Capreomycin-Hisun Pharm

Actions: Capreomycin-Hisun Pharm is active against human strains of Mycobacterium tuberculosis.

Frequent cross-resistance occurs between Capreomycin-Hisun Pharm and viomycin. Varying degrees of cross-resistance between Capreomycin-Hisun Pharm and kanamycin and neomycin have been reported. No cross-resistance has been observed between Capreomycin-Hisun Pharm and isoniazid, aminosalicylic acid, cycloserine, streptomycin, ethionamide or ethambutol.

Indications: Capreomycin-Hisun Pharm should be used concomitantly with other appropriate antituberculous agents for the treatment of pulmonary infections caused by Capreomycin-Hisun Pharm-susceptible strains of Mycobacterium tuberculosis when the primary agents (isoniazid, rifampicin, streptomycin and ethambutol) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli.

Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) , which is to be used concomitantly with other appropriate antituberculosis agents, is indicated in pulmonary infections caused by capreomycin-susceptible strains of M. tuberculosis when the primary agents (isoniazid, rifampin, ethambutol, aminosalicylic acid, and streptomycin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli.

Susceptibility studies should be performed to determine the presence of a capreomycin­susceptible strain of M. tuberculosis.

The usual dose is 1g daily (but 20mg/kg/day should not be exceeded) given by deep intramuscular injection only for 60 to 120 days, followed by 1g intramuscularly two or three times a week. Capreomycin-Hisun Pharm is always administered in combination with at least one other antituberculous agent to which the patient's strain of tubercle bacillus is susceptible.

Capreomycin-Hisun Pharm should be dissolved in 2ml of 0.9% Sodium Chloride Intravenous Infusion BP or Water for Injections PhEur. Two to three minutes should be allowed for complete solution.

For administration of a 1g dose, the entire contents of the vial should be given. For dosages of less than 1g the following dilution table may be used:

The elderly: As for adults. Reduce dosage if renal function is impaired.

Patients with reduced renal function: A reduced dosage should be given based on creatinine clearance using the guidance given in the following table. These dosages are designed to achieve a mean steady-state Capreomycin-Hisun Pharm level of 10 micrograms/ml, at various levels of renal function:

Paediatric population

Not for paediatric use since the safety of Capreomycin-Hisun Pharm for use in infants and children has not been established. No data are available.

Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) may be administered intramuscularly or intravenously following reconstitution. Reconstitution is achieved by dissolving the vial contents (1 g) in 2 mL of 0.9% Sodium Chloride Injection or Sterile Water for Injection. Two to 3 minutes should be allowed for complete dissolution.

Intravenously - For intravenous infusion, reconstituted Capreomycin-Hisun Pharm Sulfate should be diluted in 100 mL of 0.9% Sodium Chloride Injection and administered over 60 minutes.

Intramuscularly - Reconstituted Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) should be given by deep intramuscular injection into a large muscle mass, since superficial injection may be associated with increased pain and the development of sterile abscesses.

For administration of a 1-g dose, the entire contents of the vial should be given. For doses lower than 1 g, the following dilution table may be used.

DILUTION TABLE

The solution may acquire a pale straw color and darken with time, but this is not associated with loss of potency or the development of toxicity. After reconstitution, all solutions of Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) may be stored for up to 24 hours under refrigeration.

Capreomycin is always administered in combination with at least 1 other antituberculosis agent to which the patient's strain of tubercle bacilli is susceptible. The usual dose is 1 g daily (not to exceed 20 mg/kg/day) given intramuscularly or intravenously for 60 to 120 days, followed by 1 g by either route 2 or 3 times weekly. (Note - Therapy for tuberculosis should be maintained for 12 to 24 months. If facilities for administering injectable medication are not available, a change to appropriate oral therapy is indicated on the patient's release from the hospital.)

Patients with reduced renal function should have dosage reduction based on creatinine clearance using the guidelines included in Table 1. These dosages are designed to achieve a mean steady-state capreomycin level of 10 µg/mL.

Table 1. Estimated Dosages to Attain Mean Steady-State Serum Capreomycin Concentration of 10 µg/mL (Based on Creatinine Clearance)

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Hypersensitivity to the active substance.

Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) is contraindicated in patients who are hypersensitive to capreomycin.

Warnings

The use of Capreomycin-Hisun Pharm in patients with renal insufficiency or pre-existing auditory impairment must be undertaken with great caution, and the risk of additional eighth cranial nerve impairment or renal injury should be weighed against the benefits to be derived from treatment.

Capreomycin-Hisun Pharm must be used only in conjunction with adequate doses of other antituberculous drugs. The use of Capreomycin-Hisun Pharm alone allows the rapid development of strains resistant to it.

Precautions

As Capreomycin-Hisun Pharm is potentially ototoxic, audiometry and assessment of vestibular function should be performed before starting treatment and at regular intervals during treatment.

