Dosage guidance:
Dosing: Dose should be based on lean body weight for patients with drug-susceptible tuberculosis (Ref); ideal weight metric for drug-resistant tuberculosis has not been determined. Optimal dosing for patients with obesity has not been established.
Tuberculosis, treatment, drug-susceptible: Note: Always administer in combination with other antitubercular drugs (Ref).
6-month regimen:
Once-daily therapy:
40 to 55 kg: Oral: 1 g once daily. Note: The preferred frequency of administration is once daily; however, 5-days per week administration by directly observed therapy (DOT) is an acceptable alternative (Ref).
56 to 75 kg: Oral: 1.5 g once daily (Ref).
76 to 90 kg: Oral: 2 g once daily (Ref).
Three-times-weekly DOT:
40 to 55 kg: Oral: 1.5 g 3 times weekly (Ref).
56 to 75 kg: Oral: 2.5 g 3 times weekly (Ref).
76 to 90 kg: Oral: 3 g 3 times weekly (Ref).
Twice-weekly DOT:
40 to 55 kg: Oral: 2 g twice weekly (Ref).
56 to 75 kg: Oral: 3 g twice weekly (Ref).
76 to 90 kg: Oral: 4 g twice weekly (Ref).
Regimens: Treatment regimens for pulmonary tuberculosis and tuberculous meningitis consist of an initial 2-month phase of a 4-drug regimen that includes pyrazinamide, followed by a continuation phase of a 2-drug regimen (does not include pyrazinamide) of an additional 4 to 7 months for pulmonary tuberculosis and a continuation phase of an additional 7 to 10 months of a 2-drug regimen (does not include pyrazinamide) for tuberculous meningitis (optimal duration is not defined although continuation phase must continue for a minimum of 7 additional months). Adjunctive corticosteroid therapy (eg, dexamethasone, prednisolone) tapered over 6 to 8 weeks is also recommended for tuberculous meningitis; pyrazinamide frequency and dosing differs depending on treatment regimen selected; consult current drug-sensitive TB guidelines (Ref).
4-month rifapentine-moxifloxacin–based regimen:
Note: Reserve use for patients ≥40 kg with pulmonary TB who are not pregnant or breastfeeding; for patients with HIV infection, only use if CD4 count ≥100 cells/mm3 and in patients on an efavirenz-based antiretroviral regimen (Ref). In the clinical study evaluating this regimen, ≥5 doses per week were given by DOT (Ref).
40 to <55 kg: Oral: 1 g once daily (Ref).
≥55 to 75 kg: Oral: 1.5 g once daily (Ref).
>75 kg: Oral: 2 g once daily (Ref).
Duration: Administer in combination with rifapentine, moxifloxacin, and isoniazid for 8 weeks, followed by a 9-week continuation phase that does not include pyrazinamide (Ref).
Tuberculosis, treatment, drug-resistant (alternative agent):
Note: Expert consultation for optimal regimen and duration of treatment is advised.
Oral: 25 to 40 mg/kg once daily (Ref).
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: Note: The following recommendations are expert opinion derived from ATS/CDC/ERS/IDSA (Nahid 2019), ATS/CDC/IDSA (Nahid 2016), HHS (OI adult 2022), and WHO 2014. Dosage adjustment recommendations utilize the indication-specific usual recommended daily dose but extend the dosing interval to 3 times weekly.
Tuberculosis, treatment (drug-susceptible): Oral:
40 to 55 kg: 1 g 3 times weekly.
56 to 75 kg: 1.5 g 3 times weekly.
76 to 90 kg: 2 g 3 times weekly.
Tuberculosis, treatment (drug-resistant) (alternative agent): Oral: 25 to 40 mg/kg 3 times weekly.
Hemodialysis, intermittent (thrice weekly): Dialyzable (~45 to 55%) (Ref): Oral: Dose as CrCl <30 mL/minute; administer 3 times weekly after hemodialysis on dialysis days (Ref). Consider therapeutic drug monitoring when available (Ref). Close monitoring of response and adverse effects (eg, hepatotoxicity (Ref)) due to drug accumulation is important (Ref).
