Pyrazinamide, the pyrazine analogue of nicotinamide, is an anti-tuberculous agent. It is a white crystalline powder, stable at room temperature, and sparingly soluble in water. Pyrazinamide has the following structural formula:

C₅H₅N₃O                          M.W. 123.11

Each pyrazinamide tablet for oral administration contains 500 mg of pyrazinamide and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate (dihydrate), microcrystalline cellulose, and stearic acid.

Last updated on RxList: 12/3/2008

Pyrazinamide is indicated for the initial treatment of active tubercuIosis in adults and children when combined with other antitubercu-lous agents. (The current recommendation of the CDC for drug-susceptible disease is to use a six-month regimen for initial treatment of active tuberculosis, consisting of isoniazid, rifampin and pyrazinamide given for 2 months, followed by isoniazid and rifampin for 4 months.^*4)

(Patients with drug-resistant disease should be treated with regimens individualized to their situation. Pyrazinamide frequently will be an important component of such therapy.)

(In patients with concomitant HIV infection, the physician should be aware of current recommendation of CDC. It is possible these patients may require a longer course of treatment.)

It is also indicated after treatment failure with other primary drugs in any form of active tuberculosis.

Pyrazinamide should only be used in conjunction with other effective antituber-culous agents.

Pyrazinamide should always be administered with other effective antituberculous drugs. It is administered for the initial 2 months of a 6-month or longer treatment regimen for drug-susceptible patients. Patients who are known or suspected to have drug-resistant disease should be treated with regimens individualized to their situation.

Pyrazinamide frequently will be an important component of such therapy.

Patients with concomitant HIV infection may require longer courses of therapy. Physicians treating such patients should be alert to any revised recommendations from CDC for this group of patients.

Usual dose: Pyrazinamide is administered orally, 15 to 30 mg/kg once daily. Older regimens employed 3 or 4 divided doses daily, but most current recommendations are for once a day. Three grams per day should not be exceeded. The CDC recommendations do not exceed 2 g per day when given as a daily regimen (see table).

Alternatively, a twice weekly dosing regimen (50 to 75 mg/kg twice weekly based on lean body weight) has been developed to promote patient compliance with a regimen on an outpatient basis. In studies evaluating the twice weekly regimen, doses of pyrazinamide in excess of 3 g twice weekly have been administered. This exceeds the recommended maximum 3 g/daily dose. However, an increased incidence of adverse reactions has not been reported.

This table is taken from the CDC-American Thoracic Society joint recommendations.⁴

Recommended Drugs for the Initial Treatment of Tuberculosis in Children and Adults

	Daily Dose*
Drug	Children	Adults
Isoniazid	10 to 20 mg/kg PO or IM	5 mg/kg PO or IM
Rifampin	10 to 20 mg/kg PO	10 mg/kg PO
Pyrazinamide	15 to 30mg/kg PO	15 to 30mg/kg PO
Streptomycin	20 to 40mg/ kg IM	15mg/kg** IM
Ethambutol	15 to 25mg/kg PO	15 to 25mg/kg PO
Maximal Daily Dose in Children and Adults
Drug
Isoniazid	300 mg
Rifampin	600 mg
Pyrazinamide	2 g
Streptomycin	1 g**
Ethambutol	2.5 g
Twice Weekly Dose
Drug	Children	Adults
Isoniazid	20 to 40 mg/kg Max. 900 mg	15 mg/kg Max. 900 mg
Rifampin	10 to 20 mg/kg Max. 600 mg	10 mg/kg Max. 600 mg
Pyrazinamide	50 to 70 mg/kg	50 to 70 mg/kg
Streptomycin	25 to 30 mg/kg IM	25 to 30 mg/kg IM
Ethambutol	50 mg/kg	50 mg/kg
Definition of abbreviations: PO = perorally; IM = intramuscularly *Doses based on weight should be adjusted as weight changes. ** In persons older then 60 yr of age the daily dose of streptomycin should be limited to 10 mg/kg with a maximal dose of 750 mg.

Pyrazinamide Tablets USP contain pyrazinamide 500 mg. They are supplied as white, round, scored tablets debossed “VP/012”

in containers of 60 tablets NDC 61748-012-06,
in containers of 90 tablets NDC 61748-012-09,
in containers of 100 tablets NDC 61748-012-01,
in containers of 500 tablets NDC 61748-012-05,
and in hospital unit-dose cartons of 100 tablets (in strips of 10 tablets per strip) NDC 61748-012-11.

Storage: Store in a well-closed container at controlled room temperature, 15°C to 30°C (59°F to 86°F).

Dispense in a well-closed container with a child-resistant closure.

REFERENCES

*See recommendations of Center for Disease Control (CDC) and American Thoracic Society for complete regimen and dosage recommendations.⁴

4. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis. 1986 ; 134 : 363-368.

