Usual Adult Dose for Tuberculosis - Extrapulmonary

Initial dose: 250 mg orally every 12 hours for the first 2 weeks
Maintenance dose: 500 to 1000 mg orally per day, given in divided doses
Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be determined by blood levels.
• Treatment of urinary tract infections should be considered in patients for whom conventional therapy has failed, and when the organism has demonstrated susceptibility to this drug.
• This drug should be given concomitantly with other effective anti-tuberculous options; use of treatment as the only therapeutic agent should be avoided.

Uses:

• Treatment of active pulmonary and extrapulmonary tuberculosis (e.g., renal disease) with susceptible causative organisms AND when the response to primary treatment options (e.g., ethambutol, isoniazid, rifampin/rifamycin, streptomycin) are inadequate
• Treatment of acute urinary tract infections caused by susceptible gram-positive and negative bacteria

American Thoracic Society (ATS), US Centers for Disease Control and Prevention (US CDC), and Infectious Diseases Society of America (IDSA) Recommendations:
10 to 15 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be titrated and determines by serum levels.
• This drug is usually given as 250 to 500 mg orally once to 2 times a day.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US Department of Health and Human Services (US HHS), and IDSA Recommendations:
10 to 15 mg/kg orally once to 2 times a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comments:

• This drug may be started with 250 mg orally once a day, and doses may be titrated based on serum levels.
• Some experts state that usual doses are 500 to 750 mg/day in 2 divided doses.

Uses:

• Second-line treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis with known/presumed susceptibility
• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Temporary treatment of acute hepatitis in combination with other non-hepatotoxic drugs

US HHS, National Institutes of Health (NIH), Health Resources and Services Administration (HRSA), and US CDC Recommendations:
Initial dose: 250 mg orally once a day
Maintenance dose: 250 to 1000 mg orally per day, given once a day or in divided doses
Maximum dose: 1000 mg/day

Comments:

• This drug should be given via directly observed therapy (DOT).
• Initial doses may be increased based on tolerability.
• The recommended maintenance dose range is 10 to 15 mg/kg/day, given in 2 divided doses.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Usual Adult Dose for Tuberculosis - HIV Positive

Initial dose: 250 mg orally every 12 hours for the first 2 weeks
Maintenance dose: 500 to 1000 mg orally per day, given in divided doses
Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be determined by blood levels.
• Treatment of urinary tract infections should be considered in patients for whom conventional therapy has failed, and when the organism has demonstrated susceptibility to this drug.
• This drug should be given concomitantly with other effective anti-tuberculous options; use of treatment as the only therapeutic agent should be avoided.

Uses:

• Treatment of active pulmonary and extrapulmonary tuberculosis (e.g., renal disease) with susceptible causative organisms AND when the response to primary treatment options (e.g., ethambutol, isoniazid, rifampin/rifamycin, streptomycin) are inadequate
• Treatment of acute urinary tract infections caused by susceptible gram-positive and negative bacteria

American Thoracic Society (ATS), US Centers for Disease Control and Prevention (US CDC), and Infectious Diseases Society of America (IDSA) Recommendations:
10 to 15 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be titrated and determines by serum levels.
• This drug is usually given as 250 to 500 mg orally once to 2 times a day.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US Department of Health and Human Services (US HHS), and IDSA Recommendations:
10 to 15 mg/kg orally once to 2 times a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comments:

• This drug may be started with 250 mg orally once a day, and doses may be titrated based on serum levels.
• Some experts state that usual doses are 500 to 750 mg/day in 2 divided doses.

