Carboplatin

Carboplatin is a platinum-based cytotoxic medicine. Its biochemical properties are similar to those of cisplatin: it damages the DNA of dividing cells, mainly by creating cross-links between and within DNA strands. It has a narrow therapeutic index, and suppression of the bone marrow is the toxicity that limits the dose.

Mechanism of Action

• DNA cross-links: carboplatin binds to DNA and, like cisplatin, produces mainly inter- and intrastrand cross-links.
• Blocked DNA copying: the cross-links stop the two strands from separating, so the DNA cannot be copied or read. When repair enzymes try to correct the damage, the DNA can fragment.
• Genotoxic: carboplatin can also cause mutations. This genotoxic potential is the reason for the contraception advice for men and women during and after treatment.
• Dose-limiting effect: leukopenia, neutropenia and thrombocytopenia are dose-dependent and dose-limiting.

Pharmacokinetics

• Dose–exposure relationship: plasma levels of total platinum and of free ultrafilterable platinum rise in a linear relationship with the dose, and the area under the curve for total platinum is also linear with dose. Repeating the dose on four consecutive days did not make platinum accumulate in plasma.
• Distribution: the apparent volume of distribution is about 16 L after a 30-minute infusion of 300–500 mg/m². Carboplatin itself is not bound to plasma proteins, but platinum released from it binds irreversibly: about 87% of plasma platinum is protein-bound within 24 hours of administration.
• Metabolism: carboplatin is eliminated largely as the unchanged parent compound. Early after the dose, most free ultrafilterable platinum is present as carboplatin itself.
• Elimination: the terminal half-life is about 1.5 hours for carboplatin, about 6 hours for free ultrafilterable platinum and about 24 hours for total plasma platinum. Elimination is mainly renal: about 70% of the administered platinum is recovered in urine within 24 hours, most of it in the first 6 hours. Total body and renal clearance of free ultrafilterable platinum follow the glomerular filtration rate rather than tubular secretion, which is why the dose can be calculated from kidney function (Calvert formula).
• Special populations: in children, carboplatin clearance has been reported to vary 3- to 4-fold, and the literature suggests that kidney function contributes to this variability as it does in adults.

These indications follow the Spanish SmPC used as the source for this page; national product information can differ slightly.

• Advanced ovarian carcinoma of epithelial origin: as first-line treatment (treatment of choice), and as second-line treatment after other treatments have failed.
• Small cell lung cancer: in combination with other chemotherapy.

• Hypersensitivity to carboplatin, to other platinum-containing compounds or to any of the excipients.
• Severe pre-existing renal impairment (creatinine clearance below 30 mL/min), unless the doctor and the patient judge that the possible benefit outweighs the risks.
• Severe myelosuppression.
• Bleeding tumours.
• Concomitant use with the yellow fever vaccine.
• Breastfeeding.

Suppression of the bone marrow is the dose-limiting toxicity. The frequencies below come from a pooled database of 1,893 patients who received carboplatin alone, together with post-marketing experience.

In patients with normal baseline values, platelets fell below 50,000/mm³ in 25%, granulocytes below 1,000/mm³ in 18% and white cells below 2,000/mm³ in 14%, with the lowest counts usually around day 21; haemoglobin fell below 8 g/dL in 15%. Infectious and haemorrhagic complications occurred in 4% and 5% of patients and led to death in under 1%. Vomiting occurs in about 65% of patients (severe in a third of them) and nausea in a further 15%; both usually settle within 24 hours of treatment and generally respond to antiemetics or are prevented by them. Peripheral neuropathy, mainly paraesthesia and reduced tendon reflexes, occurred in about 4% of patients.

Very common (≥1/10): thrombocytopenia, neutropenia, leukopenia, anaemia, vomiting, nausea, abdominal pain, decreased renal creatinine clearance, raised blood urea, alkaline phosphatase and aspartate aminotransferase, abnormal liver function tests, and low blood sodium, potassium, calcium and magnesium.