Marketed by: VersaPharm Incorporated, Marietta, GA 30062. Manufactured by: MIKART INC., Atlanta, GA 30318. Rev. 04/01. FDA revision date: 8/13/2002

Last updated on RxList: 12/3/2008

General: Fever, porphyria and dysuria have rarely been reported. Gout (see PRECAUTIONS).

Gastrointestinal: The principal adverse effect is a hepatic reaction (see WARNINGS). Hepatotoxicity appears to be dose related, and may appear at any time during therapy. Gl disturbances including nausea, vomiting and anorexia have also been reported.

Hematologic and Lymphatic: Thrombocytopenia and sideroblastic anemia with erythroid hyperplasia, vacuolation of erythrocytes and increased serum iron concentration have occurred rarely with this drug. Adverse effects on blood clotting mechanisms have also been rarely reported.

Other: Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, and pruritis have been reported. Fever, acne, photosensitivity, porphyria, dysuria and interstitial nephritis have been reported rarely.

Drug/Laboratory Test Interactions: Pyrazinamide has been reported to interfere with ACETEST® and KETOSTIX® urine tests to produce a pink-brown color.⁵

Last updated on RxList: 12/3/2008

Patients started on pyrazinamide should have baseline serum uric acid and liver function determinations. Those patients with preexisting Iiver disease or those at increased risk for drug related hepatitis (e.g., alcohol abusers) should be followed closely.

Pyrazinamide should be discontinued and not be resumed if signs of hepatocel-lular damage or hyperuricemia accompanied by an acute gouty arthritis appear.

General

Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, pyrazinamide should be discontinued.

Pyrazinamide should be used with caution in patients with a history of diabetes mellitus, as management may be more difficult.

Primary resistance of M. tuberculosisto pyrazinamide is uncommon. In cases with known or suspected drug resistance, in vitro susceptibility tests with recent cultures of M. tuberculosis against pyrazinamide and the usual primary drugs should be performed. There are few reliable in vitro tests for pyrazinamide resistance. A reference laboratory capable of performing these studies must be employed.

Laboratory Tests

Baseline liver function studies [especially ALT (SGPT), AST (SGOT) determinations] and uric acid levels should be determined prior to therapy. Appropriate laboratory testing should be performed at periodic intervals and if any clinical signs of symptoms occur during therapy.

Carcinogenicity, Mutagenicity, Impairment of Fertility

^6,7,8 In lifetime bioas-says in rats and mice, pyrazinamide was administered in the diet at concentrations of up to 10,000 ppm. This resulted in estimated daily doses for the mouse of 2 g/kg, or 40 times the maximum human dose, and for the rat of 0.5 g/kg, or 10 times the maximum human dose. Pyrazinamide was not carcinogenic in rats or male mice and no conclusion was possible for female mice due to insufficient numbers of surviving control mice.

Pyrazinamide was not mutagenic in the Ames bacterial test, but induced chro-mosomal aberrations in human Iymphocyte cell cultures.

Pregnancy

Teratogenic Effects - Pregnancy Category C Animal reproduction studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pyrazinamide should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Pyrazinamide has been found in small amounts in breast milk. Therefore, it is advised that pyrazinamide be used with caution in nursing mothers taking into account the risk-benefit of this therapy.⁹

Pediatric Use

Pyrazinamide regimens employed in adults are probably equally effective in pediatric patients.^4,10,11 Pyrazinamide appears to be well tolerated in pediatric patients.

Geriatric Use

¹² Clinical studies of pyrazinamide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or renal function, and of concomitant disease or other drug therapy.

It does not appear that patients with impaired renal function require a reduction in dose. It may be prudent to select doses at the low end of the dosing range, however.¹³

REFERENCES

4. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis. 1986 ; 134 : 363-368.

5. Reynolds JEF, Parfitt K, Parsons AV, Sweetman SC. Martindale The Extra Pharmacopoeia, ed 29. London, The Pharmaceutical Press. 1989; 569-570.

6. Bioassay of pyrazinamide for possible carcinogenicity. National Cancer Institute Carcinogenesis Technical Report Series No. 48, 1978.

7. Zerger E, Anderson B, Haworth S, Lawlor T, Mortelmans K, Speck W. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ Mutagen. 1987; 9 (Suppl 9) : 1-109.

8. Roman IC, Georgian L. Cytogenetic effects of some antituberculosis drugs in vitro. Mutation Research. 1977; 48: 215-224.

