OROXINE Tablet Ref.[49827] Active ingredients: Levothyroxine

Thyroid hormones must not be given for weight reduction. In euthyroid patients, normal doses do not cause any weight reduction. Higher doses may cause serious or even life-threatening undesirable effects such as symptoms of hyperthyroidism (see section 4.9).

In combination with certain weight-reduction agents such as orlistat reduced control of hypothyroidism may occur. This could be due to a decreased absorption of iodine salts and/or levothyroxine.To avoid this levothyroxine and weight reduction agents such as orlistat should be administered at least 4 hours apart. Regular monitoring for changes in thyroid function is required.

When switching from another levothyroxine product to this product, the values of TSH and T4 should be measured after four to six weeks. It is recommended that the dose should be adjusted according to the patient’s clinical response and the laboratory values.

Caution in the following circumstances is required to maintain thyroid balance, namely:

• Women who are pregnant or are planning conception (see section 4.6);
• Hypothyroidism, congenital or acquired in childhood;
• Suppressive therapy in patients with previous thyroid cancer, especially if frail or elderly;
• Patients with central hypothyroidism;
• Patients with cardiac symptoms, or diabetes mellitus or insipidus.

Before starting thyroid hormone therapy, the following diseases or conditions must be excluded or treated:

• Coronary heart disease;
• Angina pectoris;
• Hypertension;
• Pituitary and/or adrenocortical insufficiency;
• Thyroid autonomy.

Prior to performing thyroid suppression tests, these diseases or conditions must likewise be excluded or treated, with the exception of thyroid autonomy, which may be the reason for performing the suppression test.

Even relatively mild, medicinal product induced hyperthyroid function must be strictly avoided in cases of coronary heart disease, heart failure, tachyarrhythmias, chronic hypothyroidism or in patients with a history of myocardial infarction. The initial dose and any dose increments should be carefully chosen, too high initial dose or too rapid increase may cause or aggravate symptoms of angina, arrhythmias, myocardial infarction, cardiac failure or a sudden raise in blood pressure. In thyroid hormone therapy, more frequent monitoring of thyroid hormone parameters must be performed in these patients (see section 4.2).

In secondary hypothyroidism or panhypopituitarism, it must be established whether adrenocortical insufficiency is also present. Treatment with levothyroxine in patients with adrenal insufficiency may cause reactions, including dizziness, weakness, malaise, weight loss, hypotension and adrenal crisis. It is advisable to initiate corticosteroid therapy before giving levothyroxine sodium in these cases.

If thyroid autonomy is suspected, it is recommended that a TRH test or suppression scintigram be performed.

In women, long-term levothyroxine sodium therapy has been associated with increased bone resorption, thereby decreasing bone mineral density. When administering levothyroxine therapy to postmenopausal women, who are at increased risk of osteoporosis, thyroid function should be monitored more frequently to avoid supraphysiological blood levels of levothyroxine and the dosage of levothyroxine should be titrated to the lowest possible level.

Thyroid replacement therapy may cause an increase in dosage requirements of insulin or other anti-diabetic therapy (see section 4.5). Care is needed for patients with diabetes mellitus and diabetes insipidus.

Parents of children receiving 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.

Haemodynamic parameters should be monitored when levothyroxine therapy is initiated in very low birth weight preterm neonates as circulatory collapse may occur due to the immature adrenal function.

Care is required when levothyroxine is administered to patients with known history of epilepsy. Seizures have been reported rarely in association with the initiation of levothyroxine sodium therapy, and may be related to the effect of thyroid hormones on seizure threshold.

For patients on anticoagulant therapy, see section 4.5.

Patients with myxoedema have an increased sensitivity to thyroid hormones; in these patients the starting dose should be low with slow dosing increments.

Levothyroxine absorption is decreased in patients with malabsorption syndromes. It is advised to treat the malabsorption condition to ensure effective levothyroxine treatment with regular levothyroxine dose.

Interactions decreasing levothyroxine absorption

Ion exchange resins

Cholestyramine, calcium, aluminium, magnesium, iron supplements, polystyrene sulfonates, sucralfate, lanthanum, bile acid sequestrants (e.g. colestipol), anion/cation exchange resins (e.g. kayexelate, sevelamer) and proton pump inhibitors decrease the absorption of levothyroxine. Separate the dosages of levothyroxine and the above mentioned medicines as much as possible to avoid interaction in the stomach or the small bowel.

Soya productsand high-fibre diets

Soya productsand high-fibre dietscan reduce the intestinal absorption of levothyroxine. In children, there have been reports of a rise in the serum TSH level when they were given a diet containing soya and treatment with levothyroxine for congenital hypothyroidism. Unusually high doses of levothyroxine may be required to achieve normal serum levels of T~4' und TSH. During and upon termination of a diet containing soya, close monitoring of serum T₄ and TSH levels is necessary; a dose adjustment of levothyroxine may be required.

