Fixcom 2/Fixcom 3/Fixcom 4 Special Precautions

Fixcom 2: Monitoring of serum concentrations of hepatic transaminases, where possible, is useful in patients with pre-existing chronic liver disease. Patients at risk of peripheral neuropathy, as a result of malnutrition, chronic alcohol dependence or diabetes, should additionally receive pyridoxine, 10 mg daily. Where the standard of health in the community is low, this should be offered routinely.
Since isoniazid interacts with anticonvulsants used for epilepsy, it may be necessary to reduce the dosage of these drugs during treatment with isoniazid.
Rifampicin: Serious immunological reactions resulting in renal impairment, haemolysis or thrombocytopenia are on record in patients who resume taking rifampicin after a prolonged lapse of treatment. In this rare situation, it should be immediately and definitely withdrawn.
Careful monitoring of liver function is required in the elderly and in patients who are alcohol-dependent or have hepatic disease. Patients should be warned that treatment may produce reddish coloration of urine, tears, saliva and sputum and that contact lenses may be irreversibly stained.
Liver disorders: Isoniazid, rifampicin and pyrazinamide are all associated with hepatitis. Of the three drugs, rifampicin is least likely to cause hepatocellular damage, although it is associated
with cholestatic jaundice. Of the three agents, pyrazinamide is the most hepatotoxic.
Patients with the following conditions can receive the usual short-course chemotherapy regimens provided there is no clinical evidence of chronic liver disease: However, hepatotoxic reactions to antituberculosis drugs may be more common among these patients and should therefore be anticipated.
Established chronic liver disease: Patients with liver disease should not receive pyrazinamide. Isoniazid plus rifampicin plus one or two non-hepatotoxic drugs such as streptomycin and ethambutol can be used for a total treatment duration of 8 months. Alternative regimens are 9 Rifampicin/Ethambutol (RE) or Streptomycin/isoniazid Ethambutol (SHE) in the initial phase followed by Isoniazid/Ethambutol (HE) in the continuation phase. with a total treatment duration of 12 months. Recommended regimens are therefore 2SHRE/6HR. 9 RE or 2SHE/10HE.
Acute hepatitis (e.g. acute viral hepatitis): Uncommonly, a patient has TB and concurrently acute hepatitis unrelated to TB or TB treatment. Clinical judgement is necessary. In some cases, it is possible to defer TB treatment until the acute hepatitis has resolved. In other cases, when it is necessary to treat TB during acute hepatitis, the combination of Streptomycin/Ethambutol for 3 months is the safest option. If the hepatitis has resolved, the patient can then receive a continuation phase of 6 months isoniazid and rifampicin 6(HR). If the hepatitis has not resolved, Streptomycin/ethambutol should be continued for a total of 12 months.
Renal failure: Isoniazid, rifampicin and pyrazinamide are either eliminated almost entirely by biliary excretion or metabolized into non-toxic compounds. These drugs can therefore be given in normal dosage to patients with renal failure. Patients with severe renal failure should receive pyridoxine with isoniazid in order to prevent peripheral neuropathy.
Fixcom 3: Rifampicin: Liver functions should be checked before treatment with rifampicin and special care should be taken in alcoholic patients or those with preexisting liver disease who require regular monitoring during therapy. Rifampicin is contraindicated in patients with jaundice. A self-limiting hyperbilirubinemia may occur in the first 2 or 3 weeks of treatment. Alkaline phosphatase values may be raised moderately due to rifampicin's enzyme-inducing capacity. When other liver functions tests are within normal limits, hyperbilirubinemia in the 1st few weeks of moderately elevated alkaline phosphates are not indications to withdraw rifampicin. However, dose adjustment is necessary when there is other evidence of hepatic impairment and treatment should be suspended when there is evidence of more serious liver toxicity.
Blood counts should be monitored during prolonged treatment and in patients with hepatic disorders. Should thrombocytopenia or purpura occur then rifampicin should be withdrawn permanently. In patients who develop hemolytic anemia or renal failure, withdrawal of rifampicin is recommended.
Administration of rifampicin following interruption of treatment has been associated with increased risk of serious adverse effects.
Patients should be advised that rifampicin may color feces, saliva, sputum, sweat, tears, urine and other body fluids. Soft contact lenses worn by patients receiving rifampicin may become permanently stained.