Common (≥1/100 to <1/10): infections, haemorrhage, hypersensitivity and anaphylactoid reactions, peripheral neuropathy, paraesthesia, reduced tendon reflexes, sensory disturbance, taste disturbance, visual disturbance (rarely loss of vision), ototoxicity, cardiovascular disorders, respiratory disorders, interstitial lung disease, bronchospasm, diarrhoea, constipation, mucosal disorders, alopecia, skin disorders, musculoskeletal disorders, urogenital disorders, asthenia, and raised blood bilirubin, creatinine and uric acid.

Not known: pneumonia, treatment-related secondary malignancies, bone marrow failure, febrile neutropenia, haemolytic uraemic syndrome, dehydration, anorexia, hyponatraemia, tumour lysis syndrome, stroke, posterior reversible encephalopathy syndrome (PRES), heart failure, Kounis syndrome, embolism, hypertension, hypotension, stomatitis, pancreatitis, urticaria, rash, erythema, pruritus, malaise, and necrosis, reaction, extravasation and erythema at the administration site.

Infections, haemorrhage and cardiovascular events (heart failure, embolism and stroke combined) were fatal in under 1% of patients. Serious reactions to watch for include severe myelosuppression with infection or bleeding, haemolytic anaemia (which can be fatal), haemolytic uraemic syndrome, hypersensitivity reactions that may progress to Kounis syndrome, PRES, veno-occlusive liver disease, tumour lysis syndrome and hearing loss. Acute promyelocytic leukaemia and myelodysplastic syndrome or acute myeloid leukaemia have been reported years after treatment.

The interactions below are those listed in the SmPC, plus a herbal product named in DrugBank.

• Yellow fever vaccine (contraindicated): risk of fatal generalised vaccine disease.
• Other live attenuated vaccines (not recommended): risk of systemic, possibly fatal disease, greater in people already immunosuppressed by their underlying disease. Use an inactivated vaccine where one exists (for example against poliomyelitis).
• Phenytoin and fosphenytoin (not recommended): risk of worsening seizures because the cytotoxic medicine reduces absorption of phenytoin from the gut, or risk of toxicity or loss of efficacy of the cytotoxic medicine because phenytoin increases its metabolism in the liver.
• Complex-forming compounds (avoid): in theory they can reduce the anti-tumour effect of carboplatin. In animal and clinical studies, however, diethyldithiocarbamate did not alter its effect.
• Ciclosporin, and by extrapolation tacrolimus and sirolimus (to be taken into account): excessive immunosuppression with a risk of lymphoproliferation.
• Nephrotoxic and ototoxic medicines (for example aminoglycoside antibiotics and loop diuretics): cumulative kidney and ear toxicity, particularly in patients with kidney impairment.
• Other myelosuppressive medicines: myelosuppression is made worse when carboplatin is combined with them.
• Oral anticoagulants: anticoagulants are often used in cancer because of the higher risk of thrombosis. Clotting varies widely within the same patient during illness and may interact with chemotherapy, so the INR should be monitored more often.
• Echinacea: avoid.

Carboplatin must be given only by physicians experienced in cancer chemotherapy, and only intravenously, as a short infusion of 15 to 60 minutes. The concentrate may be diluted with 5% glucose or 0.9% sodium chloride solution for injection, to a concentration as low as 0.5 mg/mL. Blood counts and kidney and liver function are checked regularly, and treatment is stopped if bone marrow depression or kidney or liver function becomes abnormal.

Recommended Dose

• Adults not previously treated, with normal kidney function: 400 mg/m² as a single intravenous dose, infused over 15 to 60 minutes.
• Repeat cycles: not before four weeks after the previous carboplatin dose, and not until the neutrophil count is at least 2,000 cells/mm³ and the platelet count at least 100,000 cells/mm³.
• Dose increase: if neutrophils and platelets stay above 2,000 and 100,000/mm³ respectively (no haematological toxicity), the dose may be increased by 25%, alone or in combination (for example with cyclophosphamide).
• Dose reduction: reduce the starting dose by 20–25% in patients with risk factors such as earlier myelosuppressive treatment or poor general condition (ECOG-Zubrod 2–4, or Karnofsky below 80).
• Blood counts: weekly counts during the first cycles show the lowest point (nadir) and guide the dose in the following cycles.

