Use great caution in patients with renal insufficiency or preexisting auditory impairment; weigh risk of additional eighth-cranial nerve impairment or renal injury against benefits of the drug.
Concomitant use with other parenteral antituberculosis agents (streptomycin, viomycin [not commercially available in the US]) with similar and sometimes irreversible toxic effects, particularly on eighth-cranial nerve and renal function, not recommended. Use concomitantly with other ototoxic or nephrotoxic drugs (e.g., amikacin, colistimethate/colistin, gentamicin, kanamycin, neomycin, polymyxin A sulfate, tobramycin, vancomycin) with great caution. (See Interactions.)
Safe use during pregnancy not established. (See Pregnancy under Cautions.)
Safety and efficacy not established in pediatric patients.
Second-line agent used in treatment of drug-resistant TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to capreomycin.
For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months). Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months, ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy. A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.
Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.
Dosage and Administration
Administration
Administer by IV infusion or deep IM injection.
IV Administration
Reconstitution and Dilution
Reconstitute 1-g vial by adding 2 mL of 0.9% sodium chloride injection or sterile water for injection. Alternatively, reconstitute 1-g vial with 2.15, 2.63, 3.3, or 4.3 mL of 0.9% sodium chloride injection or sterile water for injection to provide solutions containing approximately 370, 315, 260, or 210 mg/mL, respectively, taking into account the retention volume. Allow 2–3 minutes for complete dissolution.
For IV infusion, reconstituted solution must be further diluted with 100 mL of 0.9% sodium chloride injection.
Rate of Administration
Administer by IV infusion over 60 minutes.
IM Administration
Administer by deep IM injection into a large muscle mass.
Avoid superficial IM injections since they may be associated with increased pain and development of sterile abscesses.
Reconstitution
Reconstitute 1-g vial by adding 2 mL of 0.9% sodium chloride injection or sterile water for injection. Alternatively, reconstitute 1-g vial with 2.15, 2.63, 3.3, or 4.3 mL of 0.9% sodium chloride injection or sterile water for injection to provide solutions containing approximately 370, 315, 260, or 210 mg/mL, respectively, taking into account the retention volume. Allow 2–3 minutes for complete dissolution.
Dosage
Available as capreomycin sulfate; dosage expressed in terms of capreomycin.
Should not be used alone for treatment of active (clinical) TB; must be given in conjunction with other antituberculosis agents.
Can be used in daily or intermittent (2 times weekly) multiple-drug TB regimens.
Pediatric Patients
Tuberculosis
Treatment of Active (Clinical) Tuberculosis
IV or IM
Children <15 years of age or weighing ≤40 kg†: 15–30 mg/kg daily (up to 1 g) given once daily or twice weekly recommended by ATS, CDC, IDSA, and AAP.
Children ≥15 years of age†: 15 mg/kg daily (up to 1 g) given as a single daily dose 5–7 times weekly for the first 2–4 months or until culture conversion recommended by ATS, CDC, and IDSA; dosage can then be reduced to 15 mg/kg daily (up to 1 g) given 2 or 3 times weekly, depending on efficacy of the other drugs in the regimen.
Adults
Tuberculosis
Treatment of Active (Clinical) Tuberculosis
IV or IM
15 mg/kg daily (up to 1 g) given as a single daily dose 5–7 times weekly for the first 2–4 months or until culture conversion recommended by ATS, CDC, and IDSA; dosage can then be reduced to 15 mg/kg daily (up to 1 g) given 2 or 3 times weekly, depending on efficacy of the other drugs in the regimen.
Manufacturer recommends 1 g (up to 20 mg/kg) daily for 60–120 days, followed by 1 g 2–3 times weekly.
Prescribing Limits
Pediatric Patients
Tuberculosis
Treatment of Active (Clinical) Tuberculosis
IV or IM
Maximum 1 g per dose in once-daily or 2- or 3-times weekly regimens.
Adults
Tuberculosis
Treatment of Active (Clinical) Tuberculosis
IV or IM
Maximum 1 g per dose in once-daily or 2- or 3-times weekly regimens.
Adults >59 years of age: Maximum 750 mg per dose in once-daily or 2- or 3-times weekly regimens.
Special Populations
Renal Impairment
Reduce dosage based on the degree of renal impairment. Use with caution and monitor serum capreomycin concentrations. (See Ototoxicity and Nephrotoxicity under Cautions.)
Manufacturer recommends that dosage in adults with renal impairment be based on Clcr and adjusted to maintain mean steady-state serum capreomycin concentrations of 10 mcg/mL. Consult manufacturer's literature for specific dosage recommendations for these patients.
Some experts suggest a reduced dosage of 12–15 mg/kg given 2 or 3 times weekly.
Doses in patients undergoing hemodialysis should be given after dialysis since the drug is removed by this procedure.
Geriatric Patients
Manufacturer states no dosage adjustments except those related to renal impairment. Select dosage with caution (usually starting at low end of dosage range). (See Geriatric Use under Cautions.)
Adults >59 years of age: ATS, CDC, and IDSA recommend 10 mg/kg (up to 750 mg) per dose. (See Geriatric Use under Cautions.)
Nephrotoxicity and ototoxicity, the most serious adverse effects of capreomycin, are most likely to occur in patients with renal impairment, in geriatric patients, and in patients receiving other nephrotoxic and/or ototoxic drugs. (See Interactions.)
Renal toxicity may be manifested by tubular necrosis, increased BUN, increased Scr, decreased Clcr, abnormal urinary sediment, proteinuria, and presence of casts, erythrocytes, and leukocytes in the urine. Usually reversible when the drug is discontinued, but fatal toxic nephritis has occurred rarely. Nephrotoxicity is most closely related to AUC of the drug. Electrolyte disturbances resembling Bartter's syndrome reported rarely.
