SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE MEDICINAL PRODUCT
<[Invented name]> 25 µg tablets <[Invented name]> 50 µg tablets <[Invented name]> 63 µg tablets <[Invented name]> 75 µg tablets <[Invented name]> 88 µg tablets <[Invented name]> 100 µg tablets <[Invented name]> 112 µg tablets <[Invented name]> 125 µg tablets <[Invented name]> 137 µg tablets <[Invented name]> 150 µg tablets <[Invented name]> 175 µg tablets <[Invented name]> 200 µg tablets
Active substance: levothyroxine sodium
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 tablet <[Invented name]> 25 µg contains 25 µg levothyroxine sodium. 1 tablet <[Invented name]> 50 µg contains 50 µg levothyroxine sodium. 1 tablet <[Invented name]> 63 µg contains 63 µg levothyroxine sodium. 1 tablet <[Invented name]> 75 µg contains 75 µg levothyroxine sodium. 1 tablet <[Invented name]> 88 µg contains 88 µg levothyroxine sodium. 1 tablet <[Invented name]> 100 µg contains 100 µg levothyroxine sodium. 1 tablet <[Invented name]> 112 µg contains 112 µg levothyroxine sodium. 1 tablet <[Invented name]> 125 µg contains 125 µg levothyroxine sodium. 1 tablet <[Invented name]> 137 µg contains 137 µg levothyroxine sodium. 1 tablet <[Invented name]> 150 µg contains 150 µg levothyroxine sodium. 1 tablet <[Invented name]> 175 µg contains 175 µg levothyroxine sodium. 1 tablet <[Invented name]> 200 µg contains 200 µg levothyroxine sodium.
Excipients with known effect: Contains sodium: less than 1 mmol (23 mg) per tablet (in all presentations), see section 4.4.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablets. White, round tablets with facet, a break mark on one side and the reference 1L, 2L, 2.5L, 3L, 3.5L, 4L, 4.5L, 5L, 5.5L, 6L, 7L or 8L engraved on both sides. The tablets can be divided into equal halves.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
The following indications are for all <[Invented name]> 25 / 50 / 63 / 75 / 88 / 100 / 112 / 125 / 137 / 150 / 175 / 200 µg strengths:
− Replacement therapy in all forms of hypothyroidism,
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− Prophylaxis against recurrence after surgery for euthyroid goitre, depending on the postoperative hormone status, − Therapy of benign euthyroid goitre, − Suppression and replacement therapy in patients with malignant thyroid tumours, particularly after thyroidectomy.
In addition for <[Invented name]> 25 / 50 / 63 / 75 / 88 / 100 µg strengths:
− As an adjunct to treatment of hyperthyroidism with antithyroid drugs after achievement of the euthyroid state.
In addition for <[Invented name]> 100/150/200 µg strengths
− Thyroid suppression test.
4.2 Posology and method of administration
Dosage Information concerning dosages is given only for guidance.
The individual daily dose should be determined by laboratory and clinical monitoring. A lower replacement dose may be sufficient if there is some residual thyroid function.
In elderly patients, in patients with coronary heart disease, and in patients with severe or long- existing hypothyroidism, special caution is required when initiating therapy with thyroid hormones, that is, a low initial dose should be given which should then be increased slowly and at lengthy intervals with frequent monitoring of thyroid hormones. Experience has shown that a lower dose is sufficient in low- weight patients and in patients with a large goitre.
As T4 or fT4 levels can be elevated in some patients, serum TSH concentrations are more suitable for monitoring the treatment regimen.
Indication Dose (micrograms of levothyroxine sodium/day)
Hypothyroidism: Adults (increase by 25- initially 25–50 50 micrograms in 2-to thereafter 100–200 4-week intervals)
Prophylaxis against recurrence of goitre: 75–200 Benign euthyroid goitre: 75–200 Adjunct to treatment of hyperthyroidism with antithyroid 50–100 drugs: After thyreoidectomy for thyroid malignant tumour: 150–300 Thyroid suppression <[Invented name]> 100 µg 200 micrograms (equivalent to 2 tablets)/day (for test: 14 days before scintigraphy)
<[Invented name]> 150 µg 150 micrograms (equivalent to 1 tablet)/day (for 14 days before scintigraphy)
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<[Invented name]> 200 µg 200 micrograms (equivalent to 1 tablet)/day (for 14 days before scintigraphy)
Paediatric population
The maintenance dose is generally 100 to 150 micrograms per m² body surface area.
