Eltroxin 50 and 100
- thyroid hormone replacement in hypothyroidism of any aetiology,
- prophylaxis of recurrent goitre following resection of a goitre with euthyroid status,
- benign goitre with euthyroid status,
- concomitant therapy in antithyroid treatment of hyperthyroidism after euthyroid status has been achieved,
- suppression and replacement therapy in thyroid malignancy, especially post thyroidectomy,

Eltroxin 100
- thyroid suppression test.

Posology
For individual treatment, tablets containing 50 and 100 micrograms levothyroxine sodium are available. In children, it may be necessary to switch to preparations with other dosage strengths.

The dosage statements serve as a guideline. If any residual thyroid function remains, a lower replacement dose may be sufficient.

The individual daily dose should be determined by laboratory diagnostic and clinical tests. In elderly patients, in patients with coronary heart disease and in patients with severe or chronic hypothyroidism, treatment with thyroid hormones must be initiated with particular care, i.e. selecting a low initial dose and increasing it slowly and at longer intervals with frequent thyroid hormone monitoring. Experience has shown that a lower dose is sufficient even in patients with low body weight or with a large nodular goitre.

In patients whose medication incorporates levothyroxine and active substances with known interactions, these should be administered at an interval of at least 4 hours (see section 4.5 Interaction).

If the dose strength is not tolerated in individual cases or if overdose occurs, symptoms like those occurring in hyperthyroidism may occur, particularly if the dose is increased too quickly at the start of treatment (see also section 4.8). In this case, the daily dose should be reduced or the patient should stop taking the medicinal product for several days. Once the adverse reaction has resolved, treatment can be resumed with careful dosing. It is useful to record a reference ECG before therapy, as curve changes caused by hypothyroidism may be mistaken for cardiac ischaemia.

Elderly and patients with cardiac disorders

In patients over 50 years of age, it is not advisable to exceed doses above 50 micrograms per day. In patients with coronary heart disease, daily doses of 25 micrograms or 50 micrograms every other day are more suitable. In this disease, the daily dose should be increased by 25 micrograms or 50 micrograms every other day every 4 weeks.

Children

For congenital hypothyroidism and juvenile myxoedema, the highest possible dose not to cause any toxic effects should be given. The dosage is based on clinical reactions, growth assessment and appropriate thyroid function tests - clinically normal pulse rate and absence of diarrhoea or constipation are among the most useful indicators. During the first year of life in a child with neonatal hypothyroidism, the level of thyrotropin may remain elevated due to the resetting of the hypothalamic-pituitary axis. In infants with congenital hypothyroidism, the appropriate starting dose is 50 micrograms levothyroxine sodium every other day, with an increase every 2 to 4 weeks of 50 micrograms every other day until an optimal response is achieved. The same dosing regimen is used in the treatment of juvenile myxoedema, although the initial dose in children over one year old is 2.5 to 5 micrograms/kg/day. To determine the actual prescribed dose, the equivalent of the calculated daily dose must be rounded to the nearest 25 micrograms.

In infants with congenital hypothyroidism, the appropriate starting dose is 25 micrograms levothyroxine daily, or 50 micrograms levothyroxine every other day, with an increase of 25 micrograms daily, or 50 micrograms every other day every 2 to 4 weeks, until an optimal response is achieved. The same dosing regimen is used in the treatment of juvenile myxoedema, although the initial dose in children over one year old is 2.5 to 5 micrograms/kg/day. To determine the actual prescribed dose, the equivalent of the calculated daily dose must be rounded to the nearest 25 micrograms.

Method of administration

The total daily dose is taken whole in the morning with some liquid in the fasting state at least half an hour before breakfast.

Due to a lack of data, it is not recommended to crush Eltroxin 50/Eltroxin 100 tablets.

If the patient has forgotten to take a dose, he/she should make up for the missed dose as soon as he/she remembers. However, should the next dose be imminent, the patient should skip the missed dose and only take the subsequent dose. No double dose should be taken at any one time.

