Myrin-p

Uses

Isoniazid is used for the treatment of all forms of tuberculosis in which organisms are susceptible.

Pyrazinamide is used for the initial treatment of active tuberculosis in adults and children when combined with other antituberculous 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
• 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 used after treatment failure with other primary drugs in any form of active tuberculosis.

Pyrazinamide should only be used in conjunction with other effective antituberculous agents.

In the treatment of both tuberculosis and the meningococcal carrier state, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Bacteriologic cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to rifampinand they should be repeated throughout therapy to monitor the response to treatment. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. If test results show resistance to rifampin and the patient is not responding to therapy, the drug regimen should be modified.

Myrin-p is also used to associated treatment for these conditions: Active Tuberculosis, Mycobacterium kansasii infection, Late phase TuberculosisActive Tuberculosis, Pulmonary Tuberculosis (TB)Cholestatic pruritus, MRSA Infection, Prosthetic Joint Infection, Asymptomatic Neisseria meningitidis carrier of the nasopharynx, Initial phase Tuberculosis, Late phase Tuberculosis, Antibacterial therapy

How Myrin-p works

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.

Pyrazinamide diffuses into active M. tuberculosis that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids. However, this theory was thought to have been discounted. However, further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I.

It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Pyrazinoic acid has also been shown to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.

Rifampin acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death.

Dosage

Myrin-p dosage

Adult:

• Active tuberculosis: 5 mg/kg/day. Max: 300 mg/day or 15 mg/kg up to 900 mg/day, 2 or 3 times wkly.
• Latent tuberculosis: 300 mg/day for 6 mth. Nontuberculous mycobacterial infections 5 mg/kg/day for at least 12 mth of culture-negative sputum. Max: 300 mg/day.

Child:10-15 mg/kg/day, max 300 mg/day q 12-24 hourlyWith directly observed biweekly therapy, dosage is 20-30 mg/kg, max 900 mg/dose twice weekly

Usual Adult Dose for Tuberculosis: Active:

15 to 30 mg/kg (up to 2 g) orally once a day in combination with three other antituberculous drugs for the initial 2 months of a 6-month or 9-month treatment regimen, until drug susceptibility tests are known. An alternate dosing regimen of 50 to 75 mg/kg (up to 3 g) orally twice a week may be used after 2 weeks of daily therapy to increase patient compliance.

Alternatively, the CDC, The American Thoracic Society, and the Infectious Diseases Society of America suggest the following dosing based on estimated lean body weight:

Daily dosing:

• 40 to 45 kg: 1000 mg
• 56 to 75 kg: 1500 mg
• 76 to 90 kg: 2000 mg

Twice weekly dosing:

• 40 to 55 kg: 2000 mg
• 56 to 75 kg: 3000 mg
• 76 to 90 kg: 4000 mg

Thrice weekly dosing:

• 40 to 55 kg: 1500 mg
• 56 to 75 kg: 2500 mg
• 76 to 90 kg: 3000 mg

Usual Adult Dose for Tuberculosis: Latent:

A public health expert should be consulted prior to the use of the combination regimen with rifampin.

15 to 20 mg/kg, based on actual body weight (lean), orally once daily (maximum 2 g) for 2 months. Alternatively, a dosage of 50 mg/kg may be administered orally twice-weekly (maximum 4 g).

Usual Pediatric Dose for Tuberculosis: Active:

(Used as part of a multidrug regimen. Treatment regimens consist of an initial 2-month phase, followed by a continuation phase of 4 or 7 additional months. Frequency of dosing may differ depending on phase of therapy)

Infants, Children less than 40 kg and Adolescents 14 years and younger and less than 40 kg:Non-HIV patients:

• Daily therapy: 15 to 30 mg/kg/dose (maximum: 2 g/dose) once daily
• Directly observed therapy (DOT): 50 mg/kg/dose (maximum: 2 g/dose) twice weekly

HIV-exposed/infected patients:

• Daily therapy: 20 to 40 mg/kg/dose once daily (maximum: 2 g/day)

Rifampin can be administered by the oral route or by IV infusion. IV doses are the same as those for oral.

Tuberculosis:

• Adults: 10 mg/kg, in a single daily administration, not to exceed 600 mg/day, oral or IV
• Pediatric Patients: 10–20 mg/kg, not to exceed 600 mg/day, oral or IV

It is recommended that oral rifampin be administered once daily, either 1 hour before or 2 hours after a meal with a full glass of water.