For neonates and infants with congenital hypothyroidism, where rapid replacement is important, the initial recommended dosage is 10 to 15 micrograms per kg BW per day for the first 3 months. Thereafter, the dose should be adjusted individually according to the clinical findings and thyroid hormone and TSH values.
For children with acquired hypothyroidism, the initial recommended dosage is 12.5-50 micrograms per day. The dose should be increased gradually every 2 to 4 weeks according to the clinical findings and thyroid hormone and TSH values until the full replacement dose is reached.
Method of administration The total daily dose should be taken in the morning, at least half an hour before breakfast, swallowed whole, preferably with liquid.
Infants should be given the total daily dose at least half an hour before the first meal of the day. If necessary, tablets are to be disintegrated in some water (10 to 15 ml) and the resultant suspension, which must be prepared freshly as required, is to be administered with some more liquid (5 to 10 ml).
Duration of administration Duration of treatment is usually for life in the case of substitution in hypothyroidism and after strumectomy or thyroidectomy and for relapse prophylaxis after euthyroid goiter removal. Concomitant therapy of hyperthyroidism is indicated for the period in which the antithyroid drug is given.
For benign euthyroid goiter, a treatment duration of 6 months up to two years is necessary. If treatment with <[Invented name]> is not successful within this period, other treatment possibilities should be considered.
Thyroid suppression test 150-200 micrograms of levothyroxine sodium daily for 14 days are taken for the thyroid suppression test.
Dosage in the elderly In elderly patients, in some cases, e.g. those with cardiac problems, it is best to administer levothyroxine sodium in gradually increasing doses whilst monitoring TSH levels regularly.
4.3 Contraindications
− Hypersensitivity to the active substance or to any of the in section 6.1 stated excipients, − untreated hyperthyroidism, − untreated adrenal insufficiency, − untreated pituitary insufficiency (when leading to adrenal insufficiency requiring treatment), − acute myocardial infarction, − acute myocarditis, − acute pancarditis.
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Concomitant administration of levothyroxine and an antithyroid drug is not indicated during pregnancy.
Use in pregnancy and lactation, see section 4.6.
4.4 Special warnings and precautions for use
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, - thyroid autonomy.
These diseases/conditions must also be excluded or treated before a thyroid suppression test is performed, except in the case of thyroid autonomy, which may be the reason for undertaking the suppression test.
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 (see section 4.2).
In cases of secondary hypothyroidism, simultaneous adrenal insufficiency must be ruled out. If found, hydrocortisone substitution must precede thyroid hormone replacement therapy. Thyroid replacement therapy might precipitate an acute adrenal crisis in patients with adrenal insufficiency or pituitary insufficiency without adequate corticosteroid coverage.
In low birth weight premature neonates, extreme caution should be taken when initiating levothyroxine, due to the immature adrenal function, circulatory collapse may occur. (See section 4.8). 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.
If thyroid autonomy is suspected, a TRH test or suppression scintigram is recommended before treatment.
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 (see section 4.8).
Thyroid hormones should not be administered for weight reduction. Normal doses do not result in any weight reduction in euthyroid patients. Higher doses may cause severe or even life-threatening adverse events, particularly in combination with certain substances, especially sympathomimetic amines, for weight reduction.
Hypersensitivity reactions (including angioedema), sometimes serious, have been reported with <[Invented name]> use. If signs and symptoms of allergic reactions occur, treatment with <[Invented name]> must be discontinued and appropriate symptomatic treatment initiated (see Section 4.3 and 4.8).
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Once a levothyroxine treatment has been established, a switch to another thyroid hormone containing medicinal product should only take place under close monitoring of laboratory and clinical parameters during the transition period due to a potential risk of thyroid imbalance. In some patients, a dose adjustment could be necessary.
