Capreomycin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection, as sulfate [preservative free]:

Capastat Sulfate: 1 g (1 ea)

Pharmacology

Mechanism of Action

Capreomycin is a cyclic polypeptide antimicrobial. It is administered as a mixture of capreomycin IA and capreomycin IB. The mechanism of action of capreomycin is not well understood. Mycobacterial species that have become resistant to other agents are usually still sensitive to the action of capreomycin. However, significant cross-resistance with viomycin, kanamycin, and neomycin occurs.

Pharmacokinetics/Pharmacodynamics

Absorption

Oral: Not absorbed

Excretion

Urine (52% unchanged within 12 hours)

Time to Peak

Serum: IM: 1 to 2 hours

Half-Life Elimination

CrCl 100 to 110 mL/minute: 5 to 6 hours; CrCl 50 to 80 mL/minute: 7 to 10 hours; CrCl 20 to 40 mL/minute: 12 to 20 hours; CrCl 10 mL/minute: 29 hours; CrCl 0 mL/minute: 55 hours

Use: Labeled Indications

Tuberculosis, pulmonary: Treatment of pulmonary infections caused by capreomycin-susceptible strains of Mycobacterium tuberculosis, in combination with other appropriate antituberculosis agents, when the primary agents (eg, isoniazid, rifampin, ethambutol, pyrazinamide) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli.

Contraindications

Hypersensitivity to capreomycin or any component of the formulation

Dosage and Administration

Dosing: Adult

Tuberculosis, pulmonary: IM, IV:

15 mg/kg once daily (maximum: 1 g/dose) for 5 to 7 days per week for 2 to 4 months, followed by 15 mg/kg (maximum: 1 g/dose) 2 to 3 times weekly (MMWR 2003)

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. 1 g once daily (maximum: 20 mg/kg/dose) for 60 to 120 days, followed by 1 g 2 to 3 times weekly

Dosing: Geriatric

Use with caution because of the increased potential for preexisting renal dysfunction or impaired hearing.

Adults >59 years of age: 10 mg/kg once daily (maximum: 750 mg/dose) for 5 to 7 days per week for 2 to 4 months, followed by 10 mg/kg (maximum: 750 mg/dose) 2 to 3 times weekly (MMWR 2003)

Dosing: Pediatric

Active tuberculosis infection; treatment multidrug resistant (MDR) (second-line therapy): Limited data available: Note: Always use as part of a multidrug regimen. Any regimens using less than once daily dosing should administer dosing as directly observed therapy (DOT). Treatment regimens for MDR TB are variable depending upon sensitivity and clinical response. Capreomycin frequency and dosing differs depending on treatment regimen selected; consult current drug-sensitive TB guidelines for detailed information (ATS/CDC/IDSA [Nahid 2016]; Schaaf 2015).

Primary pulmonary disease:

Once-daily therapy:

Infants, Children, and Adolescents <15 years, weighing ≤40 kg: Note: Suggested expert dosing range is large and variable (Schaaf 2015): IM, IV: 15 to 30 mg/kg/dose once daily; some experts recommend an initial dose range of 15 to 20 mg/kg/dose once daily; maximum daily dose: 1,000 mg/day; monitor serum concentrations (ATS/CDC/IDSA [Nahid 2016]; DHHS [pediatric] 2013; Schaaf 2015; Seddon 2012)

Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: IM, IV: 15 mg/kg/dose once daily; maximum daily dose: 1,000 mg/day; monitor serum concentrations (ATS/CDC/IDSA [Nahid 2016]; HHS [adult] 2016; Seddon 2012)

Three-times weekly DOT:Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: IM, IV: 25 mg/kg/dose three times weekly; maximum dose: 1,000 mg/dose (ATS/CDC/IDSA [Nahid 2016]

Twice-weekly DOT: Infants, Children, and Adolescents <15 years, weighing ≤40 kg: IM, IV: 25 to 30 mg/kg/dose twice weekly; maximum dose: 1,000 mg/dose (ATS/CDC/IDSA [Nahid 2016])

Meningitis (independent of HIV-status): Infants, Children, and Adolescents: Suggested expert dosing range is large and variable (Schaaf 2015): IM, IV: 15 to 30 mg/kg/dose once daily; some experts recommend an initial range of 15 to 20 mg/kg/dose once daily; maximum daily dose: 1,000 mg/day; monitor serum concentrations (ATS/CDC/IDSA [Nahid 2016]; DHHS [pediatric] 2013; Red Book [AAP 2015]; Schaaf 2015)

Reconstitution

Reconstitute with 2 mL of NS or SWFI; allow 2 to 3 minutes for dissolution.

For IV administration: Further dilute in NS 100 mL.

For IM administration:

1 g dose: Administer contents of reconstituted vial

<1 g dose: See table:

Table has been converted to the following text.

