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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ethambutol 400 mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains Ethambutol hydrochloride 400 mg

3    PHARMACEUTICAL FORM

Film-coated tablet.

Grey, round biconvex, film coated tablet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For 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.

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

4.2    Posology and method of administration

For oral use.

Dosage should be determined according to the body weight of the patient. The usual daily dosage is 15-25mg/kg body weight given as a single dose.

Ethambutol should not be used as a sole anti-tuberculosis agent, but should be given with at least one other anti-tuberculosis drug to avoid development of resistant strains.

Adults

For primary treatment and prophylaxis: Ethambutol should be administered in a single daily dose of 15 mg/kg body weight; concomitant drugs should be maintained at their usual recommended dosage.

For re-treatment: For the first 60 days of treatment, ethambutol should be administered in a single daily dose of 25 mg/kg body weight. Thereafter the dosage should be reduced to 15 mg/kg body weight; concomitant drugs should be maintained at their usual recommended dosage levels.

Children

For primary treatment and re-treatment: For the first 60 days of treatment, a single daily dose of 25 mg/kg body weight. Thereafter the dosage should be reduced to 15 mg/kg body weight; concomitant drugs being maintained at their usual recommended dosage levels.

For prophylaxis: A single daily dose of 15 mg/kg body weight; concomitant drugs being maintained at their usual recommended dosage levels.

As children may be less likely or unable to report ocular toxicity, particular caution may be warranted (see Section 4.4).

Elderly

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

4.3 Contraindications

Known hypersensitivity to ethambutol or to any of the other ingredients.

Known optic neuritis or retrobulbar neuritis, unless clinical judgement determines that the benefit outweighs the potential risk.

4.4 Special warnings and precautions for use

Ocular toxicity:

Ethambutol causes ocular toxicity and patients should be advised to report any changes of visual acuity. Visual acuity should be examined prior to the start of therapy and should be monitored every four weeks during treatment. For patients with pre-existing visual defects or renal insufficiency the frequency of tests should be increased to every second or third week or more, depending on clinical assessment. Each eye should be tested separately as ocular toxicity can be unilateral or bilateral. Opthalmologic examination should include tests for black-white/chromatic visual acuity (e.g Snellen eye chart and 65-test) and opthalmoscopy.

Patients who are unable to report their visual acuity should be more closely monitored for any signs of deterioration during treatment with ethambutol. Ethambutol should be used in young children and those with language or communication difficulties, where appropriate, with advice concerning the need to report visual side-effects being given to parents or other family members.

Ethambutol therapy should be stopped immediately if visual disturbances are observed (see section 4.8).

Renal impairment:

Renal function should be checked before treatment with antituberculosis 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.

4.5 Interaction with other medicinal products and other forms of interaction

Aluminium hydroxide impairs the absorption of ethambutol. Acid suppressing drugs or antacids that do not contain aluminium hydroxide should be used during ethambutol therapy.

4.6 Fertility, pregnancy and lactation

The potential for risk in humans is unknown as there are no adequate and well controlled studies in pregnant or lactating women. Studies in animals have shown reproductive toxicity. Ethambutol should not therefore be used during pregnancy, in women of childbearing potential or in lactating women unless the potential benefit to the mother is considered to outweigh any possible risks.

4.7 Effects on ability to drive and use machines

Ethambutol may produce a unique type of visual impairment (see section 4.8). Numbness and paraesthesia of the extremities has been reported. Therefore, patients should be advised not to drive or operate machinery if they experience any of these effects.

Undesirable effects

The most important adverse effect resulting from Ethambutol use is retrobulbar neuritis with a reduction in visual acuity.

The adverse event data below contains all reactions that are considered at least possibly related to Ethambutol and is based on data collected, mainly from published literature post authorisation. The undesirable effects have been arranged by body system, organ class and absolute frequency, and are defined using the following convention:

Very common (£1/10); common (£1/100, < 1/10); uncommon (£1/1,000, < 1/100); rare ( £ 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Not known: thrombocytopenia, leukopenia, neutropenia, eosinophilia.

Immune system disorders

Not known: hypersensitivity, allergic reactions, anaphylaxis, allergic pneumonitis. Metabolism and nutrition disorders

Very common: hyperuricaemia.

Not known: gout.

Psychiatric disorders:

Not known: confusion, disorientation, hallucination.