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) which may affect the thyroid function. See also section 4.5.
Caution is advised when levothyroxine is administered to patients with a known history of epilepsy as there is an increased risk of seizures in these patients.
For diabetic patients and patients under anticoagulant therapy, see section 4.5.
<[Invented name]> contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Antidiabetic drugs: Levothyroxine can reduce the hypoglycaemic effects of antidiabetic drugs (such as metformin, glimepiride, and glibenclamide, as well as insulin). Therefore, blood sugar values should be monitored regularly in diabetics, especially at the beginning and at the end of thyroid hormone replacement therapy, with adjustment of the dose of antidiabetic medication if necessary.
Coumarin derivatives: Levothyroxine can potentiate the action of coumarin derivatives through displacement from their plasma protein binding. Regular monitoring of coagulation is therefore necessary in the case of concomitant treatment; if necessary, the dosage of the anticoagulant must be adjusted (dose reduction).
Ion exchange resins: Ion-exchange resins such as colestyramine, colestipol, sevelamer or calcium and sodium salts of polystyrene sulphonic acid inhibit the absorption of levothyroxine by binding with thyroid hormones in the gastro-intestinal tract. These drugs should therefore be given not less than 4 - 5 hours after administration of <[Invented name]>.
Bile acid sequestrant: Colesevelam binds to levothyroxine and reduces levothyroxine absorption from the gastro-intestinal tract. No interaction was observed when levothyroxine was taken at least 4 hours before colesevelam. Therefore levothyroxine should be administered at least 4 hours prior to colesevelam.
Aluminium- containing antacids, iron-containing drugs, calcium carbonate: Resorption of levothyroxine can be reduced by concomitant ingestion of aluminium-containing gastric acid-binding agents (antacids, sucralfate), iron-containing drugs and calcium carbonate. <[Invented name]> should therefore be given at least two hours before these drugs.
Propylthiouracil, glucocorticoids and beta-receptor blockers (especially propranolol):
These substances inhibit the peripheral conversion of T4 toT3 and may lead to a reduced serum concentration of T3.
Amiodarone and iodine-containing contrast media- due to their high iodine content- may cause either hyperthyroidism or hypothyroidism. Special caution is required in cases of nodular goitre in which autonomy has not been ruled out. Amiodarone inhibits the peripheral conversion of T4
(levothyroxine) to T3 resulting in a reduced serum concentration of T3 and an increased serum TSH level. Due to this effect of amiodaron on the thyroid function a dose adjustment of <[Invented 6 name]> may be necessary.
Salicylates, dicumarol, furosemide, clofibrate: Salicylates (specifically at doses greater than 2.0 g/day), dicumarol, high doses (250 mg) of furosemide, clofibrate and other substances can displace levothyroxine sodium from plasma proteins, thereby lead to an initial transient increase in free thyroid hormones and followed by an overall decrease of total thyroid hormones levels.
Oestrogen-based contraceptives, drugs for postmenopausal hormone replacement: Levothyroxine requirements may increase during administration of oestrogen-based contraceptives or during postmenopausal hormone replacement therapy. Estrogens increase the thyroxin binding leading to diagnostic and therapeutic errors.
Sertraline, chloroquine/proguanil: These substances decrease the efficacy of levothyroxine and increase the serum TSH level.
Effect of drugs inducing cytochrome P-450: Enzyme-inducing drugs: such as Barbiturates, rifampicin, carbamazepine, phenytoin, barbiturates, and products containing St John’s wort (Hypericum perforatum) other drugs possessing hepatic enzyme inducing properties can may increase hepatic clearance of levothyroxine, resulting in reduced serum concentrations of thyroid hormones. Therefore, patients on thyroid replacement therapy may require an increase in their dose of thyroid hormone if these drugs are given concurrently.
Protease inhibitors: There have been reports of loss of therapeutic effect of levothyroxine when used concomitantly with lopinavir/ritonavir. Therefore, clinical symptoms as well as thyroid function tests should be carefully monitored in patients receiving levothyroxine and protease inhibitors concomitantly.