Dosing by Target AUC (Calvert Formula)

• Principle: the starting dose can also be calculated with the Calvert formula, which is based on kidney function (glomerular filtration rate, GFR). It lowers the risk of under- or overdosing caused by individual differences in kidney function.
• Formula: total dose (mg) = target AUC × (GFR + 25), with GFR in mL/min. The result is in mg, not mg/m².
• Target AUC: 5–7 mg/mL·min for carboplatin alone in patients not previously treated; 4–6 mg/mL·min for carboplatin alone in previously treated patients; 4–6 mg/mL·min for carboplatin plus cyclophosphamide in patients not previously treated.
• Not to be used after intensive earlier treatment with mitomycin C, a nitrosourea, the combination doxorubicin/cyclophosphamide/cisplatin, a combination of five or more cytostatic medicines, or radiotherapy of about 5,000 rad or more to a 20 × 20 cm area or several areas.

Renal Impairment

• Patients with creatinine clearance below 60 mL/min are at high risk of severe myelosuppression. With the doses below, severe leukopenia, neutropenia or thrombocytopenia stayed at about 25%.
• Creatinine clearance 41–59 mL/min: starting dose 250 mg/m² intravenously on day 1.
• Creatinine clearance 16–40 mL/min: starting dose 200 mg/m² intravenously on day 1.
• There are not enough data at a creatinine clearance of 15 mL/min or less to recommend a dose.
• These doses apply to the first cycle. Later doses are adjusted to the patient’s tolerance and an acceptable degree of myelosuppression. Frequent monitoring of blood count nadirs, electrolytes and kidney function is needed.

Other Groups

• Combination therapy: with other myelosuppressive medicines, the dose must be adjusted to the regimen used.
• Elderly (over 65 years): the dose has to be adjusted in the first and in later cycles.
• Paediatric population: there is not enough information to recommend a dose.

Preparation and Handling

• Do not use needles or intravenous sets that contain aluminium parts for preparation or administration: aluminium reacts with carboplatin, forming a precipitate and/or causing loss of potency.
• Carboplatin is a hazardous substance. It must be prepared by trained personnel wearing protective gloves, a mask and protective clothing, following the safety measures for hazardous substances.
• The vial is for single use.

Supervision and Monitoring

Only physicians experienced in cancer chemotherapy should give carboplatin. Blood counts and kidney and liver function tests are done regularly, and the medicine is stopped if abnormal bone marrow depression or abnormal kidney or liver function appears.

Bone Marrow Suppression and Infection

• Leukopenia, neutropenia and thrombocytopenia are dose-dependent and dose-limiting. Peripheral blood counts are checked frequently, and until recovery after any toxicity. The lowest counts occur on average on day 21 with carboplatin alone and on day 15 in combination with other chemotherapy.
• A single cycle should not be repeated until white cell, neutrophil and platelet counts are back to normal, and not before 4 weeks after the previous cycle.
• Anaemia is common and cumulative and only very rarely needs a transfusion. Haemolytic anaemia with drug-induced serological antibodies has been reported and can be fatal.
• Myelosuppression is more severe in patients who have had earlier treatment (particularly cisplatin) or who have kidney impairment. Their starting doses are reduced and counts are checked often between cycles. Combinations with other myelosuppressive treatment must be planned carefully to limit additive effects.
• Severe, persistent myelosuppression carries a high risk of infection, including fatal outcomes. Dosing is interrupted and a dose change or stop is considered.

Nausea and Vomiting

Carboplatin can cause nausea and vomiting. Antiemetic premedication reduces how often and how severe they are.

Haemolytic Uraemic Syndrome

This is a potentially fatal adverse effect. Carboplatin is stopped at the first sign of microangiopathic haemolytic anaemia, such as a rapid fall in haemoglobin with thrombocytopenia and a rise in serum bilirubin, creatinine, blood urea nitrogen or LDH. Kidney failure may not reverse after stopping, and dialysis may be needed.

Hypersensitivity Reactions

As with other platinum medicines, allergic reactions can occur, most often during the infusion. The infusion is stopped and appropriate symptomatic treatment given. Cross-reactions, sometimes fatal, have been reported between platinum compounds. Hypersensitivity reactions that progressed to Kounis syndrome (acute allergic coronary artery spasm that can cause a myocardial infarction) have been reported.

