Approved Drug Label (PDF)
4
Contraindications
4 CONTRAINDICATIONS
(Physician
Labeling Rule (PLR) Conversion)
Cisplatin for injection is contraindicated
in patients with severe hypersensitivity to cisplatin.
5
Warnings and Precautions
5.1 Nephrotoxicity
(Physician
Labeling Rule (PLR) Conversion)
Cisplatin for injection can cause
dose-related nephrotoxicity, including acute renal failure that becomes more
prolonged and severe with repeated courses of the drug. Renal toxicity
typically begins during the second week after a dose of cisplatin for
injection. Patients with baseline renal impairment, geriatric patients,
patients who are taking other nephrotoxic drugs, or patients who are not well
hydrated may be more susceptible to nephrotoxicity.
Ensure adequate hydration before, during,
and after cisplatin for injection administration. Measure serum creatinine,
blood urea nitrogen, creatinine clearance, and serum electrolytes including
magnesium prior to initiating therapy, and as clinically indicated. Consider magnesium supplementation as
clinically needed.
Consider alternative treatments or reduce
the dose of cisplatin for injection for patients with baseline renal impairment
or who develop significant reductions in creatinine clearance during treatment
with cisplatin for injection according to clinical treatment guidelines.
5.2 Peripheral Neuropathy
(Physician
Labeling Rule (PLR) Conversion)
Cisplatin for injection can cause
dose-related peripheral neuropathy that becomes more severe with repeated
courses of the drug. Neurologic symptoms
have been reported to occur after a single dose. Neuropathy can also have a
delayed onset from 3 to 8 weeks after the last dose of cisplatin for
injection. Manifestations include paresthesias
in a stocking-glove distribution, areflexia, and loss of proprioception and
vibratory sensation. The neuropathy may
progress further even after stopping treatment. Peripheral neuropathy may be
irreversible in some patients.
Perform a neurological examination before
initiating cisplatin for injection, at appropriate intervals during therapy,
and after completion of therapy. Consider discontinuation of cisplatin for
injection for patients who develop symptomatic peripheral neuropathy. Geriatric
patients may be more susceptible to peripheral neuropathy.
5.3 Nausea and Vomiting
(Physician
Labeling Rule (PLR) Conversion)
Cisplatin for injection is a highly
emetogenic antineoplastic agent. Premedicate with anti-emetic agents. 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
(Physician
Labeling Rule (PLR) Conversion)
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.
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
(Physician
Labeling Rule (PLR) Conversion)
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
(Physician
Labeling Rule (PLR) Conversion)
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.
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
(Physician
Labeling Rule (PLR) Conversion)
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
(Physician
Labeling Rule (PLR) Conversion)
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
(Physician
Labeling Rule (PLR) Conversion)
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.
5.10 Injection Site Reactions
(Physician
Labeling Rule (PLR) Conversion)
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
6 ADVERSE REACTIONS
(Physician
Labeling Rule (PLR) Conversion)
The following adverse reactions are
described in greater detail, in other sections:
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
7
Drug Interactions
7 DRUG INTERACTIONS
(Physician
Labeling Rule (PLR) Conversion)
The following drug interactions are
described in other sections:
Nephrotoxic
drugs
Ototoxic
drugs
8
Use in Specific Populations
8 USE IN SPECIFIC POPULATIONS
(Pregnancy
and Lactation Labeling Rule (PLLR) Conversion)
8.1
Pregnancy
Risk Summary
Based on human data from published
literature, cisplatin for injection can cause fetal harm when administered to
pregnant women. Advise pregnant women and females of reproductive potential of
the potential risk to a fetus. Data demonstrates transplacental transfer of
cisplatin. Exposure of pregnant women to cisplatin-containing chemotherapy has
been associated with oligohydramnios, intrauterine growth restriction, and
preterm birth. Cases of neonatal acute
respiratory distress syndrome, cytopenias, and hearing loss have been reported.
Cisplatin for injection administration to animals during and after
organogenesis resulted in teratogenicity. A published study in mice showed
placental transfer of cisplatin increased with placenta maturation.
The background risk of major birth defects
and miscarriage for the indicated populations are unknown. However, the background risk in the U.S.
general population of major birth defects is 2-4% and of miscarriage is 15-20%
of clinically recognized pregnancies.
8.2 Lactation
(Pregnancy
and Lactation Labeling Rule (PLLR) Conversion)
Risk Summary
Limited data from published literature
report the presence of cisplatin in human milk in low amounts. Because of the
potential for serious adverse reactions from cisplatin for injection in a
breastfed child and because of the potential for tumorigenicity shown for
cisplatin for injection, advise lactating women not to breastfeed during
treatment with cisplatin for injection.