Duration of use

Duration of use: in hypothyroidism and post thyroidectomy due to thyroid malignancy - usually life-long; for euthyroid goitre and prophylaxis against goitre recurrence - a few months or years to life-long; in concomitant therapy for the treatment of hyperthyroidism - depending on the duration of antithyroid medication. For the treatment of euthyroid goitre, a treatment period of six months up to two years is necessary. If treatment with Eltroxin has not produced the desired response within this time, other treatment options should be considered.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 - untreated hyperthyroidism of any aetiology - untreated adrenal insufficiency - untreated pituitary insufficiency - acute myocardial infarction - acute myocarditis - acute pancarditis - during pregnancy, concomitant intake of levothyroxine and an antithyroid agent is contraindicated.

Laboratory monitoring
Levothyroxine has a narrow therapeutic index. The appropriate levothyroxine dosage is based on clinical assessment and laboratory investigation of thyroid function tests. In the initial phase of uptitration, careful dose escalation and monitoring is necessary to avoid the sequelae of under- and overdosing. The symptoms of an overdose with levothyroxine are essentially those of endogenous thyrotoxicosis.

Levothyroxine should not be used for treatment of obesity or weight loss.

In patients with euthyroid status, doses within the daily hormone requirement range show no weight-reducing effect. Higher doses can lead to serious or even life-threatening manifestations of toxicity, especially when administered in combination with sympathomimetic amines, e.g. those used on the basis of their anorectic effect.

Medicinal products for weight reduction: orlistat may reduce the uptake of levothyroxine and thus cause hypothyroidism. To avoid this, orlistat and levothyroxine should be administered at an interval of at least 4 hours. Regular monitoring of thyroid function is required.

Special patient populations

Prior to initiation of thyroid hormone therapy, the following diseases should be excluded or treated:
- Coronary heart disease
- Angina pectoris
- Hypertension
- Pituitary and/or adrenocortical insufficiency
- Thyroid autonomy.

In coronary heart disease, heart failure or tachyarrhythmias and diabetes mellitus or insipidus, even milder forms of pharmacologically induced hyperthyroidism must be avoided at all costs. In such cases, more frequent monitoring of thyroid hormone parameters must be performed (see 4.2). Special care during use is necessary in elderly patients, in patients with symptoms of myocardial insufficiency and with ECG changes suggestive of cardiac ischaemia, as well as in patients with diabetes mellitus or diabetes insipidus.

In secondary hypothyroidism, it must be established whether adrenocortical insufficiency is present at the same time. If so, this must firstly be replaced with hydrocortisone.

Treatment with levothyroxine may lead to intolerance, including dizziness, asthenia, malaise, weight loss, hypotension and acute adrenocortical insufficiency in patients with pituitary insufficiency or adrenal insufficiency due to other causes. It is therefore advisable to administer corticosteroid therapy first, before levothyroxine is given.

Patients with myxoedema have increased sensitivity to thyroid hormones; in these patients, a low initial dose with slow dose escalation should be selected.

Patients with malabsorption syndromes have reduced thyroxine absorption. It is recommended to treat malabsorption to ensure effective thyroxine treatment at the regular levothyroxine dose.

During pregnancy, a reduction in thyroxine serum levels may occur with a concomitant increase in TSH serum levels to values outside the normal range. In patients taking levothyroxine, TSH measurements should be performed on a quarterly basis. Elevated serum TSH levels should be corrected by increasing the levothyroxine dose. As postpartum serum TSH levels are comparable to pre-conception levels, the levothyroxine dose may again be reduced to the pre-pregnancy dose.

In the levothyroxine treatment of postmenopausal women with hypothyroidism at increased risk of osteoporosis, thyroid function should be monitored more frequently to avoid supraphysiological blood levels of levothyroxine. In order to minimise the risk of osteoporosis, the levothyroxine dose should be titrated to the lowest possible value.

Interactions that reduce levothyroxine absorption

Cholestyramine and colestipol inhibit the absorption of levothyroxine.
Levothyroxine absorption may be reduced by concomitant intake of antacids containing aluminium, magnesium, calcium and iron, polystyrene sulphonate ion exchange resins (kayexalate, sevelamer), sucralfate, lanthanum and proton-pump inhibitors. Hence, the longest possible interval should elapse between taking levothyroxine and any of the above medicinal products, in order to prevent interactions in the stomach and small intestine (see section 4.2).

