LEVOTHYROXINE TABLETS 50 MICROGRAMS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Levothyroxine Tablets BP 50 microgram

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Levothyroxine Sodium 55.6 micrograms per tablet

Equivalent to Levothyroxine Sodium Anhydrous 50 micrograms per tablet

3 PHARMACEUTICAL FORM

Uncoated, white, biconvex tablet, engraved E 905 on one side, plain on the other

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of hypothyroidism (congenital or acquired), diffuse non toxic goitre or Hashimoto's thy­roiditis and thyroid carcinoma

4.2 Posology and method of administration

The treatment of any thyroid disorder should be determined on an individual basis, taking account of clinical response, biochemical tests and regular monitoring. A pre-therapy ECG is valuable as changes induced by hypothyroidism may be confused with evidence of ischaemia. If too rapid an increase of metabolism is produced (causing diarrhoea, nervousness, rapid pulse, insomnia, tremors and sometimes anginal pain where there is latent myocardial ischaemia), reduce the dose or withhold for 1–2 days and start again at a lower dose.

Levothyroxine is best taken as a single dose on an empty stomach, usually before breakfast.

Adults, children over 12 years

Initial dose:                       ­50 – 100 micrograms daily before breakfast.

Usual maintenance dose:         100 – 200 microgram­s daily.

The initial dose is adjusted by 25 to 50 microgram increments at 3 – 4 week intervals until clinical response and measurements of plasma thyroxine and thyroid stimulating hormone indicate that the thyroid deficiency is corrected and a maintenance dose established.

Elderly patients (over 50 years of age), or those with cardiac insufficiency or in those with severe hypothyroidism

Initial dose:                   ­25 micrograms daily before breakfast.

Usual maintenance dose:     50 to 200 micrograms daily.

The initial dose is adjusted by 25 microgram increments at 4 week intervals until clinical response and measurements of plasma thyroxine and thyroid stimulating hormone indicate that the thyroid deficiency is corrected and a maintenance dose is established.

Paediatric patients

The maintenance dose is generally 100 to 150 micrograms per m2 body surface area.

For neonates and infants with congenital hypothyroidism, where rapid replacement is important, the initial recommended dosage is 10 to 15 micrograms per kg BW per day for the first 3 months. Thereafter, the dose should be adjusted individually according to the clinical findings and thyroid hormone and TSH values.

For children with acquired hypothyroidism, the initial recommended dosage is 12.5–50 micrograms per day. The dose should be increased gradually every 2 to 4 weeks according to the clinical findings and thyroid hormone and TSH values until the full replacement dose is reached.

Infants should be given the total daily dose at least half an hour before the first meal of the day.

In children under 5 years of age, the administration of whole tablets is not recommended. It is also not recommended that tablets are crushed and dispersed in water or other liquids, owing to limited solubility which could lead to dosing inaccuracy. In this age group it is preferable to administer an approved oral solution of levothyroxine.

4.3 Contraindications

Thyrotoxicosis, hypersensitivity to any component. In patients with adrenal insufficiency without adequate corticosteroid co­ver.

4.4 Special warnings and precautions for use

Thyroid treatments should be used with caution in patients with cardiovascular disorders, including myocardial insufficiency and hypertension.

Thyroid replacement therapy should be introduced gradually in elderly patients, and those with severe long standing hypothyroidism.

Special care is needed when there are symptoms of myocardial insufficiency or ECG evidence of myocardial infarction and for similar reasons the treatment of hypothyroidism in the elderly should be initiated cautiously. Patients with adrenal insufficiency may react unfavourably to levothyroxine treatment so it is advisable to initiate corticosteroid therapy before giving levothyroxine. Caution should also be exercised when administering levothyroxine to diabetics or digitalised patients.

Subclinical hyperthyroidism may be associated with bone loss. To minimise the risk of osteoporosis, dosage of levothyroxine sodium should be titrated to the lowest possible effective level.

Parents of children receiving a thyroid agent should be advised that partial loss of hair may occur during the first few months of therapy, but this effect is usually transient and subsequent regrowth usually occurs.

4.5 Interaction with other medicinal products and other forms of interaction

The effects of warfarin, dicoumarol, nicoumalone, phenindione and probably other anticoagulants are increased by the concurrent use of thyroid compounds. The antidepressant response to imipramine, amitriptyline and possibly other tricyclic antidepressants can be accelerated by the concurrent use of levothyroxine.

The absorption of levothyroxine is reduced by sucralfate, sodium polystyrene sulphonate or colestyramine binding within the gut. Cimetidine, aluminium hydroxide, calcium carbonate and ferrous sulphate also reduce absorption of levothyroxine from the G.I. tract. Dosages should be separated by an interval of several hours.

The concurrent use of carbamazepine, phenytoin, phenobarbital, primadone or rifampicin with levothyroxine has been found to increase levothyroxine metabolism. A possible interaction occurs with hypoglycaemic agents, hence diabetic patients should be monitored for increased requirements of insulin or oral hypoglycaemic agents.

If levothyroxine therapy is initiated in digitalised patients, the dose of digoxin may require adjustment, hyperthyroid patients may need their digoxin dosage gradually increased as treatment proceeds, because initially patients are relatively sensitive to digoxin.