Peritoneal dialysis: Dialyzable (15% of total clearance) (Ref): Oral: Due to limited pharmacokinetic data in this population, dose as for CrCl <30 mL/minute; consider therapeutic drug monitoring when available (Ref). Close monitoring of response and adverse effects (eg, hepatotoxicity (Ref)) due to drug accumulation is important (Ref).
CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse effects (eg, hepatotoxicity (Ref)) due to drug accumulation is important.
Oral: There are no data in patients receiving CRRT (has not been studied); however, no dosage adjustment is likely necessary since pyrazinamide is predicted to be somewhat dialyzed by CRRT; consider therapeutic drug monitoring when available (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse effects (eg, hepatotoxicity (Ref)) due to drug accumulation is important.
Oral: There are no data in patients receiving PIRRT (has not been studied); however, no dosage adjustment is likely necessary since pyrazinamide is predicted to be somewhat dialyzed by PIRRT; consider therapeutic drug monitoring when available (Ref).
Non-PIRRT days: Dose as for CrCl <30 mL/minute (Ref).
There are no dosage adjustments provided in the manufacturer's labeling. Use is contraindicated in cases of severe hepatic impairment.
Optimal dosing for patients with obesity has not been established; using lean body weight in patients with obesity may lead to underdosing. Consider therapeutic drug monitoring in patients with obesity (Ref).
(For additional information see "Pyrazinamide: Pediatric drug information")
Tuberculosis, active, treatment; drug-susceptible: Note: Always use in combination with other antitubercular drugs. Any regimens using less than once-daily dosing should be administered as directly observed therapy (DOT).
6-month standard regimen (Ref): Note: Treatment regimens for active tuberculosis consist of an initial 2-month intensive phase of a 4-drug regimen (including pyrazinamide), followed by a 2-drug regimen continuation phase (not including pyrazinamide) of ≥4 months; see guidelines for details.
Once-daily therapy: Note: The preferred frequency of administration is once daily; however, 5-days-per-week administration by DOT at the same daily dose is an acceptable alternative (Ref).
Infants, Children, and Adolescents weighing <40 kg: Oral: 35 mg/kg/dose once daily; suggested range: 30 to 40 mg/kg/dose.
Children and Adolescents weighing ≥40 kg: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established).
40 to 55 kg: Oral: 1,000 mg once daily.
56 to 75 kg: Oral: 1,500 mg once daily.
76 to 90 kg: Oral: 2,000 mg once daily.
Three-times-weekly DOT:
Infants, Children, and Adolescents weighing <40 kg: Oral: 50 mg/kg/dose three times weekly.
Children and Adolescents weighing ≥40 kg: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established).
40 to 55 kg: Oral: 1,500 mg three times weekly.
56 to 75 kg: Oral: 2,500 mg three times weekly.
76 to 90 kg: Oral: 3,000 mg three times weekly.
Twice-weekly DOT: Note: Regimen not generally recommended; associated with worse outcomes (treatment failure, relapse, and drug resistance) compared to daily dosing. Do not use in patients with HIV or those with smear-positive and/or cavitary disease; only for use in continuation phase (Ref).
Infants, Children, and Adolescents weighing <40 kg: Oral: 50 mg/kg/dose twice weekly.
Children and Adolescents weighing >40 kg:
40 to 55 kg: Oral: 2,000 mg twice weekly.
56 to 75 kg: Oral: 3,000 mg twice weekly.
76 to 90 kg: Oral: 4,000 mg twice weekly.
4-month rifapentine and moxifloxacin-based regimen (Ref): Note: Use only for treatment of pulmonary tuberculosis in combination with isoniazid, moxifloxacin, and rifapentine; pyrazinamide is included for the initial 8 weeks, followed by an additional 9 weeks without pyrazinamide; see guidelines for regimen details (Ref).
Children ≥12 years and Adolescents weighing ≥40 kg:
40 to <55 kg: Oral: 1,000 mg once daily for 8 weeks (56 doses).
55 to 75 kg: Oral: 1,500 mg once daily for 8 weeks (56 doses).
