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CARBOplatin
Carboplatin is a cisplatin derivative and shares the same mechanism of action. Highly reactive platinum complexes are formed intracellularly. These complexes inhibit DNA synthesis through covalent binding of DNA molecules to form intrastrand and interstrand DNA crosslinks. Carboplatin is considered to be cell cycle phase-nonspecific, but recent studies have shown complex and variable effects on the cell cycle.
Intraperitoneal: 65% after a 4-hour dwell period.
Widely distributed, highest concentration in liver, kidney and skin. Pharmacokinetics are dose proportional. No apparent accumulation with repeated daily dosing, after 4 days.
| Cross blood brain barrier? |
Yes; Low concentrations |
| PPB | 87% within 24 h (platinum-containing products) |
Carboplatin is hydrolyzed to aquated and hydroxylated compounds
| Active metabolites | Platinum complexes |
| Inactive metabolites | No information found |
Primarily renal via glomerular filtration, clearance correlates with glomerular filtration rate.
| Urine | 70% as carboplatin |
| Half-life | total plasma platinum: 24 hours |
| Half-life | free plasma platinum: 6 hours |
| Half-life | carboplatin: 1.5 hours |
| Half-life | total platinum from erythrocytes: 12 days |
- For the treatment of ovarian cancer of epithelial origin in first-line therapy or second-line therapy after other treatments have failed.
Other Uses:
- Brain and CNS tumours
- Breast cancer
- Neuroendocrine Tumours
- Bladder cancer
- Gynecological cancers: endometrial, fallopian tube, cervical, vulvar, primary peritoneal, sarcoma
- Lung cancer: small cell, non-small cell
- Testicular cancer
- Anal cancer
- Colorectal cancer
- Gastroesophageal cancer
- Hepatobiliary cancer
- Pancreatic cancer
- Prostate cancer
- Head and Neck cancer
- Mesothelioma
- Thymoma
- Thyroid cancer
- Melanoma
- Merkel cell cancer
- Cancer of unknown primary origin
- Cutaneous squamous cell cancer
- Part of combination therapy for lymphomas
Emetogenic Potential:
Moderate (Carboplatin AUC < 5)
Extravasation Potential: None
The following table contains adverse effects reported with single agent carboplatin in the product monograph. It also includes severe, life-threatening and post-marketing adverse effects from other sources.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Auditory | Hearing impaired (15%) | E | |||
| Tinnitus (1%) | E | ||||
| Cardiovascular | Arterial thromboembolism (rare) | E | |||
| Venous thromboembolism (rare) | E | ||||
| Dermatological | Alopecia (2%) | E | |||
| Gastrointestinal | Constipation (3%) | E | |||
| Diarrhea (6%) | E | ||||
| Nausea, vomiting (53%) | I | ||||
| General | Fatigue (11%) (may be severe) | E | |||
| Flu-like symptoms (1%) | E | ||||
| Hematological | Hemolytic anemia (rare) | E | |||
| Hemolytic uremic syndrome (rare) | E | ||||
| Myelosuppression ± infection, bleeding (59%) | E | ||||
| Hepatobiliary | ↑ LFTs (16%) (AST; transient) | L | |||
| Veno-occlusive disease (rare) | E | ||||
| Hypersensitivity | Hypersensitivity (<2%) | I | |||
| Injection site | Injection site reaction (<1%) | I | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (≤37%) (↓Mg 37% ↓K 16%, ↓Ca 5%, ↓Na; may be severe) | E | |||
| Tumor lysis syndrome (rare) | E | ||||
| Neoplastic | Secondary malignancy (rare) | L | |||
| Nervous System | Dysgeusia (<1%) | E | |||
| Encephalopathy (rare) | E | ||||
| Other (5%) (CNS symptoms) | E | ||||
| Peripheral neuropathy (6%) | E | ||||
| Ophthalmic | Other (1%) Visual disturbances | E | |||
| Renal | ↑ BUN (16%) | E | |||
| Creatinine increased (7%) | E | ||||
| Nephrotoxicity (25%) (may be severe) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for CARBOplatin include myelosuppression ± infection, bleeding, nausea, vomiting, abnormal electrolyte(s), nephrotoxicity, ↑ LFTs, ↑ BUN, hearing impairment and fatigue.
