L-Thyroxine Serb

/ Raz Pharmaceutics

• Before treatment and in order to adjust the dose, it is recommended that testing of T3, T4 and TSH levels be performed.
• The administered doses vary depending on the degree of hypothyroidism, the subject’s age and individual tolerance.
• Daily administration of levothyroxine injection should be continued until the patient is able to tolerate an oral dose and is clinically stable.

 Myxedema coma:
An initial loading dose of 500 micrograms the first day is recommended, as a slow intravenous infusion in 250 ml of saline solution to achieve a concentration of the diluted solution of 2 micrograms/ml. Due to an increased risk of serious cardiovascular events or death, this loading dose must not exceed 500 μg.
Maintenance treatment should then be initiated at a daily dose of 100 μg on average.
Replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology:
• Gastrointestinal absorption of oral levothyroxine tablet is approximately 70%–80% in healthy fasting adults.
• Complete hormone replacement therapy in adults requires 100 to 150 μg as a single daily dose, on average.
• This dosage will be established gradually and with caution: start with 25 μg per day, then increase the daily dose by 25 μg at weekly intervals.
• Once the dosage has been stable for a long enough period, repeat testing of thyroid hormones levels. Monitor T3 and T4 levels to check that there is no overdose and monitor normalisation of TSH levels in the event of peripheral hypothyroidism.
Replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology:
• The maintenance dose is generally 100 to 150 micrograms per m² of body surface area.
• For neonates and infants with congenital hypothyroidism, in whom rapid replacement is important, the initial recommended dosage is 10 to 15 micrograms per kg bodyweight per day for the first 3 months. Thereafter, the dose should be individually adjusted based on clinical and laboratory findings (thyroid hormones and TSH).
• For children with acquired hypothyroidism, the recommended initial dosage is 12.5 to 50 micrograms per day. The dose should be increased gradually every 2 to 4 weeks based on clinical and laboratory findings (thyroid hormones and TSH) until the full replacement dose is reached.
In all cases, the dose should be adjusted on the basis of the needs of each individual.
See prescribing information for full details.

• Replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology.
• Myxedema coma.

• Hypersensitivity to the active substance or to any of the excipients.
• Decompensated cardiac diseases (e.g. acute myocardial infarction, acute myocarditis, acute pancarditis).
• Untreated adrenal insufficiency.
• Untreated hyperthyroidism.
• Untreated pituitary insufficiency (when leading to adrenal insufficiency requiring treatment).
• Combination of levothyroxine with an antithyroid agent for hyperthyroidism is not indicated during pregnancy.

