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Drugs List
Therapeutic Indications
Dosage
Administration
Contraindications
Precautions and Warnings
Pregnancy and Lactation
Side Effects
Monograph

Dosage

Adults
Elderly
Children
Patients with Renal Impairment
Patients with Hepatic Impairment
Additional Dosage Information

Patients with body weight less than 30kg

Contraindicated in patients weighing less than 30kg

Dosage should be calculated according to patient weight based on the ratio 8-12mg/kg rifampicin, 4-6mg/kg isoniazid, 20-30mg/kg pyrazinamide and 15-20mg/kg ethambutol as follows:

30 - 39kg bodyweight: 2 tablets daily for 2 months
40 - 54kg bodyweight: 3 tablets daily for 2 months
55 - 70kg bodyweight: 4 tablets daily for 2 months
over 70kg bodyweight: 5 tablets daily for 2 months

Precautions and Warnings

Treatment should be given under close supervision of a physician trained in the management of tuberculosis.

Consideration should be given to official guidance on the appropriate use of antituberculosis agents.

Pregnancy - see Pregnancy section
Breastfeeding - see Breastfeeding section

Patients with hepatic impairment see Dosage; Hepatic impairment.
Patients with renal impairment see Dosage; Renal impairment.

Rifampicin with isoniazid and pyrazinamide and ethambutol should be used with caution in patients with:
History of psychosis
HIV infection

Patients with extremely fast or extremely slow acetylating capability should receive the four components (rifampicin, isoniazid, pyrazinamide and ethambutol) separately in order to facilitate the dose adjustment of isoniazid.

Rifampicin with isoniazid, pyrazinamide and ethambutol tablets should be withdrawn immediately if severe acute hypersensitivity reactions, such as thrombocytopenia, purpura, haemolytic anaemia, dyspnoea and asthma-like attacks, shock or renal failure occur. Patients developing such reactions must never be treated with rifampicin again.

Rifampicin with isoniazid, pyrazinamide and ethambutol tablets should be used with care in patients with visual defects. Ocular examinations including acuity, colour discrimination and visual field are recommended before starting treatment and periodically during treatment, especially if high doses are used. Patients should be questioned at every visit about their vision and advised to discontinue use if a visual disturbance arises pending clinical evaluation.

For undernourished or elderly patients supplementation of pyridoxine (vitamin B6) may be useful, because isoniazid in high doses can lead to pyridoxine (vitamin B6) deficiency.

Use with caution in patients with a history of gout. Regular monitoring of serum uric acid should be undertaken. Treatment should be stopped in gouty arthritis.

Full blood count should be monitored during prolonged treatment and in patients with hepatic disorders. Rifampicin should be withdrawn permanently if thrombocytopenia or purpura occurs. The possibility of pyrazinamide having an undesirable effect on blood clotting time or vascular integrity should be borne in mind in patients with haemoptysis.

Use with caution in patients with diabetes mellitus. Increased difficulty has been reported in controlling diabetes mellitus when such patients are given isoniazid.

Patients suffering from convulsive disorders must be kept under special observation during treatment because of the neurotoxic effects of isoniazid and ethambutol hydrochloride.

Caution should be exercised in subjects with peripheral or optic neuritis. Regular neurological examination is necessary with special care in patients with a history of alcohol abuse. Use of pyridoxine (vitamin B6) may prevent or diminish neuropathy due to isoniazid treatment especially in elderly and in malnourished patients. Pyridoxine should be given in line with official guidelines.

Advise patients of importance of full compliance. If initial intensive phase treatment with rifampicin with isoniazid, pyrazinamide and ethambutol tablets is interrupted for any reason, including non-compliance, this fixed drug combination product is contraindicated for the resumption of treatment. Rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride must be administered separately for the resumption of treatment, because rifampicin needs to be reintroduced at a lower dose. Reference should be made to official guidance on the appropriate resumption of treatment with anti-tuberculosis agents.

Patients should abstain from alcohol while receiving treatment.

Isoniazid may increase the formation of toxic metabolites of paracetamol if paracetamol is taken during isoniazid treatment. Advise patients that they should limit the use of paracetamol-containing products during treatment with isoniazid and, preferably, seek medical advice before taking paracetamol-containing products.

Food with a high content of tyramine or histamine should be avoided. Isoniazid may inhibit monoamine oxidase and diamine oxidase. Intake of food containing tyramine (e.g. cheese, red wine) or histamine (e.g. tuna fish) may lead to headache, palpitations, flushing.

Warn patient that red discolouration of body fluids may occur.

Discolours soft contact lenses.

Additional non-hormonal means of contraception must be employed to prevent the possibility of pregnancy during treatment.

Ability to drive or operate machinery may be affected by side effects.

May cause vitamin K dependent coagulopathy and severe bleeding. Consider vitamin K supplementation, risk of vitamin K dependent coagulopathy.

Pregnancy and Lactation

Pregnancy

Use rifampicin with isoniazid, pyrazinamide and ethambutol tablets with caution during pregnancy.

Rifampicin
Animal studies have reported spina bifida in mice and rats and cleft palates in mice when administered rifampicin. Teratogenicity has been reported in rats. Rifampicin crosses the human placenta to the foetus. No controlled studies link the use of rifampicin to congenital defects in humans. One report described a 4.4% incidence of malformations, which is similar to the expected frequency of defects in the healthy population, but higher than the rate noted for other tuberculosis patients. Briggs concludes rifampicin is not a proven teratogen.