8.3 Females and Males of Reproductive Potential
(Pregnancy
and Lactation Labeling Rule (PLLR) Conversion)
Pregnancy Testing
Verify the pregnancy status of females of
reproductive potential prior to initiation of cisplatin for injection.
Contraception
Females
Cisplatin for injection can cause fetal
harm when administered to a pregnant. Advise females of reproductive potential
to use effective contraception during treatment and for 14 months following the
last dose of cisplatin for injection.
Males
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.
Infertility
Females
The use of cisplatin has been associated
with cumulative dose-dependent ovarian failure, premature menopause, and
reduced fertility.
Males
The use of cisplatin has been associated
with a cumulative dose-dependent impairment of spermatogenesis (oligospermia,
azoospermia; possibly irreversible) and reduced fertility.
8.4 Pediatric Use
(Physician
Labeling Rule (PLR) Conversion)
Ototoxic effects may be more severe and
detrimental in pediatric patients receiving cisplatin for injection,
particularly in patients less than 5 years of age. Consider audiometric and
vestibular function monitoring in all patients receiving cisplatin for
injection. The prevalence of hearing loss in pediatric patients is particularly
high and is estimated to be 40% to 60%.
Earlier detection of hearing loss can
limit the potential impact of hearing impairment on a pediatric patient’s cognitive
and social development.
8.5 Geriatric Use
(Physician
Labeling Rule (PLR) Conversion)
For the treatment of metastatic testicular
tumors or advanced bladder cancer, clinical studies of cisplatin for injection
did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. In four clinical trials of combination
chemotherapy for advanced ovarian carcinoma, 1,484 patients received cisplatin
either in combination with cyclophosphamide or with paclitaxel. Of these, 426
(29%) were older than 65 years. In these trials, age was not found to be a
prognostic factor for survival. However, in a later secondary analysis for one
of these trials, geriatric patients were found to have shorter survival
compared with younger patients.
In all four trials, geriatric patients
experienced more severe neutropenia than did younger patients. Higher
incidences of severe thrombocytopenia and leukopenia were also seen in
geriatric patients compared with younger patients, although not in all
cisplatin-containing treatment arms. In the two trials where nonhematologic
toxicity was evaluated according to age, geriatric patients had a numerically
higher incidence of peripheral neuropathy than did younger patients. Other
reported clinical experience suggests that geriatric patients may be more
susceptible to nephrotoxicity, myelosuppression, and infectious complications
than are younger patients.
Cisplatin is known to be substantially
excreted by the kidney. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and renal
function should be monitored.
8.6 Use in Patients
with Renal Impairment
(Physician
Labeling Rule (PLR) Conversion)
Patients with baseline renal impairment
may be more susceptible to nephrotoxicity. Ensure adequate hydration before, during, and
after cisplatin for injection
administration. Measure serum creatinine, blood urea nitrogen, creatinine
clearance, and serum electrolytes prior to initiating therapy, and as
clinically indicated. Consider
alternative treatments or reduce the dose of cisplatin for injection for
patients with baseline renal impairment or who develop significant reductions
in creatinine clearance during treatment with cisplatin for injection according
to clinical treatment guidelines.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Physician Labeling Rule (PLR) Conversion)
Nephrotoxicity
Inform
patients that cisplatin for injection
can
cause nephrotoxicity and
that renal function and electrolyte
monitoring during treatment
is necessary. If indicated,
inform patients about the use of electrolyte supplements.
Peripheral Neuropathy
Advise patients to report any new
paresthesias to their healthcare provider.
Nausea and
Vomiting
Advise patients concerning the use of
antiemetics to prevent nausea and vomiting and to report persistent
or severe symptoms to their healthcare provider.
Myelosuppression
Advise patients that
cisplatin for injection can reduce the absolute neutrophil count and
the platelet count resulting
in an increased risk of
infection and bleeding and
to contact
their healthcare provider for new
onset fever, symptoms of infection, or bleeding.
Ototoxicity
Advise patients to report any symptoms of hearing loss or vestibular
dysfunction to their healthcare
provider and that periodic monitoring of hearing
may be performed.
Embryo-Fetal Toxicity
Advise females of reproductive potential to use effective
contraception during treatment and for 14 months following 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 following the last dose of cisplatin for injection.
Lactation
Advise females not to breastfeed during treatment with cisplatin for injection.
Infertility
Inform
patients that treatment with cisplatin
for injection may lead to permanent
impairment of spermatogenesis, ovarian failure or premature menopause,
and reduced fertility in both genders.
Alopecia
Inform patients that cisplatin for
injection can cause alopecia.
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