Uses:

• Second-line treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis with known/presumed susceptibility
• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Temporary treatment of acute hepatitis in combination with other non-hepatotoxic drugs

US HHS, National Institutes of Health (NIH), Health Resources and Services Administration (HRSA), and US CDC Recommendations:
Initial dose: 250 mg orally once a day
Maintenance dose: 250 to 1000 mg orally per day, given once a day or in divided doses
Maximum dose: 1000 mg/day

Comments:

• This drug should be given via directly observed therapy (DOT).
• Initial doses may be increased based on tolerability.
• The recommended maintenance dose range is 10 to 15 mg/kg/day, given in 2 divided doses.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Usual Adult Dose for Tuberculosis - Resistant

Initial dose: 250 mg orally every 12 hours for the first 2 weeks
Maintenance dose: 500 to 1000 mg orally per day, given in divided doses
Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be determined by blood levels.
• Treatment of urinary tract infections should be considered in patients for whom conventional therapy has failed, and when the organism has demonstrated susceptibility to this drug.
• This drug should be given concomitantly with other effective anti-tuberculous options; use of treatment as the only therapeutic agent should be avoided.

Uses:

• Treatment of active pulmonary and extrapulmonary tuberculosis (e.g., renal disease) with susceptible causative organisms AND when the response to primary treatment options (e.g., ethambutol, isoniazid, rifampin/rifamycin, streptomycin) are inadequate
• Treatment of acute urinary tract infections caused by susceptible gram-positive and negative bacteria

American Thoracic Society (ATS), US Centers for Disease Control and Prevention (US CDC), and Infectious Diseases Society of America (IDSA) Recommendations:
10 to 15 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be titrated and determines by serum levels.
• This drug is usually given as 250 to 500 mg orally once to 2 times a day.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US Department of Health and Human Services (US HHS), and IDSA Recommendations:
10 to 15 mg/kg orally once to 2 times a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comments:

• This drug may be started with 250 mg orally once a day, and doses may be titrated based on serum levels.
• Some experts state that usual doses are 500 to 750 mg/day in 2 divided doses.

Uses:

• Second-line treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis with known/presumed susceptibility
• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Temporary treatment of acute hepatitis in combination with other non-hepatotoxic drugs

US HHS, National Institutes of Health (NIH), Health Resources and Services Administration (HRSA), and US CDC Recommendations:
Initial dose: 250 mg orally once a day
Maintenance dose: 250 to 1000 mg orally per day, given once a day or in divided doses
Maximum dose: 1000 mg/day

Comments:

• This drug should be given via directly observed therapy (DOT).
• Initial doses may be increased based on tolerability.
• The recommended maintenance dose range is 10 to 15 mg/kg/day, given in 2 divided doses.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Usual Adult Dose for Tuberculosis - Active

Initial dose: 250 mg orally every 12 hours for the first 2 weeks
Maintenance dose: 500 to 1000 mg orally per day, given in divided doses
Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be determined by blood levels.
• Treatment of urinary tract infections should be considered in patients for whom conventional therapy has failed, and when the organism has demonstrated susceptibility to this drug.
• This drug should be given concomitantly with other effective anti-tuberculous options; use of treatment as the only therapeutic agent should be avoided.

Uses:

• Treatment of active pulmonary and extrapulmonary tuberculosis (e.g., renal disease) with susceptible causative organisms AND when the response to primary treatment options (e.g., ethambutol, isoniazid, rifampin/rifamycin, streptomycin) are inadequate
• Treatment of acute urinary tract infections caused by susceptible gram-positive and negative bacteria

American Thoracic Society (ATS), US Centers for Disease Control and Prevention (US CDC), and Infectious Diseases Society of America (IDSA) Recommendations:
10 to 15 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be titrated and determines by serum levels.
• This drug is usually given as 250 to 500 mg orally once to 2 times a day.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US Department of Health and Human Services (US HHS), and IDSA Recommendations:
10 to 15 mg/kg orally once to 2 times a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comments:

• This drug may be started with 250 mg orally once a day, and doses may be titrated based on serum levels.
• Some experts state that usual doses are 500 to 750 mg/day in 2 divided doses.