Tyrosine kinase inhibitors (e.g. imatinib, sunitinib, sorafenib or motesanib) may decrease the efficacy of levothyroxine. Therefore, clinical symptoms as well as the thyroid function should be carefully monitored in patients receiving levothyroxine and a tyrosine kinase inhibitor concomitantly. Levothyroxine dose may need to be adjusted.
Soya products may reduce the intestinal absorption of levothyroxine. In children receiving a soya- based diet and treated with levothyroxine due to congenital hypothyroidism an increase in TSH serum level was reported. Uncommonly high doses of levothyroxine may be necessary to achieve normal serum levels of T4 and TSH. During and after ending a soya-based diet serum levels of T4 and TSH should be monitored closely, where required, a dose adjustment of levothyroxine may be necessary.
4.6 Fertility, pregnancy and lactation
Treatment with thyroid hormones should be given consistently during pregnancy and breast-feeding in particular.
Pregnancy
Maintenance of thyroid hormone levels within the normal range is vital for pregnant women to ensure optimal maternal and foetal health. To date, despite extensive use during pregnancy, no adverse effects of levothyroxine on pregnancy or on the health of the foetus/newborn have been identified.
During pregnancy, levothyroxine requirements may increase due to oestrogen. Thyroid functions should therefore be controlled both during and after a pregnancy and the dose of thyroid hormone adapted if necessary. 7
Since elevations in serum TSH may occur as early as 4 weeks of gestation, pregnant women taking levothyroxine should have their TSH measured during each trimester, in order to confirm that the maternal serum TSH values lie within the trimester-specific pregnancy reference range. An elevated serum TSH level should be corrected by an increase in the dose of levothyroxine. Since postpartum TSH levels are similar to preconception values, the levothyroxine dosage should return to the pre- pregnancy dose immediately after delivery. A serum TSH level should be obtained 6–8 weeks postpartum.
During pregnancy levothyroxine sodium is contraindicated as an adjunct to treatment of hyperthyroidism with antithyroid drugs. Additional intake of levothyroxine may increase the required dosage of antithyroid drugs. Antithyroid drugs, unlike levothyroxine, cross the placental barrier in effective doses and therefore hypothyroidism in the foetus may result. Therefore, hyperthyroidism during pregnancy should be treated with low-dose single-substance therapy using an antithyroid drug.
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.
The suppression test should not be conducted during pregnancy and lactation.
Hypothyroidism or hyperthyroidism are likely to have an effect on fertility. Treatment of hypothyroidism with <[Invented name]> must be adjusted based on monitoring of laboratory parameters because an insufficient dose is not likely to improve the hypothyroidism and an overdose can lead to hyperthyroidism.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable effe cts
If the patient does not tolerate the dosage given or overdosage occurs, the typical symptoms of hyperthyroidism may occur, especially if the dose is increased too rapidly at the start of treatment. In these cases, the daily dosage should be reduced, or the medication should be stopped for several days. Treatment may be restarted with cautious dose adjustment once the side effects have disappeared.
In case of hypersensitivity against levothyroxine or against other ingredients of <[Invented name]>, allergic reactions on the skin (e.g. angioedema, rash, urticaria) and on the respiratory tract may occur.
Classification of expected frequencies:
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Immune system disorders not known: hypersensitivity
Endocrine disorders Common: hyperthyroidism
Cardiac disorders very common: palpitations
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common :tachycardia not known: cardiac arrhythmias, anginal pain
Skin and subcutaneous disorders Not known: angioedema, rash, urticaria, sweating
Psychiatric disorders very common: insomnia common: nervousness not known: agitation
Musculoskeletal and connective tissue disorders not known: muscle weakness and cramps, osteoporosis at suppressive doses of levothyroxine, especially in postmenopausal women, mainly when treated for a long period.
Vascular disorders not known: flushing, circulatory collapse in low birth weight preterm neonates (see section 4.4)
Reproductive system and breast disorders not known: menstrual irregularities
Gastrointestinal disorders not known: diarrhoea, vomiting and nausea
Investigations not known: weight loss
Nervous system disorders very common: headache rare: pseudotumor cerebri particularly in children not known: tremors,
General disorder and administration site conditions not known: heat intolerance, fever
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 national reporting system <[to be completed nationally]>.