9. Holdiness M. Antituberculosis drugs and breast-feeding. Arch Intern Med. 1984 ; 144 : 1888.

10. Turcios N, Evans H. Preventing and managing tuberculosis in children. J Resp Dis. 1989 ; 10 (6) (Jun): 23.

11. Starke JR. Multidrug therapy for tuberculosis in children. Pediatr Infec Dis J. 1990 ; 9: 785-793.

12. Specific requirements on content and format of labeling for human prescription drugs; proposed addition of “geriatric use” subsection in the labeling. Federal Register. 1990 ; 55 (212) (Nov 1): 46134-46137.

13. Stamathakis G, Montes C, Trouvin JH, et al. Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure. Clinical Nephrology. 1988 ; 30 : 230-234.

Last updated on RxList: 12/3/2008

Overdosage experience is limited. In one case report of overdose, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped. Clinical monitoring and supportive therapy should be employed. Pyrazinamide is dialyzable.¹³

Pyrazinamide is contraindicated in persons: with severe hepatic damage; who have shown hypersensitivity to it; with acute gout.

REFERENCES

13. Stamathakis G, Montes C, Trouvin JH, et al. Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure. Clinical Nephrology. 1988 ; 30 : 230-234.

Last updated on RxList: 12/3/2008

Pyrazinamide is well absorbed from the Gl tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mcg/mL with doses of 20 to 25 mg/kg. It is widely distributed in body tissues and fluids including the liver, lungs and cerebrospinal fluid (CSF). The CSF concentration is approximately equal to concurrent steady-state plasma concentrations in patients with inflamed meninges.¹ Pyrazinamide is approximately 10% bound to plasma proteins.² The half-life (t 1/2) of pyrazi-namide is 9 to 10 hours in patients with normal renal and hepatic function. The plasma half-life may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazi-noic acid. Pyrazinoic acid is hydroxylated to the main excretory product, 5-hydrox-ypyrazinoic acid.³

Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours.³

Pyrazinamide may be bacteriostatic or bactericidal against Mycobacterium tuberculosis depending on the concentration of the drug attained at the site of infection. The mechanism of action is unknown. In vitro and in vivo the drug is active only at a slightly acidic pH.

REFERENCES

1. Drug Information, American Hospital Formulary Service. American Society of Hospital Pharmacists. Bethesda, Md. 1991.

2. USPDI, Drug Information for the Health Care Professional. United States Pharmacopeial Convention, Inc. Rockville, Md. 1991: 1B: 2226-2227.

3. Goodman-Gilman A, Rall TW, Nies AS, Taylor P. The Pharmacological Basis of Therapeutics, ed 8. New York, Pergamon Press. 1990 ; 1154.

Last updated on RxList: 12/3/2008

Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, pain or swelling of the joints.

Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.

Last updated on RxList: 12/3/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PYRAZINAMIDE - ORAL

(pir-uh-ZIN-uh-mide)

USES: This medication is used with other medications to treat active tuberculosis (TB) infection. Pyrazinamide belongs to a class of drugs known as antibiotics that are active against tuberculosis.

HOW TO USE: Take this medication by mouth with or without food, usually once daily or twice weekly for the first 2 months of treatment or as directed by your doctor. This medication is usually taken for 6-9 months.

Dosage is based on your age, weight, medical condition, and response to therapy.

It is very important to continue taking this medication (and other TB medications) exactly as prescribed by your doctor.

This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, take it on the same day(s) of the week and at the same time each day. If you are taking this medication on a schedule other than every day (e.g., twice a week), it may help to mark your calendar with a reminder.

Do not take more or less of this drug than prescribed or stop taking it (or other TB medicines) even for a short time unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause the amount of TB bacteria to increase, make the infection more difficult to treat (resistant), or worsen side effects. If TB becomes resistant to this medication, it might also be resistant to other TB medications.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Headache, aching joints, upset stomach, or nausea may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: persistent nausea, vomiting, weakness, tiredness, stomach/abdominal pain, yellowing eyes/skin, loss of appetite, bloody/pink/cloudy/dark urine, painful/swollen joints, increase/decrease in the amount of urine.

Tell your doctor immediately if any of these rare but very serious side effects occur: fever, easy bleeding/bruising, sudden weakness, pale skin, fast breathing.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking pyrazinamide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe liver problems, a certain liver/blood condition (porphyria), current gout attack.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: gout, HIV infection, liver problems, alcohol consumption, diabetes.

This drug may worsen liver problems you may already have. Avoid alcoholic beverages while taking this medication.

If you have diabetes, this product may rarely increase your blood sugar levels. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms of high blood sugar such as increased thirst and urination. Your anti-diabetic medication or diet may need to be adjusted.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This medication passes into breast milk. Though there have been no reports of harm to nursing infants, consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: rifampin.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Keep all medical and laboratory appointments.

Laboratory and/or medical tests (e.g., TB cultures, liver function tests, blood cell counts, blood chemistries) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

This medication may interfere with certain laboratory tests (including blood folate/B12, certain acetone/ketone urine tests), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.