Weight loss agents (including orlistat)

In combination with certain weight-reduction agents, such as orlistat, reduced control of hypothyroidism may occur. This may be due to a decreased absorption of iodine salts and/or levothyroxine. To avoid this levothyroxine and weight reduction agents such as orlistat should be administered at least 4 hours apart. Regular monitoring for changes in thyroid function is required.

Interactions affecting levothyroxine

Propylthiouracil, glucocorticoids, propranolol, lithium, iodide, oral contrast agents and beta receptor blockers

These substances inhibit conversion of T₄ to T₃ and therefore also lower the therapeutic effect.

Amiodarone and iodinated contrast media

Due to their high iodine content the media can initiate both hyperthyroidism and hypothyroidism. Particular caution should be exercised in patients with nodular goitres with possibly undetected autonomy. As a result of this effect of amiodarone on thyroid function, a dose adjustment of Levothyroxine sodium may be required.

Salicylates, furosemide, clofibrate

Levothyroxine may be displaced from plasma protein binding by salicylates, high doses (250 mg) of furosemide, clofibrate, and other substances. This leads to an increase in the plasma level of free thyroxine (fT₄).

Anticonvulsants

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

Oestrogen based contraceptives, medications used in postmenopausal hormone replacement

Levothyroxine requirements may increase during intake of oestrogen based contraceptives or during postmenopausal hormone replacement therapy.

Statins

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

Sertraline, chloroquine/proguanil

These substances reduce the efficacy of levothyroxine and increase the serum TSH level.

Tyrosine kinase inhibitors

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

Enzyme inducing medications

Barbiturates, rifampicin, and other medicinal products with liver enzyme inducing properties can increase hepatic clearance of levothyroxine.

Protease inhibitors

Post-marketing cases have been reported indicating a potential interaction between ritonavir containing products and levothyroxine. Thyroid-stimulating hormone (TSH) should be monitored in patients treated with levothyroxine at least the first month after starting and/or ending ritonavir treatment.

Methadone, and 5-fluorouracil may increase serum concentration of thyroxine-binding globulin, and therefore increase levothyroxine dosage requirements.

Interactions affecting other drugs

Antidiabetic agents

Levothyroxine may reduce the antihyperglycaemic effect of antidiabetics. Blood glucose levels must therefore be regularly monitored in patients with diabetes, particularly at the start of thyroid hormone therapy. The antihyperglycaemic dosage should be adjusted as necessary. Lowering the dose of levothyroxine can cause hypoglycaemia if the insulin or oral antidiabetics dose remains unchanged.

Coumarin derivatives

Levothyroxine may potentiate the effect of coumarin derivatives due to plasma protein binding displacement. With concomitant treatment, regular monitoring of blood coagulation is therefore required and the anticoagulant dosage must be adjusted as necessary (dose reduction).

Digitalis preparations

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

Tricyclic antidepressants

Levothyroxine increases receptor sensitivity to catecholamines thus accelerating the response to tricyclic antidepressants (e.g. amitriptyline, imipramine).

Sympathomimtetic agents

The effects of sympathomimetic agents (e.g. adrenaline) are enhanced.

Phenytoin

Phenytoin levels may be increased by levothyroxine.

Laboratory test interactions

A number of drugs may decrease serum concentration of thyroxine-binding globulin, and therefore decrease levothyroxine dosage requirements, including androgens and anabolic steroids. False low plasma concentrations have been observed with concurrent anti-inflammatory treatment such as phenylbutazone or acetylsalicylic acid and levothyroxine therapy. Administration of acetylsalicylic acid together with levothyroxine results in an initial transient increase in serum free T4. Continued administration results in normal free T4 and TSH concentrations, and therefore, patients become clinically euthyroid.

Pregnancy

Levothyroxine 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.

Levothyroxine requirements may increase during pregnancy due to increased oestrogen levels. Thyroid function should therefore be monitored both during and after pregnancy and the thyroid hormone dose adjusted as appropriate. Patients taking levothyroxine should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of levothyroxine. Since postpartum TSH serum levels are similar to preconception values, levothyroxine dosage can be reduced to the pre-pregnancy dose.

Particularly during pregnancy and lactation, treatment with thyroid hormones must be consistently administered.

See section 4.3 for information on concomitant intake of levothyroxine and antithyroid agents during pregnancy.

Breastfeeding

Even during high dose therapy with levothyroxine, the amount of thyroid hormone secreted into breast milk during breastfeeding is insufficient to induce the development of hyperthyroidism or suppression of TSH secretion in the infant. However, it may be sufficient to interfere with neonatal screening for hypothyroidism.

Suppression tests must not be performed during pregnancy and breastfeeding.

There are no available studies on the effects on the ability to drive and use machines. As levothyroxine is identical to the naturally occurring thyroid hormone, Levothyroxine sodium is not expected to have any influence on the ability to drive and use machines.

All adverse reactions are listed by system organ class and frequency; rare (≥1/10,000 to <1/1,000) and not known (cannot be estimated from the available data).

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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Not applicable.