Cisplatin

Nephrotoxicity - Dose-related and cumulative renal insufficiency is the major dose-limiting toxicity of cis-platin. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m2. It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of cisplatin (cisplatin injection) can be given. Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).

Impairment of renal function has been associated with renal tubular damage. The administration of cis-platin using a 6- to 8- hour infusion with intravenous hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of these procedures.

Ototoxicity -Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin (cisplatin injection) 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz). Decreased ability to hear normal conversational tones may occur occasionally. Deafness after the initial dose of cisplatin (cisplatin injection) has been reported rarely. Ototoxic effects may be more severe in children receiving cisplatin (cisplatin injection) . Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated doses. Ototoxicity may be enhanced with prior or simultaneous cranial irradiation. It is unclear whether cisplatin (cisplatin injection) induced ototoxicity is reversible. Ototoxic effects may be related to the peak plasma concentration of cisplatin (cisplatin injection) . Careful monitoring of audiometry should be performed prior to initiation of therapy and prior to subsequent doses of cisplatin (cisplatin injection) .

Vestibular toxicity has also been reported.

Ototoxicity may become more severe in patients being treated with other drugs with nephrotoxic potential.

Hematologic - Myelosuppression occurs in 25% to 30% of patients treated with cisplatin (cisplatin injection) . The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses ( > 50 mg/m2). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infections have also been reported in patients with neutropenia. Elderly patients may be more susceptible to myelosuppression (see PRECAUTIONS: Geriatric Use).

In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has been reported. In the presence of cisplatin (cisplatin injection) hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician.

The development of acute leukemia coincident with the use of cisplatin (cisplatin injection) has rarely been reported in humans. In these reports, cisplatin (cisplatin injection) was generally given in combination with other leukemogenic agents.

Gastrointestinal - Marked nausea and vomiting occur in almost all patients treated with cisplatin (cisplatin injection) , and are occasionally so severe that the drug must be discontinued. Nausea and vomiting usually begin within 1 to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after treatment.

Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of cisplatin (cisplatin injection) therapy.

Diarrhea has also been reported.

Other Toxicities

Vascular toxicities coincident with the use of cisplatin (cisplatin injection) in combination with other antineoplastic agents have been reported rarely. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (HUS), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud's phenomenon occurring in patients treated with the combination of bleomycin, vinblastine with or without cisplatin (cisplatin injection) . It has been suggested that hypomagnesemia developing coincident with the use of cisplatin (cisplatin injection) may be an added, although not essential, factor associated with this event. However, it is currently unknown if the cause of Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vin-blastine, hypomagnesemia, or a combination of any of these factors.

Serum Electrolyte Disturbances - Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been reported to occur in patients treated with cisplatin (cisplatin injection) and are probably related to renal tubular damage. Tetany has occasionally been reported in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing cisplatin (cisplatin injection) .

Inappropriate antidiuretic hormone syndrome has also been reported.

Hyperuricemia - Hyperuricemia has been reported to occur at approximately the same frequency as the increases in BUN and serum creatinine.

It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels.

Neurotoxicity (see WARNINGS section) - Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neu-rologic symptoms have been reported to occur after a single dose. Although symptoms and signs of cis-platin neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of cisplatin (cisplatin injection) , although this is rare. Cisplatin (cisplatin injection) therapy should be discontinued when the symptoms are first observed. The neuropathy, however, may progress further even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric Use).

Lhermitte's sign, dorsal column myelopathy, and autonomic neuropathy have also been reported.

Loss of taste and seizures have also been reported.

Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and were usually associated in patients receiving a relatively high cumulative dose of cisplatin (cisplatin injection) and with a relatively advanced symptomatic stage of peripheral neuropathy.

Ocular Toxicity - Optic neuritis, papilledema, and cerebral blindness have been reported infrequently in patients receiving standard recommended doses of cisplatin (cisplatin injection) . Improvement and/or total recovery usually occurs after discontinuing cisplatin (cisplatin injection) . Steroids with or without mannitol have been used; however, efficacy has not been established.

Blurred vision and altered color perception have been reported after the use of regimens with higher doses of cisplatin (cisplatin injection) or greater dose frequencies than those recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area.