Several reviews have concluded that rifampicin was not a proven teratogen and recommended the use of rifampicin with isoniazid and ethambutol if necessary. Schaefer concludes that rifampicin is a drug of choice for the treatment of tuberculosis during pregnancy, Schaefer also suggests the use of rifampicin as prophylaxis against meningococcal infection. When administered during the last few weeks of pregnancy, post-natal haemorrhage in the mother and neonate may occur and therapy with vitamin K1 may be required.

Isoniazid
Isoniazid crosses the human placenta to the foetus. Animal studies in mice, rats and rabbits have not revealed teratogenic effects, but embryocidal effects were observed in rats and rabbits. Supplementation of pyridoxine (vitamin B6) is recommended during pregnancy, because isoniazid might exert neurotoxic effects on the child. Briggs concludes that isoniazid does not appear to be a human teratogen. Schaefer states isoniazid as the drug of choice for prophylaxis and treatment of tuberculosis in pregnancy and recommends combination with pyridoxine (vitamin B6) and monthly liver function tests.

Pyrazinamide
No animal reproductive studies have been conducted with pyrazinamide. It known whether pyrazinamide can cause foetal damage when administered to a pregnant woman. A small number of human pregnancy exposures without fetal harm have been reported. Briggs concludes because the indication being treated is of far greater risk to the embryo-foetus than the drug, pyrazinamide, if indicated should not be withheld in pregnancy.

Ethambutol
Ethambutol crosses the placenta, and may result in foetal plasma concentrations that are approximately 30% of maternal plasma concentrations. Limited clinical data on exposed pregnancies suggest no increase in the rate of foetal malformations in humans. Animal studies have shown a teratogenic potential.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Use rifampicin with isoniazid, pyrazinamide and ethambutol tablets with caution during breastfeeding.

Schaefer concludes that isoniazid (in combination with 0.5 to 1mg of vitamin B6 prophylaxis per day for the infant), rifampicin and pyrazinamide are the tuberculostatics of choice during breastfeeding. Ethambutol is also acceptable, however the manufacturer does not recommend breastfeeding in view of the theoretical possibility of neurotoxic effects due to isoniazid and ethambutol.

Rifampicin, isoniazid, pyrazinamide and ethambutol pass into the breast milk, but no undesirable effects on breastfed infants have been observed.

The Centres for Disease Control and prevention state that breastfeeding should not be discouraged in patients taking rifampicin with isoniazid, pyrazinamide and ethambutol tablets.

The Drugs and Lactation Database (LactMed) suggests the breastfed infant should be monitored for rare cases of jaundice, hepatitis and arthralgia.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Presentation

Tablets containing 150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide and 275mg ethambutol

Drugs List

rifampicin 150mg and isoniazid 75mg and pyrazinamide 400mg and ethambutol hydrochloride 275mg tablets

VORACTIV tablets

Therapeutic Indications

Uses

For the initial treatment of tuberculosis according to World Health Organisation (WHO) guidelines. Consideration should also be given to other official guidance on the appropriate use of antituberculosis agents.

Dosage

Treatment should be given under close supervision of a physician trained in the management of tuberculosis.

Dose and dose schedules may be different from those given in other official guidance.

Adults

Patients with body weight less than 30kg
Contraindicated in patients weighing less than 30kg

Dosage should be calculated according to patient weight based on the ratio 8-12mg/kg rifampicin, 4-6mg/kg isoniazid, 20-30mg/kg pyrazinamide and 15-20mg/kg ethambutol as follows:

Elderly

See Dosage; Adults.

Supplementation of pyridoxine (vitamin B6) may be useful in elderly patients.

Children

Patients with body weight less than 30kg
Contraindicated in patients weighing less than 30kg

Children under 8 years
Contraindicated in children under 8 years old because of risk of aspiration and difficulties in evaluation of changes of visual acuity.

Patients with Renal Impairment

Patients with moderate renal impairment (creatinine clearance 30-60ml/min)
Use with caution.

Patients with severe renal impairment (creatinine clearance less than 30ml/min)
Contraindicated. In severe renal insufficiency, the elimination of isoniazid, pyrazinamide and ethambutol can be delayed leading to a higher systemic exposure, which can result in an increase in adverse events.

Patients with Hepatic Impairment

Patients with a history of drug induced hepatitis and patients with acute liver diseases
Rifampicin with isoniazid, pyrazinamide and ethambutol tablets are contraindicated patients with a history of drug induced hepatitis and patients with acute liver diseases.

Patients with impaired hepatic function
Use with caution and under strict supervision in patients with impaired hepatic function. In these patients, careful monitoring of liver function should be carried out prior to and weekly or fortnightly during therapy. If signs of hepatocellular damage occur treatment should be discontinued.

Severe and sometimes fatal hepatitis caused by isoniazid may occur and may develop even after many months of treatment. The incidence of severe hepatotoxicity can be minimised by careful monitoring of liver function. Patients should be monitored for symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea or vomiting. If these symptoms appear or if signs of hepatic damage are detected, treatment should be discontinued promptly. Continued use in these patients may cause a more severe form of liver damage.

Additional Dosage Information

Advise patients of importance of full compliance.

If initial intensive phase treatment with rifampicin with isoniazid, pyrazinamide and ethambutol tablets is interrupted for any reason, including non-compliance, this fixed drug combination product is contraindicated for the resumption of treatment. Rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride must be administered separately for the resumption of treatment, because rifampicin needs to be reintroduced at a lower dose. Reference should be made to official guidance on the appropriate resumption of treatment with anti-tuberculosis agents.

Administration

For oral administration.

Tablets should be administered as a single dose and on an empty stomach at least 1 hour before food.

Contraindications

Children weighing less than 30kg
Children under 8 years
Renal impairment - creatinine clearance below 30 ml/minute
History of drug induced hepatic impairment
Acute hepatic disorder
Porphyria
Optic neuritis
Acute gout