This information is intended for use by health professionals

1. Name of the medicinal product

Ethambutol 100 mg Tablets

2. Qualitative and quantitative composition

Each film coated tablet contains 100mg Ethambutol Hydrochloride.

For a full list of excipients see section 6.1.

3. Pharmaceutical form

Film coated tablet.

Smooth, yellow, circular, biconvex film coated tablet, 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-tuberculinpositive reaction. Ethambutol should only be used in conjunction with other anti-tuberculous drugs to which the patient's organisms are susceptible.

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

4.2 Posology and method of administration

Route of administration:

Oral

Posology:

Recommended Dosage

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

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

The usual daily dosage is 15-25mg/kg body weight given as a single dose.

Adults

For primary treatment and prophylaxis: Ethambutol should be administered in a single daily 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 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

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

Elderly

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

Ethambutol is contraindicated in patients who are known to be hypersensitive to the active substance or any of the excipients.

Ethambutol is contraindicated in patients who have optic neuritis, or retrobulbar neuritis unless clinical judgement determines that the benefit outweighs the risk.

4.4 Special warnings and precautions for use

Occular 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 week or more, depending on clinical assessment. Each eye should be tested separately as ocular toxicity can be unilateral or bi-lateral. 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 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.

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 Pregnancy and lactation

There are no adequate and well-controlled studies in pregnant or lactating women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Ethambutol should not be used in pregnant women, women of childbearing potential or 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 4.8 Undesirable effects). Numbness and paraesthesia of the extremities have been reported. Therefore, patients should be cautioned about their ability to drive a car or operate hazardous machinery if they experience any if these symptoms.

4.8 Undesirable effects

In this section, frequencies of undesirable effects are defined as follows: Frequency: 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).

Blood & lymphatic system disorders:

Rare: Thrombocytopenia

Very rare: Leucopenia, neutropenia

Immune system disorders:

Very rare: Hypersensitivity, anaphylactoid reactions, (see also Skin and subcutaneous tissue disorders)

Metabolic & nutrition disorders:

Uncommon: Hyperuricaemia

Very rare: Gout

Nervous system disorders:

Rare: Peripheral neuropathy, numbness, paraesthesia of the extremities

Very rare: headache, dizziness, disorientation

Psychiatric disorders:

Very rare: mental confusion, hallucinations

Eye disorders:

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

Respiratory, thoracic & mediastinal disorders:

Very rare: Pneumonitis, pulmonary infiltrates, with or without eosinophilia

Gastrointestinal disorders:

Gastrointestinal disorders such as anorexia, nausea, vomiting, abdominal pain and diarrhoea have been noted in patients on multiple drug anti-tuberculosis 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 very rarely, 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:

Rare: Rash, pruritus, urticaria

Very rare: photosensitive lichenoid eruptions, bullous dermatitis, Stevens- Johnson syndrome, epidermal necrolysis

Musculoskeletal and connective tissue disorders:

Very rare: Joint pains

Renal & urinary disorders:

Very rare: Interstitial nephritis

General disorders and administration site conditions:

Very rare: Malaise, pyrexia

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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

Treatment: No specific antidote, but gastric lavage should be employed if necessary

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycobacterial , ATC code: J04AK02.

Mode of Action

Ethambutol is bacteriostatic. It is effective against Mycobacterium tuberculosis and M. bovis with an MIC of 0.5 - 8 µg per ml. the exact mechanisim 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.

Mechanism of Resistance

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.

5.2 Pharmacokinetic properties

Absorption

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

Distribution

After a single dose of 25mg/kg body weight, within 4 hours peak plasma concentrations of up to 5µg/ml are obtained; by 24 hours the concentration decreases to less than 1µg/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 faeces, within 48 hours. From 8 - 15% of a dose appears in urine as inactive metabolites.

5.3 Preclinical safety data

Ethambutol hydrochloride had 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

Tablet core:

Sodium starch glycollate

Maize starch

Povidone

Colloidal anhydrous silica

Microcrystalline cellulose

Magnesium stearate

Film coating:

Opadry II 45F32810 Yellow.

Containing Polydextrose, hydroxypropylmethylcellulose, polyethylene glycol 4000, titanium dioxide (E171), iron oxide yellow (E172), and purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store below 30°C.

Store in original package to protect from moisture.

Keep out of reach and sight of children.

6.5 Nature and contents of container

HDPE bottles with a HDPE/PP/EPE cap containing 56 tablets.

6.6 Special precautions for disposal and other handling

No special precautions. Any unused product should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Intrapharm Laboratories Limited,

The Courtyard Barns,

Choke Lane,

Maidenhead,

Berks,

SL6 6PT,

United Kingdom

8. Marketing authorisation number(s)

PL 17509/0081

9. Date of first authorisation/renewal of the authorisation

05/06/2018

10. Date of revision of the text