Capreomycin Dilution for Doses <1 g (IM Administration):

Diluent volume 2.15 mL and capreomycin solution volume 2.85 mL for a final concentration of ~370 mg/mL

Diluent volume 2.63 mL and capreomycin solution volume 3.33 mL for a final concentration of ~315 mg/mL

Diluent volume 3.3 mL and capreomycin solution volume 4 mL for a final concentration of ~260 mg/mL

Diluent volume 4.3 mL and capreomycin solution volume 5 mL for a final concentration of ~210 mg/mL

Administration

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

IV: Administer over 60 minutes.

Storage

Store intact vials at 15°C to 30°C (59°F to 86°F). Following reconstitution, may store under refrigeration for up to 24 hours.

Drug Interactions

Aminoglycosides: Capreomycin may enhance the neuromuscular-blocking effect of Aminoglycosides. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Avoid combination

Colistimethate: Capreomycin may enhance the neuromuscular-blocking effect of Colistimethate. Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Mecamylamine: Capreomycin may enhance the neuromuscular-blocking effect of Mecamylamine. Avoid combination

Neuromuscular-Blocking Agents: Capreomycin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Polymyxin B: Capreomycin may enhance the neuromuscular-blocking effect of Polymyxin B. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Adverse Reactions

Frequency not always defined.

>10%:

Otic: Ototoxicity (subclinical hearing loss: 11%; clinical loss: 3%)

Genitourinary: Nephrotoxicity (36%, increased blood urea nitrogen)

1% to 10%: Hematologic: Eosinophilia (dose-related, mild)

<1%, postmarketing, and/or case reports: Hepatic insufficiency (decreased sulfobromophthalein excretion), hypersensitivity (includes fever, maculopapular rash, urticaria), hypocalcemia, hypokalemia, hypomagnesemia, increased serum creatinine, injection site reaction (includes abscess at injection site, bleeding at injection site, induration at injection site, and pain at injection site), leukocytosis, leukopenia, nephritis (toxic), renal tubular necrosis, thrombocytopenia (rare), tinnitus, urine sedimentation abnormality, vertigo

Warnings/Precautions

Concerns related to adverse effects:

• Electrolyte imbalance: Hypocalcemia, hypokalemia, and hypomagnesemia have been reported with use. Monitor electrolytes periodically during treatment.
• Nephrotoxicity: May cause nephrotoxicity, including tubular necrosis, increased BUN or serum creatinine, and abnormal urinary sediment; slight elevations in BUN and serum creatinine with urinary RBCs, WBCs, and casts have been observed with prolonged treatment. Monitor renal function at baseline and periodically during treatment. A BUN >30 mg/dL or other evidence of decreasing renal function should prompt clinical evaluation and dosage adjustment or therapy discontinuation.
• Ototoxicity: May cause impairment of cranial nerve VIII, which may be irreversible; perform audiometric assessment and assessment of vestibular function prior to initiation and periodically during treatment.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Allergies: Use with caution in patients who demonstrate some form of allergy.
• Auditory impairment: [US Boxed Warning]: Use in patients with preexisting auditory impairment must be undertaken with great caution, and the risk of additional cranial nerve VIII impairment should be weighed against the benefits to be derived from therapy.
• Renal impairment: [US Boxed Warning]: Use in patients with renal impairment must be undertaken with great caution, and the risk of additional renal injury should be weighed against the benefits to be derived from therapy. Dosage reductions are recommended for known or suspected renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Drugs with ototoxic or nephrotoxic potential: [US Boxed Warning]: Use with nonantituberculous drugs (eg, polymyxin A sulfate, colistin sulfate, gentamicin, tobramycin, vancomycin, neomycin) having ototoxic or nephrotoxic potential should be undertaken only with great caution.
• Parenteral antituberculous agents: [US Boxed Warning]: Because other parenteral antituberculous agents (eg, streptomycin, viomycin) also have similar and sometimes irreversible toxic effects, particularly on cranial nerve VIII and renal function, simultaneous administration of these agents with capreomycin is not recommended.

Special populations:

• Elderly: Use with caution.
• Pediatric: [US Boxed Warning]: Safety has not been established in pediatric patients.
• Pregnancy: [US Boxed Warning]: Safety has not been established in pregnant women.

Monitoring Parameters

Audiometric measurements and vestibular function at baseline and during therapy; renal function at baseline and weekly during therapy; baseline and frequent assessment of serum electrolytes (including calcium, magnesium, and potassium), liver function tests

Pregnancy

Pregnancy Considerations

Adverse events have been reported in animal reproduction studies. [US Boxed Warning]: Safety has not been established in pregnant women; avoid use during pregnancy because of the risk of fetal nephrotoxicity and congenital hearing loss (MMWR 2003).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Have patient report immediately to prescriber signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of infection, severe dizziness, muscle weakness, bruising, bleeding, trouble hearing, noise or ringing in the ears, or injection site pain or irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.