Myelosuppression is dose-limiting, especially thrombocytopenia. Myelosuppression may be more pronounced than with cisplatin. Patients with renal dysfunction, receiving nephrotoxic drugs, with poor performance status, the elderly or with prior exposure to cisplatin may experience more prolonged and severe myelosuppression. Anemia may be cumulative and transfusions may be required.
Nausea and vomiting usually occur within 6 to 12 hours after administration and may persist for up to 24 hours or longer. Incidence and severity of vomiting may be reduced by prophylactic antiemetics.
Neurotoxicity is usually limited to paresthesia and decreased deep tendon reflexes, although visual changes and ototoxicity may occur. The incidence and severity of neurotoxicity are less with carboplatin than with cisplatin but severity increases in patients on prolonged therapy, who were previously treated with cisplatin or other nephrotoxic drugs and in elderly patients. Visual disturbances including vision loss has been reported rarely; this is usually reversible when carboplatin is discontinued.
Infusion reactions have been reported in up to 2% of patients who recently started treatment and are receiving carboplatin alone, in 10-12% when given with other agents, and in > 40% of patients who have received several lines of treatment. They vary from mild to severe and may occur within minutes after administration. Reactions are similar to other platinum agents and include rash, fever, pruritis and anaphylaxis. Risk of reaction is increased in patients with previous exposure to platinum therapy; however, exact cross sensitivity with other platinum agents is not known. With appropriate precautions (eg. desensitization and/or antihistamine/steroid prophylaxis etc.) patients with hypersensitivity to carboplatin may tolerate retreatment or switch to other platinum agents; however, recurrent reactions can still occur in some patients and may be severe.
Secondary malignancies: Acute promyelocytic leukemia (APL) and myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) have been reported years after use of combination treatment.
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 myelosuppression. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy, in the elderly or in patients with poor performance status.
Pre-medications (prophylaxis for infusion reactions):
-
There is insufficient evidence that routine prophylaxis with pre-medications reduce infusion reaction (IR) rates.
-
Corticosteroids and H1-receptor antagonists ± H2-receptor antagonists may reduce IR rates for some patients (e.g. gynecological patients with a PFI >12 months or a history of drug allergy who are receiving carboplatin starting from the 7th cycle) but no optimal pre-medication regimen has been established.
Carboplatin dosing by BSA does not take into account renal function, which may result in overdosing (i.e. in patients with poor renal function) or underdosing (i.e. in patients with above average renal function). Alternative methods that consider the area under the curve (AUC) and the direct relationship between glomerular filtration and carboplatin clearance are more commonly used to calculate carboplatin dose.
Calvert Formula:
Dose (mg) = Target AUC (mg/mL per min) x [CrCl† (mL/min) + 25]
(See "References - Appendix" section)
†Note: Serum creatinine measured by Isotope Diluted Mass Spectrometry (IDMS) is a standardized and more accurate measure of creatinine compared to older laboratory methods, which overestimated serum creatinine values when values were low. However, the IDMS method generally produces lower serum creatinine levels in patients with normal renal function, which could result in an overestimation of the calculated creatinine clearance (CrCl) and the estimated GFR, in these patients, compared to previous methods. A Calvert formula-calculated carboplatin dose, based on estimated GFR using IDMS serum creatinine, could be higher than desired and result in increased toxicity.
To avoid toxicity, FDA recommends capping the carboplatin dose for a desired AUC. The maximum dose is based on a capped GFR estimate at 125 mL/min for patients with normal renal function:
Maximum Carboplatin Dose (mg) = target AUC (mg/mL per min) x (125 mL/min + 25)
For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg
For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg
For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg
(See FDA communication on carboplatin dosing)
Modify according to protocol by which patient is being treated.
