Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
CISplatin
Cisplatin is biochemically similar to bifunctional alkylating agents as it inhibits DNA synthesis through covalent binding leading to intrastrand, interstrand, and protein cross-linking causing apoptosis. It is cell cycle phase-nonspecific and based on animal studies, may increase the host immune response.
Well distributed with highest levels in kidney, liver and prostate. Accumulation of free (ultrafilterable) platinum in plasma can potentially occur when cisplatin is administered on a daily basis. Platinum has been detected in many tissues for up to 6 months after the last dose.
| Cross blood brain barrier? | Not readily |
| PPB |
Cisplatin: not significantly |
Non-enzymatically transformed to multiple metabolites.
| Active metabolites |
Yes |
| Inactive metabolites | Yes |
Renal clearance is non-linear and depends on dose, urine flow rate, individual variations in tubular secretion and reabsorption.
| Urine |
>90%; 10-40% (platinum) in 24 hours |
| Half-life |
Cisplatin: 20-30 minutes |
- Bladder cancer
- Ovarian cancer
- Testicular cancer
Refer to the product monograph for a full list and details of approved indications
Other Uses:
- Gynecological cancers (cervical, endometrial, uterine sarcoma, gestational trophoblastic disease)
- Penile cancer
- Head and neck cancer
- Lung cancer (small cell; non-small cell; mesothelioma)
- GI cancers (anal, esophageal, gastric, biliary cancers)
- Adrenocortical cancer
- Neuroendocrine tumours
- Thymoma
- Bladder (combination chemotherapy)
- Non-Hodgkin's or Hodgkin's lymphoma
- Breast cancer
- Skin cancer
- Small cell carcinoma
- Osteogenic sarcoma
- Soft tissue sarcoma
- Merkel cell cancer
- CNS cancer
- Unknown primary
Emetogenic Potential:
High (≥ 70 mg/m2)
Extravasation Potential: Irritant
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Auditory | Hearing impaired (31%) | D | |||
| Cardiovascular | Arterial thromboembolism (rare) | E | |||
| Conduction disorder (left bundle branch block, rare) | I E | ||||
| Venous thromboembolism (<10%) | E | ||||
| Dermatological | Alopecia (mild; infrequent) | E | |||
| Rash (infrequent) | I E | ||||
| Gastrointestinal | Anorexia | E | |||
| Diarrhea | E | ||||
| Mucositis (rare) | E | ||||
| Nausea, vomiting (100%) (early and delayed) | I E | ||||
| General | Fatigue | E | |||
| Hematological | Hemolysis (Coombs positive) | E | |||
| Hemolytic uremic syndrome (rare) | E | ||||
| Myelosuppression ± infection, bleeding (30%) (may be severe; including anemia) | E | ||||
| Thrombotic microangiopathy (rare) | E | ||||
| Hepatobiliary | ↑ Amylase (infrequent) | E | |||
| ↑ LFTs (transient) | E | ||||
| Hypersensitivity | Hypersensitivity (including anaphylaxis - rare) | I | |||
| Injection site | Injection site reaction (<10%) | I | |||
| Other - Soft tissue toxicity (if extravasated) (rare) | I E | ||||
| Metabolic / Endocrine | Abnormal electrolyte(s) (↓ Mg (40-90%), Na (up to 43%), K, Ca, PO4) | E | |||
| Hyperuricemia | I E | ||||
| SIADH (rare) | D | ||||
| Musculoskeletal | Musculoskeletal pain | E | |||
| Neoplastic | Secondary malignancy (rare) | L | |||
| Nervous System | Dysgeusia | E | |||
| Leukoencephalopathy (rare) | E D | ||||
| Neurotoxicity (peripheral - approximately 50%, autonomic, myelopathy, vestibular toxicity, slurred speech, memory loss) | D | ||||
| Optic neuritis (rare) | E | ||||
| Posterior reversible encephalopathy syndrome (PRES) (rare) | E | ||||
| Seizure (rare) | D | ||||
| Ophthalmic | Eye disorders (including papilledema, blurred vision, cerebral blindness, altered colour perception - rare) | D | |||
| Renal | Nephrotoxicity (36%) | I E | |||
| Reproductive and breast disorders | Infertility | L | |||
| Respiratory | Hiccups (infrequent) | E | |||
| Other - Pulmonary toxicity (in combination with bleomycin or 5-fluorouracil) | E | ||||
| Vascular | Peripheral ischemia (Raynaud's syndrome - rare, with bleomycin, vinblastine ± cisplatin) | D | |||
| Vasculitis (cerebral arteritis- rare) | 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 cisplatin include nausea, vomiting, abnormal electrolytes (Mg, Na), nephrotoxicity, hearing impaired and myelosuppression ± infection.