Regular tests of renal function should be made throughout the period of treatment, and reduced dosage should be used in patients known, or suspected, renal impairment (see “Dosage and Administration”).

Since hypokalaemia may occur during Capreomycin-Hisun Pharm therapy, serum potassium levels should be determined frequently.

A partial neuromuscular block can occur after large doses of Capreomycin-Hisun Pharm.

Capreomycin-Hisun Pharm should be administered cautiously to patients with a history of allergy, particularly to drugs.

WARNINGS

No information provided.

PRECAUTIONS

General

Audiometric measurements and assessment of vestibular function should be performed prior to initiation of therapy with Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) and at regular intervals during treatment.

Renal injury, with tubular necrosis, elevation of the blood urea nitrogen (BUN) or serum creatinine, and abnormal urinary sediment, has been noted. Slight elevation of the BUN and serum creatinine has been observed in a significant number of patients receiving prolonged therapy. The appearance of casts, red cells, and white cells in the urine has been noted in a high percentage of these cases. Elevation of the BUN above 30 mg/100 mL or any other evidence of decreasing renal function with or without a rise in BUN levels calls for careful evaluation of the patient, and the dosage should be reduced or the drug completely withdrawn. The clinical significance of abnormal urine sediment and slight elevation in the BUN (or serum creatinine) observed during long-term therapy with Capreomycin-Hisun Pharm Sulfate has not been established.

The peripheral neuromuscular blocking action that has been attributed to other polypeptide antibiotics (colistin sulfate, polymyxin A sulfate, paromomycin, and viomycin) and to aminoglycoside antibiotics (streptomycin, dihydrostreptomycin, neomycin, and kanamycin) has been studied with Capreomycin-Hisun Pharm Sulfate (capreomycin for injection). A partial neuromuscular blockade was demonstrated after large intravenous doses of Capreomycin-Hisun Pharm Sulfate (capreomycin for injection). This action was enhanced by ether anesthesia (as has been reported for neomycin) and was antagonized by neostigmine.

Caution should be exercised in the administration of antibiotics, including Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) , to any patient who has demonstrated some form of allergy, particularly to drugs.

Laboratory Tests

Regular tests of renal function should be made throughout the period of treatment, and reduced dosage should be employed in patients with known or suspected renal impairment.

Renal function studies should be made both before therapy with Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) is started and on a weekly basis during treatment.

Since hypokalemia, hypomagnesemia and hypocalcemia may occur during therapy, these serum electrolyte levels should be determined frequently.

DRUG INTERACTIONS

For neuromuscular blocking action of this drug, see PRECAUTIONS, General.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been performed to determine potential for carcinogenicity, mutagenicity, or impairment of fertility.

Usage in Pregnancy - Pregnancy Category C

Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) has been shown to be teratogenic in rats when given in doses 3 1/2 times the human dose. There are no adequate and well-controlled studies in pregnant women. Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Boxed Warnings and Animal Pharmacology).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see Boxed Warnings).

Geriatric Use

Clinical studies of Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) did not analyze the safety and efficacy of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) is known to be substantially excreted by the kidney (see CLINICAL PHARMACOLOGY), and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS, Laboratory Tests). Patients with reduced renal function should have dosage reduction based on creatinine clearance using the guidelines included in Table 1 (see DOSAGE AND ADMINISTRATION).

The geriatric population is also more likely to have impaired hearing at baseline. Audiometric measurements and assessment of vestibular function should be performed prior to initiation of therapy with Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) and at regular intervals during treatment (see PRECAUTIONS, General).

Renal: Elevation of serum creatinine or blood urea and abnormal urine sediment have been observed. Toxic nephritis was reported in one patient with tuberculosis and portal cirrhosis who was treated with Capreomycin-Hisun Pharm (1g) and aminosalicylic acid daily for one month. This patient developed renal insufficiency and oliguria and died. The post-mortem showed subsiding acute tubular necrosis.

Electrolyte disturbances resembling Bartter's syndrome have been reported in one patient.

Hepatic: A decrease in bromsulphthalein excretion without change in serum enzymes has been noted in the presence of pre-existing liver disease. Abnormal results in liver function tests have occurred in many patients receiving Capreomycin-Hisun Pharm in combination with other antituberculous agents which are also known to cause changes in hepatic function. Periodic determinations of liver function are recommended.

Haematological: Leucocytosis and leucopenia have been observed. Rare cases of thrombocytopenia have been reported. Most patients receiving daily Capreomycin-Hisun Pharm have had eosinophilia exceeding 5%, but this has subsided with the reduction of Capreomycin-Hisun Pharm dosage to two or three times weekly.

Hypersensitivity: Urticaria and maculopapular rashes associated in some cases with febrile reactions have been reported when Capreomycin-Hisun Pharm and other antituberculous drugs were given concomitantly.

Otic: Clinical and subclinical auditory loss has been noted. Some audiometric changes have proved reversible and others, with permanent loss have not been progressive following withdrawal of Capreomycin-Hisun Pharm. Tinnitus and vertigo have occurred.