Before starting a thyroid hormone therapy, the following diseases or conditions should be excluded or treated: coronary heart disease, angina pectoris, hypertension,
pituitary and/or adrenal insufficiency, and thyroid autonomy.
It is essential that even mild, drug-induced hyperthyroidism be avoided in patients with coronary heart disease, heart failure, tachyarrhythmias, myocarditis of non-acute course, chronic hypothyroidism or in patients who have already suffered a myocardial infarction. In these patients, more frequent monitoring of thyroid hormone parameters is essential during thyroid hormone therapy.
Thyroid hormones should not be given for weight reduction. In euthyroid patients, treatment with levothyroxine does not cause weight reduction. Substantial doses may cause serious or even life-threatening undesirable effects, particularly in combination with certain substances for weight reduction, and especially with sympathomimetic amines.
If a switch to another levothyroxine-containing product is required, there is a need to undertake a close monitoring including a clinical and biological monitoring during the transition period due to a potential risk of thyroid imbalance. In some patients, a dose adjustment could be necessary.
Due to the difference of bioavailability of the oral dosage form versus injectable form, the dose should be carefully adapted when switching from one form to another.
Patients with cardiovascular disorders or with a history of cardiovascular disorders:
Levothyroxine by the intravenous/intramuscular route can be associated with cardiac toxicity (in particular arrhythmia, tachycardia, myocardial ischaemia and myocardial infarction or exacerbation of congestive heart failure and death) in patients with underlying cardiovascular disease (in particular coronary disorders, arrhythmias, hypertension, decompensated heart failure).
Due to the increased prevalence of cardiovascular diseases in the elderly, caution is required when administering levothyroxine solution for injection or concentrate for solution for infusion in elderly patients or those with known cardiac risk factors. Cautious use may be required in these populations, including at doses at the lower end of the recommended dosage range.
Regular and careful monitoring of cardiac conditions is necessary at treatment initiation and throughout treatment.
Patients with adrenal insufficiency:
In case of adrenocortical dysfunction, patients should be treated by adequate glucocorticoid treatment to prevent acute adrenal insufficiency prior to starting the therapy with levothyroxine .
As an adrenal insufficiency linked with myxedema coma can occur, an empiric intravenous glucocorticoid treatment should be administered in association to levothyroxine until confirmation or exclusion of adrenal insufficiency.
Low birth weight preterm neonates:
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.
Diabetes:
The addition of levothyroxine to an anti-diabetic treatment or insulin therapy can lead to an increase in insulin or anti-diabetic drug requirements. Careful monitoring of metabolic control is recommended in diabetic patients.
Patients with a history of epilepsy:
Due to the risk of seizures in patients with a history of epilepsy, monitoring of these patients is recommended throughout treatment with levothyroxine.
Hypersensitivity:
Hypersensitivity reactions (including angioedema), sometimes serious, have been reported. If signs and symptoms of allergic reactions occur, treatment must be discontinued and appropriate symptomatic treatment initiated.
Pregnant women:
Clinical and laboratory monitoring must be reinforced at the most earliest stage possible in pregnant women, particularly during the first half of the pregnancy, in order to adjust the treatment if necessary.
Osteoporosis:
During levothyroxine therapy of postmenopausal women with increased risk of osteoporosis, dosage of levothyroxine sodium should be titrated to the lowest possible effective level and thyroid function should be monitored more frequently to avoid levels of levothyroxine above the physiological range.
Interferences with laboratory test:
Biotin may interfere with thyroid immunoassays that are based on a biotin/streptavidin interaction, leading to either falsely decreased or falsely increased test results. The risk of interference increases with higher doses of biotin.
When interpreting results of laboratory tests, possible biotin interference has to be taken into consideration, especially if a lack of coherence with the clinical presentation is observed.
For patients taking biotin-containing products, laboratory personnel should be informed when a thyroid function test is requested. Alternative tests not susceptible to biotin interference should be used, if available.
Levothyroxine and other treatments:
Monitoring is required in patients receiving concomitant administration of levothyroxine and medicinal products (such as amiodarone, tyrosine kinase inhibitors, salicylates and furosemide at high doses, selpercatinib, …) which may affect the thyroid function.
For patients receiving selpercatinib, hypothyroidism has been reported. Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism should be treated as per standard medical practice prior to the start of selpercatinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction during selpercatinib treatment. Thyroid function should be monitored periodically throughout treatment with selpercatinib. Patients who develop thyroid dysfunction should be treated as per standard medical practice, however patients could have an insufficient response to substitution with levothyroxine (T4) as selpercatinib may inhibit the conversion of levothyroxine to liothyronine (T3) and supplementation with liothyronine may be needed.
See prescribing information for full details.

very common: insomnia, headache, palpitations.
common: hyperthyroidism, nervousness, tachycardia.
See prescribing information for full details.