Anaphylactic reactions consisting of facial edema, wheezing, flushing, tachycardia, or hypotension, and may be severe. These usually occur in patients with prior exposure to cisplatin (e.g. at least 5 doses), but can also occur after the first dose within a few minutes of drug administration.
Aortic thrombosis has been reported and may be fatal. Some cases were identified after the last dose of cisplatin. Possible confounding factors in the Canadian reported cases included a higher coagulation state associated with the malignancy, and other known risk factors such as smoking, obesity and previous history of vascular disease (e.g. TIA). Some of these cases stabilized or resolved after starting anticoagulation or thrombectomy.
The relative risk of venous thromboembolism (VTE) was 1.67-fold higher in advanced solid tumour patients treated with cisplatin-based therapies versus those treated with non-cisplatin therapies (Seng 2012). Patients receiving an equivalent weekly dose greater than 30 mg/m2 were at higher risk.
Hyperuricemia has been reported with cisplatin and more pronounced at doses greater ≥ 50 mg/m2. Peak levels of uric acid generally occur between 3-5 days after the dose.
Severe myelosuppression including fatalities due to infection (secondary to myelosuppression) have been reported. Nadirs in circulating platelets and leukocytes occur after about 2 weeks with levels returning to pre-treatment values in most patients within 4 weeks. Leukopenia and thrombocytopenia are dose-related and may become clinically relevant in patients receiving high doses of cisplatin or in patients who have received prior myelosuppressive treatments.
The major dose-limiting toxicity of cisplatin is cumulative nephrotoxicity. Tubular necrosis or degeneration of both proximal and distal renal tubules may occur. Although reversible, effects are cumulative. They occur in 28-36% of patients treated with a single dose of 50mg/m2. Renal toxicity may be permanent with high doses or prolonged treatment. Nephrotoxicity can be minimized or prevented by IV hydration.
Renal tubular abnormality such as acidosis, hypomagnesemia, hypocalcemia, hypophosphatemia, hyponatremia or hypokalemia may be present with normal glomerular function. Hypomagnesemia may become severe enough to cause tetany; it usually develops within 3-4 weeks after starting treatment and appears to increase in severity with subsequent treatment courses. Hypomagnesemia may persist for greater than one year following treatment. Children are particularly at risk.
Cisplatin produces moderate to severe nausea and vomiting in virtually all patients. Nausea and vomiting may start within one hour and may persist for more than 24 hours after chemotherapy. Tolerance may improve with 5-day continuous infusion as compared to rapid, intermittent IV administration. Various degrees of nausea and anorexia may persist for up to 1 week, even with well-controlled acute nausea and vomiting. The use of prophylactic and continuing antiemetic medication is recommended.
Neurotoxicity consists of peripheral neuropathy, which is sensory in nature in a stocking-glove distribution, but can also include motor effects, reduced deep-tendon reflexes, loss of proprioception and vibratory sensation. Symptoms usually occur after prolonged therapy (4-7 months) or high dose treatment and may be irreversible in some patients. Symptoms usually develop during treatment but rarely may begin after the last dose of cisplatin. Seizures, altered taste, slurred speech, and memory loss have occurred rarely. Sudden onset of muscle cramps have been reported, and are usually observed in patients with a high cumulative cisplatin dose and with relatively severe peripheral neuropathy.
Optic neuritis, papilledema and cerebral blindness are infrequent at standard cisplatin doses; they usually recover after cisplatin discontinuation. Blurred vision and altered colour perception have occurred at higher cisplatin doses or at greater dose frequencies than recommended.