Uses:

• Second-line treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis with known/presumed susceptibility
• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Temporary treatment of acute hepatitis in combination with other non-hepatotoxic drugs

US HHS, National Institutes of Health (NIH), Health Resources and Services Administration (HRSA), and US CDC Recommendations:
Initial dose: 250 mg orally once a day
Maintenance dose: 250 to 1000 mg orally per day, given once a day or in divided doses
Maximum dose: 1000 mg/day

Comments:

• This drug should be given via directly observed therapy (DOT).
• Initial doses may be increased based on tolerability.
• The recommended maintenance dose range is 10 to 15 mg/kg/day, given in 2 divided doses.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Usual Adult Dose for Urinary Tract Infection

Initial dose: 250 mg orally every 12 hours for the first 2 weeks
Maintenance dose: 500 to 1000 mg orally per day, given in divided doses
Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be determined by blood levels.
• Treatment of urinary tract infections should be considered in patients for whom conventional therapy has failed, and when the organism has demonstrated susceptibility to this drug.
• This drug should be given concomitantly with other effective anti-tuberculous options; use of treatment as the only therapeutic agent should be avoided.

Uses:

• Treatment of active pulmonary and extrapulmonary tuberculosis (e.g., renal disease) with susceptible causative organisms AND when the response to primary treatment options (e.g., ethambutol, isoniazid, rifampin/rifamycin, streptomycin) are inadequate
• Treatment of acute urinary tract infections caused by susceptible gram-positive and negative bacteria

American Thoracic Society (ATS), US Centers for Disease Control and Prevention (US CDC), and Infectious Diseases Society of America (IDSA) Recommendations:
10 to 15 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comments:

• Maintenance doses should be titrated and determines by serum levels.
• This drug is usually given as 250 to 500 mg orally once to 2 times a day.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US Department of Health and Human Services (US HHS), and IDSA Recommendations:
10 to 15 mg/kg orally once to 2 times a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comments:

• This drug may be started with 250 mg orally once a day, and doses may be titrated based on serum levels.
• Some experts state that usual doses are 500 to 750 mg/day in 2 divided doses.

Uses:

• Second-line treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis with known/presumed susceptibility
• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Temporary treatment of acute hepatitis in combination with other non-hepatotoxic drugs

US HHS, National Institutes of Health (NIH), Health Resources and Services Administration (HRSA), and US CDC Recommendations:
Initial dose: 250 mg orally once a day
Maintenance dose: 250 to 1000 mg orally per day, given once a day or in divided doses
Maximum dose: 1000 mg/day

Comments:

• This drug should be given via directly observed therapy (DOT).
• Initial doses may be increased based on tolerability.
• The recommended maintenance dose range is 10 to 15 mg/kg/day, given in 2 divided doses.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Usual Adult Dose for Mycobacterium avium-intracellulare - Treatment

US HHS, NIH, HRSA, and US CDC Recommendations:
5 mg/kg orally 2 times per day

• Maximum dose: 1000 mg/day

Comments:

• Use is supported by anecdotal evidence.
• Antiretroviral therapy (ART) should be optimized in patients with unsuccessful initial treatment OR with resistance to antimycobacterial agents.

Use: Second-line adjunct therapy (with azithromycin/clarithromycin and other drugs as salvage therapy) in the treatment of Mycobacterium avium intracellulare complex (MAC) in patients with HIV

Usual Pediatric Dose for Tuberculosis - Extrapulmonary

American Academy of Pediatrics (AAP) Recommendations:
Infants, children, and adolescents: 10 to 20 mg/kg orally per day, given in 2 divided doses

• Maximum dose: 1 gram/day

Use: Adjunctive treatment of drug-resistant tuberculosis

ATS, US CDC, and IDSA Recommendations:
Children: 15 to 20 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comment: Maintenance doses should be titrated and based on serum levels.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US HHS, and IDSA Recommendations:
Children: 10 to 15 mg/kg orally once a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comment: Maintenance doses should be titrated and based on serum levels.