Anaphylactic-like Reactions -Anaphylactic-like reactions have been occasionally reported in patients previously exposed to cisplatin (cisplatin injection) . The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteriods and/or antihistamines as indicated. Patients receiving cisplatin (cisplatin injection) should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication.

Hepatotoxicity - Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with cisplatin (cisplatin injection) administration at the recommended doses.

Other Events - Other toxicities reported to occur infrequently are cardiac abnormalities, hiccups, elevated serum amylase, and rash. Alopecia, malaise, and asthenia have been reported as part of postmarketing surveillance.

Local soft tissue toxicity has rarely been reported following extravasation of cisplatin (cisplatin injection) . Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin (cisplatin injection) solution. Infusion of solutions with a cisplatin (cisplatin injection) concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, and necrosis.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Cisplatin may cause harm to the unborn baby. It is advisable to avoid pregnancy while on cisplatin.

Cisplatin injection comes as a solution (liquid) to be injected in a vein through an IV over 6 to 8 hours by a doctor or nurse in a hospital or a medical clinic. It is usually given once every 3–4 weeks.

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Cisplatin can cause side effects that may impair your vision. Be careful if you drive or do anything that requires you to be able to see clearly.

• Risk of nausea, vomiting, nephrotoxicity, myelosuppression, and ototoxicity.1

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 Necessity for clinicians to advise women to avoid pregnancy during therapy; advise pregnant women of risk to the fetus.1

• Importance of informing patients of other important precautionary information. (See Cautions.)

Use cisplatin as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

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 Injection, 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 Injection therapy.

Advanced Bladder Cancer

Cisplatin Injection 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.

Nephrotoxicity

Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of Cisplatin. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m2. It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of Cisplatin can be given. Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use).

Impairment of renal function has been associated with renal tubular damage. The administration of Cisplatin using a 6 hour to 8 hour infusion with intravenous hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of these procedures.

Ototoxicity

Ototoxicity has been observed in up to 31% of patients treated with a single dose of Cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz). The prevalence of hearing loss in children is particularly high and is estimated to be 40 to 60%. Decreased ability to hear normal conversational tones may occur. Deafness after the initial dose of Cisplatin has been reported. Ototoxic effects may be more severe in children receiving Cisplatin.

Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated Cisplatin doses. It is unclear whether Cisplatin-induced ototoxicity is reversible. Vestibular toxicity has also been reported. Ototoxic effects may be related to the peak plasma concentration of Cisplatin. Ototoxicity can occur during treatment or be delayed. Audiometric monitoring should be performed prior to initiation of therapy, prior to each subsequent dose, and for several years post therapy.

The risk of ototoxicity may be increased by prior or simultaneous cranial irradiation, and may be more severe in patients less than 5 years of age, patients being treated with other ototoxic drugs (e.g., aminoglycosides and vancomycin), and in patients with renal impairment.

Genetic factors (e.g., variants in the thiopurine S-methyltransferase [TPMT] gene) may contribute to Cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs.

Hematologic

Myelosuppression occurs in 25% to 30% of patients treated with Cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infection have also been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Elderly patients may be more susceptible to myelosuppression (see PRECAUTIONS, Geriatric Use).

In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has been reported. In the presence of Cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician.

The development of acute leukemia coincident with the use of Cisplatin has been reported. In these reports, Cisplatin was generally given in combination with other leukemogenic agents.

Gastrointestinal

Marked nausea and vomiting occur in almost all patients treated with Cisplatin, and may be so severe that the drug must be discontinued. Nausea and vomiting may begin within 1 hour to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after treatment.

Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of Cisplatin therapy.

Diarrhea has also been reported.

To report SUSPECTED ADVERSE REACTIONS, contact Athenex Pharmaceutical Division, LLC. at 1-855-273-0154 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Vascular toxicities coincident with the use of Cisplatin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud's phenomenon occurring in patients treated with the combination of bleomycin, vinblastine with or without Cisplatin. It has been suggested that hypomagnesemia developing coincident with the use of Cisplatin may be an added, although not essential, factor associated with this event. However, it is currently unknown if the cause of Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.

Serum Electrolyte Disturbances

Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been reported to occur in patients treated with Cisplatin and are probably related to renal tubular damage. Tetany has been reported in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing Cisplatin.

Inappropriate antidiuretic hormone syndrome has also been reported.

Hyperuricemia

Hyperuricemia has been reported to occur at approximately the same frequency as the increases in BUN and serum creatinine.

It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels.

Neurotoxicity

(See WARNINGS).

Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of Cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of Cisplatin. Cisplatin therapy should be discontinued when the symptoms are first observed. The neuropathy, however, may progress further even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS, Geriatric Use).

Lhermitte's sign, dorsal column myelopathy, and autonomic neuropathy have also been reported.

Loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported.

Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and were usually associated in patients receiving a relatively high cumulative dose of Cisplatin and with a relatively advanced symptomatic stage of peripheral neuropathy.

Ocular Toxicity

Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving standard recommended doses of Cisplatin. Improvement and/or total recovery usually occurs after discontinuing Cisplatin. Steroids with or without mannitol have been used; however, efficacy has not been established.

Blurred vision and altered color perception have been reported after the use of regimens with higher doses of Cisplatin or greater dose frequencies than recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area.

Anaphylactic-Like Reactions

Anaphylactic-like reactions have been reported in patients previously exposed to Cisplatin. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving Cisplatin should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication.

Hepatotoxicity

Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with Cisplatin administration at the recommended doses.

Other Events

Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and dehydration have been reported.

Local soft tissue toxicity has been reported following extravasation of Cisplatin. Severity of the local tissue toxicity appears to be related to the concentration of the Cisplatin solution. Infusion of solutions with a Cisplatin concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

Cisplatin is administered by slow intravenous infusion. Cisplatin SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.

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 4 weeks (DAY 1).

The dose of cyclophosphamide when used in combination with Cisplatin is 600 mg/m2 IV once every 4 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 4 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 4 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 hour 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.

Preparation of Intravenous Solutions

Preparation Precautions

Caution should be exercised in handling the aqueous solution. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and IV sets containing Cisplatin.

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. More information is available in the references listed below.

Instructions for Preparation

The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6 hour to 8 hour period (see DOSAGE AND ADMINISTRATION).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

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

Stability

Cisplatin is a sterile, multiple dose vial without preservatives.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. 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.

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.

Athenex
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©2017 Athenex.

June 2017

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 70860-206-50

Cisplatin Injection

50 mg per 50 mL (1 mg per mL)

Rx only

For Intravenous Use

Caution: Cytotoxic Agent

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Carton

NDC 70860-206-50

Cisplatin Injection

50 mg per 50 mL (1 mg per mL)

Rx only

For Intravenous Use

Caution: Cytotoxic Agent

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 70860-206-51

Cisplatin Injection

100 mg per 100 mL (1 mg per mL)

Rx only

For Intravenous Use

Caution: Cytotoxic Agent

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Carton

NDC 70860-206-51

Cisplatin Injection

100 mg per 100 mL (1 mg per mL)

Rx only

For Intravenous Use

Caution: Cytotoxic Agent

(SIS pla tin)

Bladder cancer, advanced: Treatment (as a single agent) of advanced bladder cancer (transitional cell) in patients who are no longer candidates for local therapy including surgery and/or radiation therapy

Ovarian cancer, metastatic: Treatment of metastatic ovarian cancer (in combination with other chemotherapy agents) in patients who have previously received appropriate surgery and/or radiation therapy, or as a single agent for refractory tumors in patients who have not previously received cisplatin

Testicular cancer, metastatic: Treatment of metastatic testicular cancer (in combination with other chemotherapy agents) in patients who have previously received appropriate surgery and/or radiation therapy

Breast cancer (triple-negative)

Data from a small study supports the use of cisplatin (as a single agent) in the neoadjuvant treatment of triple-negative breast cancer [Silver 2010]. Additional data may be necessary to further define the role of cisplatin in this condition.

Cervical cancer

Data from phase III randomized trials support the use of cisplatin (in combination with fluorouracil and radiation) in the management of patients with cervical cancer [Morris 1999], [Peters 2000], [Whitney 1999].

Endometrial carcinoma, recurrent, metastatic, or high-risk

Data from a phase III clinical trial in patients with recurrent, metastatic, or high-risk endometrial carcinoma, supports the use of cisplatin (in combination with doxorubicin ± paclitaxel) for the treatment of this condition [Fleming 2004].

Germ cell tumors, malignant (pediatric)

Data from a small study supports the use of cisplatin (in combination with bleomycin and either etoposide or vinblastine) in the treatment of advanced malignant germ cell tumors in children [Pinkerton 1986]. Additional data may be necessary to further define the role of cisplatin in this condition.

Esophageal cancer

Data from a large, randomized, phase III trial supports the use of cisplatin in combination with epirubicin and fluorouracil (ECF regimen) pre- and postoperatively for the management of adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus [Cunningham 2006].

Another large phase III trial (REAL-2) investigated whether fluorouracil could be replaced by capecitabine, and cisplatin could be replaced by oxaliplatin, in the ECF regimen for the treatment of esophagogastric cancers; data from the two-by-two design showed that capecitabine and oxaliplatin were inferior to fluorouracil and cisplatin, respectively (in combination with epirubicin) [Cunningham 2008].

Two large phase III trials illustrated that cisplatin in combination with docetaxel and fluorouracil is effective in the treatment of gastric and gastroesophageal cancer [Ajani 2007], [Van Cutsem 2006]. Additionally, data from a small phase III trial (CALGB 9781) supports the use of cisplatin (in combination with fluorouracil and radiation) as preoperative therapy for esophageal cancer [Tepper 2008].

Gastric cancer

Data from a large, randomized, phase III trial supports the use of cisplatin in combination with epirubicin and fluorouracil (ECF regimen) pre- and postoperatively for the management of adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus [Cunningham 2006].

Another large phase III trial (REAL-2) investigated whether fluorouracil could be replaced by capecitabine, and cisplatin could be replaced by oxaliplatin, in the ECF regimen for the treatment of esophagogastric cancers; data from the two-by-two design showed that capecitabine and oxaliplatin were inferior to fluorouracil and cisplatin, respectively (in combination with epirubicin) [Cunningham 2008].

Two large phase III trials illustrated that cisplatin in combination with docetaxel and fluorouracil is effective in the treatment of gastric and gastroesophageal cancer [Ajani 2007], [Van Cutsem 2006]. Additionally, data from a small phase III trial (CALGB 9781) supports the use of cisplatin (in combination with fluorouracil and radiation) as preoperative therapy for esophageal cancer [Tepper 2008].

Head and neck cancer (locally advanced disease)

Data from large randomized phase III trials support the use of cisplatin in combination with radiation [Bernier 2004], [Cooper 2004] or in combination with docetaxel and fluorouracil followed by chemoradiation [Posner 2007] for the treatment of locally advanced head and neck cancer. In addition, another large phase III trial combining cisplatin with docetaxel and fluorouracil demonstrated efficacy in patients with unresectable disease [Vermorken 2007].

Head and neck cancer (metastatic disease)

Cisplatin (in combination with fluorouracil and cetuximab) demonstrated efficacy in a large phase III randomized trial of patients with recurrent or metastatic head and neck cancer [Vermorken 2008].

Hepatoblastoma (pediatric)

Data from an international study supports the use of cisplatin (in combination with doxorubicin) in the treatment of hepatoblastoma in children [Pritchard 2000]. Additional data may be necessary to further define the role of cisplatin in this condition.

Hodgkin lymphoma

Data from phase II studies supports the use of cisplatin in combination with dexamethasone and cytarabine (DHAP regimen) or in combination with etoposide, methylprednisolone and cytarabine (ESHAP regimen) for the treatment of relapsed/refractory Hodgkin lymphoma [Aparicio 1999], [Josting, 2002]. Additional data may be necessary to further define the role of cisplatin in this condition.

Malignant pleural mesothelioma

Data from a large randomized phase III trial supports the use of cisplatin in combination with pemetrexed for the treatment of malignant pleural mesothelioma [Vogelzang 2003]. Data from two additional phase II studies support the use of cisplatin in combination with gemcitabine for management of this disease state [Nowak 2002], [van Haarst 2002].

Medulloblastoma (pediatric)

Data from a large randomized phase III study supports the use of cisplatin (in combination with vincristine and either lomustine or cyclophosphamide) following craniospinal radiation in children with medulloblastoma [Packer 2006].

Multiple myeloma

Data from large randomized phase III trials supports the use of cisplatin (in combination with bortezomib, dexamethasone, thalidomide, doxorubicin, cyclophosphamide, and etoposide) as induction therapy for the management of multiple myeloma [Lee 2003], [Pineda-Roman 2008].

Neuroblastoma

Data from a large cooperative Children’s Oncology Group trial, as well as data from a smaller trial, supports the use of cisplatin as part of a multiagent chemotherapy regimen in the management of neuroblastoma [Kushner 1994], [Naranjo 2011].

Non-Hodgkin lymphoma, relapsed/refractory

Data from phase II studies supports the use of cisplatin in combination with dexamethasone and cytarabine (DHAP regimen) or in combination with etoposide, methylprednisolone and cytarabine (ESHAP regimen) for the treatment of relapsed/refractory Hodgkin lymphoma [Velasquez 1988], [Velasquez 1994]. Additional data may be necessary to further define the role of cisplatin in this condition.

Non-small cell lung cancer

Data from multiple large randomized phase III trials have demonstrated the efficacy of cisplatin-based chemotherapy regimens for the treatment of non-small cell lung cancer [Arriagada 2004], [Comella 2000], [Kelly 2001], [Ohe 2007], [Scagliotti 2008], [Wozniak 1998].

Osteosarcoma

Data from a multicenter randomized phase III trial supports the use of cisplatin (as part of a combination chemotherapy regimen) in the management of nonmetastatic osteosarcoma [Goorin 2003].

Penile cancer (metastatic)

Data from a small phase II study supports the use of neoadjuvant chemotherapy (cisplatin, paclitaxel, and ifosfamide) in patients with penile cancer who have bulky regional lymph node metastases [Pagliaro 2010]. Additional trials may be necessary to further define the role of cisplatin in this condition.

Small cell lung cancer (extensive-stage disease)

Data from large randomized phase III trials supports the use of cisplatin in combination with etoposide [Ihde 1994], [Lara 2009] or irinotecan [Lara 2009] for the treatment of extensive stage small cell lung cancer.

Based on American Society of Clinical Oncology Guidelines for Treatment of Small-Cell Lung Cancer, platinum-based therapy in combination with either etoposide or irinotecan is recommended over other chemotherapy regimens for extensive stage disease[Rudin 2015].

Small cell lung cancer (limited-stage disease)

Data from a large randomized phase III trial supports the combination of cisplatin and etoposide with concurrent radiotherapy in the management of limited stage small cell lung cancer [Turrisi 1999].

Based on American Society of Clinical Oncology Guidelines for Treatment of Small-Cell Lung Cancer, platinum-based therapy in combination with either etoposide or irinotecan is recommended over other chemotherapy regimens for limited stage disease[Rudin 2015].

Additional Off-Label Uses

Anal carcinoma (metastatic); Central nervous system tumors; Gestational trophoblastic disease (refractory); Hepatobiliary cancer; Melanoma (metastatic); Neuroendocrine tumors; Pancreatic cancer (advanced); Primary CNS lymphoma; Prostate cancer; Thymoma/thymic carcinoma; Unknown primary cancers

History of allergic reactions to cisplatin, other platinum-containing compounds, or any component of the formulation; preexisting renal impairment; myelosuppressed patients; hearing impairment

Refer to adult dosing. Select dose cautiously and monitor closely in the elderly; may be more susceptible to nephrotoxicity and peripheral neuropathy.

>10%:

Central nervous system: Neurotoxicity (peripheral neuropathy is dose and duration dependent)

Gastrointestinal: Nausea and vomiting (76% to 100%)

Genitourinary: Nephrotoxicity (28% to 36%; acute renal failure and chronic renal insufficiency)

Hematologic & oncologic: Anemia (≤40%), leukopenia (25% to 30%; nadir: Day 18 to 23; recovery: By day 39; dose related), thrombocytopenia (25% to 30%; nadir: Day 18 to 23; recovery: By day 39; dose related)

Hepatic: Increased liver enzymes

Otic: Ototoxicity (children 40% to 60%; adults 10% to 31%; as tinnitus, high frequency hearing loss)