Ototoxicity usually results in impairment of acuity in the high frequency range, but may affect the normal hearing range in 6% of cases. Ototoxicity is cumulative, dose-related and generally irreversible. Ototoxicity appears to be related to peak levels of cisplatin, as significant hearing loss has been reported with single high doses. Cranial irradiation may lower the cumulative dose at which cisplatin will cause hearing loss. Vestibular ototoxicity is rare, but the risk may increase with cumulative dosage.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
All patients should receive adequate hydration and premedication for emesis, according to local guidelines.
|
Frequency
|
Schedule
|
Dose
|
|
Q3-4 weekly
|
Day 1
|
50-75* mg/m2
|
|
Day 1-5
|
15-20 mg/m2
|
* A higher dose has been used for some curative regimens.
|
Worst Toxicity in Previous Cycle |
Dose for Next Cycle*
|
|
Grade 4 platelets, grade 4 ANC ≥ 5 days, thrombocytopenic bleeding or febrile neutropenia |
↓ 25%
|
|
Grade 2 neurotoxicity /ototoxicity |
↓ 25% or discontinue depending on risk-benefit
|
|
Grade 3 or 4 neurotoxicity/ototoxicity
|
Discontinue
|
|
Other grade 3 non-hematologic/organ toxicity |
↓ 25%
|
|
Other grade 4 non-hematologic/organ toxicity
|
Discontinue
|
|
Hemolysis, optic neuritis, arterial or venous thromboembolism, grade 3 or 4 ↑ LFTs, PRES, leukoencephalopathy |
Discontinue
|
|
* Do not retreat until platelets ≥100 x 109/L, ANC ≥ 1.5 x 109/L, toxicity has recovered to ≤ grade 2 (grade 1 for neurotoxicity) and creatinine ≤ ULN. |
|
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 adjustment required.
Refer to specific protocol.
A repeat course of Cisplatin should not be given until creatinine is ≤ ULN. If continued treatment is considered to be mandatory, the following dose modifications could be considered at the physician's discretion (Kintzel 1995).
|
Creatinine Clearance
|
% Previous Dose
|
|
46-60
|
75%
|
|
30-45
|
50%*
|
|
<30
|
Discontinue
|
* if clinically appropriate, consider discontinuing or using alternative (i.e. carboplatin).
Geriatric patients may be at higher risk of developing nephrotoxicity, ototoxicity/neurotoxicity or hematologic adverse effects with cisplatin.
Refer to protocol by which patient is being treated. May be at higher risk of ototoxicity (including delayed-onset cases).
-
Cisplatin is physically incompatible with any IV set, needle or syringe containing aluminum.
-
Drug dilution and infusion durations vary according to the regimen. Some centres dilute cisplatin in 500 to 1000 mL of NS, depending on the dose.
-
All patients should receive adequate hydration and premedication for emesis, according to local guidelines.
-
Additional hydration may be ordered for hypovolemic patients.
-
Hydration and diuresis for patients with pre-existing renal, cardiac, or diabetic history at discretion of physician.
-
Adequate hydration and urinary output must be maintained for 24 hours following cisplatin treatment.
-
Oral hydration with 8 glasses of fluid per day is strongly encouraged on treatment day and for 1-2 days after cisplatin; if nausea and vomiting prevent oral hydration, the patient may need to return for more IV hydration.
-
Store unopened vials between 15°C to 25°C and protect from light. Do not refrigerate or freeze since precipitation will occur.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
-
Patients with known severe hypersensitivity to platinum containing compounds
-
Patients who are myelosuppressed
-
Patients with pre-existing renal impairment and hearing impairment, unless the possible benefits of treatment outweigh the risks
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Mutagenicity:
Yes
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
-
Teratogenicity:
Yes
-
Crosses placental barrier:
Yes
Cisplatin is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 26 weeks (in females) and 14 weeks (in males) after the last dose.
For patients with end-stage renal disease, adequate contraception should be used during treatment, and for 31 weeks (in females) and 19 weeks (in males) after the last dose, due to a longer cisplatin washout period.
Male patients should not donate semen while using cisplatin and up to 2 years after the last dose.