Isolated reports of marked hypertension and tachycardia have been reported with concurrent ketamine administration. Lovastatin has been reported to cause one case each of hypothyroidism and hyperthyroidism in two patients taking levothyroxine.

False low total plasma concentrations have been observed with concurrent anti-inflammatory treatment such as phenylbutazone or acetylsalicylic acid and levothyroxine therapy. Levothyroxine accelerates the metabolism of propranolol.

Oestrogen, oestrogen containing products and oral contraceptives may increase the requirement of thyroid therapy dosage. Conversely, androgens and corticosteroids may decrease serum concentrations of thyroxine-binding globulins.

Amiodarone may reduce the effects of thyroid hormones used in the treatment of hypothyroidism.

4.6 Fertility, Pregnancy and lactation

Pregnancy

Women on a maintenance dose for hypothyroidism who become pregnant, must be monitored closely. Levothyroxine sodium does not readily cross the placenta in the second and third trimester, but may do so in the first. Levothyroxine sodium is not known to have either carcinogenic or tetragenic effects.

Lactation

Minimal concentrations of levothyroxine are excreted in breast milk and may mask hypothyroidism in a newborn baby. It is considered that there is insufficient thyroid hormone in breast milk to meet the needs of a suckling infant with a non-functioning thyroid gland.

4.7 Effects on ability to drive and use machines

None known

4.8 Undesirable effects

The following side effects are usually due to excessive dosage, and correspond to symptoms of hyperthyroidism. They include arrhythmias, anginal pain, tachycardia, cramps in skeletal muscles, headache, restlessness, excitability, flushing, sweating, diarrhoea, excessive weight loss and muscular weakness, insomnia, tremor, fever, vomiting, palpitations and heat intolerance. These reactions usually disappear after dose reduction or withdrawal of treatment. Hypersensitivity reactions including rash, pruritus and oedema have also been reported.

Thyroid crisis have occasionally been reported following massive or chronic intoxication and cardiac arrhythmias, heart failure, coma and death have occurred.

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 via Yellow Card Scheme Website www.mhra.gov/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms of mild to moderate overdose: fever, angina, tachycardia, arrhythmias, muscle cramps, headache, restlessness, flushing, sweating, diarrhoea. Reduction of dose or withdrawal of therapy reverses mild overdose effects.

Symptoms of severe overdose: this may resemble thyroid crisis with collapse and coma.

Signs and symptoms of hyperthyroidism may be delayed for up to 5 days due to the gradual peripheral conversion of levothyroxine to triiodothyronine. Overdosage following recent ingestion of tablets can be treated using gastric lavage/emesis. Propranolol and other supportive measures are used to maintain the circulation. Antithyroid drugs such as propylthiouracil and lithium are unlikely to be of benefit to prevent thyrotoxic crisis due to delayed absorption/onset of action.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Thyroxine (T4) is a naturally occurring hormone containing iodine, produced by the thyroid gland. It is converted to its more active principle triiodothyronine (T3) in the peripheral tissues. Receptors for T3 are found on cell membranes, mitochondria and cell nuclei. Thyroid hormones are required for normal growth and development of the body, especially the nervous system. They increase the basal metabolic rate of the whole body and have stimulatory effects on the heart, skeletal muscle, liver and kidney.

5.2 Pharmacokinetic properties

Levothyroxine sodium is incompletely and variably absorbed from the gastrointestinal tract. Levothyroxine is extensively metabolised in the thyroid, liver, kidney and anterior pituitary. Some enterohepatic re-circulation occurs. Part of the levothyroxine is metabolised to triiodothyronine. Levothyroxine is excreted in the urine and faeces, partly as free drug and partly as conjugates and de-iodinated metabolites.

It has a half life of 7 days but this may be shortened or prolonged depending on the disease condition. Levothyroxine is almost completely bound to plasma protein, mainly thyroxine binding globulin, with approx. 0.03% of levothyroxine unbound. The unbound levothyroxine is converted to triiodothyronine.

There are four main pathways of metabolism:

1) Deiodination to triiodothyronine (active) – T3 or to reverse triiodothyronine (inactive). Further deiodination of T3 leads to the formation of thyroacetic acid.

2) Deamination to the tetrone.

3) Conjugation to the glucoronide or sulphate.

4) Ether bond cleavage to diiodotyrosines.

The most important metabolic pathway is deiodination. Between 30 – 55% of the levothyroxine dose is excreted in the urine and 20 – 40% in the faeces.

5.3 Preclinical safety data

Not applicable since Levothyroxine Tablets have been used in clinical practice for many years and its effects in man are well known.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Sucrose

Maize Starch

Magnesium Stearate

6.2 Incompatibilities

None known

6.3 Shelf life

24 months in polypropylene containers, 18 months in blister packs

6.4 Special precautions for storage

Store below 25°C and protect from light

6.5 Nature and contents of container

Opaque polypropylene containers having snap-on polythene lids, with integral tear-off security seals containing 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 500 or 1000 tablets.

PVC/PVDC/aluminium blisters containing 14 tablets. Blisters are packaged into cartons to give packs of 28, 42, or 56 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special precautions are required

7 MARKETING AUTHORISATION HOLDER

RPH Pharmaceuticals AB

Box 603

101 32 Stockholm

Sweden

8 MARKETING AUTHORISATION NUMBER(S)

PL 36301/0047