Soya products and a high-fibre diet may reduce the intestinal absorption of Eltroxin. An adjustment in the dose of Eltroxin may become necessary, especially at the start and upon completion of a diet containing soya.

Medicinal products for weight reduction: orlistat may reduce the absorption of levothyroxine and thus cause hypothyroidism. To avoid this, orlistat and levothyroxine should be administered at an interval of at least 4 hours. Regular monitoring of thyroid function is required.

Interactions that affect levothyroxine

Anticonvulsants, such as carbamazepine and phenytoin, increase the metabolism of thyroid hormones and may displace them from their plasma protein binding sites. Initiation or discontinuation of anticonvulsant therapy may alter levothyroxine requirements.

Rapid intravenous administration of phenytoin may lead to increased plasma levels of free levothyroxine and liothyronine and, in isolated cases, may promote the development of cardiac arrhythmias.

Medicinal products with enzyme-inducing properties such as rifampicin increase the metabolism and excretion of thyroxine, which increases levothyroxine requirements.

Barbiturates and other medicinal products with liver enzyme-inducing properties may increase the hepatic clearance of levothyroxine.

Propylthiouracil, glucocorticoids, beta-blockers, lithium, iodide and iodine-containing contrast media inhibit the conversion of T4 to T3.

Amiodarone can have numerous effects on thyroid function. These include increased levothyroxine requirements in patients with hypothyroidism. Due to its high iodine content, amiodarone may cause both hyperthyroidism and hypothyroidism. Particular caution is advised in cases of nodular goitre with possibly undetected autonomy.

Treatment with tyrosine kinase inhibitors (e.g. imatinib and sunitinib) has been associated with increased levothyroxine requirements in patients with hypothyroidism.

Salicylates, dicoumarol, high doses of furosemide (250 mg), clofibrate and other substances may displace levothyroxine from its plasma protein binding sites, thereby leading to an increase in the plasma level of free thyroxine.

Sertraline and chloroquine/proguanil reduce the efficacy of levothyroxine and increase the serum TSH level.

Co-administration of oral contraceptives, as well as other medications such as oestrogens, tamoxifen, methadone and 5-fluorouracil, may increase the serum concentration of thyroxine-binding globulin and thereby increase levothyroxine requirements.

There have been reports that some HMG-CoA reductase inhibitors (statins) such as simvastatin and lovastatin may increase thyroid hormone requirements in patients receiving levothyroxine treatment. It is not known whether this is the case with all statins. Thus, during concomitant use of statins, close monitoring of thyroid function and appropriate adjustment of the levothyroxine dose may be required.

Post-marketing cases have been reported that indicate a potential interaction between medicines containing ritonavir and levothyroxine. In patients treated with levothyroxine, the thyroid stimulating hormone (TSH) should be monitored at least in the first month after the start and/or end of ritonavir treatment.

A large number of medicinal substances can affect thyroid function tests. This should be taken into account when monitoring a patient on levothyroxine treatment.

Interactions affecting other medicinal products

Levothyroxine may reduce the hypoglycaemic effect of antidiabetic agents. Therefore, blood sugar levels must be checked regularly in patients with diabetes and the dosage of the antidiabetic agent must be adjusted as necessary.

Levothyroxine may potentiate the effect of anticoagulants by plasma protein binding displacement. Thus, during concomitant treatment, regular monitoring of blood coagulation is required and, if necessary, the anticoagulant dosage must be reduced if excessive hypoprothrombinaemia and bleeding are to be avoided.

Phenytoin levels may be increased by levothyroxine.

If co-administered with cardiac glycosides, it may be necessary to adjust the dosage of these cardiac glycosides.

The effects of co-administered sympathomimetic agents may be potentiated.

Levothyroxine increases the sensitivity of catecholamine receptors and accelerates their response to tricyclic antidepressants.

Interactions in association with laboratory tests

Some medicinal products, e.g. androgens and anabolic steroids, can lower the serum concentration of levothyroxine-binding globulin and therefore reduce levothyroxine requirements.

