Dose-related and cumulative renal insufficiency, including acute renal failure,
is the major dose-limiting toxicity of PLATINOL-AQ. 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 PLATINOL-AQ
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 PLATINOL-AQ 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 has been observed in up to 31% of patients treated with a single
dose of PLATINOL-AQ 50 mg/m2, and is manifested by tinnitus and/or
hearing loss in the high frequency range (4000 to 8000 Hz). The prevelance of
hearing loss in children is particularly high and is estimated to be 40-60%.
Decreased ability to hear normal conversational tones may occur. Deafness after
the initial dose of PLATINOL-AQ has been reported. Ototoxic effects may be more
severe in children receiving PLATINOLAQ.
Hearing loss can be unilateral or bilateral and tends to become more frequent
and severe with repeated cisplatin doses. It is unclear whether PLATINOL-AQ-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 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. Variants in the thiopurine S-methyltransferase
gene (TPMT) have been reported to be associated with an increased risk of ototoxicity
in children treated with cisplatin (see CLINICAL PHARMACOLOGY).
Other genetic factors may also contribute to the cisplatin-induced ototoxicity.
Myelosuppression occurs in 25% to 30% of patients treated with PLATINOL-AQ.
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:
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 PLATINOL-AQ has
been reported. In these reports, PLATINOL-AQ was generally given in combination
with other leukemogenic agents.
Marked nausea and vomiting occur in almost all patients treated with PLATINOL-AQ,
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 24 hours. Various
degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after
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 PLATINOL-AQ
Diarrhea has also been reported.
Vascular toxicities coincident with the use of PLATINOL-AQ 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 PLATINOL-AQ. It has been
suggested that hypomagnesemia developing coincident with the use of PLATINOL-AQ
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 PLATINOL-AQ 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 PLATINOL-AQ.
Inappropriate antidiuretic hormone syndrome has also been reported.
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, 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 PLATINOL-AQ neuropathy usually develop during treatment,
symptoms of neuropathy may begin 3 to 8 weeks after the last dose of PLATINOL-AQ.
PLATINOL-AQ 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 PLATINOL-AQ and with
a relatively advanced symptomatic stage of peripheral neuropathy.
Optic neuritis, papilledema, and cerebral blindness have been reported in patients
receiving standard recommended doses of PLATINOL-AQ. Improvement and/or total
recovery usually occurs after discontinuing PLATINOL-AQ. 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 PLATINOL-AQ 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
Anaphylactic-like reactions have been reported in patients previously exposed
to PLATINOL-AQ. 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 PLATINOL-AQ should be observed carefully for
possible anaphylactic-like reactions and supportive equipment and medication
should be available to treat such a complication.
Transient elevations of liver enzymes, especially SGOT, as well as bilirubin,
have been reported to be associated with PLATINOL-AQ administration at the recommended
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 PLATINOL-AQ.
Severity of the local tissue toxicity appears to be related to the concentration
of the PLATINOL-AQ solution. Infusion of solutions with a PLATINOL-AQ concentration
greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis,
pain, edema, and erythema.
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin
In a randomized trial in advanced ovarian cancer, response duration was adversely
affected when pyridoxine was used in combination with altretamine (hexamethylmelamine)