>75 kg: Oral: 2,000 mg once daily for 8 weeks (56 doses).
Tuberculosis, active, treatment; drug-resistant: Note: Duration should be individualized based on extent of disease, rapidity of culture conversion, clinical response, and toxicity; expert consultation for optimal regimen and duration of treatment is advised (Ref).
Infants, Children, and Adolescents: Oral: 30 to 40 mg/kg/dose once daily as part of an appropriate combination regimen (Ref).
There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment suggested.
There are no dosage adjustments provided in the manufacturer’s labeling. Use is contraindicated in cases of severe hepatic impairment.
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Postmarketing:
Dermatologic: Acne vulgaris, exfoliative dermatitis (Jaisuresh 2013), maculopapular rash (Khayyam 2010), skin photosensitivity (including phototoxicity) (Katiyar 2010)
Endocrine & metabolic: Hyperuricemia (Pham 2014), increased serum iron, porphyria
Gastrointestinal: Anorexia, nausea, vomiting
Genitourinary: Dysuria
Hematologic & oncologic: Abnormal erythrocytes (vacuolation of erythrocytes), acquired blood coagulation disorder, sideroblastic anemia (with erythroid hyperplasia) (Colucci 2012), thrombocytopenia (Kant 2010)
Hepatic: Hepatotoxicity (Wang 2022)
Hypersensitivity: Hypersensitivity reaction (Katran 2023)
Neuromuscular & skeletal: Arthralgia, gout, myalgia
Renal: Interstitial nephritis (Namba 1991)
Miscellaneous: Fever
Hypersensitivity to pyrazinamide or any component of the formulation; acute gout; severe hepatic damage
Concerns related to adverse effects:
• Hepatotoxicity: Dose-related hepatotoxicity ranging from transient ALT/AST elevations to jaundice, hepatitis and/or liver atrophy (rare) has occurred.
Disease-related concerns:
• Alcoholism: Due to concerns for preexisting hepatic dysfunction, use with caution in patients with a history of alcoholism (even if ethanol consumption is discontinued during therapy).
• Diabetes: Use with caution in patients with diabetes mellitus.
• Gout: May inhibit uric acid excretion; acute gouty attacks have been reported. Use with caution in patients with chronic gout; contraindicated with acute gout.
• Porphyria: Use with caution in patients with porphyria.
• Renal impairment: Use with caution in patients with renal failure.
Concurrent drug therapy issues:
• Hepatotoxic agents: Use with caution in patients receiving concurrent medications associated with hepatotoxicity (particularly with rifampin). The 2-month rifampin-pyrazinamide regimen for the treatment of tuberculosis (TB) infection (latent TB) has been associated with severe and fatal liver injuries; incidence increased with pyrazinamide doses >30 mg/kg/day. The Infectious Diseases Society of America and Centers for Disease Control and Prevention recommend that the 2-month rifampin-pyrazinamide regimen should not generally be used in patients with LTBI.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 500 mg
Yes
Tablets (Pyrazinamide Oral)
500 mg (per each): $6.15 - $8.94
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Tebrazid: 500 mg [DSC]
Generic: 500 mg
Oral: May take without regard to food (Ref).
Oral: May take without regard to food (Ref).
Tuberculosis: Treatment of tuberculosis in combination with other antituberculosis agents.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Benzbromarone: Pyrazinamide may diminish the therapeutic effect of Benzbromarone. Risk C: 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. Risk X: Avoid combination
CycloSPORINE (Systemic): Pyrazinamide may enhance the myopathic (rhabdomyolysis) effect of CycloSPORINE (Systemic). Pyrazinamide may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Favipiravir: May enhance the adverse/toxic effect of Pyrazinamide. Specifically, the risk for increased uric acid concentrations may be increased. Risk C: Monitor therapy
Fecal Microbiota (Live) (Oral): May diminish the therapeutic effect of Antibiotics. Risk X: Avoid combination
Fecal Microbiota (Live) (Rectal): Antibiotics may diminish the therapeutic effect of Fecal Microbiota (Live) (Rectal). Risk X: Avoid combination
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Mycophenolate: Antibiotics may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be reduced. Risk C: Monitor therapy
RifAMPin: Pyrazinamide may enhance the hepatotoxic effect of RifAMPin. Severe (even fatal) liver injury has been reported in patients receiving these 2 drugs as a 2-month treatment regimen for latent TB infection. Management: Rifampin-pyrazinamide is generally not preferred for the treatment of latent tuberculosis (TB) due to the risk of hepatotoxicity. However, it is an option for patients at high risk of developing active TB who are unlikely to complete preferred treatment. Risk C: 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. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Evaluate pregnancy status prior to treatment of multidrug-resistant tuberculosis in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment for multidrug-resistant tuberculosis (Esmail 2018).