Rifampin is indicated in the treatment of all forms of tuberculosis. A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide is recommended in the initial phase of shortcourse therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and theCenters for Disease Control and Preventionrecommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Should be taken on an empty stomach. Best taken on an empty stomach 1 hr before or 2 hr after meals.

Preparation Of Solution For IV Infusion: Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of rifampin for injection. Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for up to 30 hours. Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours. Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 8 hours and should be prepared and used within this time. Precipitation of rifampin from the infusion solution may occur beyond this time. Dilutions in normal saline are stable at room temperature for up to 6 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

Side Effects

Peripheral neuropathy (dose-related incidence, 10-20% incidence with 10 mg/kg/d), Loss of appetite, Nausea, Vomiting, Stomach pain, Weakness 1-10%, Dizziness, Slurred speech, Lethargy, Progressive liver damage (increases with age; 2.3% in pts > 50 yo), Hyperreflexia, Agranulocytosis, Anemia, Megaloblastic anemia, Thrombocytopenia, Systemic lupus erythematosus, Seizure

General: Fever, porphyria and dysuria have rarely been reported. Gout.

Gastrointestinal: The principal adverse effect is a hepatic reaction. Hepatotoxicity appears to be dose related, and may appear at any time during therapy. GI 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.

Facial flushing and itching, with or without a rash, flu-like syndrome characterised by episodes of fever, chills, headache, dizziness, bone pain, shortness of breath, and malaise; GI adverse effects (e.g. nausea, vomiting, anorexia, diarrhoea, epigastric distress), pseudomembranous colitis, eosinophilia, leucopenia, haemolytic anaemia; alterations in kidney function and renal failure, menstrual disturbances, oedema, myopathy, muscular weakness; orange-red discolouration of the urine, faeces, sweat, saliva, sputum, tears, and other body fluids; thrombophlebitis, local irritation and inflammation after prolonged IV infusion. Rarely, eye irritation and visual disturbances, anaphylaxis or shock.

Toxicity

LD₅₀ 100 mg/kg (Human, oral). Adverse reactions include rash, abnormal liver function tests, hepatitis, peripheral neuropathy, mild central nervous system (CNS) effects. In vivo, Isoniazid reacts with pyridoxal to form a hydrazone, and thus inhibits generation of pyridoxal phosphate. Isoniazid also combines with pyridoxal phosphate; high doses interfere with the coenzyme function of the latter.

Side effects include liver injury, arthralgias, anorexia, nausea and vomiting, dysuria,malaise and fever, sideroblastic anemia, adverse effects on the blood clotting mechanism or vascular integrity, and hypersensitivity reactions such as urticaria, pruritis and skin rashes.

LD₅₀=1570 mg/kg (rat), chronic exposure may cause nausea and vomiting and unconsciousness

Precaution

Renal or hepatic impairment; convulsive disorders; history of psychosis; patients at risk of neuropathy or pyridoxine deficiency eg, diabetic, alcoholic, malnourished, uraemic, infected with HIV. Careful monitoring of hepatic function is necessary for black and hispanic women. Check hepatic function before and during treatment. Pregnancy and lactation.

Pyrazinamide is contraindicated in patients with severe hepatic disease and with acute gout.

Patients started on pyrazinamide should have baseline serum uric acid and liver function test results. Liver function should be monitored closely during therapy. Patients with preexisting liver disease or those at increased risk of drug related hepatitis should be monitored closely.

Pyrazinamide should be discontinued and not restarted if signs of hepatocellular damage or hyperuricemia with an acute gouty arthritis appear.

Polyarthralgias have been reported in patients. The pain may respond to aspirin or other nonsteroidal anti-inflammatory agents.

Caution should be used in patients with a history of diabetes mellitus, as management of the disease may be more difficult.

Primary resistance of Mycobacterium tuberculosis to pyrazinamide is not common. In cases with known or suspected drug resistance, in vitro susceptibility tests with recent cultures of Mycobacterium tuberculosis against pyrazinamide and the usual primary drugs should be conducted. There are few reliable in vitro tests for pyrazinamide resistance. A reference laboratory capable of performing these tests must be utilized.

Clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased renal or hepatic function, and of concomitant disease or other drug therapy.

Rifampicin has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Patients with impaired liver function should be given rifampin only in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially SGPT/ALT and SGOT/AST should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, rifampin should be withdrawn.

In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient's clinical condition.

Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration.

Interaction

Inhibit the hepatic metabolism of antiepileptics (e.g. carbamazepine, ethosuximide, primidone, phenytoin), benzodiazepines (e.g. diazepam, triazolam), chlorzoxazone, theophylline, disulfiram, sometimes leading to increased toxicity. Increased metabolism of enflurane, resulting in potentially nephrotoxic levels of fluoride. Increased concentrations and enhanced effects or toxicity of clofazimine, cycloserine and warfarin. Reduced absorption with Al-containing antacids. Increased risk of peripheral neuropathy with zalcitabine and stavudine.

Antagonises the effect of uricosuric agents (e.g. probenecid, sulfinpyrazone). May reduce the contraceptive effect of oestrogens. May inactivate oral typhoid vaccine. May increase the serum concentration of ciclosporin. May enhance the hepatotoxic effect of rifampicin.

May accelerate the metabolism and reduce the effect of drugs that are metabolised by CYP450 enzymes (e.g. quinidine, phenytoin, theophylline). Decreased concentrations of atovaquone and increased concentrations of rifampicin when taken concomitantly. Concurrent use of ketoconazole and rifampicin may result in decreased serum concentrations of both drugs. May decrease serum concentrations of enalaprilat. Reduced absorption by antacids. Increased risk of hepatotoxicity with halothane or isoniazid.

Elimination Route

Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.

Rapidly and well absorbed from the gastrointestinal tract.

Well absorbed from gastrointestinal tract.

Half Life

Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours.

9-10 hours (normal conditions)

3.35 (+/- 0.66) hours

Clearance

• 0.19 +/- 0.06 L/hr/kg [300 mg IV]
• 0.14 +/- 0.03 L/hr/kg [600 mg IV]

Elimination Route

From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours.

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

Less than 30% of the dose is excreted in the urine as rifampin or metabolites.

Pregnancy & Breastfeeding use

Pregnancy Category C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Lactation: distributed into milk but safe for nursing infants

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.

Pregnancy: When administered during the last few weeks of pregnancy, rifampin can cause post natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.

Nursing Mothers: Because of the potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Acute liver disease or history of hepatic damage during INH therapy; hypersensitivity.

Pyrazinamide is contraindicated in persons:

• With severe hepatic damage.
• Who have shown hypersensitivity to it.
• With acute gout.

Rifampicin is contraindicated in patients with a history of hypersensitivity to rifampin or any of the components, or to any of the rifamycins. Rifampin is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity.

Rifampin is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.

Special Warning

Usage in Children: Pyrazinamide regimens employed in adults are probably equally effective in children. Pyrazinamide appears to be well tolerated in children.

Geriatric Use: 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.

Renal Dose Adjustments: The manufacturer recommends to start therapy at low end of dosage range and monitor patient closely.For the treatment of active tuberculosis, the CDC, ATS, and IDSA recommend against daily dosing. For patients with CrCl less than 30 mL/min or patients receiving hemodialysis the recommended dose is 25 to 35 mg/kg per dose three times per week.

Liver Dose Adjustments: Monitor patients closely.

Dose Adjustments: 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.

If organism is susceptible to isoniazid and rifampin, pyrazinamide is continued for the first 2 months of a 6-month course of therapy (9-months if HIV positive). If primary drug resistance is shown, drug regimens should be adjusted as needed and continued for at least 6 months, or 3 months beyond culture conversion (9 months, or 6 months beyond culture conversion if HIV positive). If multiple-drug resistance is demonstrated, therapy should be continued for 12 to 24 months following culture conversion.

Geriatric Use: Clinical studies of Rifampicin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using rifampin in elderly patients.

Acute Overdose

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.

Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces will occur, and its intensity is proportional to the amount ingested.

Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly. Hepatic involvement may be more marked in patients with prior impairment of hepatic function. Other physical findings remain essentially normal. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.

Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

Storage Condition

Store between 15-30° C.

Store between 15-30° C. Avoid excessive heat and protect from light.

Innovators Monograph

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