4.9 Overdose
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 (see section 4.8). Depending on the extent of the overdosage it is recommended that treatment is interrupted and that tests are carried out.
In incidents of poisoning (attempts of suicide) in humans, 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 9 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, gastrointestinal absorption can be reduced by administration of medicinal charcoal. 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 (attempted suicide), 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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Thyroid hormones, ATC-Code: H03AA01.
The synthetic levothyroxine contained in <[Invented name]> is identical in effect with the naturally occurring major hormone secreted by the thyroid. The body is not able to differentiate between endogenously-formed and exogenous levothyroxine.
Following partial conversion to liothyronine (T3), particularly in the liver and kidneys, and passage into body cells, its characteristic thyroid hormone effects on development, growth and metabolism are observed through activation of T3 receptors.
Thyroid hormone replacement leads to normalisation of the processes of metabolism. For example, the rise in cholesterol caused by hypothyroidism is significantly reduced by the administration of levothyroxine.
5.2 Pharmacokinetic properties
Levothyroxine administered orally on an empty stomach shows up to 80% absorption in the upper small intestine, largely dependent on formulation. If the product is taken at mealtimes, resorption is markedly reduced.
The peak plasma concentration occurs approx. 2 to 3 hours after ingestion. The onset of action is 3 to 5 days after starting oral therapy.
The volume of distribution amounts to approx. 10 to 12 l. Levothyroxine exhibits an extremely high binding to specific transport proteins of about 99.97%. This protein hormone binding is not covalent and so the bound hormone in plasma is in continuous and very rapid exchange with the fraction of the free hormone.
The metabolic clearance for levothyroxine is about 1.2 l plasma/day. Metabolism occurs mainly in the liver, kidneys, brain and muscle. The metabolites are excreted in the urine and faeces.
The half-life of levothyroxine amounts to approx. 7 days; it is shorter (3 to 4 days) in hyperthyroidism and longer in hypothyroidism (approx. 9 to 10 days).
Only small amounts of levothyroxine cross the placenta. Under normal dosage, only small amounts 10 of levothyroxine are secreted into breast milk.
Due to its high protein binding levothyroxine undergoes neither hemodialysis nor hemoperfusion. Bioavailability A bioavailability study conducted in 1998/1999 with different tablet strengths in comparison with a reference oral solution produced a comparable bioavailability with all eight strengths.
Study method Dosage: The total dose was 600 micrograms levothyroxine sodium in each case for the tablet strengths 25, 50, 75, 100, 150 and 200 micrograms. The total dose with the 125 microgram tablets was 625 micrograms, and 700 micrograms with the 175 microgram tablets.
These different total dosages are due to the differing multiplier of the various tablet strengths. The total dose of the reference oral solution was matched for the respective investigation.
Study design: Prospective, randomised, open, single cross-over, intra-individual comparison between the test preparation and a reference oral solution.
Duration of study: Single dose with a wash-out phase of at least six weeks before the second medication.
Bioavailability of different strengths of <[Invented name]> in comparison with a reference oral solution
Test preparation (T) N* Peak plasma Time to peak plasma Area under the concentration concentration concentration-time
Reference oral solution (Cmax) in ng/ml: (tmax) in h: curve (R) (AUC) in ng x h/ml: 24 x 25 µg (T) 24 50.86 ± 8.94 2.17 ± 0.65 1389 ± 250 600 µg (R) 51.72 ± 7.36 1.98 ± 1.42 1416 ± 262 12 x 50 µg (T) 24 48.16 ± 8.04 2.42 ± 0.89 1335 ± 287 600 µg (R) 50.38 ± 7.76 2.00 ± 0.94 1439 ± 207 8 x 75 µg (T) 26 48.43 ± 11.30 2.55 ± 1.21 1387 ± 311 600 µg (R) 50.70 ±11.17 2.03 ± 1.29 1380 ± 280 6 x 100 µg (T) 24 51.01 ± 10.38 2.60 ± 1.12 1473 ± 317 600 µg (R) 54.53 ± 10.41 1.88 ± 1.11 1532 ± 277 5 x 125 µg (T) 26 54.62 ± 10.7 2.63 ± 1.26 1541 ± 347 625 µg (R) 54.83 ± 13.35 2.01 ± 0.856 1519 ± 426 4 x 150 µg (T) 24 48.59 ± 10.29 2.40 ± 0.86 1335 ± 319 600 µg (R) 50.60 ± 8.73 1.98 ± 1.07 1424 ± 251 4 x 175 µg (T) 26 56.53 ± 10.23 2.40 ± 1.20 1596 ± 336 700 µg (R) 57.41 ± 13.88 1.85 ± 1.04 1641 ± 418 3 x 200 µg (T) 24 45.73 ± 9.67 2.21 ± 0.85 1297 ± 287 600 µg (R) 49.48 ± 8.90 1.781 ± 1.140 1320 ± 277 Figures given as mean and scatter. N* = number of subjects.
