Platinol Side Effects

Generic Name: cisplatin

Please note - some side effects for Platinol may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Platinol - for the Consumer

Platinol AQ

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Platinol AQ:

Diarrhea; loss of appetite; muscle pain; nausea; vomiting; weakness.

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blindness; blood in the urine or stools; blurred vision; chest pain; decreased urine volume or frequency; dizziness; hearing problems; inability to distinguish colors; infection (fever, chills, sore throat, cough); joint pain; lightheadedness; loss of balance; loss of motor function; loss of taste; numbness, tingling, or pain of the hands or feet; pain, redness, or swelling at the site of injection; ringing in the ears; seizures; unusual bruising or bleeding; unusual tiredness; wheezing.

Platinol Side Effects - for the Professional

Platinol

Nephrotoxicity

Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of Platinol. 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 can be given. Elderly patients may be more susceptible to nephrotoxicity.

Impairment of renal function has been associated with renal tubular damage. The administration of Platinol 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 Platinol 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000 Hz). Decreased ability to hear normal conversational tones may occur occasionally. Deafness after the initial dose of Platinol (cisplatin for injection, USP) has been reported rarely. Ototoxic effects may be more severe in children receiving Platinol. 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 Platinol-induced ototoxicity is reversible. Ototoxic effects may be related to the peak plasma concentration of Platinol. Careful monitoring of audiometry should be performed prior to initiation of therapy and prior to subsequent doses of Platinol.

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 Platinol. 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 as part of postmarketing surveillance. Elderly patients may be more susceptible to myelosuppression.

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 has been reported rarely in humans. In these reports, Platinol was generally given in combination with other leukemogenic agents.

Gastrointestinal

Marked nausea and vomiting occur in almost all patients treated with Platinol, 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 Platinol therapy.

Diarrhea has also been reported.

OTHER TOXICITIES

Vascular toxicities coincident with the use of Platinol 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 Platinol. It has been suggested that hypomagnesemia developing coincident with the use of Platinol 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 and are probably related to renal tubular damage. Tetany has been reported occasionally in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing Platinol.

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

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 neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of Platinol, although this is rare. Platinol 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.

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 Platinol 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 Platinol. Improvement and/or total recovery usually occurs after discontinuing Platinol. 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 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 occasionally in patients previously exposed to Platinol. 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 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 Platinol administration at the recommended doses.

Other Events

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

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

Side Effects by Body System

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.

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.

Gastrointestinal

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.)

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.

Nervous system

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, and cortical blindness. Ototoxicity, headache, encephalopathy, and strokes have also been reported.

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.

Hematologic

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.

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.

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.

Other

Other side effects including vascular toxicities have rarely been reported with the use of cisplatin in combination with other neoplastic agents. Vascular events may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic uremic syndrome), or cerebral arteritis. Raynaud's phenomenon has been reported in patients receiving bleomycin and vinblastine, with or without cisplatin. Four cases of distal ischemic changes have been reported in patients receiving combination chemotherapy with cisplatin and gemcitabine.

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.

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

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.

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.

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

Cardiovascular

Cardiovascular side effects including chronic lipid and blood pressure abnormalities have been reported. Possible cardiotoxicity (ST-T wave abnormalities and bundle branch block) have rarely been reported. Atrial fibrillation, supraventricular tachycardia, and a case of bradycardia have also been reported.

Endocrine

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

Dermatologic

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

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