Doctor Pharmacy

Product Name:

THYROXINE

TITLE:

Thyroxine sodium.

SCOPE:

Trade Names

THYROXINE® Tablets 100 MCG
THYROXINE® Tablets 50 MCG

MANUFACTURER:

Glaxo Wellcome GmbH & CO. Bad Oldesloe Germany

Formulation and Strength:

Eltroxin Tablet containing 50 mcg (0.05mg) or 100 mcg (0.1mg) anhydrous thyroxine sodium respectively, which is the monosodium salt of the levorotary isomer of thyroxine.

Excipients:

Microcrystalline cellulose (in titurate)

Microcrystalline cellulose
Pregelatinised starch
Talc
Silica colloidal anhydrous
Magnesium stearate

CLINICAL INFORMATION:

Indications:

Treatment of hypothyroidism, cretinism and juvenile myxodema.

Dosage and Administration:

If the dose of thyroxine is increased too rapidly, symptoms such as diarrhoea, nervousness, rapid pulse, insomnia, tremors and sometimes anginal pain where there is latent myocardial ischaemia, may occur, and the dosage must be reduced or withheld for a day or two, then restarted at a lower level. A pre-therapy ECG is valuable, as changes induced by hypothyroidism may be confused with ECG evidence of ischaemia.

Due to a lack of data it is not appropriate to crush thyroxine tablets and thyroxine tablets without a score-line must not be halved.

Thyroxine tablets should preferably be taken on an empty stomach.
 
Missed dosage:

If a scheduled daily dose is missed, the dose should be taken as soon as the patient remembers, unless it is almost time for the patient’s next dose. Two doses should not be taken together.

Populations:

Adults:

Initially 50 to 100 micrograms daily and adjust at 4 to 6 week intervals by 50 micrograms until normal metabolism is steadily maintained. This may require doses of 100 to 200 micrograms daily.

With patients aged over 50 years, it is not advisable to exceed 50 micrograms a day initially. Where there is cardiac disease 25 micrograms, given as 50 micrograms on alternate days, is more suitable. In this condition the daily dosage may be slowly increased by 25 micrograms increments (given as 50 micrograms on alternate days) at intervals of perhaps four weeks. This dosing regimen is illustrated in Table 1 below;

TABLE 1 - Recommended Dosage Regimen for Levothyroxine Tablets

DAILY DOSE       DOSING REGIMEN
    
25 microgram    One 50 microgram tablet on alternate days
    
50 microgram    One 50 microgram tablet daily
    
75 microgram    One 50 microgram tablet daily and one 50 microgram tablet on alternate days
    
100 microgram   One 100 microgram tablet daily
    
125 microgram   One 100 microgram tablet daily and one 50 microgram tablet on alternate days
    
Children:

In congenital hypothyroidism and juvenile myxoedema, The largest dose consistent with freedom from toxic effects should be given. The dosage is guided by clinical response, growth assessment and appropriate thyroid function tests - clinically normal pulse rate and absence of diarrhoea or constipation are the most useful indicators. Thyrotrophin levels may remain elevated during the first year of life in children with neonatal hypothyroidism due to resetting of the hypothalamic-pituitary axis.

For infants with congenital hypothyroidism a suitable starting dose is 50 mcg thyroxine sodium on alternate days, with increments of 50 mcg on alternate days at intervals of every two to four weeks until optimal response is achieved. The same dosing regimen applies to juvenile myxoedema, except that the starting dose for children older than one year may be 2.5 to 5 micrograms/kg/day. The calculated daily dose equivalent should be rounded to the nearest 25 micrograms to determine the actual prescribed dose.
 
Contraindications:

-    Hypersensitivity to any component of the preparation.

-    Thyrotoxicosis.

Warnings and Precautions:

Thyroxine has a narrow therapeutic index. Appropriate thyroxine dosage is based upon clinical assessment and laboratory monitoring of thyroid function tests. During the initial titration period, careful dosage titration and monitoring is necessary to avoid the consequences of under- or over-treatment. The symptoms of excessive thyroxine dosage are the same as many features of endogenous thyrotoxicosis.