5.3 Preclinical safe ty data
Acute toxicity Levothyroxine has a very slight acute toxicity. 11
Chronic toxicity The chronic toxicity of levothyroxine was studied in various animal species (rat, dog). At high doses, signs of hepatopathy, increased occurrence of spontaneous nephroses as well as changes in organ weights were observed in rats. In dogs no appreciable adverse effects occurred.
Mutagenicity: No information is available on this subject. So far no indications of any kind have become known suggesting damage to the progeny due to changes in the genome caused by thyroid hormones.
Carcinogenicity No long-term animal studies on a tumourigenic potential have been carried out with levothyroxine.
Reproduction toxicity Only small amounts of thyroid hormones pass through the placenta. No information is available on harmful effects on male or female fertility. There have been no indications of any kind in this connection.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Maize starch pregelatinised starch (maize) microcrystalline cellulose sodium carbonate sodium thiosulphate colloidal anhydrous silica hydrogenated castor oil.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
<[Invented name]> 25 µg: 18 months. <[Invented name]> 50 µg, 63 µg, 75 µg, 88 µg, 100 µg, 112 µg, 125 µg, 137 µg: 2 years. <[Invented name]> 150 µg, 175 µg, 200 µg: 3 years.
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
PVC/aluminium blister strips (transparent). Packs of 28, 50, 84, 98, 100 tablets Sample packs of 25 tablets Hospital pack of 500 (10 x 50) tablets Not all pack sizes may be marketed.
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6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
{Name and address} <{tel}> <{fax}> <{e-mail}>
8. MARKETING AUTHORISATION NUMBERS
<[To be completed nationally]>
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
<{DD/MM/YYYY}> <[To be completed nationally]>
11. PRESCRIPTION STATUS/LEGAL CATEGORY
Prescription-only medicine.
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LABELLING
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
{carton/folding box}
1. NAME OF THE MEDICINAL PRODUCT
<[Invented name]> 88 µg tablets
Active substance: levothyroxine sodium
2. STATEMENT OF ACTIVE SUBSTANCE(S)
1 tablet contains 88 µg levothyroxine sodium.
3. LIST OF EXCIPIENTS
Contains sodium (see leaflet for further information).
4. PHARMACEUTICAL FORM AND CONTENTS
25 tablets 28 tablets (calendar pack) 50 tablets 84 tablets (calendar pack) 98 tablets (calendar pack) 100 tablets 500 tablets (10 x 50 tablets)
For sample packs (25 tablets) additionally: "Sample pack"
For multipacks (10 x 50) additionally: "Component of a multipack, can’t be sold separately”
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
((blank for dosage instructions)) Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Not applicable
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Not applicable.
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
12. MARKETING AUTHORISATION NUMBER(S)
<[To be completed nationally]>
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription. Thyroid therapeutic
15. INSTRUCTIONS ON USE
Not applicable.