Below are suggested dose modifications.
|
Toxicity / Counts (x 109/L) |
Dose Modification |
|
ANC < 1.5 but ≥ 0.5 and/or Platelets < 100 but ≥ 25 |
Hold#; may consider dose ↓ at restart |
|
Febrile Neutropenia OR ANC < 0.5 for ≥ 5-7 days OR Platelets < 25 |
Hold# Restart by ↓ 25% |
|
Grade 3 related organ / non-hematologic |
Hold# Restart by ↓ 25% |
|
Grade 4 related organ / non- hematologic |
Discontinue |
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
There is insufficient evidence that routine prophylaxis with extended infusion reduces IR rates.
| Grade | Management | Re-challenge |
| 1 or 2 |
Restart:
|
|
| 3 or 4 |
|
|
* Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2-receptor antagonist
No dose adjustment required.
|
Creatinine Clearance (ml/min) |
Carboplatin (% previous dose)
|
|
20 - 50 |
Use Calvert formula
|
|
< 20 |
Discontinue
|
Caution should be exercised and dose reduction considered as elderly patients may have reduced renal function, more severe myelosuppression and neuropathy.
Safety and efficacy have not been systematically studied.
- Mix in 100mL to 250mL bag (5% Dextrose or Normal Saline); infuse IV over 15 to 60 minutes.
- There is insufficient evidence that routine prophylaxis with extended infusion reduces IR rates.
- Incompatible with sets, needles or syringes containing aluminum – leads to precipitation and loss of potency.
- Protect from light.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- Patients who have a severe allergic reaction to this drug or other platinum-containing compounds
- Patients with pre-existing severe renal impairment
- Patients with severe myelosuppression or bleeding tumours
- Patients with abnormal renal function or who are receiving concomitant nephrotoxic drugs
- Patients who have received extensive prior treatment, have poor performance status and those over 65 years of age
- Avoid live vaccines. Reduced immunogenicity may occur with the use of inactivated vaccines.
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Embryotoxicity:
Yes
-
Teratogenicity:
Yes
Carboplatin is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation).
-
Excretion into breast milk:
Probable
Breastfeeding is not recommended. -
Fertility effects:
Unknown
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Aminoglycosides | Exacerbates nephro- and ototoxicity | Additive | Monitor |
| Phenytoin | ↓ serum phenytoin level | possibly ↓ absorption or increased metabolism of phenytoin | Monitor serum phenytoin level; ↑ dose of phenytoin if necessary |
| Other nephrotoxic drugs | ↑ incidence of renal dysfunction | Additive | Monitor closely |
| Warfarin | Risk of ↑ INR or bleeding | Unknown | Monitor INR and adjust warfarin dose accordingly |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Renal function tests, including electrolytes |
Baseline and before each cycle |
CBC |
Baseline and before each cycle |
Clinical toxicity assessment for neurotoxicity, ototoxicity, hypersensitivity, bleeding, infection, nausea and vomiting |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and as clinically indicated |
| INR | Baseline and as clinically indicated |
Product Monograph: Carboplatin Injection BP. Pfizer Canada., December 31, 2018
Lexicomp drug monograph: Carboplatin. Access January 18, 2019.
Product Monograph: Carboplatin Injection. Novopharm Limited., November 16, 2004
Drug Monograph: Carboplatin. BC Cancer Agency Cancer Drug Manual. Revised January 1, 2014.
Calvert AH. Dose optimisation of carboplatin in adults. Anticancer Res 1994; 14(6A): 2273-8.
U.S. Food and Drug Administration, Center for Drug Evaluation and research. Carboplatin dosing. 10 October 2010
Markman M, Kennedy A, Webster K, et al. Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 1999; 17: 1141-5.
McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 963-71.
Micromedex 2.0. Truven Health Analytics Inc, 2014.
Product Monograph: Carboplatin Injection. Hospira Healthcare Corp., July 17, 2014.
Sliesoraitis S, Chikhale PJ. Carboplatin hypersensitivity. Int J Gynecol Cancer 2005; 15: 13-8.
van der Vijgh WJ. Clinical pharmacokinetics of carboplatin. Clin Pharmacokinet 1991;21(4)242-61.
Appendix:
Calvert Formula:
Dose (mg) = Target AUC (mg/mL per min) x {CrCl (mL/min)+ 25}
Refer to regimen for target AUC.
(see Creatinine Clearance Calculation)
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: 1748-56.
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