Nervous system disorders:

Common: visual disturbances caused by optic neuritis (retrobulbar neuritis). This effect is thought to be dose related and frequency is dependent on both dose and duration of treatment. It occurs most frequently with doses of 25 mg/kg body weight and after two months of therapy, however optic neuritis has also occurred after only a few days of therapy. The effect is often reversible upon discontinuation of therapy. To avoid permanent damage visual acuity should be checked regularly during treatment and therapy discontinued immediately when visual disturbances occur. Visual disturbances may be unilateral or bilateral; therefore each eye should be tested separately (see section 4.4). Typical signs include: blurred vision, eye pain, impairment of colour vision (red-green colour blindness), constriction of visual field (central or peripheral scotoma), and any loss in vision.

Not known: peripheral neuritis, paraesthesia (especially in legs), numbness, burning pain, weakness (hands and feet), dizziness, headache, tremor.

Respiratory, thoracic and mediastinal disorders:

Not known: pneumonitis, pulmonary infiltrates, with or without eosinophilia.

Gastrointestinal disorders:

Not known: metallic taste, nausea, vomiting, anorexia, flatulence, abdominal pain, loss of appetite, upset stomach.

Hepatobiliary disorders:

Not known: hepatitis, hepatic failure, jaundice, transient increase in liver enzymes. Skin & subcutaneous tissue disorders

Not known: rash, pruritus, urticaria, photosensitive lichenoid eruptions, bullous dermatitis, Stevens Johnson syndrome, epidermal necrolysis.

Renal and urinary disorders:

Not known: nephrotoxicity including interstitial nephritis.

General disorders and administration site conditions:

Not known: malaise, joint pains, pyrexia.

4.9 Overdose

Symptoms: Gastrointestinal disturbances, vomiting, fever, headache, anorexia, dizziness, hallucinations and/or visual disturbances.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code : J04AK02 - Other drugs for treatment of tuberculosis

Ethambutol is bacteriostatic. It is effective against Mycobacterium tuberculosi and M.bovis with an MIC of 0.5 - 8pg per ml. The exact mechanism of action is unknown. While it has activity against some atypical mycobacteria including M.Kansasii, activity against other micro-organisms has not yet been reported.

It is effective against tubercle bacilli resistant to other tuberculostatics.

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

Pharmacokinetic properties

Absorption: Ethambutol is readily absorbed after oral administration and this absorption is not significantly impaired by food.

Distribution: After a single oral dose of 25 mg/kg bodyweight, within 4 hours peak plasma concentrations of up to 5pg/ml are obtained, by 24 hours the concentration decreases to less than 1pg/ml. 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.

Metabolism and Excretion: Most of a dose is excreted unchanged in the urine and up to 20% in the faeces, within 48 hours. From 8 - 15% of a dose appears in the urine as inactive metabolites.

5.3 Preclinical safety data

Ethambutol has been shown to be teratogenic in pregnant mice and rabbits when given in high doses. When pregnant mice or rabbits were treated with high doses of ethambutol hydrochloride, fetal mortality was slightly but not significantly (P>0.05) increased. Female rats treated with ethambutol hydrochloride displayed slight but insignificant (>0.05) decreases in fertility and litter size. In foetuses born of mice treated with high doses of ethambutol hydrochloride during pregnancy, a low incidence of cleft palate, exencephaly and abnormality of the vertebral column were observed. Minor abnormalities of the cervical vertebra were seen in the newborn of rats treated with high doses of ethambutol hydrochloride during pregnancy. Rabbits receiving high doses of ethambutol hydrochloride during pregnancy gave birth to two foetuses with monophthalmia, one with a shortened right forearm accompanied by bilateral wrist-joint contracture and one with hare lip and cleft palate.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium starch glycolate Maize starch Povidone

Colloidal anhydrous silica Microcrystalline cellulose Magnesium stearate

6.2    Incompatibilities

None.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Do not store above 25°C.

6.5    Nature and contents of container

Al/PVC/PVDC blisters. Pack size of 56 tablets.

PP tablet containers. Pack size of 56 tablets.

6.6    Special precautions for disposal

None.

7    MARKETING AUTHORISATION HOLDER

Fannin (UK) Limited 42-46 Booth Drive Park Farm South Wellingborough NN8 6GT UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 20417/0103

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/11/2012

10    DATE OF REVISION OF THE TEXT

26/06/2013