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The Complete Drug Reference Martindale
Drugs.com Principle &practice of pediatric
Oncology; P.Pizzo Drug Interactions in the therapy of malignant tumors(BAXTER Pub.) Medscape
References
cisplatin, carboplatin, and oxaliplatin are heavy metal coordination complexes which
exert their cytotoxic effects by platination of DNA a mechanism of action that is analogous to alkylation
Introduction
The rate of reaction of these platinum analogs with water to form reactive intermediates is an important determinant of the stability of the compounds in solution and influences the drugs' pharmacokinetic
Cisplatin is more reactive than carboplatin and is less stable in aqueous solution
The stability of oxaliplatin is intermediate.
Pharmacokinetics
The chemical stability (reactivity) of the platinum analogs is a critical determinant of
their pharmacokinetics. The reactive intermediates of cisplatin and
carboplatin are rapidly and covalently bound to plasma protein and tissue
Pharmacokinetics
Platinum coordination compound that inhibits DNA synthesis; cross-links and denatures strands of DNA; disrupts DNA function by covalently binding to DNA bases; can also produce DNA intrastrand cross-linking and breakage
Not a true alkylating agent
Mechanism of Action
Half-life elimination (terminal): 24hr to 47 days
Protein bound: >90% Excretion: Urine (90%); feces (10%) Clearance: 15 L/hr/m² Vd: 11 L/m²
Special pharmacokinetic points about cisplatin
Anaphylactic-like reactions have occurred. Facial edema, bronchoconstriction, tachycardia, and hypotension may occur within minutes of cisplatin administration
Failure to differentiate daily doses from total dose per treatment cycle may result in cisplatin overdose
Warnings & precautions
Hypersensitivity to cisplatin, other platinum compounds
Severe myelosuppression, renal impairment, hearing impairment
Pregnancy, lactation
Contraindications
Irritant; injection site reactions may occur during administration; use extravasation precautions
Avoid aluminum needles/equipment Use with caution in: hearing impairment,
neuropathy, neuromuscular disease, with neurotoxic agents, with ototoxic agents, elderly
cautions
Risk of cumulative nephrotoxicity (exacerbated by aminoglycoside antibiotics); renal toxicity becomes more prolonged and severe with repeated courses
renal function must return to normal before administering another dose
cautions
Patients taking ACE inhibitor with cisplatin are prone to RF 4 times more than other patients
Amphotericin B found to increase the uptake of cisplatin & carboplatin
Anti convulsant drugs one report about lowering plasma level of phenytoin in combination of cisplatin
Bleomycin; as cisplatin dose increased creatinine clearance & bleomycin elimination were decreased
Drug interactions
Fludarabine was shown to enhance the cytotoxicity effect of cisplatin
Irradiation to inner ear developed hearing loss in combination with cisplatin
MTX nephrotoxicity of MTX becomes irreversible in combination with cisplatin
Topotecan severe myelosupression in concomitant use of cisplatin were observed
Rituximab renal toxicity in concomitant use of cisplatin were observed
Drug interactions
Further dilution stability is dependent on chloride ion concentration & should be mixed in solutions of NS (at least 0.3% NaCl)
May administer 12.5-50 g mannitol/L Standard dilution: dose/250-1000 mL NS,
D5W/NS or D5/½NS
IV Preparation
Perform pretreatment hydration Do not use aluminum-containing needles or
IV administration sets that may come in contact with carboplatin (aluminum can react causing precipitate formation & loss of potency)
Administration rate has varied from a 15-120 min infusion, 1 mg/min infusion, 6-8 hr infusion, 24 hr infusion, or per protocol
IV Administration
Maximum rate of infusion: 1 mg/min in patients with CHF
When administered as sequential infusions, taxane derivatives (docetaxel, paclitaxel) should be administered before platinum derivatives to limit myelosuppression & to enhance efficacy
IV Administration
Large extravasations (>20 mL) of concentrated solutions (>0.5 mg/mL) produce tissue necrosis
Tx is not recommended unless a large amount of highly concentrated solution is extravasated
Mix 4 mL of 10% sodium thiosulfate with 6 mL SWI; inject 1-4 mL through existing IV line cannula; administer 1 mL for each mL extravasated; inject SC if needle is removed
Extravasation Management
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.
Adverse Reaction
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
Adverse Reaction
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
Adverse Reaction
As a result of its nephrotoxic effects, cisplatin can alter its own elimination rate and that of other drugs, such as methotrexate
renal clearance of ultrafilterable platinum
fell from almost 500mL/min with the first course to 150 mL/min by the fourth course in patients receiving repeated doses
Adverse Reaction
Gastrointestinal Acute cisplatin-induced emesis occurs one to four
hours after cisplatin administration and is primarily serotonin mediated.