16. INFORMATION IN BRAILLE
<[Invented name]> 88 microgram
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC: SN: NN:
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
1. NAME OF THE MEDICINAL PRODUCT
<[Invented name]> 88 µg tablets
Active substance: levothyroxine sodium
2. NAME OF THE MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
For calendar packs additionally:
Mo Tue We Thu Fr Sa Su
Mo Tue We Thu Fr Sa Su
PACKAGE LEAFLET
Package leaflet: Information for the user
<[Invented name]> 88 microgram tablets
Active substance: levothyroxine sodium
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. – Keep this leaflet. You may need to read it again. – If you have any further questions, ask your doctor or pharmacist. – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. – If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet 1. What <[Invented name]> 88 µg is and what it is used for 2. What you need to know before you take <[Invented name]> 88 µg 3. How to take <[Invented name]> 88 µg 4. Possible side effects 5. How to store <[Invented name]> 88 µg 6. Contents of the pack and other information
1. What<[Invented name]> 88 µg is and what it is used for
<[Invented name]> 88 µg is a medicine that contains levothyroxine, a thyroid hormone, as its active substance. This has the same effect as the hormone produced naturally. You are receiving <[Invented name]> 88 µg to replace missing thyroid hormone or/and to relieve stress on your thyroid gland.
<[Invented name]> 88 µg is used to replace the missing hormone in all forms of hypothyroidism (underactive thyroid), to prevent the return of new goitres (thyroid enlargement) after goitre surgery in patients with normal thyroid function (depending on thyroid function after surgery), to treat harmless goitres (benign struma) in patients with normal thyroid function, as add-on therapy for hyperthyroidism (overactive thyroid) in patients receiving thyrostatic agents (antithyroid medication), after normal metabolic status has been achieved, for malignant thyroid tumours, especially after surgery to suppress new tumour growth and as a supplement when thyroid hormone is lacking,
2. What you need to know before you take <[Invented name]> 88 µg
Do not take <[Invented name]> 88 µg if you are hypersensitive (allergic) to levothyroxine sodium or any of the other ingredients of this medicine (listed in section 6), if you have any of the following disorders or any of the conditions listed: an untreated overactive thyroid, untreated adrenocortical insufficiency (poor adrenal cortex function), untreated poor pituitary gland function, if this has resulted in adrenocortical insufficiency (poor adrenal cortex function) that requires treatment, recent heart attack, acutely inflamed heart muscle (myocarditis), acute inflammation of all layers of the heart wall (pancarditis).
If you are pregnant, you must not take <[Invented name]> 88 µg at the same time as overactive thyroid medication (so-called thyrostatic agents) (see also under section “Pregnancy and breast- feeding”).
Checks for medical conditions Before the start of therapy with <[Invented name]> 88 µg, the following disorders or conditions must be ruled out or treated: coronary heart disease, chest pain with feelings of tightness (angina pectoris), high blood pressure, poor pituitary gland function and/or poor adrenal cortex function, areas in the thyroid gland that produce uncontrolled amounts of thyroid hormone (thyroid autonomy).
Warnings and precautions Take special care with <[Invented name]> 88 µg if you have already suffered a heart attack, or if you have coronary heart disease, heart failure, heart rhythm disorders (tachycardias) or chronic cardiomyopathy (non-acute inflammation of the heart muscle), or if you have had an underactive thyroid for a long time. In these cases, excessively high hormone levels in the blood must be avoided. Your thyroid levels should therefore be monitored more frequently. Talk to your doctor if milder signs of an overactive thyroid occur as a result of administering <[Invented name]> 88 µg (see section 4. “Possible side effects”). if you have an underactive thyroid caused by a disease of the pituitary gland. In this case, you may also have poor adrenal cortex function, which will firstly have to be treated by your doctor (hydrocortisone treatment). It can lead to an acute adrenal crisis without adequate treatment. if you are suspected of having areas in the thyroid gland which produce uncontrolled amounts of thyroid hormone. Before the start of treatment, this should be investigated with further thyroid function tests. if you are a woman who has gone through the menopause, and you are at increased risk of brittle bones (osteoporosis) – your thyroid function should be checked more frequently by the treating doctor. This is to avoid increased blood levels of thyroid hormone and to ensure the lowest required dose. if you have diabetes. Please note the information in section “Other medicines and <[Invented name]> 88 µg”. if you are being treated with certain anticoagulants (blood thinners such as dicumarol) or medicines which may affect the thyroid function (e.g. amiodarone, thyrosine kinase inhibitors [for the treatment of cancer], salicylates and furosemide at high doses). Please note the information in section “Other medicines and <[Invented name]> 88 µg”. in low birth weight premature neonates. Extreme caution should be taken when initiating levothyroxine, because immature adrenal function, circulatory collapse may occur (see section 4. “Possible side effects”). Blood pressure will be regularly monitored when levothyroxine treatment is started in very low birth weight preterm neonates because rapid fall in blood pressure (known as circulatory collapse) may occur. if you have a history of epilepsy as the risk of seizures is increased when levothyroxine is administered if you experience an allergic reaction (see section Possible side effects). Contact your doctor or healthcare professional immediately or go to the nearest hospital emergency room right away.