Falsely low plasma levels have been observed with concomitant use of anti-inflammatory agents such as phenylbutazone or acetylsalicylic acid and levothyroxine therapy. The use of acetylsalicylic acid together with levothyroxine initially leads to a transient increase in free T4 serum levels. With continued treatment, free T4 and TSH levels return to normal and patients subsequently achieve clinical euthyroid status.

Pregnancy

Levothyroxine has been taken by a large number of pregnant women and women of childbearing potential, without any disturbances in the reproductive process having been observed. However, hyper- or hypothyroidism in the mother may negatively affect the course of pregnancy or the well-being of the child.
Replacement treatment with thyroid hormones should be administered consistently, especially during pregnancy. To date, there have been no reports of any risk to the foetus, despite extensive use during pregnancy.

During pregnancy, levothyroxine requirements in patients with hypothyroidism may increase due to oestrogen. Thyroid function should therefore be monitored both during and after pregnancy and the replacement dose adjusted as necessary.

During pregnancy, levothyroxine is contraindicated for use as concomitant therapy in the treatment of hyperthyroidism with antithyroid agents, as a higher antithyroid dosage would be required. Since antithyroid agents, unlike levothyroxine, can cross the placental barrier at effective doses, this may induce hypothyroidism in the foetus. For this reason, in the presence of hyperthyroidism, antithyroid agents should always be administered as low-dose monotherapy during pregnancy.

During pregnancy, suppression tests should be avoided.

Breast-feeding

Levothyroxine is excreted in human milk at low concentrations; this might be enough to interfere with neonatal hypothyroidism screening. The amount of thyroid hormone secreted into breast milk during lactation, even with high-dose levothyroxine therapy, is not sufficient for the development of hyperthyroidism or suppression of TSH secretion in the infant.

No studies on the effects on the ability to drive and use machines have been performed.

With proper use and monitoring of clinical findings and laboratory diagnostic values, adverse reactions are not to be expected during treatment with Eltroxin. Classification of adverse reactions by frequency is not possible on the basis of the data available.

If the dose strength is not tolerated in individual cases or if overdose occurs, symptoms like those occurring in hyperthyroidism may occur, particularly if the dose is increased too quickly at the start of treatment. In this case, the daily dose should be reduced or the medication should be discontinued for several days. Once the adverse reaction has resolved, treatment can be resumed with careful dosing (see section 4.2).

To reports any side effect(s):
Saudi Arabia:

-The National Pharmacovigilance Centre (NPC): - Fax: +966-11-205-7662 - Call NPC at +966-11-2038222, Ext 2317-2356-2340 - SFDA Call Center: 19999 - E-mail: npc.drug@sfda.gov.sa - Website: https://ade.sfda.gov.sa/

Other GCC States:

- Please contact the relevant competent authority.

 

Signs and symptoms
Symptoms of a moderate-to-severe increase in metabolism may occur in the event of overdose and intoxication (see section 4.8), including agitation, confusion, irritability, hyperactivity, headache, sweating, mydriasis, tachycardia, arrhythmias, tachypnoea, fever, increased intestinal activity and intestinal spasms. The clinical manifestation of such hyperthyroidism may be delayed for up to five days. Thyrotoxic crisis, leading to irregular heartbeat, heart failure and coma, has occasionally been reported to occur after massive or chronic intoxication.

Treatment
The therapeutic objective is to restore clinical and biochemical euthyroid status, by interrupting the administration of levothyroxine or reducing the levothyroxine dose and, if necessary, by further measures depending on clinical status.
Discontinuation of tablet-taking and a follow-up examination are recommended.
In the event of severe beta-sympathomimetic effects (e.g. tachycardia), symptoms can be alleviated by beta-blockers. For neurological/psychological symptoms, benzodiazepines and/or neuroleptics can be used.
Antithyroid agents are not appropriate, as the thyroid is already fully quiescent. At extreme doses (suicide attempt), plasmapheresis may be helpful.

Other appropriate measures must be performed depending on severity or in accordance with national recommendations.