Isoniazid: Isoniazid should be administered with caution to patients with convulsive disorders, a history of psychosis or hepatic or renal dysfunction. Patients who are at risk of neuropathy or pyridoxine deficiency, including those who are diabetic, alcoholic, malnourished, uremic, pregnant or HIV-infected, should receive pyridoxine usually in a dose of 10 mg daily, although some have suggested using up to 50 mg daily. If symptoms of hepatitis eg, malaise, fatigue, anorexia and nausea develop, isoniazid should be discontinued pending evaluation.
Liver function should be checked before treatment with isoniazid and special care should be taken in alcoholic patients or those with preexisting liver disease. Regular monitoring of liver function is recommended in patients with preexisting liver disease and isoniazid treatment should be suspended if serum aspartate aminotransferase concentrations are elevated to 3-5 times the normal upper limit or the bilirubin concentration rises. Periodic eye examination during isoniazid treatment have also been suggested.
Ethambutol: It should be used with great care in patients with visual defects, the elderly and in children whom evaluation changes in visual acuity may be difficult. Ocular examination is recommended before treatment with ethambutol and some consider regular examinations are necessary during treatment especially in children. Patients should be advised to report visual disturbances immediately and to discontinue ethambutol pending visual evaluation. Ethambutol may precipitate attacks of gout. Although ethambutol crosses the placenta and teratogenicity has been observed in animals, problems in humans have not been documented.
Fixcom 4: Pyrazinamide: Liver function should be assessed before and regularly during treatment. It should be used with caution in patients with a history of gout. Caution should also be observed in patients with impaired renal function. Increased difficulty has been reported in controlling diabetes mellitus when diabetics are given by pyrazinamide.
Use in Pregnancy: Fixcom 2: A woman should be asked before starting TB treatment if she is pregnant. Most antituberculosis drugs are safe for use in pregnancy. A pregnant woman should be advised that successful treatment of TB with the recommended standardized regimen is important for successful outcome of pregnancy.
Fixcom 3: There are no adequate and well-controlled studies from the use of rifampicin, isoniazid and ethambutol on pregnancy and the fetus. Thus, these drugs should be used during pregnancy only if the benefit justifies the potential risk to the fetus.
Rifampicin: The International Union Against Tuberculosis and the WHO Expert Committee on Leprosy recommend treatment of pregnant patients with the same rifampicin-containing multidrug regimens as would be used in nonpregnant patients.
While administration of rifampicin to pregnant patients is generally considered to be safe, the drug does cross into the fetus and malformations and bleeding tendencies have been reported. It was considered that rifampicin did not increase the overall risk of congenital malformations.
Rifampicin treatment can increase the metabolism of vitamin K resulting in clotting disorders associated with vitamin K deficiency. Thus, it is recommended to have blood coagulation monitoring and prophylactic administration of vitamin K to mothers and neonates when the mother has received rifampicin during pregnancy.
Isoniazid: Isoniazid is recognized as being suitable for use in regimens for the treatment of tuberculosis in pregnant patients. Pyridoxine supplementation is recommended. Preventive therapy with isoniazid is generally delayed until after delivery unless other risk factors are present.
Ethambutol: Ethambutol crosses the placenta and is present in fetal tissue in amounts of at least 74.5% of the maternal serum concentration. Use of ethambutol during pregnancy has not been associated with fetal abnormalities. It is generally considered that the benefits of ethambutol in the treatment of tuberculosis outweigh any potential risks in pregnancy.
Use in Lactation: Fixcom 2: A breastfeeding woman who has TB should receive a full course of TB treatment. Timely and properly applied chemotherapy is the best way to prevent transmission of tubercle bacilli to her baby. All tuberculosis are compatible with breastfeeding; a woman taking them can safely continue to breastfeed. Mother and baby should stay together and the baby continue to be breastfed in the normal way, but be given prophylactic Isoniazid for at least 3 months beyond the time the mother is considered to be non-infectious. BCG vaccination of the newborn should be postponed until the end of isoniazid prophylaxis.
Fixcom 3: The use of these drugs during breastfeeding should be considered only if the expected benefit to the mother outweighs the potential risk to the infant.
Rifampicin is present in small amounts in breast milk. Mothers taking rifampicin may breastfeed.
Isoniazid is distributed into breast milk. Adverse effects on infants during breast feeding have not been reported, although such infants should be monitored for toxic reactions. Ethambutol diffuses into breast milk to produce concentrations similar to those in plasma.