PRECAUTIONS
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It is essential that appropriate blood
studies be made during treatment with chloramphenicol. While blood
studies may detect early peripheral blood changes, such studies
cannot be relied on to detect the rare and generally irreversible
bone marrow depression prior to development of aplastic anemia.
Baseline blood studies should
be followed by periodic blood studies at intervals during therapy.
Dependent upon the severity of the disease being treated, the drug
may be discontinued upon appearance of reticulocytopenia, leukopenia,
thrombocytopenia, anemia, or other blood alterations attributable
to chloramphenicol. However, it should be noted that such studies
do not exclude the possible later appearance of the irreversible
type of bone marrow depression.
Repeated courses of the drug should be avoided, if at all possible.
Treatment should not be continued longer than required to produce
a cure with little or no risk of relapse of the disease.
Concurrent therapy with other drugs that may cause bone marrow depression
should be avoided.
Excessive blood levels may result from administration of the recommended
dose to patients with impaired liver or kidney function, including
that due to immature metabolic processes in the infant. The dosage
should be adjusted accordingly and the blood concentration should
be determined at appropriate intervals, if possible.
Caution should be used in therapy of premature and full-term infants
to avoid "gray syndrome" toxicity (see Adverse Effects).
Serum drug levels should be carefully followed during therapy of
the neonate.
Pregnancy: There are no studies which establish the safety
of this drug for use in pregnancy. Benefit to the mother must be
weighed against a possible risk to the fetus. Use of the drug at
term or during labor may pose an additional hazard to the fetus
since chloramphenicol readily crosses the placental barrier. One
case of "gray syndrome" has been reported in a neonate
born to a mother having received chloramphenicol intravenously during
labor.
The use of this antibiotic, as with other antibiotics, may result
in the overgrowth of nonsusceptible organisms, including fungi.
ADVERSE
EFFECTS
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Blood Dyscrasias: The most
serious adverse effect of chloramphenicol is bone marrow depression.
Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic
anemia, thrombocytopenia, and granulocytopenia) are known to occur
rarely after the administration of chloramphenicol. A generally
irreversible type of marrow depression leading to aplastic anemia
with a high rate of mortality is characterized by the appearance
weeks or months after therapy of bone marrow aplasia or hypoplasia.
Peripherally, pancytopenia is most often observed, but in a small
number of cases only one or two of the three major cell types (erythrocytes,
leukocytes, platelets) may be depressed. There have been reports
of aplastic anemia attributed to chloramphenicol later terminating
in leukemia.
A reversible type of bone marrow depression which is dose related,
may occur. This type of marrow depression is characterized by vacuolization
of the erythroid cells, reduction of reticulocytes and leukopenia,
and responds to withdrawal of chloramphenicol.
Paroxysmal nocturnal hemoglobinuria has also been reported.
Gastrointestinal Reactions: Nausea, vomiting, glossitis and
stomatitis, diarrhea and enterocolitis may occur in low incidence.
Neurotoxic Reactions: Headache, mild depression, mental confusion
and delirium have been described in patients receiving chloramphenicol.
Optic and peripheral neuritis have been reported, usually following
long-term therapy. If this occurs, the drug should be promptly discontinued.
Hypersensitivity Reactions:
Fever, macular and vesicular rashes, angioedema, urticaria and anaphylaxis
may occur.
The Herxheimer reaction has
occurred during therapy for typhoid fever.
Gray Syndrome: Toxic reactions including fatalities have
occurred in the premature and newborn age group. The signs and symptoms
associated with these reactions have been referred to as the "gray
syndrome". The following summarizes the clinical and laboratory
studies that have been made on these patients.
In most cases therapy with chloramphenicol had been instituted within
the first 48 hours of life.
Symptoms first appeared after 3 to 4 days of continued treatment
with high doses of chloramphenicol.
The symptoms appeared in the following order:
a. abdominal distention with or without emesis
b. progressive pallid cyanosis
c. vasomotor collapse frequently accompanied by irregular respiration
d. death within a few hours of onset of these symptoms.
