SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ethambutol 400mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film coated tablet contains:

Ethambutol hydrochloride 400 mg For a full list of excipients see section 6.1

3 PHARMACEUTICAL FORM

Grey, circular biconvex film coated tablets, plain on both sides

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The primary treatment and re-treatment of tuberculosis and for prophylaxis in cases of inactive tuberculosis or large-tuberculin-positive reaction. Ethambutol should only be used in conjunction with other anti-tuberculosis drugs to which the patient’s organisms are susceptible.

Before prescribing Ethambutol Tablets, consideration should be given to national and/or local guidance on the appropriate use of anti-bacterial agents

4.2 Posology and method of administration

Route of administration:

Oral

Posology:

The dosage of ethambutol must be adjusted according to the body weight of the patient.

Adults

For primary treatment and prophylaxis:

Ethambutol should be administered in a single daily oral dose of 15mg/kg, concomitant drugs being maintained at their recommended dosage levels.

For re-treatment:

For the first 60 days of treatment, ethambutol should be administered in a single daily oral dose of 25mg/kg. Thereafter the dosage should be reduced to 15mg/kg, concomitant drugs being maintained at their recommended dosage levels.

Children

For primary treatment and re-treatment :

For the first 60 days of treatment, a single daily oral dose of 25mg/kg. Thereafter the dosage should be reduced to 15mg/kg, concomitant drugs being maintained at their recommended dosage levels.

For prophylaxis :

A single daily oral dose of 15mg/kg, concomitant drugs being used at their recommended dosage levels.

Elderly

As for adults. However, patients with decreased renal function may need to have the dosage adjusted as determined by blood levels of ethambutol.

In order to obtain maximum effect due to high serum levels, drug administration should be once daily.

4.3 Contraindications

Ethambutol is contra-indicated in patients who are known to be hypersensitive to the drug or to any of the excipients. It is also contra-indicated in patients with known optic neuritis unless clinical judgement determines that it may be used.

4.4 Special warnings and precautions for use

Renal function should be checked before treatment with antituberculous drugs and appropriate dosage adjustments made. Ethambutol should preferably be avoided in patients with renal impairment, but if used the dose should be reduced and the plasma-drug concentration monitored. Toxic effects are more common if renal function is impaired.

Because this drug has a unique effect on the eye, it is recommended that patients undergo a full ophthalmic examination before starting treatment. This should include visual acuity, colour vision, perimetry and ophthalmoscopy. Many physicians consider that routine ophthalmological examination for adults is not thereafter necessary, but patients should be informed the importance of reporting any change in vision.

However, routine ophthalmological examinations may be considered desirable when treating young children.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been carried out with ethambutol.

4.6 Pregnancy and lactation

Pregnancy

There are no adequate data from the use of ethambutol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Lactation

Ethambutol should not be used in pregnant women or women of childbearing potential unless the potential benefit to the mother is considered to outweigh any possible risk to the foetus.

4.7 Effects on ability to drive and use machines

Patients who suffer from visual impairment during treatment with ethambutol should not drive or operate machinery.

4.8 Undesirable effects

Modern clinical data required to determine the frequency of undesirable effects are lacking for ethambutol. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.

Blood & lymphatic disorders

Thrombocytopaenia, leucopenia, neutropenia, eosinophilia Immune system disorders

Hypersensitivity, anaphylactoid reactions, (see also Skin & subcutaneous tissue disorders)

Metabolic & nutrition disorder Hyperuricaemia, gout

Psychiatric disorders

Mental confusion, disorientation, hallucination.

Nervous system & psychiatric disorders

Peripheral neuropathy, numbness, paraesthesia of the extremities, dizziness, headache

Eye disorders

Optic neuritis (decreased visual acuity, loss of vision, scotoma, colour blindness, visual disturbance, visual field defect, eye pain)

Ethambutol may produce a unique type of visual impairment which is generally reversible and which appears to be due to optic neuritis and to be related to dose and duration of treatment. Less than 1% of patients undergoing treatment with the higher dose regimen of 25mg/kg/day for two months, and 15mg/kg/day thereafter, have exhibited decrease in visual acuity. The change may be unilateral or bilateral and hence both eyes must be tested individually. The effects are generally reversible when administration of the drug is discontinued promptly. In rare cases recovery may be delayed for up to one year or more and the effect may possibly be irreversible in these cases.

Recovery of visual acuity has usually occurred over a period of weeks to months after the drug was discontinued, and patients have then received Ethambutol at lower dosages without toxicity.

