Chloromycetin Injection (Chloramphenicol)

CHLOROMYCETIN® INJECTION

Parke-Davis

Chloramphenicol

Antibiotic

Indications And Clinical Uses: In accordance with the concepts in the Contraindications section and this Indications section, chloramphenicol should be used only in those conditions for which it may be the antibiotic of choice.

These would include:

  • Acute infections caused by Salmonella typhi. It is not recommended for the routine treatment of the typhoid carrier state.
  • Serious infections caused by susceptible strains: (a) Salmonella species with systemic involvement. (b) H. influenzae, specifically meningeal infections. (c) Rickettsia; psittacosis in children. (d) Various gram-negative bacteria causing bacteremia, meningitis or other serious gram-negative infections. (e) Other susceptible organisms which have been demonstrated to be resistant to other appropriate antimicrobial agents.
  • Cystic fibrosis regimens.

Contra-Indications: Chloramphenicol is contraindicated in individuals with a history of previous hypersensitivity and/or toxic reaction to it.

Manufacturers’ Warnings In Clinical States: Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia and bone marrow depression) are known to occur after the administration of chloramphenicol. In addition, there have been reports of aplastic anemia attributed to chloramphenicol which later terminated in leukemia. Blood dyscrasias have occurred after both short term and prolonged therapy with this drug. Chloramphenicol must not be used when less potentially dangerous agents will be effective. It must not be used in the treatment of trivial infections or where it is not indicated as in colds, influenza, infections of the throat, or as a prophylactic agent to prevent bacterial infections.

Precautions: It is essential that appropriate blood studies be made during treatment with chloramphenicol. While blood studies may detect early peripheral blood changes, such as leukopenia, reticulocytopenia, or granulocytopenia, before they become irreversible, such studies cannot be relied on to detect bone marrow depression prior to development of aplastic anemia.

Baseline blood studies should be followed by periodic blood studies at intervals during therapy. The drug should 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 neonates to avoid gray syndrome toxicity (see Adverse Effects). Serum drug levels should be carefully followed during therapy of the neonate.

Pregnancy and Lactation: 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. One case of ‘gray syndrome’ has been reported in a neonate born to a mother having received chloramphenicol i.v. during labor. Chloramphenicol is excreted in human breast milk. Precaution should be used in therapy during lactation because of the possibility of toxic effects on the nursing infant.

The use of this antibiotic, as with other antibiotics, may result in an overgrowth of nonsusceptible organisms, including fungi. If infections caused by nonsusceptible organisms appear during therapy, appropriate measures should be taken.

Adverse Reactions: 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 1 or 2 of the 3 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 premature infants and neonates. 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: abdominal distension with or without emesis; progressive pallid cyanosis; vasomotor collapse, frequently accompanied by irregular respiration; 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 reversed the process with complete recovery.

Drug Interactions: Chloramphenicol has been shown to retard the biotransformation of tolbutamide, phenytoin, and dicumarol in man.

Chloramphenicol should be used with caution if administered concomitantly with lincomycin, clindamycin, or erythromycin. In vitro experiments have demonstrated that binding sites for erythromycin, lincomycin, clindamycin and chloramphenicol overlap and competitive inhibition may occur. Rifampin therapy can reduce chloramphenicol concentrations.

Dosage And Administration: 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 i.v. chloramphenicol sodium succinate should be changed to the oral form as soon as practicable. The use of the i.m. route should be restricted to those patients where oral dosing is not possible and i.v. use is impossible or impracticable. Blood levels achieved following i.m. administration of 50 mg/kg/day may be inadequate. If i.m. administration is deemed essential, it is advisable to give 75 mg/kg/day in divided doses in order to achieve desired blood levels.

I.V. dosage – 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 Neonates).

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; however, 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.

Neonates: 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 neonates 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 neonates and full term neonates 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.

Availability And Storage: Each vial contains: chloramphenicol sodium succinate equivalent to 1 g of chloramphenicol for i.m., i.v. or s.c. use. Cartons of 10.

CHLOROMYCETIN® INJECTION Parke-Davis Chloramphenicol Antibiotic

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