Pharmacotherapeutic group: thyroid hormones (chemically defined), ATC code: H03AA01.

The synthetic levothyroxine contained in Eltroxin is identical in its action to the naturally occurring thyroid hormone mainly produced by the thyroid gland. Following partial conversion to liothyronine (T3) - especially in the liver and kidney - and transfer to body cells, the characteristic thyroid hormone effects on development, growth and metabolism are observed.

Absorption
Largely dependent on the type of pharmaceutical formulation, orally administered levothyroxine is absorbed up to a maximum of 80% in the fasting state, mainly from the small intestine. Peak plasma levels are reached approximately six hours post ingestion. The onset of action occurs after 3 to 5 days upon initiation of oral therapy.
Distribution
The volume of distribution is calculated to be 1/2 L/kg. Levothyroxine is more than 99% bound to plasma proteins.
Biotransformation
The primary metabolic pathway of thyroxine (T4) is its conversion by deiodination to the active metabolite triiodothyronine (T3). Further deiodination of T4 and T3 leads to the formation of inactive products.
Elimination
Metabolic clearance is approximately 1.2 L plasma per day, with degradation occurring mainly in the liver, kidney, brain and muscle.
Due to the high protein binding, thyroid hormones appear only in small amounts in the haemodialysate.
In a typical person, levothyroxine is eliminated with a half-life of seven days. This may turn out to be lower in cases of hyperthyroid status and higher in patients with hypothyroidism.
In humans, 20-40% of levothyroxine is excreted in the faeces and 30-55% of a levothyroxine dose in the urine.
Bioavailability
A bioavailability study, conducted in 2003 on 36 subjects, revealed the following for T4 compared to the reference product:

	Reference product	Eltroxin
Peak plasma concentration (Cmax)	177.4 (115.6 to 284.3) pmol/L	166.6 (115.9 to 262.1) pmol/L
Time to peak plasma concentration(tmax)	2.0 (1.0 to 8.0) h	2.5 (1.5 to 8.0) h
Area under the concentration-time curve (AUC)	6,495 (4,647 to 11,442) pmol x h/L	6,371 (4,594 to 9,949) pmol x h/L

 

 

 

 

 

 

Values expressed as mean and range

 

Acute toxicity:
The acute toxicity of levothyroxine is very low. Doses of up to 10 mg levothyroxine have been tolerated without complications in the event of intoxication (suicide attempts) in humans. Serious complications, such as a threat to vital functions (respiration and circulation), are not to be expected unless coronary heart disease is present (see also section 4.9).

Chronic toxicity:
Chronic toxicity studies have been performed on various animal species (rat, dog). At high doses, signs of hepatopathy, increased occurrence of spontaneous nephrosis and abnormal organ weights were seen in rats. No significant adverse reactions were observed in dogs. Several cases of sudden cardiac death have been described in patients with long-term levothyroxine abuse.

Mutagenicity:
There are no available data on the mutagenic potential of levothyroxine. To date, there has been no suspicion or evidence of any damage to offspring due to changes in the genome caused by thyroid hormones.

Carcinogenicity:
No long-term animal studies have been performed to investigate any tumorigenic potential of levothyroxine.

Toxicity to reproduction:
Only a very small proportion of thyroid hormones cross the placenta. Following injection of small doses (up to 24 micrograms) of levothyroxine into chick embryos, the incidence of strophosomy was increased. In humans, there is considerable experience with levothyroxine therapy in all phases of pregnancy. There is no evidence of any toxic effect on the foetus or induction of malformations.

There are no available data with regard to harmful effects on male or female fertility. Nor is there any suspicion or evidence of such effects.

Microcrystalline cellulose, pregelatinised starch (maize starch 1500), magnesium stearate (Ph.Eur.), talc, colloidal anhydrous silica.

Not applicable.

The shelf life is 2 years. This medicinal product must not be used after the expiry date.

Do not store above 25°C.

Keep tablets in the tightly sealed multidose container in order to protect from light and moisture.

Eltroxin 50
Packs with 100 tablets [N3]

Eltroxin 100
Packs with 100 tablets [N3]

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.