Uses:

• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Second-line treatment of drug-resistant tuberculosis caused by organisms with known/presumed susceptibility to the agent
• Temporary treatment of acute hepatitis in combination with other nonhepatotoxic drugs

US HHS, NIH, HRSA, and US CDC Recommendations:
Children: 10 to 20 mg/kg orally once a day

• Maximum dose: 1000 mg/day
• Duration of therapy: At least 12 months (minimal disease); 18 to 24 months (after non-bacteriological diagnosis OR after culture conversion)

Comments:

• This drug should be given via DOT.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Usual Pediatric Dose for Tuberculosis - HIV Positive

American Academy of Pediatrics (AAP) Recommendations:
Infants, children, and adolescents: 10 to 20 mg/kg orally per day, given in 2 divided doses

• Maximum dose: 1 gram/day

Use: Adjunctive treatment of drug-resistant tuberculosis

ATS, US CDC, and IDSA Recommendations:
Children: 15 to 20 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comment: Maintenance doses should be titrated and based on serum levels.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US HHS, and IDSA Recommendations:
Children: 10 to 15 mg/kg orally once a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comment: Maintenance doses should be titrated and based on serum levels.

Uses:

• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Second-line treatment of drug-resistant tuberculosis caused by organisms with known/presumed susceptibility to the agent
• Temporary treatment of acute hepatitis in combination with other nonhepatotoxic drugs

US HHS, NIH, HRSA, and US CDC Recommendations:
Children: 10 to 20 mg/kg orally once a day

• Maximum dose: 1000 mg/day
• Duration of therapy: At least 12 months (minimal disease); 18 to 24 months (after non-bacteriological diagnosis OR after culture conversion)

Comments:

• This drug should be given via DOT.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Usual Pediatric Dose for Tuberculosis - Resistant

American Academy of Pediatrics (AAP) Recommendations:
Infants, children, and adolescents: 10 to 20 mg/kg orally per day, given in 2 divided doses

• Maximum dose: 1 gram/day

Use: Adjunctive treatment of drug-resistant tuberculosis

ATS, US CDC, and IDSA Recommendations:
Children: 15 to 20 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comment: Maintenance doses should be titrated and based on serum levels.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US HHS, and IDSA Recommendations:
Children: 10 to 15 mg/kg orally once a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comment: Maintenance doses should be titrated and based on serum levels.

Uses:

• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Second-line treatment of drug-resistant tuberculosis caused by organisms with known/presumed susceptibility to the agent
• Temporary treatment of acute hepatitis in combination with other nonhepatotoxic drugs

US HHS, NIH, HRSA, and US CDC Recommendations:
Children: 10 to 20 mg/kg orally once a day

• Maximum dose: 1000 mg/day
• Duration of therapy: At least 12 months (minimal disease); 18 to 24 months (after non-bacteriological diagnosis OR after culture conversion)

Comments:

• This drug should be given via DOT.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Usual Pediatric Dose for Tuberculosis - Active

American Academy of Pediatrics (AAP) Recommendations:
Infants, children, and adolescents: 10 to 20 mg/kg orally per day, given in 2 divided doses

• Maximum dose: 1 gram/day

Use: Adjunctive treatment of drug-resistant tuberculosis

ATS, US CDC, and IDSA Recommendations:
Children: 15 to 20 mg/kg orally, given in divided doses 1 to 2 times a day

• Maximum dose: 1000 mg/day

Comment: Maintenance doses should be titrated and based on serum levels.

Use: Second-line treatment of tuberculosis caused by known/suspected drug-susceptible organisms

ATS, US CDC, US HHS, and IDSA Recommendations:
Children: 10 to 15 mg/kg orally once a day

• Maximum dose: 1000 mg/day
• Duration of therapy: Up to 18 to 24 months

Comment: Maintenance doses should be titrated and based on serum levels.

Uses:

• Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms
• Second-line treatment of drug-resistant tuberculosis caused by organisms with known/presumed susceptibility to the agent
• Temporary treatment of acute hepatitis in combination with other nonhepatotoxic drugs

US HHS, NIH, HRSA, and US CDC Recommendations:
Children: 10 to 20 mg/kg orally once a day

• Maximum dose: 1000 mg/day
• Duration of therapy: At least 12 months (minimal disease); 18 to 24 months (after non-bacteriological diagnosis OR after culture conversion)

Comments:

• This drug should be given via DOT.
• Toxicities and drug-drug interactions should be reviewed at each visit.

