Carboplatin - Drug Monograph

Introduction

Carboplatin is a second-generation platinum-containing alkylating-like antineoplastic agent widely used in oncology practice. As an analog of cisplatin with a more favorable toxicity profile, carboplatin has become a cornerstone in the treatment of various solid tumors. It was first approved by the FDA in 1989 and remains an essential component of many chemotherapy regimens due to its predictable toxicity and dosing based on renal function.

Mechanism of Action

Carboplatin exerts its cytotoxic effects through formation of DNA adducts, similar to other platinum compounds. After intracellular activation, carboplatin forms reactive platinum complexes that covalently bind to nucleophilic sites on DNA, primarily at the N7 position of guanine and adenine residues. This binding creates primarily intrastrand crosslinks and some interstrand crosslinks, resulting in DNA distortion and inhibition of DNA replication and transcription. The resulting DNA damage triggers apoptosis (programmed cell death) in rapidly dividing cancer cells. Carboplatin is cell cycle non-specific but is most active against proliferating cells.

Indications

FDA-approved indications:

• Advanced ovarian carcinoma (first-line and subsequent therapy)
• Palliative treatment of recurrent ovarian cancer

Common off-label uses (supported by NCCN guidelines and clinical evidence):

• Non-small cell lung cancer (NSCLC)
• Small cell lung cancer
• Head and neck cancers
• Bladder cancer
• Cervical cancer
• Endometrial cancer
• Germ cell tumors
• Pediatric tumors (including neuroblastoma, retinoblastoma)

Carboplatin is typically used in combination regimens with other chemotherapeutic agents, most commonly with paclitaxel for ovarian and lung cancers.

Dosage and Administration

• Target AUC dosing: 4-6 mg/mL•min (most common: AUC 5-6)
• Calvert formula: Dose (mg) = Target AUC × (GFR + 25)
• GFR is ideally measured by 51Cr-EDTA method; alternatively, calculated using Cockcroft-Gault formula

• 300-400 mg/m² every 4 weeks
• 100 mg/m² daily for 5 days every 4 weeks

• Route: Intravenous infusion only
• Duration: 15-60 minute infusion
• Dilution: In 5% dextrose or 0.9% sodium chloride
• Concentration: Typically 0.5-10 mg/mL

• Renal impairment: Dose reduction required (use Calvert formula)
• Hepatic impairment: No specific recommendations (limited data)
• Elderly: Consider reduced dose due to decreased renal function
• Pediatrics: AUC-based dosing recommended

Pharmacokinetics

• Volume of distribution: 16-22 L
• Protein binding: Minimal (<10%)
• Rapid distribution to tissues with preferential accumulation in kidney, liver, and tumor tissue
• Poor CNS penetration

• Minimal hepatic metabolism
• Undergoes non-enzymatic transformation to active species
• Reacts with water and other nucleophiles to form active platinum complexes

• Primary route: Renal excretion (60-90% within 24 hours)
• Half-life: Terminal half-life 2.6-5.9 hours
• Total body clearance correlates strongly with glomerular filtration rate
• Elimination follows first-order kinetics

Contraindications

• History of severe hypersensitivity to carboplatin, cisplatin, or other platinum compounds
• Severe bone marrow suppression (pre-existing)
• Severe bleeding
• Pregnancy (unless potential benefit justifies potential risk)
• Breastfeeding

Warnings and Precautions

• Thrombocytopenia: Most significant effect (nadir 14-21 days)
• Neutropenia: Common but generally less severe than with cisplatin
• Anemia: Cumulative effect with repeated cycles

• Usually occur within minutes of administration
• May include bronchospasm, hypotension, urination, facial flushing

• Monitor renal function before each cycle
• Hydration not required as with cisplatin

• Peripheral sensory neuropathy possible
• Ototoxicity rare

Drug Interactions

Adverse Effects

• Thrombocytopenia (dose-limiting)
• Leukopenia/neutropenia
• Anemia
• Nausea/vomiting (less severe than cisplatin)
• Asthenia/fatigue
• Alopecia

• Elevated liver enzymes
• Peripheral neuropathy
• Constipation/diarrhea
• Anorexia
• Taste alteration
• Hypomagnesemia

• Anaphylactic reactions
• Hemolytic uremic syndrome
• Vision changes
• Interstitial lung disease
• Secondary leukemia

Monitoring Parameters

• Complete blood count with differential
• Renal function (serum creatinine, calculated GFR)
• Electrolytes (magnesium, potassium, sodium)
• Liver function tests

• Vital signs (especially for first-time exposure)
• Signs of hypersensitivity

• Neurological examination (for neuropathy)
• Audiometric testing (if symptomatic)
• Signs of bleeding or infection

• Secondary malignancies
• Renal function recovery

Patient Education

• Explain that treatment is given intravenously every 3-4 weeks
• Describe the infusion process and expected duration

• Report signs of infection (fever >38°C, chills) immediately
• Watch for bleeding tendencies (bruising, petechiae, bleeding gums)
• Manage nausea with prescribed antiemetics
• Maintain adequate hydration unless contraindicated

• Use reliable contraception during and for several months after treatment
• Do not breastfeed during treatment
• Practice good oral hygiene to prevent mucositis
• Avoid crowds and people with infections when blood counts are low

• Keep all scheduled blood tests and appointments
• Report any new or worsening symptoms promptly
• Carry identification indicating chemotherapy treatment

References

1. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7(11):1748-1756. 2. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Various cancer sites. 2023. 3. Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol. 1999;17(1):409-422. 4. Package Insert. Carboplatin injection. Various manufacturers. 2023. 5. McEvoy GK, ed. AHFS Drug Information. American Society of Health-System Pharmacists; 2023. 6. Egorin MJ. Cancer pharmacology and carboplatin dosing. Cancer Treat Rev. 1993;19 Suppl C:41-53. 7. FDA Approved Drug Products: Carboplatin injection labeling. 8. American Society of Clinical Oncology (ASCO) guidelines for various cancer types.