Combinations not recommended
St. John’s Wort (Hypericum perforatum L.): Risk of increased hepatic clearance of levothyroxine resulting in reduced serum concentrations of thyroid hormone and risk of decreased clinical effects. Therefore, patients on thyroid replacement therapy may require an increase in their dose of thyroid hormone if these products are given concurrently.
Combinations requiring precautions for use
Anti-diabetic agents: Levothyroxine can reduce the blood sugar-lowering effect of antidiabetics (e.g. metformin, glimepiride, glibenclamide and insulin). Therefore, blood sugar levels in diabetic patients must be regularly checked, particularly at the start and at the end of thyroid hormone treatment. The dose of the blood sugar-lowering drug should also be adapted.
Coumarin derivatives: Levothyroxine can intensify the effect of coumarin-derivatives through plasma protein binding displacement. Therefore, regular blood coagulation checks are necessary in the case of simultaneous treatment; the dose of the anticoagulant must be adapted, if necessary (dose reduction).
Propylthiouracil, glucocorticoids and beta-receptor blockers (especially propranolol):  These substances inhibit the conversion of T4 into T3 and can result in a lowered T3 serum concentration.
Amiodarone and contrast media containing iodine: Due to their iodine content, these agents can trigger hyperthyroidism as well as hypothyroidism. Special care should be taken in the case of nodular goiter with possibly undetected functioning autonomies. Amiodarone inhibits the conversion of T4 into T3, resulting in a lowered T3 serum concentration and an increased TSH serum level.
Salicylate, dicumarol, furosemide, clofibrate: Levothyroxine can be displaced from the plasma protein binding through salicylate (particularly in doses greater than 2.0 grams per day), dicumarol, high doses (250 milligrams) of furosemide, clofibrate and other substances. This can lead to an initial, temporary increase of free thyroid hormones, jointly followed by a decrease of the total thyroid hormone level.
Contraceptives containing oestrogen, drugs for post-menopausal hormone substitution: The levothyroxine demand can increase during the intake of contraceptives containing oestrogen or during post-menopausal hormone replacement treatment. There may be increased binding of levothyroxine, which may lead to diagnostic and therapeutic errors.
Sertraline, chloroquine/proguanil : These substances reduce the efficacy of levothyroxine and increase the TSH serum level.
Enzyme inducing drugs: Barbiturates, rifampicin, carbamazepine, phenytoin and other drugs with liver enzyme-inducing characteristics can increase the hepatic clearance of levothyroxine and result in a decreased plasma level.
Protease inhibitors:  There are reports stating that protease inhibitors can result in a loss of the therapeutic effect of levothyroxine if simultaneously administered with lopinavir/ritonavir. Therefore, careful monitoring of clinical symptoms and thyroid function should be carried out in patients who use levothyroxine and protease inhibitors simultaneously.
Tyrosine kinase inhibitors (e.g. Imatinib, sunitinib, sorafenib, motesanib): These agents can reduce the efficacy of levothyroxine. Therefore, careful monitoring of clinical symptoms and thyroid function should be carried out in patients who use levothyroxine and tyrosine kinase inhibitors simultaneously.
Selpercatinib:  Levothyroxine may be less effective when given with selpercatinib.
Selpercatinib could inhibit D2 deiodinase and thereby decrease the conversion of levothyroxine (T4) to liothyronine (T3). Patients could therefore have an insufficient response to substitution with levothyroxine and supplementation with liothyronine may be needed.
Interferences with laboratory test: Biotin may interfere with thyroid immunoassays that are based on a biotin/streptavidin interaction, leading to either falsely decreased or falsely increased test results.

Pregnancy:
Data concerning the use of levothyroxine injections in pregnant women are limited. Levothyroxine does not readily cross the placenta and its administration in appropriate doses has no effects on the foetus.
It is essential that thyroid hormone treatment be continued throughout pregnancy to maintain the balance required in the mother to ensure a healthy pregnancy (and, in particular, to reduce the risk of foetal hypothyroidism). Clinical and laboratory monitoring must be reinforced as soon as possible, particularly during the first half of the pregnancy, so that the treatment can be adjusted if necessary. In all cases, it is recommended that a thyroid assessment be performed on the newborn infant.
During pregnancy, levothyroxine must not be combined with anti-thyroid agents for hyperthyroidism. Only small quantities of levothyroxine cross the placenta, whereas large quantities of anti-thyroid drugs cross from the mother to the infant. This can cause foetal hypothyroidism.
Breast-feeding:
In breast-feeding women with balanced T4 levels, levothyroxine is secreted into breast milk in low concentrations. Consequently, replacement therapy using levothyroxine is possible while breast-feeding.

This is manifested in adults by thyrotoxicosis. In the event of a thyrotoxic crisis (thyroid storm), substantially reduce the doses or suspend treatment for a few days, then resume it at lower doses, following biological monitoring.
Treatment with levothyroxine solution for injection or concentrate for solution for infusion must be adjusted (dose reduction or temporary suspension) in the event of severe overdose. In addition, appropriate supportive measures including, in particular, beta-blockers, should be initiated on the basis of the patient’s clinical condition. An elevated T3 level is a reliable indicator of overdosage, more than elevated T4 or fT4 levels.
In overdosage and intoxication, symptoms of moderate to severe increases in metabolism occur. Depending on the extent of the overdosage it is recommended that treatment is interrupted and that tests are carried out.
In incidents of poisoning in humans, oral doses of 10 mg levothyroxine were tolerated without complications. Severe complications involving a threat to vital functions (respiration and circulation) are not to be expected, except in coronary heart disease. However, there exist reports on cases of thyrotoxic crisis, cramps, cardiac insufficiency and coma. Isolated cases of sudden cardiac death have been reported in patients with many years of levothyroxine abuse.
In case of acute overdosage, treatment is generally symptomatic and supportive. Beta-blockers may be given if severe beta-sympathomimetic symptoms such as tachycardia, anxiety, agitation and hyperkinesia occur.
Antithyroid drugs are not appropriate, because of prior complete inactivation of the thyroid.
In cases of intoxication with extremely high doses, plasmapheresis may be helpful.
Levothyroxine overdosage requires a prolonged monitoring period. Owing to the gradual transformation of levothyroxine into liothyronine, symptoms may occur with a delay of up to six days.

Store below 25°C. Protect from light.