-
Breastfeeding:
Not recommended
Cisplatin is secreted into breast milk. -
Fertility effects:
Yes
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Renally excreted drugs (especially high dose methotrexate, bleomycin) | ↓ renal clearance and increased t½; toxicities of these drugs may be enhanced | ↓ renal function caused by cisplatin | ascertain renal function prior to giving potentially toxic renally-excreted drugs (such as other chemotherapy) and modify doses as necessary |
| Nephrotoxic drugs (e.g. aminoglycosides amphotericin) | ↑ nephrotoxicity | Additive | Avoid or use with extreme caution during or shortly after cisplatin therapy (for 1-2 weeks) |
| Pyridoxine (high dose > 300mg/m2) | ↓ efficacy when given with cisplatin and altretamine | Unknown | Avoid concomitant use with the combination of cisplatin and altretamine |
| Ototoxic drugs (e.g. furosemide, ethacrynic acid) | ↑ ototoxicity | Additive, especially in the presence of renal impairment | Avoid concomitant use; use furosemide if a diuretic is essential (may be less ototoxic than ethacrynic acid) |
| Ifosfamide | ↑ ototoxicity, ↓ renal clearance and ↑ toxicity | Possibly additive (ototoxicity); ↓ renal function caused by cisplatin | Caution and monitor; ascertain renal function prior to administration |
| Paclitaxel (given after cisplatin) | ↑ toxicity (may ↑ paclitaxel exposure by 33% and ↓ efficacy) | ↑ neutropenia and neurotoxicity; ↓ efficacy because of reduced cycling of cells | give paclitaxel prior to cisplatin when used in combination |
| Anticonvulsant agents (phenytoin, carbamazepine, valproate sodium) | ↓ anticonvulsant serum levels | decreased absorption and/or increased metabolism of anticonvulsant agent | monitor serum levels; increase dose if necessary |
| Lithium | ↓ lithium serum levels (observed with cisplatin, bleomycin, and etoposide combination) | Unknown | Monitor lithium levels |
| Warfarin | ↑ INR has been reported | Unknown | Monitor INR |
| Topotecan | ↑ topotecan toxicity | Unknown. Appears to be sequence dependent. Higher hematologic toxicity was observed even when topotecan was given 8 days after carboplatin | Consider giving platinum after topotecan (e.g. day 5 platinum in a 5 day regimen). Lower topotecan doses are recommended when platinum is given before topotecan. Monitor for myelosuppression. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and as clinically indicated |
CBC |
Baseline and at each cycle |
Renal function tests |
Baseline and at each cycle |
Electrolytes, including magnesium, sodium, potassium, phosphate and calcium. |
Baseline and at each cycle |
Audiogram |
Baseline and as clinically indicated |
Clinical toxicity assessment of injection site reactions, infection, bleeding, nausea/vomiting, neurotoxicity, ototoxicity, ocular toxicity, arterial and venous thromboembolism |
At each cycle |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Canadian Adverse Reaction Newsletter: Cisplatin aortic thrombosis. Volume 24, Issue 3 July 2014.
Cisplatin product monograph. Accord Healthcare Inc., July 2020.
Cisplatin product monograph. Sandoz Canada, January 25, 2019.
Cisplatin product monograph. Mylan Pharmaceuticals. May 15, 2014.
Cisplatin: Lexicomp Drug Information. Accessed July 2019.
Health Product Info Watch. Cisplatin and venous thromboembolism. January 2015.
Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treatment Reviews 1995;21:33-64.
McEvoy GK, editor. AHFS Drug Information 2013. Bethesda: American Society of Health-System Pharmacists, p. 941-57.
Product Monograph: Taxol® (paclitaxel). Bristol Myers Squibb Canada, February 22, 2010.
Seng S, Liu Z, Chiu SK, et al. Risk of venous thromboembolism in patients with cancer treated with Cisplatin: a systematic review and meta-analysis. J Clin Oncol 2012;30(35):4416-26.
Shah MA, Schwartz GK. Cell cycle-mediated drug resistance: an emerging concept in cancer therapy. Clin Cancer Res 2001;7(8):2168-81.
Vanhoefer U, Harstrick A, Wikle H, et al. Schedule-dependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro. Eur J Cancer 1995;31(1):92-7.
Wiernik PH, Yeap B, Vogl SE, et al. Hexamethylmelamine and low or moderate dose cisplatin with or without pyridoxine for treatment of advanced ovarian carcinoma: a study of the Eastern Cooperative Oncology Group. Cancer Invest 1992;10(1):1-9.
Yano R, Kurokawa T, Tsuyoshi H, et al. Transient elevation of international normalized ratio during cisplatin-based chemotherapy in patients who are taking warfarin. Ann Pharmacother. 2011;45(10):e55.
April 2023 Updated Dosage in renal impairment, Dosing (children), Drug Interactions, and Pregnancy/lactation sections.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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