LEVOTHYROXINE Oral solution Ref.[6943] Active ingredients: Levothyroxine

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

To minimise the risk of adverse effects of undetected overtreatment, such as atrial fibrillation and fractures associated with low serum levels of thyroid stimulating hormone (TSH) in older patients, it is important to monitor serum TSH and adjust the dose accordingly during long term use.

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 patients on glycosides.

Sub-clinical 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 re-growth usually occurs.

Even slight drug-induced hyperthyroidism must be avoided in patients with coronary failure, cardiac insufficiency or tachycardiac arrhythmias. Hence frequent checks of thyroid hormone parameters must be made in these cases.

In the case of secondary hypothyroidism the cause must be determined before replacement therapy is given and if necessary replacement treatment of a compensated adrenal insufficiency must be commenced.

Where thyroid autonomy is suspected a TRH test should be carried out or a suppression scintigram obtained before treatment.

Levothyroxine should not be given in hyperthyreotic states other than as concomitant supplementation during anti-thyroid drug treatment of hyperthyroidism.

Thyroid hormones are not suitable for weight reduction. Physiological doses do not result in any weight loss in euthyroid patients. Supraphysiological doses may cause severe or even life-threatening undesirable effects (see section 4.9).

In individuals suspected to have cardiovascular disease or to be at high risk, it is important to perform an ECG prior to commencement of levothyroxine treatment in order to detect changes consistent with ischaemia in which case, levothyroxine should be initiated at a low dose, followed by cautious dose escalation to avoid worsening of ischaemia or precipitation of an infarct.

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.

This product contains:

• Parahydroxybenzoates – These may cause allergic reactions (possibly delayed).
• Glycerol – This may cause headache, stomach upset and diarrhoea.

Propylthiouracil, glucocorticoids, beta-sympatholytics, amiodarone and iodine containing contrast media

These substances inhibit the peripheral conversion of T4 to T3.

Due to its high iodine content amiodarone can trigger hyperthyroidism as well as hypothyroidism. Particular caution is advised in the case of nodular goitre with possibly unrecognized autonomy.

• 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, primidone or rifampicin with levothyroxine have been found to increase levothyroxine metabolism.

Soy-containing compounds

Soy-containing compounds can decrease the intestinal absorption of levothyroxine. Therefore, a dosage adjustment of Levothyroxine Oral Solution may be necessary, in particular at the beginning or after termination of nutrition with soy supplements.

Enzyme inducing medicinal products

Enzyme inducing medicinal products such as barbiturates or carbamazepine can increase hepatic clearance of levothyroxine.

• 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.
• 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.
• Effects of levothyroxine may be decreased by concomitant sertraline. Some drugs such as lithium act directly on the thyroid gland and inhibit the release of thyroid hormones leading to clinical hypothyroidism.
• Increased thyroid-stimulating hormone concentration has been noted after the use of chloroquine with proguanil for malaria prophylaxis in a patient stabilised on levothyroxine.
• False low total plasma concentrations have been observed with concurrent anti-inflammatory treatment such as phenylbutazone or acetylsalicylic acid and levothyroxine therapy.

Protease inhibitors

Protease inhibitors (e.g. ritonavir, indinavir, lopinavir) may influence the effect of levothyroxine. Close monitoring of thyroid hormone parameters is recommended. If necessary, the levothyroxine dose has to be adjusted.

Ritonavir

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.

Sevelamer

Sevelamer may decrease levothyroxine absorption. Therefore, it is recommended that patients are monitored for changes in thyroid function at the start or end of concomitant treatment. If necessary, the levothyroxine dose has to be adjusted.

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (e.g. imatinib, sunitinib) may decrease the efficacy of levothyroxine. Therefore, it is recommended that patients are monitored for changes in thyroid function at the start or end of concomitant treatment. If necessary, the levothyroxine dose has to be adjusted.

• 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.
• A possible interaction occurs with hypoglycaemic agents, hence diabetic patients should be monitored for increased requirements of insulin or oral hypoglycaemic agents.
• Thyroid drugs increase metabolic demands and should therefore be used with caution with other drugs known to influence cardiac function, such as the sympathomimetics, as they may enhance this effect. In addition, thyroid hormones may increase receptor sensitivity to catecholamines.
• Levothyroxine accelerates the metabolism of propranolol.
• Isolated reports of marked hypertension and tachycardia have been reported with concurrent ketamine administration.
• The effects of warfarin, dicoumarol, acenocoumarol, 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.

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 teratogenic effects.

Treatment with levothyroxine should be given consistently during pregnancy and breast-feeding in particular. Dosage requirements may even increase during pregnancy.

Experience has shown that there is no evidence of drug-induced teratogenicity and/or foeto-toxicity in humans at the recommended therapeutic dose level. Excessively high dose levels of levothyroxine during pregnancy may have a negative effect on foetal and postnatal development.

Combination therapy of hyperthyroidism with levothyroxine and anti-thyroid agents is not indicated in pregnancy. Such combination would require higher doses of anti-thyroid agents, which are known to pass the placenta and to induce hypothyroidism in the infant.

Thyroid suppression diagnostic tests should not be carried out during pregnancy, as the application of radioactive substances in pregnant women is contraindicated.

Breast-feeding

Levothyroxine is secreted into breast milk during lactation but the concentrations achieved at the recommended therapeutic dose level are not sufficient to cause development of hyperthyroidism or suppression of TSH secretion in the infant. Levothyroxine can be used during lactation.

Fertility

There are no fertility data available.

No studies on the effects on the ability to drive and use machines have been performed. However, since levothyroxine is identical to the naturally occurring thyroid hormone, it is not expected that Levothyroxine Oral Solution has any influence on the ability to drive and use machines.

The following side effects are usually due to excessive dosage, and correspond to symptoms of hyperthyroidism: arrhythmias, anginal pain, tachycardia, disorders of menstruation, pseudotumor cerebri, 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 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Not applicable.