A serotonin-receptor antagonist in combination with a steroid 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.
Adverse Reaction
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, cortical blindness, Lhermitte's sign, and dorsal column myelopathy
Nervous system
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)
Cisplatin neuropathies generally occur with higher dosage regimens and may be irreversible
Nervous system
at cumulative doses of 300 to 600 mg/m2. Lhermitre's sign is common at high cumulative doses of cisplatin
Symptoms may progress after discontinuation of cisplatin
Nervous system
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
Ototoxicity
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
Ototoxicity
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.
Hematologic
Treatment of anemia with recombinant erythropoietin is generally helpful.
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
Hematologic
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
Hypersensitivity
Absorption Peak Plasma Time: 2-4 hr Distribution Protein Bound: 87% (platinum) Vd: 16 L Elimination Clearance: 4.4 L/hr Excretion: Urine (70% as carboplatin) Half-life Carboplatin: 3-6 hr
pharmacokinetics of Carboplatin
Reconstitute powder to yield a final concentration of 10 mg/mL which is stable for 5 days at room temp (25°C)
IV Administration Administer as IV over 15 min or continuous
infusion over 24 hr May also be administered intraperitoneally
IV Preparation
VP16 clearance was lower when given with high dose carboplatin
Amifostine is potential inactivator of cisplatin & carboplatin
Drug Interactions
dose-limiting toxicity of carboplatin is hematological toxicity,
primarily thrombocytopenia, and the nonhematological toxicities observed with cisplatin are only seen at doses of carboplatin
exceeding 800 mg/m2
Adverse Reactions
Carboplarin's myelosuppressive effects are delayed, affecting the frequency by which the drug can be administered
Platelet nadirs are typically seen up to 3 weeks after the dose and milder granulocyte nadirs are observed 3 to 4 weeks after carboplatin administration
Adverse Reactions
carboplatin are associated with a small drop in glomerular filtration rate and serum magnesium, not clinically significant.
Hypersensitivity reactions to carboplatin are relatively common and the risk increases after
multiple cycles of therapy
Adverse Reactions
Pharmacokinetics Peak Plasma Time: 2 hr Concentration: 1.21 mcg/mL Protein Bound: >90%; Vd: 440 L Clearance: 10.1 L/hr Excretion: Urine(54%); feces (2%) Dialyzable: no
oxaliplatin (Rx) - Eloxatin
A cholinergic syndrome were evaluated in a patient whom received oxaliplatin in combination of amphotricin
Drug interactions
Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each Oxaliplatin cycle
There have been reports while on study of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/leucovorin while on anticoagulants
Recommended Laboratory Tests
Acute neuropathy is reversible and primarily of a peripheral sensory nature.
The onset occurs within hours to 2 days of dosing.
It generally resolves within 2 weeks and frequently recurs with repeat doses.
Exposure to cold temperature or cold objects may precipitate or exacerbate symptoms.
Symptoms may include transient paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat
Nervous system
Grade 0 No change or none Grade 1 Mild paresthesias, loss of deep
tendon reflexes Grade 2 Mild or moderate objective sensory
loss, moderate paresthesias Grade 3 Severe objective sensory loss or
paresthesias that interfere with function Grade 4 Not applicable
Grade Definition
Persistent neuropathy may occur with no prior neuropathy event.
Eighty percent of patients who developed Grade 3 persistent neuropathy progressed from Grade 1 or 2
Persistent neuropathy generally lasts for more than 2 weeks and is also primarily of a peripheral sensory nature.
Nervous system
Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and chest pressure have also been reported.
Ice should be avoided for mucositis prophylaxis.
Acute pharyngolaryngeal dysesthesia with sensations of dysphagia and dyspnea but no laryngospasm or bronchospasm has been reported in 1% to 2% of patients.
Nervous system
The symptoms may improve in some patients when oxaliplatin is discontinued.
Treatment measures include calcium and magnesium solutions, gabapentin, and alpha-lipoic acid
Treatment
Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the Oxaliplatin combination arm than in the control arm.
The incidence of increased bilirubin was similar on both arms.
Hepatotoxicity
Hypersensitivity reactions of an anaphylactoid and anaphylactic nature with symptoms of rash, urticaria, erythema, pruritus, and rarely, bronchospasm, and hypotension have been reported.
Anaphylactic shock has also been reported
Hypersensitivity
Patients who develop mild to moderate hypersensitivity to oxaliplatin may be pretreated with steroids as well as type 1 and type 2 histamine receptor antagonists.
However, patients who develop severe reactions are unlikely to tolerate further therapy
Hypersensitivity