The progression of symptoms from onset to death was accelerated
with higher dose schedules. Blood serum level studies revealed unusually
high concentrations of chloramphenicol (over 90 µg/mL) after
repeated doses. Termination of therapy upon early evidence of the
associated symptomatology frequently revised the process with complete
recovery.
Chloramphenicol has been shown to retard the biotransformation of
tolbutamide, phenytoin, and dicumarol in man.
OVERDOSAGE
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Levels exceeding 25 µg/mL are
frequently considered toxic.
Symptoms: Chloramphenicol toxicity can be evidenced by serious
hemopoietic effects such as aplastic anemia, thrombocytopenia, leukopenia,
as well as increasing serum iron levels, nausea, vomiting and diarrhea.
Treatment: In the case of serious overdosage, charcoal hemoperfusion
may be effective in removing chloramphenicol from plasma. Exchange
transfusion is of questionable value following massive overdosage,
especially in neonates and infants.
| DOSAGE |
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Chloramphenicol must be prescribed
in adequate dosage. Inhibition of the majority of sensitive organisms
may be expected at blood levels of 5 to 20 µg/mL. Levels of
the order of 10 µg/mL are usually achieved following oral
doses of 50 mg/kg daily.
Where possible, chloramphenicol should be administered orally. Consequently,
patients started on intravenous chloramphenicol sodium succinate
should be changed to the oral form as soon as practicable.
Adults: Adults should
receive 50 mg/kg/day in divided doses at 6-hour intervals. In exceptional
cases patients with infections due to moderately resistant organisms
may require increased dosage up to 100 mg/kg/day to achieve blood
levels inhibiting the pathogen, but these high doses should be decreased
as soon as possible.
Adults with impairment of hepatic or renal function or both may
have reduced ability to metabolize and excrete the drug. In instances
of impaired metabolic processes, dosages should be adjusted accordingly
(see discussion under Newborn Infants).
Children: Dosage of 50 mg/kg/day divided at 6-hour intervals
is effective against most susceptible organisms. Severe infections
(e.g. septicemia or meningitis) especially when adequate cerebrospinal
fluid concentrations are desired, require dosage up to 100 mg/kg/day
divided at 6 or 12 hour intervals. It is recommended that dosage
be reduced to 50 mg/kg/day as soon as possible.
Children with impaired liver or kidney functions or both may retain
excessive amounts of the drug.
Newborn Infants (premature and term): For newborn infants a total
of 25 mg/kg/day in 4 equal doses at 6-hour intervals usually produces
and maintains concentrations in blood and tissues adequate to control
most infections for which the drug is indicated. Increased dosage
in these individuals, demanded by severe infections, should be given
only to maintain the blood concentration within a therapeutically
effective range. After the first 2 weeks of life, full term infants
ordinarily may receive up to a total of 50 mg/kg/day equally divided
into 4 doses at 6-hour intervals. These dosage recommendations are
extremely important because blood concentration in all premature
infants and full term infants under 2 weeks of age differs from
that of other infants. This difference is due to variations in the
maturity of the metabolic functions of the liver and kidneys.
When these functions are immature (or seriously impaired in adults)
high concentrations of the drug are found which tend to increase
with succeeding doses. See section titled Gray Syndrome under Adverse
Effects.
Infants and Children with Immature Metabolic Processes: In young
infants and other children in whom immature metabolic functions
are suspected, a dose of 25 mg/kg/day will usually produce therapeutic
concentrations of the drug in the blood. In this group particularly,
the concentration of the drug in the blood should be carefully followed
by microbiological techniques where possible.
SUPPLIED
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Each rubber diaphragm-capped vial
contains: chloramphenicol sodium succinate equivalent to 1 g chloramphenicol.
The product has been freeze-dried in the vial. A dose of chloramphenicol
sodium succinate equivalent to 1 g of chloramphenicol contains approximately
52 mg (2.25 mEq) of sodium. Packages of 10. Store at controlled
room temperature (15-30°C).
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