (eg, amikacin, gentamycin, tobramycin) 2	increased risk of carboplatin nephrotoxicity and ototoxicity	additive	use with caution during concurrent therapy
phenytoin 24,25	decreased serum phenytoin level	possibly decreased absorption or increased metabolism of phenytoin	monitor serum phenytoin level carefully during and after carboplatin therapy; adjust phenytoin dose as needed
warfarin 25,26	increased anticoagulant effect of warfarin	unknown; possibly decreased protein binding or decreased metabolism of warfarin	monitor INR carefully during and after carboplatin therapy; adjust warfarin dose as needed

BCCA administration guideline noted in bold , italics
Subcutaneous	no information found
Intramuscular	no information found
Direct intravenous	no information found
Intermittent infusion	over 30 min; can also be given over 15-60 min 2,12
Continuous infusion 2	over 24 h
Intraperitoneal	investigational, 200-600 mg/m 2 in 2L dialysis fluid and dwell for 4 h 9,29
Intrapleural	no information found
Intrathecal	no information found
Intra-arterial	investigational, 600 mg/m 2 in NS 500 mL infused over 1 h 15
Intravesical	no information found

CrCl (mL/min)	Starting dose (mg/m 2 )
> 60	no dose reduction
41-59	250
16-40	200
<= 15	no information available

SYNONYM(S):

COMMON TRADE NAME(S):

CLASSIFICATION: