Cisplatin (Page 2 of 5)

5.3 Nausea and Vomiting

Cisplatin for injection is a highly emetogenic antineoplastic agent. Premedicate with anti-emetic agents [see Dosage and Administration (2.1)]. Without antiemetic therapy, marked nausea and vomiting occur in almost all patients treated with cisplatin for injection and may be so severe that the drug must be discontinued. Nausea and vomiting may begin within 1 to 4 hours after treatment and last up to 72 hours. Maximal intensity occurs 48 to 72 hours after administration. 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 for injection therapy. Consider the use of additional anti-emetics following infusion.

5.4 Myelosuppression

Myelosuppression suppression occurs in 25% to 30% of patients treated with cisplatin for injection. Fever and infection have been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Geriatric patients may be more susceptible to myelosuppression [see Use in Specific Populations (8.5)].

Perform standard hematologic tests before initiating cisplatin for injection, before each subsequent course, and as clinically indicated. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with cisplatin for injection. For patients who develop severe myelosuppression during treatment with cisplatin for injection, consider dose modifications and manage according to clinical treatment guidelines.

5.5 Hypersensitivity Reactions

Cisplatin for injection can cause severe hypersensitivity reactions, including anaphylaxis and death. Manifestations have included facial edema, wheezing, tachycardia, and hypotension. Hypersensitivity reactions have occurred within minutes of administration to patients with prior exposure to cisplatin for injection.

Monitor patients receiving cisplatin for injection for possible hypersensitivity reactions. Ensure supportive equipment and medications are available to treat severe hypersensitivity reactions. Severe hypersensitivity reactions require immediate discontinuation of cisplatin for injection and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with cisplatin for injection [see Contraindications (4)]. Cross-reactivity between platinum-based antineoplastic agents has been reported. Cases of severe hypersensitivity reactions have recurred after rechallenging patients with a different platinum agent.

5.6 Ototoxicity

Cisplatin for injection can cause ototoxicity, which is cumulative and may be severe. Consider audiometric and vestibular function monitoring.

Ototoxicity is manifested by tinnitus, hearing loss in the high frequency range (4,000 to 8,000 Hz) and/or decreased ability to hear normal conversational tones. Ototoxicity can occur during or after treatment and can be unilateral or bilateral. Deafness after the initial dose of cisplatin for injection has been reported. Vestibular toxicity has also been reported.

Ototoxic effects can be more severe and detrimental in pediatric patients, particularly in patients less than 5 years of age. The prevalence of hearing loss in pediatric patients is estimated to be 40-60%. Additional risk factors for ototoxicity include simultaneous cranial irradiation, treatment with other ototoxic drugs and renal impairment. Consider audiometric and vestibular testing in all pediatric patients receiving cisplatin [see Use in Specific Populations (8.4)].

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

5.7 Ocular Toxicity

Optic neuritis, papilledema, and cortical blindness have been reported in patients receiving standard recommended doses of cisplatin for injection. Blurred vision and altered color perception have been reported after the use of regimens with higher doses and dose frequencies of cisplatin for injection. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis and irregular retinal pigmentation of the macular area on fundoscopic exam. Improvement and/or total recovery usually occurs after discontinuing cisplatin for injection but can be delayed.

5.8 Secondary Malignancies

The development of acute leukemia secondary to the use of cisplatin for injection has been reported. In these reports, cisplatin for injection was generally given in combination with other leukemogenic agents.

5.9 Embryo-Fetal Toxicity

Based on human data, cisplatin for injection can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 14 months after the last dose of cisplatin for injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months after the last dose of cisplatin for injection [see Use in Specific Populations (8.1, 8.3)].

5.10 Injection Site Reactions

Injection site reactions can occur during the administration of cisplatin for injection. Local soft tissue toxicity has been reported following extravasation of cisplatin for injection. Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin for injection solution. Infusion of solutions with a cisplatin for injection concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

Because of the possibility of extravasation, closely monitor the infusion site during drug administration.

6 ADVERSE REACTIONS

The following adverse reactions are described in greater detail, in other sections:

Nephrotoxicity [see Warnings and Precautions (5.1)]
Peripheral Neuropathy [see Warnings and Precautions (5.2)]
Nausea and vomiting [see Warnings and Precautions (5.3)]
Myelosuppression [see Warnings and Precautions (5.4)]
Hypersensitivity reactions [see Warnings and Precautions (5.5)]
Ototoxicity [see Warnings and Precautions (5.6]
Ocular toxicity [see Warnings and Precautions (5.7)]
Secondary malignancies [see Warnings and Precautions (5.8)]
Injection site reactions [see Warnings and Precautions (5.10)]

Common adverse reactions are nephrotoxicity, peripheral neuropathy, nausea and vomiting myelosuppression, and ototoxicity. The following adverse reactions have been identified from clinical trials or post-marketing surveillance.

Blood and lymphatic system disorders: Coombs‑positive hemolytic anemia. hemolytic uremic syndrome, thrombotic thrombocytopenic purpura

Cardiovascular disorders: Venous thromboembolism, arterial thromboembolism, myocardial infarction, cerebrovascular accident, thrombotic microangiopathy, cerebral arteritis, pericardial effusion, cardiac failure, ventricular dysfunction, Raynaud’s phenomenon

Eye disorders: Optic neuritis, papilledema, cortical blindness, blurred vision, color blindness, retinal pigmentation

Gastrointestinal disorders: Nausea, vomiting, anorexia, diarrhea, stomatitis, gastrointestinal perforation, pancreatitis, hiccups

General disorders: Asthenia, malaise

Hepatobiliary disorders: Elevations of aminotransferases, lactate dehydrogenase, and bilirubin; hepatic failure

Hypersensitivity: Anaphylaxis, facial edema, wheezing, tachycardia, and hypotension

Local Site Reactions: Tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema

Metabolism and nutrition disorders: Hypomagnesemia, often requiring magnesium supplementation; hyperuricemia, other electrolyte abnormalities (hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia), Syndrome of Inappropriate Antidiuretic Hormone Excretion (SIADH), dehydration, tumor lysis syndrome, increased serum amylase

Musculoskeletal disorders: Muscle cramps (localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration)

Nervous system disorders: Peripheral neuropathy, Encephalopathy, loss of motor function, loss of taste, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, progressive multifocal leukoencephalopathy, seizures, Lhermitte’s sign, dorsal column myelopathy, autonomic neuropathy, seizures, involuntary skeletal muscle contractions, tetany (with hypocalcemia and hypomagnesemia)

Ototoxicity: Tinnitus, hearing loss, deafness, vestibular toxicity

Renal and urinary disorders: Nephrotoxicity including renal failure, renal electrolyte wasting, azotemia, decreased creatinine clearance

Respiratory disorders: pneumonitis/interstitial lung disease, pulmonary embolism

Skin and subcutaneous tissue disorders: Alopecia, rash

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