Adverse Reaction

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Platinium compounds
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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.)
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Medscape
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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
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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.
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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
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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
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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
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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
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Hypersensitivity to cisplatin, other platinum
compounds
Severe myelosuppression, renal impairment,
hearing impairment
Pregnancy, lactation
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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
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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
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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
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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
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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
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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
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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
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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
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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 doselimiting side effect of cisplatin, which is
dose-related, cumulative, and occurs in 36%
of patients after single doses of 50 mg/m2.
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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
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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
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As a result of its nephrotoxic effects, cisplatin
can alter its own elimination rate and that of
other drugs, such as methotrexate
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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
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
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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.
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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
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Symptoms of the sensory polyneuropathy
typically begin in toes and feet and, later,
affect the fingers and hands in a stockingand-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
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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
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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
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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
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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.
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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
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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
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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
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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
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VP16 clearance was lower when given with
high dose carboplatin
Amifostine is potential inactivator of cisplatin
& carboplatin
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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
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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
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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
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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
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A cholinergic syndrome were evaluated in a
patient whom received oxaliplatin in
combination of amphotricin
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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 5fluorouracil/leucovorin while on anticoagulants
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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
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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
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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.
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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.
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The symptoms may improve in some patients
when oxaliplatin is discontinued.
Treatment measures include calcium and
magnesium solutions, gabapentin, and
alpha-lipoic acid
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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.
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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
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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
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