Respiratory, thoracic and mediastinal disorders Pneumonitis, pulmonary infiltrates, with or without eosinophilia

Gastrointestinal disorders

Gastrointestinal disturbances such as anorexia, nausea, vomiting, abdominal pain and diarrhoea have been noted in patients on multiple drug antituberculosis therapy including ethambutol although not in test patients receiving ethambutol as sole therapy.

Hepatobiliary disorders

Hepatic reactions with hepatitis, jaundice, abnormal liver function test values, and hepatic failure, have been reported in patients treated with multiple drug therapy including ethambutol. Liver function tests should be performed in patients who develop symptoms suggestive of hepatitis or who become generally unwell during treatment

Skin & subcutaneous tissue disorders

Rash, pruritus, urticaria, photosensitive lichenoid eruptions, bullous dermatitis, Stevens Johnson syndrome, epidermal necrolysis

Renal & urinary disorders Interstitial nephritis

Other:

Malaise, joint pains, pyrexia

4.9 Overdose

Symptoms

The overdosage symptoms include nausea, abdominal pain, fever, mental confusion, visual hallucinations, and optic neuropathy (retrobulbar neuritis)

Treatment

There is no specific antidote, but gastric lavage should be employed if necessary.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycobacterial ATC Code for Ethambutol hydrochloride: J04AK02

Mechanism of action:

Ethambutol is bacteriostatic.

Cross-resistance has not yet been reported. Primary resistance to ethambutol is uncommon but resistant strains of M. tuberculosis are readily produced if ethambutol is used alone.

Spectrum of antibacterial activity:

Ethambutol is effective against Mycobacterium tuberculosi and M. bovi with an MIC of 0.5 - 8 pg per ml. While it has activity against some atypical mycobacteria including M. Kansarii, activity against other micro-organisms has not yet been reported.

It is effective against tubercle bacilli resistant to other tuberculostatics.

5.2 Pharmacokinetic properties

Ethambutol is readily absorbed after oral administration and this absorption is not significantly impaired by food. After a single dose of 25mg/kg body weight, within 4 hours peak plasma concentrations of up to 5pg/ml are obtained, by 24 hours the concentration decreases to less than 1 pg/ml. Most of a dose is excreted unchanged in the urine and up to 20% in faeces, within 48 hours. From 8 - 15% of a dose appears in urine as inactive metabolites.

Ethambutol readily diffuses into red blood cells and into the cerebrospinal fluid when the meninges are inflamed. It has also been reported to cross the placenta.

5.3 Preclinical safety data

Toxicologically studies in dogs on high prolonged doses produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of the eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in

dogs receiving ethambutol hydrochloride over a prolonged period. In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These were correlated with specific serum levels of ethambutol and with definite neuroanatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received ethambutol hydrochloride in high doses for a prolonged period.

Conflicting results are available on genotoxicity (negative Ames test, negative in human lymphocyte cell cultures, positive in mouse micronucleus). In mice, ethambutol administered together with sodium nitrite gave rise to an increased frequency of lymphomas and lung tumours, while ethambutol alone did not cause any increase in tumour frequency.

Cleft palate, exencephaly and vertebral column abnormalities have been observed with high doses in studies of reproduction toxicity in mice. Studies in rats and rabbits have shown that ethambutol in high doses causes minor abnormalities of the cervical vertebrae and monophthalmica, limb reduction defects, hare lip and cleft palate in the offspring.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core Tablet:

Magnesium Stearate, Maize Starch, Microcrystalline Cellulose, Povidone, Silica Colloidal anhydrous, Sodium Starch glycolate.

Film Coating:

Opadry II OY-GM-27600 containing

Hypromellose 15cP, Iron oxide Black (E172), Iron oxide Yellow (E172), Polydextrose, Polyethylene glycol 4000, Titanium Dioxide

6.2 Incompatibilities

Not applicable

Shelf life

36 months.

6.4 Special precautions for storage

Do not store above 25^oC. Any unused product or waste material should be disposed of in accordance with local requirements.

6.5 Nature and contents of container

Al /PVC blister. Pack sizes of 10, 14, 20, 28, 30, 56, 60, 84, 90 and 112 tablets are available

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Morningside Healthcare Ltd 115 Narborough Road Leicester.

LE3 0PA UK.

8    MARKETING AUTHORISATION NUMBER(S)

PL 20117/0160

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/07/2010

10    DATE OF REVISION OF THE TEXT

13/04/2011