Use: Second-line adjunctive treatment of drug-resistant tuberculosis in patients with HIV

Renal Dose Adjustments

Children and adults:

• Mild to moderate renal dysfunction: Frequent drug level monitoring (e.g., at least once a week) recommended.
• Severe renal dysfunction: Contraindicated

Older patients:

• Mild to moderate renal dysfunction: Doses should be adjusted to maintain blood concentrations below 30 mcg/mL.
• Severe renal dysfunction: Contraindicated

ATS, US CDC, US HHS, and IDSA Recommendations:
Adults:

• CrCl less than 50 mL/min, but not receiving hemodialysis: Not recommended.

Comment: Serum levels and monitoring for neurotoxicity should be performed.

Uses:

• Second-line treatment of drug-resistant tuberculosis caused by organisms with known/presumed susceptibility to the agent
• Temporary treatment of acute hepatitis in combination with other nonhepatotoxic drugs

Some experts recommend:
Adults:

• CrCl less than 30 mL/min: 250 mg orally once a day OR 500 mg orally 3 times a week

US HHS, NIH, HRSA, and US CDC Recommendations:
Adults:

• CrCl 50 to 80 mL/min: Frequent monitoring should be considered.
• CrCl less than 50 mL/min, but not receiving hemodialysis: Not recommended.

Liver Dose Adjustments

Frequent liver function monitoring recommended.

ATS, US CDC, and IDSA Recommendations:
Adults:
Severe, unstable liver disease: 250 mg orally once a day OR 500 mg orally 3 times a week and rifabutin, PLUS a fluoroquinolone and/or second-line injectable agent

• Duration of therapy: Approximately 12 to 18 months (disease and response-dependent)

Comments:

• Serum levels and monitoring for neurotoxicity should be performed.
• When used in combination with ethambutol, a fluoroquinolone, and second line-injectable agent, this regimen has little to no potential hepatic toxicity.

Use: Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms in patients with advanced liver dysfunction

Dose Adjustments

Allergic dermatitis or signs/symptoms of central nervous system (CNS) toxicity: Administration should be discontinued OR the dosage should be reduced

Anemia, folic acid deficiency, and/or vitamin B12: Further investigation and appropriate treatment should be started.

Hematological studies should be regularly assessed.

Therapeutic drug monitoring/range: Blood concentrations should be below 30 mcg/mL

• Blood levels over 30 mcg/mL: Doses should be decreased to maintain blood levels below 30 mcg/mL.

Monitoring should be conducted at least once a week in:

• Patients receiving doses over 500 mg/day
• Patients with signs/symptoms suggesting toxicity
• Renal dysfunction

Precautions

CONTRAINDICATIONS:

• Hypersensitivity to the active component or to any of the ingredients
• Patients with depression, psychosis, or severe anxiety
• Patients with epilepsy
• Patients with excessive concurrent use of alcohol
• Severe renal dysfunction

Safety and efficacy have not been established in pediatric patients.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

ATS, US CDC, and IDSA Recommendations:
Adults:
Hemodialysis: 250 mg orally once a day OR 500 mg orally 3 times a week

Comments:

• Serum levels should be measured and monitoring for neurotoxicity should be performed.
• Treatment should be given after hemodialysis on the day of hemodialysis.

Use: Second-line treatment of drug-susceptible tuberculosis caused by susceptible organisms

Other Comments

Storage requirements:

• Protect from moisture.

Monitoring:

• GENERAL: Drug levels routinely, especially in those with renal dysfunction, receiving higher daily doses, and/or with signs/symptoms of toxicity
• HEMATOLOGIC: Hematological function studies
• HEPATIC: Liver function studies
• IMMUNOLOGIC: Susceptibility tests to confirm susceptibility to this drug prior to initiation, and repeated throughout treatment; repeat tests for persistent positive cultures
• RENAL: Renal function studies

Patient advice:

• Inform patients that this drug may cause dizziness, and they should avoid driving or operating machinery if these side effects occur.
• Patients should be instructed to avoid alcohol during treatment.
• Advise patients to speak to their healthcare provider if they become pregnant, intend to become pregnant, or are breastfeeding.