1% to 10%: Local: Local irritation

<1%, postmarketing, and/or case reports: Alopecia (mild), ageusia, anaphylaxis, autonomic neuropathy, bradycardia (Schlumbrecht 2015), bronchoconstriction, cardiac arrhythmia, cardiac failure, cerebral arteritis, cerebrovascular accident, dehydration, diarrhea, dysgeusia (Rehwaldt 2009), extravasation, heart block, hemolytic anemia (acute), hemolytic-uremic syndrome, hiccups, hypercholesterolemia, hyperuricemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypotension, increased serum amylase, ischemic heart disease, leukoencephalopathy, Lhermitte's sign, mesenteric ischemia (acute; Morgan 2011), myocardial infarction, neutropenic enterocolitis (Furonaka 2005), optic neuritis, pancreatitis (Trivedi 2005), papilledema, peripheral ischemia (acute), phlebitis (Tokuda 2014), reversible posterior leukoencephalopathy syndrome, seizure, SIADH, skin rash, tachycardia, tetany, thrombosis (aortic; Fernandes 2011), thrombotic thrombocytopenic purpura, vasospasm (acute arterial; Morgan 2011), vision color changes, vision loss

Applies to cisplatin: compounding powder, intravenous powder for injection, intravenous solution

Renal

A study of 12 patients who received recommended doses of cisplatin incurred moderate loss of renal function 12 and 24 months after therapy was discontinued. The renal dysfunction was not progressive. However, glomerular filtration rate (GFR) and effective renal plasma flow (EPRF) were decreased by 23% and 19%, respectively. Other studies have shown moderate and permanent reduction in GFR up to 52 months after cisplatin therapy.

Elderly patients may be more susceptible to nephrotoxicity.

The risk of renal toxicity may be decreased with appropriate monitoring of renal function tests as well as aggressive hydration with chloride-containing fluids and appropriate electrolyte replacement. Amifostine, a thiol chemoprotectant, is approved to reduce cisplatin nephrotoxicity and does not interfere with antitumor activity.[Ref]

Renal side effects have been reported to present during the second week after a dose of cisplatin and become more prolonged and severe with repeated courses of cisplatin therapy. Nephrotoxicity is the most important dose-limiting side effect of cisplatin, which is dose-related, cumulative, and occurs in 36% of patients after single doses of 50 mg/m2. Renal function should return to baseline before subsequent doses are administered.

Cisplatin-induced renal tubule damage can result in clinically significant hypomagnesemia and hypokalemia as well as hypocalcemia, hyponatremia, hypophosphatemia, and hyperuricemia.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea and vomiting which can be dose-limiting in some patients. Nausea and vomiting usually begin one to four hours after treatment and may last up to five days. Diarrhea, hiccups, and elevated serum amylase have also been reported.[Ref]

Acute cisplatin-induced emesis occurs one to four hours after cisplatin administration and is primarily serotonin mediated. Appropriate antiemetics are essential. A serotonin-receptor antagonist in combination with a steroid generally controls this emesis effectively.

Delayed emesis occurs two to seven days after cisplatin administration and is more difficult to control. Oral steroid therapy, if tolerated, with or without metoclopramide may be useful in the prevention of delayed emesis. (Serotonin antagonists provide limited benefits for delayed emesis.)[Ref]

Nervous system

Symptoms of the sensory polyneuropathy typically begin in toes and feet and, later, affect the fingers and hands in a stocking-and-glove distribution. The neuropathies typically occur after prolonged therapy (4 to 7 months). However, symptoms have been reported after a single dose. Cisplatin neuropathies generally occur with higher dosage regimens and may be irreversible.

Elderly patients may be more susceptible to peripheral neuropathy.

Tinnitus and/or high-frequency (4000 to 8000 Hz) hearing loss occurs first, is unilateral or bilateral and may appear 3 to 4 days after initial treatment; however, deafness after the initial dose of cisplatin is rare. Cisplatin-induced ototoxicity is related to the loss of outer hair cells in the cochlea. Ototoxicity is associated with both high cisplatin doses and high cumulative doses. Hearing impairment is generally irreversible; however, hearing aids may help.[Ref]

Nervous system side effects can be dose limiting for patients receiving cisplatin. The most common form of nerve damage from cisplatin is a sensory polyneuropathy. Other forms of nerve damage from cisplatin include autonomic neuropathies, seizures, encephalopathy, myasthenic syndrome, cortical blindness, Lhermitte's sign, and dorsal column myelopathy. Ototoxicity, headache, loss of taste, strokes, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported.[Ref]

Hematologic

Myelosuppression is a dose-related effect and usually occurs with doses greater than 50 mg/m2. Cisplatin-based therapy may result in a cumulative, clinically significant anemia which is disproportionate to the drugs effects on other blood cells.