Kidney Function

In patients with kidney impairment the effect of carboplatin on the blood-forming system is more pronounced and lasts longer, so treatment in this group needs special caution.

Nervous System and Vision

• Peripheral neurotoxicity is usually mild (paraesthesia, reduced tendon reflexes), but it is more frequent in patients over 65 and in those previously treated with cisplatin. Neurological monitoring and examination at regular intervals are advised.
• Visual disturbances, including loss of vision, were reported after doses above those recommended in patients with kidney impairment. Vision appears to recover fully or largely within weeks of stopping such high doses.
• Posterior reversible encephalopathy syndrome (PRES) has been reported in patients on combination chemotherapy. It is a rare, fast-developing neurological condition, reversible after treatment stops, that can include seizures, hypertension, headache, confusion, blindness and other visual and neurological disturbances. The diagnosis is confirmed by brain imaging, preferably MRI.

Hearing

Hearing defects have been reported. Ototoxicity can be more pronounced in children, and delayed-onset hearing loss has been reported in paediatric patients, for whom audiometric follow-up is recommended.

Liver and Tumour Lysis Syndrome

• Veno-occlusive liver disease (sinusoidal obstruction syndrome), some cases fatal, has been reported. Patients are monitored for signs and symptoms of abnormal liver function or portal hypertension that do not clearly result from liver metastases.
• Tumour lysis syndrome has been reported after marketing, with carboplatin alone or in combination. Patients at high risk (rapidly proliferating tumours, high tumour burden, high sensitivity to cytotoxic agents) are monitored closely and given appropriate precautions.

Older Patients

In studies of carboplatin with cyclophosphamide, older patients were more likely to develop severe thrombocytopenia than younger ones. Kidney function is often reduced in older people and must be considered when setting the dose.

Vaccines

Live or live-attenuated vaccines given to patients made immunocompromised by chemotherapy, including carboplatin, can cause serious or fatal infections, so live vaccines should be avoided. Killed or inactivated vaccines can be given, but the response may be reduced.

Pregnancy, Breastfeeding and Fertility

• Contraception: because of its genotoxic potential, women of childbearing potential must use effective contraception during treatment and for 6 months after it ends. Men should use effective contraception and not father a child during treatment and for 3 months afterwards.
• Pregnancy: carboplatin can cause foetal harm. It was embryotoxic and teratogenic in rats treated during organogenesis, and there are no controlled studies in pregnant women. A patient who is or becomes pregnant must be told of the potential risk to the foetus, and a genetic examination should be carried out. Women of childbearing potential should be advised to avoid becoming pregnant.
• Breastfeeding: contraindicated. Carboplatin and/or its metabolites pass into breast milk to an extent likely to affect newborns and infants, so breastfeeding must be stopped during treatment.
• Fertility: gonadal suppression resulting in amenorrhoea or azoospermia can occur with anti-cancer therapy. The effects appear related to dose and duration of treatment and may be irreversible.

Effect on Driving

No studies on the ability to drive and use machines have been done. Carboplatin can cause nausea, vomiting, visual abnormalities and ototoxicity, so patients should be warned that these events may affect driving or using machines.

Do not store the unopened vials above 25 °C, and keep the vial in the outer carton. The vials do not need refrigeration, but they are cytotoxic medicines and are stored and handled under the hospital’s rules for hazardous medicines.

After dilution with 5% glucose or 0.9% sodium chloride solution to concentrations as low as 0.5 mg/mL, the solution is used within 3 hours when kept at room temperature (15–25 °C) and protected from light, or within 24 hours when kept at 2–8 °C, provided the dilution was made under validated aseptic conditions.

2 years in the unopened vial. Once opened, the product must be used immediately; the vial is for single use. If the product is diluted under validated aseptic conditions and cannot be used at once, it may be kept for 24 hours at most at 2–8 °C.

Prescription only (Rx). Carboplatin is a cytotoxic medicine that may be given only by physicians experienced in cancer chemotherapy, as an intravenous infusion in a hospital or specialist cancer unit. It is supplied to the hospital or clinic that administers it, where trained staff prepare it with protective equipment.