Cisplatin-Platinol-AQ®

Cisplatin - Platinol-AQ®

Usual Diluents

Dilution Data

Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8- hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute cisplatin in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours. The infusion solution should have a final sodium chloride concentration ≥0.25%.

NOTE TO THE PHARMACIST- Exercise caution to prevent inadvertent cisplatin overdosage. Please call prescriber if dose greater than 100 mg/m2 per cycle. Aluminum cap and flip-off seal of vial have been imprinted with the following statement:   CALL DR. IF DOSE >100 MG/M2/CYCLE.

Administration2:
IV Infusion: administration rate has varied from 15 to 120 minute infusion, 1 mg/minute infusion,
6 to 8 hour infusion, 24-hour infusion, or per protocol.  [Package insert:  6 to 8 hours].

Other:
Cisplatin Doses <50mg/m2
Infuse in 100-250mL bag (NS) over 15-60 minutes (follow local protocol)

Cisplatin Doses ≥50mg/m2
Infuse in 250-500mL NS over 60 minutes  (follow local protocol)

Storage:
Cisplatin Injection is a sterile, multidose vial without preservatives.  Store at 15° to 25°C (59° to 77°F). Do not refrigerate. Protect unopened container from light.   The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

Stability/Dilution2:
Further dilutions in NS, D5/0.45% NaCl or D5/NS to a concentration of 0.05 to 2 mg/mL are stable for 72 hours at 4°C to 25°C.

CLINICAL PHARMACOLOGY
Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with a half-life of about 20 to 30 minutes following bolus administration of 50 or 100 mg/m2 doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen following two hour or seven 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 to 16 L/h/m2 and 11 to 12 L/m2.

Due to its unique chemical structure, 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 in the presence of 0.1M NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis-diammine 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.

Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins including albumin, transterrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-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 five days or more.

Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest in liver, prostate, and kidney, somewhat lower in bladder, muscle, testicle, pancreas, and spleen and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. 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. Different metastatic sites in the same patient may have different platinum concentrations. 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.

Over a dose range of 40 to 140 mg cisplatin/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 five days following administration of 40 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 five daily administrations of 20, 30, or 40 mg/m2/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. Platinum-containing species excreted in the urine are the same as those found following the incubation of cisplatin with urine from healthy subjects, except that the proportions are different.

The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within one hour after administration of 50 mg/m2. The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following administration of 100 mg/m2 as 2 hour or 6 to 7 hour infusions, respectively.

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 of possible tubular reabsorption.

There is a potential for accumulation of ultrafilterable platinum plasma concentrations whenever cisplatin is administered on a daily basis but not when dosed on an intermittent basis.

No significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance.

Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant.

INDICATIONS AND USAGE
Cisplatin injection is indicated as therapy to be employed as follows:

Metastatic Testicular Tumors - In established combination therapy with other approved chemotherapeutic agents in patients with metastatic testicular tumors who have already received appropriate surgical and/or radiotherapeutic procedures.

Metastatic Ovarian Tumors - In established combination therapy with other approved chemotherapeutic agents in patients with metastatic ovarian tumors who have already received appropriate surgical and/or radiotherapeutic procedures. An established combination consists of cisplatin and cyclophosphamide. Cisplatin, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received cisplatin therapy.

Advanced Bladder Cancer - Cisplatin is indicated as a single agent for patients with transitional cell bladder cancer which is no longer amenable to local treatments such as surgery and/or radiotherapy,

CONTRAINDICATIONS
Cisplatin is contraindicated in patients with preexisting renal impairment. Cisplatin should not be employed in myelosuppressed patients, or patients with hearing impairment.

Cisplatin is contraindicated in patients with a history of allergic reactions to cisplatin or other platinum-containing compounds

DOSAGE AND ADMINISTRATION
Note: Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not be used for preparation or administration. Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency.

Metastatic Testicular Tumors - The usual cisplatin dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.

Metastatic Ovarian Tumors - The usual cisplatin dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every four weeks (DAY 1).

The dose of cyclophosphamide when used in combination with cisplatin is 600 mg/m2 IV once every four weeks (DAY 1).

For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.

In combination therapy, cisplatin and cyclophosphamide are administered sequentially.

As a single agent, cisplatin should be administered at a dose of 100 mg/m2 IV per cycle once every four weeks.

Advanced Bladder Cancer - Cisplatin should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every four weeks is recommended.

All Patients - Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8- hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute cisplatin in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours.

A repeat course of cisplatin should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level   (platelets ≥100,000/mm3, WBC ≥4,000/mm3). Subsequent doses of cisplatin should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.

As with other potentially toxic compounds, caution should be exercised in handling the aqueous solution. Skin reactions associated with accidental exposure to cisplatin may occur. The use of gloves is recommended. If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.

The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6- to 8- hour period.

NOTE TO THE PHARMACIST- Exercise caution to prevent inadvertent cisplatin overdosage. Please call prescriber if dose greater than 100 mg/m2 per cycle. Aluminum cap and flip-off seal of vial have been imprinted with the following statement:

CALL DR. IF DOSE >100 MG/M2/CYCLE.

STABILITY
Cisplatin Injection is a sterile, multidose vial without preservatives.

Store at 15° to 25°C (59° to 77°F). Do not refrigerate. Protect unopened container from light.

The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED
Cisplatin Injection is supplied as follows:

NDC 55390-187-01- Each amber vial contains 1 mg/mL; 200 mg/200 mL MULTIPLE DOSE vial of cisplatin.

NDC 55390-414-99 - Each amber vial contains 1 mg/mL; 100 mg/100 mL MULTIPLE DOSE vial of cisplatin.

NDC 55390-414-50 - Each amber vial contains 1 mg/mL; 50 mg/50 mL MULTIPLE DOSE vial of cisplatin.

Novation, the supply company of VHA and UHC, and NOVAPLUS are trademarks of Novation, LLC

2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.

Procedures for proper handling and disposal: Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents. US Government Printing Office, Washington, D.C. 20402. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985; 253(11): 1590-1592. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, SC.D, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA - A Cancer Journal for Clinicians. 1983; (Sept/Oct) 258-263. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47: 1033-1049. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm 1996; 53: 1669-1685