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Capastat

Generic Name: Capreomycin Sulfate
Class: Antituberculosis Agents
VA Class: AM500
CAS Number: 1405-37-4

Warning(s)

  • 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.102

  • 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.102 Use concomitantly with other ototoxic or nephrotoxic drugs (e.g., amikacin, colistimethate/colistin, gentamicin, kanamycin, neomycin, polymyxin A sulfate, tobramycin, vancomycin) with great caution.102 (See Interactions.)

  • Safe use during pregnancy not established.102 (See Pregnancy under Cautions.)

  • Safety and efficacy not established in pediatric patients.102

Introduction

Antituberculosis agent;100 102 polypeptide antibiotic complex of 4 microbiologically active components.102

Uses for Capastat

Tuberculosis

Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.100 101 102

Second-line agent used in treatment of drug-resistant TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to capreomycin.100 101 102

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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).100 101 Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months,100 101 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.100 A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.100 101

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.100

Capastat Dosage and Administration

Administration

Administer by IV infusion or deep IM injection.102

IV Administration

Reconstitution and Dilution

Reconstitute 1-g vial by adding 2 mL of 0.9% sodium chloride injection or sterile water for injection.102 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.102 Allow 2–3 minutes for complete dissolution.102

For IV infusion, reconstituted solution must be further diluted with 100 mL of 0.9% sodium chloride injection.102

Rate of Administration

Administer by IV infusion over 60 minutes.102

IM Administration

Administer by deep IM injection into a large muscle mass.102

Avoid superficial IM injections since they may be associated with increased pain and development of sterile abscesses.102

Reconstitution

Reconstitute 1-g vial by adding 2 mL of 0.9% sodium chloride injection or sterile water for injection.102 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.102 Allow 2–3 minutes for complete dissolution.102

Dosage

Available as capreomycin sulfate; dosage expressed in terms of capreomycin.102

Should not be used alone for treatment of active (clinical) TB; must be given in conjunction with other antituberculosis agents.100 101 102

Can be used in daily or intermittent (2 times weekly) multiple-drug TB regimens.100

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) 100 101 given once daily or twice weekly100 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.100

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.100

Manufacturer recommends 1 g (up to 20 mg/kg) daily for 60–120 days, followed by 1 g 2–3 times weekly.102

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.100 101

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.100 102

Adults >59 years of age: Maximum 750 mg per dose in once-daily or 2- or 3-times weekly regimens.100

Special Populations

Renal Impairment

Reduce dosage based on the degree of renal impairment.100 102 Use with caution and monitor serum capreomycin concentrations.100 102 (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.102 Consult manufacturer's literature for specific dosage recommendations for these patients.102

Some experts suggest a reduced dosage of 12–15 mg/kg given 2 or 3 times weekly.100

Doses in patients undergoing hemodialysis should be given after dialysis since the drug is removed by this procedure.100

Geriatric Patients

Manufacturer states no dosage adjustments except those related to renal impairment.102 Select dosage with caution (usually starting at low end of dosage range).102 (See Geriatric Use under Cautions.)

Adults >59 years of age: ATS, CDC, and IDSA recommend 10 mg/kg (up to 750 mg) per dose.100 (See Geriatric Use under Cautions.)

Cautions for Capastat

Contraindications

  • Hypersensitivity to capreomycin.102

Warnings/Precautions

Warnings

Ototoxicity and Nephrotoxicity

Nephrotoxicity and ototoxicity, the most serious adverse effects of capreomycin,a are most likely to occur in patients with renal impairment, in geriatric patients, and in patients receiving other nephrotoxic and/or ototoxic drugs.102 a (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.102 a Usually reversible when the drug is discontinued, but fatal toxic nephritis has occurred rarely.a Nephrotoxicity is most closely related to AUC of the drug.102 Electrolyte disturbances resembling Bartter’s syndrome reported rarely.102

May cause damage to both the auditory and vestibular portions of the eighth-cranial nerve.a Some audiometric changes have been reversible, but hearing loss that was permanent (but not progressive) has been reported.102 Injury to the vestibular branch of the eighth-cranial nerve has resulted in headache, tinnitus, and vertigo.a

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.102

Assess renal, auditory, and vestibular function prior to and at regular intervals during capreomycin therapy.102 Manufacturer recommends that renal function be monitored once weekly.102 (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.102 Clinical importance of abnormal urine sediment and slightly increased BUN (or Scr) during long-term capreomycin therapy not established.102

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.102

Neuromuscular Blockade

Partial neuromuscular blockade, which was enhanced by ether anesthesia and antagonized by neostigmine, has been reported with large IV doses of capreomycin.102 Neuromuscular blockade or respiratory paralysis may occur following rapid IV infusion.102

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., urticaria, photosensitivity, maculopapular rash), which may be associated with fever, have occurred.102 a

Use with caution in patients with a history of allergic reaction, especially to drugs.102

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.100 101 102

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.100 102 The antituberculosis regimen should be modified as needed.100 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).100

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.100

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical.100 Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.100

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.100 101

Laboratory Monitoring

Monitor renal function prior to and once weekly during capreomycin treatment.102 Monitor hepatic function periodically.102

Monitor serum potassium concentrations since hypokalemia may occur.102 Some experts recommend that serum potassium and magnesium be assessed at baseline and at least once monthly.100

