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.
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
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.
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin (cisplatin injection)
In a randomized trial in advanced ovarian cancer, response duration was adversely
affected when pyridoxine was used in combination with altretamine (hexamethylmelamine)
and cisplatin (cisplatin injection) .