Tuberculosis (TB) disease (active TB) is associated with adverse fetal outcomes including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020) as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020).
Due to the risks of untreated TB, pyrazinamide may be used as part of the initial treatment regimen of drug-susceptible TB disease when the probability of maternal disease is moderate to high; however, risks and benefits of use during pregnancy should be considered for each individual patient. The addition of pyrazinamide may be of benefit in pregnant patients with HIV, extrapulmonary or severe TB (ATS/CDC/IDSA [Nahid 2016]).
Use of pyrazinamide may also be considered in the treatment of multidrug-resistant TB. The treatment of multidrug-resistant TB in pregnant patients should be individualized; evidence to support a specific regimen is not available (ATS/CDC/ERS/IDSA [Nahid 2019]; WHO 2020).
Pregnancy-induced physiologic changes do not alter the pharmacokinetic properties of pyrazinamide in a clinically significant way; dose adjustment is not needed in pregnant patients (Abdelwahab 2020).
Pyrazinamide is present in breast milk.
Breast milk concentrations are less than maternal plasma concentration (Holdiness 1984).
Breastfeeding is not a contraindication during therapy for drug-susceptible tuberculosis in patients deemed noninfectious who are treated with first-line agents (ie, pyrazinamide). Exposure to pyrazinamide via breast milk should not be considered effective treatment for the breastfeeding infant (ATS/CDC/IDSA [Nahid 2016]). Infants exposed to pyrazinamide via breast milk should be monitored for jaundice (WHO 2002). Patients with multidrug-resistant tuberculosis and a sputum smear-positive test should avoid breastfeeding when possible (Esmail 2018).
Periodic liver function tests, serum uric acid, sputum culture, chest x-ray 2-3 months into treatment and at completion; pyrazinamide serum concentrations (when clinically indicated).
Pyrazinamide serum concentrations (Alsultan 2014):
Note: Obtain samples at 2 and 6 hours post dose to detect delayed absorption or malabsorption.
If the usual recommended dose is 25 mg/kg once daily: target Cmax 20 to 50 mcg/mL. Note: Some recent studies have suggested higher Cmax targets, but risk of hepatoxicity may be increased (Chideya 2009; Pasipanodya 2013).
If the usual recommended dose is 50 mg/kg twice weekly: target Cmax 60 to 90 mcg/mL.
Converted to pyrazinoic acid in susceptible strains of Mycobacterium which lowers the pH of the environment; exact mechanism of action has not been elucidated
Note: Bacteriostatic or bactericidal depending on drug's concentration at infection site.
Absorption: Well absorbed.
Distribution: Widely into body tissues and fluids including liver, lung, and cerebrospinal fluid (CSF).
Relative diffusion from blood into CSF: Adequate with or without inflammation (exceeds usual MICs).
CSF:blood level ratio: Inflamed meninges: 100%.
Protein binding: 50%.
Metabolism: Hepatic.
Half-life elimination: Prolonged with reduced renal or hepatic function.
Children: Median: 6.3 hours (interquartile range: 5.6 to 7.5 hours) (Chabala 2022).
Adults: 9 to 10 hours.
Time to peak, serum:
Children: Median: 1 hour (interquartile range: 1 to 2 hours) (Chabala 2022).
Adults: Within 2 hours.
Excretion: Urine (4% as unchanged drug).
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