Treatment with thyroxine in patients with panhypopituitarism or other causes predisposing to adrenal insufficiency may cause reactions, including dizziness, weakness, malaise, weight loss, hypotension and adrenal crisis. It is advisable to initiate corticosteroid therapy before giving thyroxine in these cases.

Special care is needed in the elderly and in patients with symptoms of myocardial insufficiency or ECG evidence of myocardial infarction or ischaemia and also those with diabetes mellitus or insipidus.

Thyroxine raises blood sugar levels and this may upset the stability of patients receiving antidiabetic agents.

Interactions:

Thyroxine increases the effect of anticoagulants and it may be necessary to reduce the dose of anticoagulant if excessive hypoprothrombinaemia and bleeding are to be avoided.

Phenytoin levels may be increased by thyroxine.

Anticonvulsants such as carbamezapine and phenytoin enhance the metabolism of thyroid hormones and may displace them from plasma proteins. Initiation or discontinuation of anticonvulsant therapy may alter thyroxine dose requirements.

If co-administered with cardiac glycosides, adjustment of dosage of cardiac glycoside may be necessary.

The effect of sympathomimetic agents are also enhanced.

Thyroxine increase receptor sensitivity to catecholamines thus accelerating the response to tricyclic antidepressants.

Cholestyramine given concurrently reduces the gastrointestinal absorption of thyroxine.

A number of other drugs may decrease absorption of thyroxine sodium, and therefore increase thyroxine dosage requirements including antacids (e.g. aluminium hydroxide), bile acid seqestrants (e.g. colestipol), anoin/cation exchange resins (e.g. kayexalate, sevelamer), sucralfate, calcium carbonate, and ferrous sulphate.
 
Co-administration of oral contraceptives, as well as a number of other drugs, including oestrogen, tamoxifene, clofibrate, methadone, and 5-fluorouracil may increase serum concentration of thyroxine-binding globulin, and therefore increase thyroxine dosage requirements.

Reports indicate that some HMG-CoA reductase inhibitors (statins), such as simvastatin and lovastatin, may increase thyroid hormone requirements in patients receiving thyroxine therapy. It is unknown if this occurs with all statins. Close monitoring of thyroid function and appropriate thyroxine dose adjustments may be necessary when thyroxine and statins are co-prescribed.

A number of drugs may decrease serum concentration of thyroxine-binding globulin, and therefore decrease thyroxine dosage requirements, including androgens and anabolic steroids.

Treatment with tyrosine kinase inhibitors (e.g., imatinib and sunitinib) was associated with increased thyroxine dosage requirements in hypothyroid patients.

Treatment with amiodarone has been associated with multiple effects on thyroid function including increased thyroxine dosage requirements in hypothyroid patients.

A number of drugs may affect thyroid function tests and this should be borne in mind when monitoring a patient on thyroxine therapy.

Pregnancy and Lactation:

Pregnancy:

Thyroxine has been taken by a large number of pregnant women and women of childbearing age without any form of definite disturbances in the reproductive process having been observed so far.
Thyroid, hypo- or hyperactivity in the mother may however unfavourably influence the foetal outcome or well-being.

Lactation:

Thyroxine is excreted in breast milk in low concentrations and this may be sufficient to interfere with neonatal screening for hypothroidism.

Ability to perform tasks that require judgement, motor or cognitive skills

From the pharmacokinetic and pharmacodynamic properties of thyroxine, treatment with thyroxine would not be expected to interfere with ability to drive or operate machinery.

Adverse Reactions:

The following effects are indicative of excessive dosage and usually disappear on reduction of dosage or withdrawal of treatment for a few days:

The frequency classification for these adverse reactions is not known due to a lack of robust clinical trial data to accurately determine frequency estimates.

Immune system disorders: Hypersensitivity reactions such as skin rash and pruritus.
 
Metabolism and nutrition disorders: Increased appetite, abdominal cramps, nausea, vomiting and diarrhea.