May cause damage to both the auditory and vestibular portions of the eighth-cranial nerve. Some audiometric changes have been reversible, but hearing loss that was permanent (but not progressive) has been reported. Injury to the vestibular branch of the eighth-cranial nerve has resulted in headache, tinnitus, and vertigo.
Damage to auditory and vestibular divisions of the eighth-cranial nerve generally associated with capreomycin therapy in patients with impaired renal function or dehydration or those receiving other drugs with additive auditory toxicities; these patients often experience dizziness, tinnitus, vertigo, and a loss of high-tone acuity.
Assess renal, auditory, and vestibular function prior to and at regular intervals during capreomycin therapy. Manufacturer recommends that renal function be monitored once weekly. (See Geriatric Use under Cautions.)
BUN concentrations >30 mg/dL or any other evidence of decreasing renal function (with or without an increase in BUN) requires careful evaluation; dosage should be decreased or the drug discontinued. Clinical importance of abnormal urine sediment and slightly increased BUN (or Scr) during long-term capreomycin therapy not established.
Use with extreme caution in patients with renal insufficiency or auditory impairment; weigh the risk of additional renal impairment or eighth cranial nerve damage against the possible benefits of capreomycin therapy.
Neuromuscular Blockade
Partial neuromuscular blockade, which was enhanced by ether anesthesia and antagonized by neostigmine, has been reported with large IV doses of capreomycin. Neuromuscular blockade or respiratory paralysis may occur following rapid IV infusion.
Sensitivity Reactions
Hypersensitivity Reactions
Hypersensitivity reactions (e.g., urticaria, photosensitivity, maculopapular rash), which may be associated with fever, have occurred.
Use with caution in patients with a history of allergic reaction, especially to drugs.
General Precautions
Precautions Related to Treatment of Tuberculosis
Should not be used alone for treatment of active (clinical) TB; must be given in conjunction with other antituberculosis agents.
Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response. The antituberculosis regimen should be modified as needed. Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).
If added as a new drug to a regimen in patients experiencing treatment failure who have proven or suspected drug-resistant TB, at least 2 (preferably 3) new drugs known or expected to be active against the resistant strain should be added at the same time.
Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical. Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.
To ensure compliance, ATS, CDC, IDSA, and AAP recommend that directly observed (supervised) therapy (DOT) be used for treatment of active TB whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.
Laboratory Monitoring
Monitor renal function prior to and once weekly during capreomycin treatment. Monitor hepatic function periodically.
Monitor serum potassium concentrations since hypokalemia may occur. Some experts recommend that serum potassium and magnesium be assessed at baseline and at least once monthly.
Specific Populations
Pregnancy
Category C.
ATS, CDC, and IDSA state that use of capreomycin should be avoided during pregnancy because of risk of fetal nephrotoxicity and ototoxicity.
Lactation
Not known whether capreomycin is distributed into milk. Use caution in nursing women.
Pediatric Use
Safety and efficacy not established.
Geriatric Use
No evidence that patients ≥65 years of age respond differently than younger adults.
Select dosage with caution (usually starting at low end of dosage range) because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Substantially eliminated by kidneys; risk of toxicity may be greater in patients with impaired renal function. Monitor renal function since geriatric patients are more likely to have renal impairment. (See Renal Impairment under Dosage and Administration.)
Because geriatric patients are more likely to have impaired hearing at baseline, perform audiometric measurements and assess vestibular function prior to and at regular intervals during capreomycin therapy.
Renal Impairment
Use with caution because of risk of nephrotoxicity and/or neurotoxicity. Dosage adjustments required in those with known or suspected renal impairment.
If BUN concentrations increase to >30 mg/dL or there is any other evidence of decreasing renal function (with or without an increase in BUN), the patient should be carefully evaluated and capreomycin dosage reduced or the drug discontinued.
Common Adverse Effects
Nephrotoxicity, ototoxicity, injection site reactions.
Interactions
Ototoxic or Nephrotoxic Drugs
Concomitant or sequential use with other drugs that have ototoxic or nephrotoxic effects may result in additive toxicity and should be avoided, if possible. Use concomitantly only with great caution.
Half-life prolonged in patients with impaired renal function.
Stability
Storage
Parenteral
Powder for Injection
15–30°C.
Following reconstitution with 0.9% sodium chloride injection or sterile water for injection, solutions may be stored for up to 24 hours in a refrigerator. Capreomycin solutions may develop a pale straw color and darken with time; this is not associated with loss of potency or development of toxicity.
Actions
Usually bacteriostatic in action.
Mechanism of antibacterial action not known.
Spectrum of activity includes many mycobacterium and some gram-positive and -negative bacteria.
Mycobacteria: Active against M. tuberculosis, M. bovis, and M. avium complex (MAC). M. kansasii generally is resistant.
Natural and acquired resistance to capreomycin demonstrated in vitro and in vivo in strains of M. tuberculosis.
Cross-resistance frequently occurs between capreomycin and viomycin (not commercially available in the US); cross-resistance also can occur between capreomycin and kanamycin or neomycin. No evidence of cross-resistance between capreomycin and other antituberculosis agents available in the US.
There have been recent reports of extensively drug-resistant (XDR) TB. XDR TB is caused by M. tuberculosis resistant to rifampin and isoniazid (multiple-drug resistant strains) that also are resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial (capreomycin, kanamycin, amikacin).
Advice to Patients
Advise patients that poor compliance with antituberculosis regimens can result in treatment failure and development of drug-resistant TB, which can be life-threatening and lead to other serious health risks.
Importance of discontinuing therapy and informing clinicians if an allergic reaction occurs.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.
Importance of advising patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