Specific Populations

Pregnancy

Category C.102

ATS, CDC, and IDSA state that use of capreomycin should be avoided during pregnancy because of risk of fetal nephrotoxicity and ototoxicity.100

Lactation

Not known whether capreomycin is distributed into milk.102 Use caution in nursing women.102

Pediatric Use

Safety and efficacy not established.102

Geriatric Use

No evidence that patients ≥65 years of age respond differently than younger adults.102

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.102

Substantially eliminated by kidneys; risk of toxicity may be greater in patients with impaired renal function.102 Monitor renal function since geriatric patients are more likely to have renal impairment.102 (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.102

Renal Impairment

Use with caution because of risk of nephrotoxicity and/or neurotoxicity.100 102 Dosage adjustments required in those with known or suspected renal impairment.100 102

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.102

Common Adverse Effects

Nephrotoxicity, ototoxicity, injection site reactions.102

Interactions for Capastat

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.102 Use concomitantly only with great caution.102

Specific Drugs

Drug

Interaction

Comments

Aminoglycosides

Possible increased risk of ototoxicity or nephrotoxicity102

Concomitant use with streptomycin not recommended;102 use concomitantly with other aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, tobramycin) only with great caution102

Colistimethate/Colistin

Possible increased risk of nephrotoxicity and/or neurotoxicity102

Use concomitantly only with great caution102

Neuromuscular blocking agents

Possible potentiation of neuromuscular blockade102

Polymyxin B

Possible increased risk of nephrotoxicity and/or neurotoxicity102

Use concomitantly only with great caution102

Vancomycin

Possible increased risk of nephrotoxicity and/or neurotoxicity102

Use concomitantly only with great caution102

Capastat Pharmacokinetics

Absorption

Bioavailability

Not appreciably absorbed from the GI tract; must be given parenterally.102

Following IM administration, peak serum concentrations attained within 1–2 hours.102

Plasma Concentrations

Peak serum concentrations after IV infusion are 30% higher than those following IM injection;102 AUC is similar for both routes.102

No evidence of accumulation in plasma in patients with normal renal function.102

Distribution

Extent

Information not available on distribution of capreomycin into body tissues or fluids.a

Does not distribute into CSF.100

Not known if capreomycin crosses the placenta or is distributed into milk.102 a

Elimination

Elimination Route

Eliminated mainly unchanged in urine by glomerular filtration.a Animal studies suggest small amounts may also be excreted in bile.a

Approximately 52% of an IM dose is excreted in urine within 12 hours.102

Removed by hemodialysis.102

Half-life

4–6 hours in patients with normal renal function.a

Special Populations

Half-life prolonged in patients with impaired renal function.a

Stability

Storage

Parenteral

Powder for Injection

15–30°C.102

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.102 Capreomycin solutions may develop a pale straw color and darken with time; this is not associated with loss of potency or development of toxicity.102

Actions and Spectrum

  • Usually bacteriostatic in action.a

  • Mechanism of antibacterial action not known.a

  • Spectrum of activity includes many mycobacterium and some gram-positive and -negative bacteria.a

  • Mycobacteria: Active against M. tuberculosis, M. bovis, and M. avium complex (MAC).a M. kansasii generally is resistant.107 108

  • Natural and acquired resistance to capreomycin demonstrated in vitro and in vivo in strains of M. tuberculosis.103 104 a

  • Cross-resistance frequently occurs between capreomycin and viomycin (not commercially available in the US);102 104 cross-resistance also can occur between capreomycin and kanamycin or neomycin.102 104 No evidence of cross-resistance between capreomycin and other antituberculosis agents available in the US.102

  • There have been recent reports of extensively drug-resistant (XDR) TB.105 106 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).105 106

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.100

  • Importance of discontinuing therapy and informing clinicians if an allergic reaction occurs.102

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.102

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.102

  • Importance of advising patients of other important precautionary information.102 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Capreomycin Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

1 g (of capreomycin)

Capastat Sulfate

Lilly

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Centers for Disease Control and Prevention. Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Recomm Rep. 2003; 52(RR-11):1-77.

101. American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

102. Eli Lilly and Company. Capastat sulfate (capreomycin for injection) prescribing information. Indianapolis, IN; 2003 Dec 8.

103. Mause CE, Plikaytis BB, Shinnick TM. Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2005; 49:571-7. [PubMed 15673735]

104. Mause CE, Plikaytis BB, Shinnick TM. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycbacterium tuberculosis. Antimicrob Agents Chemother. 2005; 49:3192-7. [PubMed 16048924]

105. World Health Organization. Extensively drug-resistant tuberculosis (XDR-TB): recommendations for prevention and control. Wkly Epidemiol Rec. 2006; 45:430-2.

106. Gandhi NR, Moll A, Sturm AW et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006; 368:1575-80. [PubMed 17084757]

107. Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175:367-416. [PubMed 17277290]

108. Shitrit D, Baum GL, Priess R et al. Pulmonary Mycobacterium kansasii infection in Israel, 1999-2004: clinical features, drug susceptibility, and outcome. Chest. 2006; 129:771-6. [PubMed 16537880]

a. AHFS Drug Information 2007. McEvoy GK, ed. Capreomycin. American Society of Health-System Pharmacists; 2007:546-8.

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