Nervous system disorders: Excitability, insomnia, restlessness, headache, tremors, seizure. Rare cases of pseudotumor cerebri (benign intracranial hypertension) have been reported especially in children.

Cardiac disorders: Anginal pain, cardiac arrhythmias, palpitations, tachycardia, increased blood pressure, heart failure, myocardial infarction.

Respiratory, thoracic and mediastinal disorders: Dyspnea.

Skin and subcutaneous tissue disorders: Sweating, flushing, hair loss.

Musculoskeletal, connective tissue and bone disorders: Cramps in the skeletal muscle, muscular weakness, decreased bone mineral density.

Excessive dose may result in craniosynostosis in infants, and premature closure of epiphyses in children with compromised adult height.

Reproductive system and breast disorders: Menstrual irregularity, impaired fertility.

General disorders and administration site conditions: Fatigue, heat intolerance, fever, excessive loss of weight.

Overdosage:

Symptoms and Signs:

In addition to exaggeration of side effects the following symptoms may be seen: agitation, confusion, irritability, hyperactivity, headache, sweating, mydriasis, tachycardia, arrhythmias, tachypnoea, pyrexia, increased bowel movements and convulsions. The appearance of clinical hyper- thyroidism may be delayed for up to five days.

Treatment:

The goal of therapy is restoration of clinical and biochemical euthyroid state by omitting or reducing the thyroxine dosage, and other measures as needed depending on clinical status.

Treatment is symptomatic, and tachycardias has been controlled in adults by 40mg doses of propranolol given every six hours and other symptoms by diazepam and/or chlorpromazine as appropriate.

Further management should be as clinically indicated or as recommended by the national poison centre, where available.

CLINICAL PHARMACOLOGY:

Thyroxine sodium is the monosodium salt of the levorotary isomer of thyroxine.
 
Pharmacodynamics:

Pharmacodynamic Effects:

Thyroxine (T4) is a naturally occurring hormone produced by the thyroid gland and converted to the more active hormone triiodothyronine (T3) in peripheral tissues. The precise signals controlling the conversion of T4 to T3 within the cell are not known. The thyroid hormones are required for normal growth and development, particularly of the nervous system. They increase the resting or basal metabolic rate of the whole organism and have stimulatory effects on the heart, skeletal muscle, liver and kidney. Thyroid hormones enhance lipolysis and the utilization of carbohydrate.

100 mcg thyroxine is equivalent in activity to 20 to 30 mcg liothyronine/triiodothyronine or

60mg Thyroid BP and/or local pharmacopoeia specification.

Pharmacokinetics:

Absorption:

Following oral administration the absorption of thyroxine is incomplete and variable especially when taken with food. The amount absorbed increases during fasting conditions.

Distribution:

Thyroxine is nearly totally bound to serum protein.

Metabolism:

The main pathway for the metabolism of thyroxine (T4) is its conversion, by deiodination, to the active metabolite triiodothyronine (T3). Further deiodination of T4 and T3 leads to production of inactive products.

Elimination:

Thyroxine is eliminated slowly from the body with a half-life of approximately 7 days in a normal person. This may be reduced in hyperthyroid states or increased in hypothyroid patients.

In man approximately 20-40% of thyroxine is eliminated in the faeces and approximately 30-55% of a dose of thyroxine is excreted in the urine.

Special Patient Populations:

Renal impairment:

Renal disease does not appear to have any significant effect on the disposition of thyroxine.

Hepatic impairment:

Hepatic disease does not appear to have any significant effect on the disposition of thyroxine.

NON-CLINICAL INFORMATION:

No additional data of relevance.
 
PHARMACEUTICAL INFORMATION:

Shelf-Life

2 years.

Storage:

Do not store at temperatures exceeding 25°C.

Store in the original container, protected from light.
Keep the container tightly closed.

Nature and Contents of Container:

Polypropylene bottles with tamper-evident, low-density polyethylene closures.

Incompatibilities:

None reported.

Use and Handling:

None.