Elderly patients may be more susceptible to myelosuppression.

Frequent anemia was reported in one study with 28 patients receiving six cycles of cisplatin in combination with 3 other chemotherapeutic agents. Thirteen patients became severely anemic, 12 became moderately anemic, and three became mildly anemic. The anemia was progressive and 66.7% of the patients became severely anemic during the third and fourth months of therapy.

Treatment of anemia with recombinant erythropoietin is generally helpful. Epoetin alfa has been approved for use in the treatment of anemia in patients with nonmyeloid malignancies where anemia is the result of concomitantly administered chemotherapy.

The nadirs in circulating erythrocytes, platelets, and leukocytes occur between days 18 to 23 (range 7.5 to 45), with most patients recovering by day 39 (range 13 to 62). Leukocytes usually recover after 14 to 21 days. Most patients are able to be retreated at 21 day intervals.[Ref]

Hematologic side effects including myelosuppression have been reported. Cisplatin causes moderate and transient myelosuppression in 25% to 30% of patients. Coombs' positive hemolytic anemia has also been reported.[Ref]

Ocular

Ocular side effects including optic neuritis, papilledema, cortical blindness, focal deficits, and cerebral blindness have been infrequently reported in patients receiving standard doses of cisplatin. Improvement and/or total recovery usually occurs after discontinuation of cisplatin. Blurred vision and altered color perception have been reported after the use of regimens with higher doses or greater dose frequencies than those recommended by the manufacturer.[Ref]

Hypersensitivity

Hypersensitivity side effects including anaphylactic-like reactions have been occasionally reported in patients previously exposed to cisplatin. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration.[Ref]

Reactions may be treated with intravenous epinephrine, corticosteroids and/or antihistamines. Supportive equipment and medications should be available for possible anaphylactic-like reactions.[Ref]

Hepatic

Hepatic side effects including transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported. However, the incidence and clinical importance is relatively low.[Ref]

Local

Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin solution. Infusions of solutions with a cisplatin concentration greater than 0.5 mg/mL may rarely result in tissue inflammation and fibrosis.[Ref]

Local side effects including soft tissue toxicity have rarely been reported following extravasation of cisplatin.[Ref]

Cardiovascular

Cardiovascular side effects including myocardial infarction, cerebrovascular accident, deep vein thrombosis, pulmonary embolism, transient ischemic attack, thrombotic microangiopathy (hemolytic uremic syndrome), cerebral arteritis, and blood pressure abnormalities have been reported. Raynaud's phenomenon has been reported in patients receiving bleomycin and vinblastine, with or without cisplatin. Distal ischemic changes have been reported in patients receiving combination chemotherapy with cisplatin and gemcitabine. Possible cardiotoxicity (ST-T wave abnormalities and bundle branch block) have rarely been reported. Atrial fibrillation, supraventricular tachycardia, and bradycardia have also been reported.[Ref]

Endocrine

Endocrine side effects including the syndrome of inappropriate antidiuretic hormone have been reported.[Ref]

Dermatologic

Dermatologic side effects including rash and alopecia have been reported. A case of digital necrosis has also been reported.[Ref]

Metabolic

Metabolic side effects have included chronic lipid abnormalities.

Some side effects of cisplatin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Data not available

One case report found milk platinum levels to be one-tenth plasma levels. Another case report found milk platinum levels to be essentially the same as maternal plasma levels. The majority of platinum found in the milk is probably bound to protein and is therefore essentially inactive. Based on the confirmed presence of platinum in breastmilk, however, fetal harm is possible and breast-feeding should be discontinued during cisplatin therapy.

Cisplatin is excreted into human milk. Breast-feeding is considered to be contraindicated by the manufacturer.

LactMed Record Number

70

Last Revision Date

20170411

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