Injection site reactions: Pain and induration at injection sites have been observed. Excessive bleeding and sterile abscesses have also been reported at these sites.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continues monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

Nephrotoxicity: In 36% of 722 patients treated with Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) , elevation of the BUN above 20 mg/100 mL has been observed. In many instances, there was also depression of PSP excretion and abnormal urine sediment. In 10% of this series, the BUN elevation exceeded 30 mg/100 mL.

Toxic nephritis was reported in 1 patient with tuberculosis and portal cirrhosis who was treated with Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) (1 g) and aminosalicylic acid daily for 1 month. This patient developed renal insufficiency and oliguria and died. Autopsy showed subsiding acute tubular necrosis.

Electrolyte disturbances including hypokalemia, hypomagnesemia and hypocalcemia, sometimes serious in nature, have been reported.

Ototoxicity: Subclinical auditory loss was noted in approximately 11% of 722 patients undergoing treatment with Capreomycin-Hisun Pharm Sulfate (capreomycin for injection). This was a 5- to 10-decibel loss in the 4000- to 8000-CPS range. Clinically apparent hearing loss occurred in 3% of the 722 subjects. Some audiometric changes were reversible. Other cases with permanent loss were not progressive following withdrawal of Capreomycin-Hisun Pharm Sulfate (capreomycin for injection).

Tinnitus and vertigo have occurred.

Liver: Serial tests of liver function have demonstrated a decrease in BSP excretion without change in AST (SGOT) or ALT (SGPT) in the presence of preexisting liver disease. Abnormal results in liver function tests have occurred in many persons receiving Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) in combination with other antituberculosis agents that also are known to cause changes in hepatic function. The role of Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) in producing these abnormalities is not clear; however, periodic determinations of liver function are recommended.

Blood: Leukocytosis and leukopenia have been observed. The majority of patients treated have had eosinophilia exceeding 5% while receiving daily injections of Capreomycin-Hisun Pharm Sulfate (capreomycin for injection). This has subsided with reduction of the Capreomycin-Hisun Pharm Sulfate dosage to 2 or 3 g weekly.

Pain and induration at the injection site have been observed. Excessive bleeding at the injection site has been reported. Sterile abscesses have been noted. Rare cases of thrombocytopenia have been reported.

Hypersensitivity:Urticaria and maculopapular skin rashes associated in some cases with febrile reactions have been reported when Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) and other antituberculosis drugs were given concomitantly.

Signs and symptoms: Hypokalaemia, hypocalcaemia, hypomagnesaemia and an electrolyte disturbance resembling Bartter's syndrome have been reported to occur in patients with Capreomycin-Hisun Pharm toxicity. Nephrotoxicity, including acute tubular necrosis; and ototoxicity, including dizziness, tinnitus, vertigo and loss of high-tone acuity (see 'Warnings' and 'Precautions'). Neuromuscular blockage or respiratory paralysis may occur following rapid intravenous administration.

If Capreomycin-Hisun Pharm is ingested, toxicity is unlikely because less than 1% is absorbed from an intact gastro-intestinal system.

Treatment: Symptomatic and supportive therapy is recommended. Activated charcoal may be more effective than emesis or lavage in reducing absorption.

Patients who have received an overdose of Capreomycin-Hisun Pharm and have normal renal function should be hydrated to maintain a urine output of 3-5ml/kg/hr. Fluid balance electrolytes and creatinine clearance should be monitored.

Haemodialysis is effective in patients with significant renal disease.

Signs and Symptoms

Nephrotoxicity following the parenteral administration of Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) is most closely related to the area under the curve of the serum concentration versus time graph. The elderly patient, patients with abnormal renal function or dehydration, and patients receiving other nephrotoxic drugs are at much greater risk for developing acute tubular necrosis.

Damage to the auditory and vestibular divisions of cranial nerve VIII has been associated with Capreomycin-Hisun Pharm Sulfate (capreomycin for injection) given to patients with abnormal renal function or dehydration and in those receiving medications with additive auditory toxicities. These patients often experience dizziness, tinnitus, vertigo, and a loss of high-tone acuity.

Neuromuscular blockage or respiratory paralysis may occur following rapid intravenous infusion.

If capreomycin is ingested, toxicity would be unlikely because it is poorly absorbed (less than 1%) from an intact gastrointestinal system.

Hypokalemia, hypocalcemia, hypomagnesemia, and an electrolyte disturbance resembling Bartter's syndrome have been reported The subcutaneous median lethal dose in mice was 514 mg/kg.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient's airway and maintain, within acceptable limits, the patient's Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.

Patients who have received an overdose of capreomycin and have normal renal function should be carefully hydrated to maintain a urine output of 3 to 5 mL/kg/h. Fluid balance, electrolytes, and creatinine clearance should be carefully monitored.

Hemodialysis may be effectively used to remove capreomycin in patients with significant renal disease.