The main mechanism of the cytotoxic action involves the binding of cisplatin to genomic DNA in the cell nucleus to form interstrand and intrastrand cross-links. This interferes with normal transcription and/or DNA replication mechanisms and triggers cytotoxic processes that lead to cell death.
Cisplatin dose not undergo the instantaneously and reversible binding to plasma protein that is characteristic of normal drug-protein binding. Platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and 2 hours after the end of a 3‑hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of 5 days or more.
Following cisplatin doses of 20 mg/m2 to 120 mg/m2 , platinum is present in tissues for as long as 180 days after the last administration. With the exception of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower than the concentrations in the organ where the tumor is located. Hepatic metastases have the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. Maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after a 100 mg/m2 dose of cisplatin and decline in a biphasic manner with a terminal half-life of 36 to 47 days.
The chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. At physiological pH, the predominant molecular species are cisplatin and monohydroxymonochloro cis -diamine platinum (II) in nearly equal concentrations. The latter, combined with the possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the instability of cisplatin in biological matrices. The ratios of cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.
Over a dose range of 40 mg to 140 mg cisplatin per m2 given as a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over 5 days following administration of 40 mg/m2 to 100 mg/m2 doses given as rapid, 2‑ to 3‑hour or 6‑ to 8‑hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following 5 daily administrations of 20 mg/m2 per day, 30 mg/m2 per day, or 40 mg/m2 per day. Only a small percentage of the administered platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is excreted within the first few hours.
The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within 1 hour after administration of 50 mg/m2. The mean renal clearance of cisplatin exceeds creatinine clearance and was 62 mL/min per m2 and 50 mL/min per m2 following administration of 100 mg/m2 as 2‑hour or 6‑ to 7‑hour infusions, respectively.
Plasma concentrations of the parent compound, cisplatin, decrease monoexponentially with a half-life of about 20 to 30 minutes following bolus administrations of 50 mg/m2 or 100 mg/m2 doses. Monoexponential decreases and plasma half-lives of about 0.5 hour are also seen following 2‑hour or 7‑hour infusions of 100 mg/m2. After the latter, the total body clearances and volumes of distribution at steady-state for cisplatin are about 15 Liters per hour per m2 to 16 Liters per hour per m2 and 11 Liters per m2 to 12 Liters per m2.
The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate, indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption.
No significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance.
The carcinogenic effect of cisplatin for injection was studied in BDIX rats. Cisplatin for injection was administered three times a week at 1 mg/kg body weight intraperitoneally to 50 BDIX rats for 3 weeks. Four hundred fifty-five days after the first application, 33 animals died, 13 of them related to malignancies (12 leukemias and 1 renal fibrosarcoma) [see Warnings and Precautions (5.8)].
Cisplatin is mutagenic in the bacteria reverse mutation (Ames) test and produces chromosome aberrations in mammalian cells.
- OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
Cisplatin for injection, USP
NDC 44567-530-01—Each single-dose amber vial contains 50 mg of cisplatin as a white to light yellow lyophilized powder for reconstitution.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Prior to reconstitution, store in original carton to protect from light. Discard unused portion.
Handling and Disposal
Cisplatin for injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
Inform patients that cisplatin for injection can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary. If indicated, inform patients about the use of electrolyte supplements [see Warnings and Precautions (5.1)].
Advise patients to report any new paresthesias to their healthcare provider [see Warnings and Precautions (5.2)].
Nausea and Vomiting
Advise patients concerning the use of antiemetics to prevent nausea and vomiting and to report persistent or severe symptoms to their healthcare provider [see Warnings and Precautions (5.3)].
Advise patients that cisplatin for injection can reduce the absolute neutrophil count and the platelet count resulting in an increased risk of infection and bleeding and to contact their healthcare provider for new onset fever, symptoms of infection, or bleeding [see Warnings and Precautions (5.4)].
Advise patients to report any symptoms of hearing loss or vestibular dysfunction to their healthcare provider and that periodic monitoring of hearing may be performed [see Warnings and Precautions (5.6)].
- Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider if they are pregnant or become pregnant [see Warnings and Precautions 5.9 and Use in Specific Populations 8.1)].
- Advise females of reproductive potential to use effective contraception during treatment and for 14 months following the last dose of cisplatin for injection [see Use in Specific Populations (8.3)].
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months following the last dose of cisplatin for injection [see Use in Specific Populations (8.3)].
Advise females not to breastfeed during treatment with cisplatin for injection [ see Use in Specific Populations (8.2)].
Inform patients that treatment with cisplatin for injection may lead to permanent impairment of spermatogenesis, ovarian failure or premature menopause, and reduced fertility in both genders [see Use in Specific Populations (8.3)].
Inform patients that cisplatin for injection can cause alopecia.
WG Critical Care, LLC
Paramus, NJ 07652
Made in Italy
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.