Inappropriate (off-label) use You must not take <[Invented name]> 88 µg for weight loss. If your thyroid hormone blood levels are within the normal range, taking additional thyroid hormones will not bring about weight loss. Serious or even life-threatening side effects may occur if you take additional thyroid hormones or increase the dose without special advice from your doctor, especially in combination with certain weight loss products.
Switching therapy Thyroid imbalance may occur if you need to change your medication to another levothyroxine containing product. Talk to your doctor if you have any questions about changing your medication. A close monitoring (clinical and laboratory parameters) is required during the transition period. You should tell your doctor if you get any side effects as this may indicate that your dose needs to be adjusted up or down.
Elderly More careful dose adjustment is required in the elderly (especially if they have heart problems) and medical check-ups should be more frequent.
Other medicines and <[Invented name]> 88 µg Tell your doctor or pharmacist if you are taking/using, have recently taken/used or might take/use any other medicines.
<[Invented name]> 88 µg influences the effect of the following agents and groups of medicines: Antidiabetic agents (blood sugar-lowering medications) (such as metformin, glimepiride, and glibenclamide, as well as insulin): If you have diabetes, you should have your blood sugar levels monitored regularly, especially at the start and at the end of thyroid hormone therapy. Your doctor may have to adjust the dose of your antidiabetic medication, as levothyroxine can reduce the effect of blood sugar-lowering medications. Blood-thinning medicines which prevent clotting – called anticoagulants (such as coumarin derivatives): In combined treatment with <[Invented name]> 88 µg and coumarin derivatives (e.g. dicumarol), you should have your blood clotting regularly checked. Your doctor may have to reduce the dose of your blood-thinning medicines, as levothyroxine can enhance their effect.
The effect of <[Invented name]> 88 µg is influenced by other medicines as follows: Ion exchange resins: After taking<[Invented name]> 88 µg, you should wait for 4 to 5 hours before taking agents used to lower blood fats (e.g. cholestyramine, colestipol) or remove high potassium or phosphate concentrations in the blood (calcium salts and sodium salts of polystyrene sulphonic acid, sevelamer). Otherwise, these medicines will block the absorption of levothyroxine from the intestine and thereby make it less effective. Bile acid sequestrants: Colesevelam (medicine used to lower high blood cholesterol levels) binds levothyroxine and thereby reduces the absorption of levothyroxine from the intestine.<[Invented name]> 88 µg should therefore be taken at least 4 hours before colesevelam. Aluminium-containing medicines used to bind stomach acid, medicines containing iron, calcium carbonate: Take <[Invented name]> 88 µg at least two hours before aluminium-containing medicines used to bind stomach acid (antacids, sucralfate), medicines containing iron or calcium carbonate. Otherwise, these medicines may reduce the absorption of levothyroxine from the intestine and thereby make it less effective. Propylthiouracil, glucocorticoids, beta-blockers (especially propranolol): Propylthiouracil (used for an overactive thyroid), glucocorticoids (adrenal cortex hormones, “cortisone”) and beta-blockers (used to reduce the heart rate and lower blood pressure) block the conversion of levothyroxine to liothyronine, the more active form, and may thereby make <[Invented name]> 88 µg less effective. Amiodarone, iodine-containing contrast media: Amiodarone (used to treat heart rhythm disorders) and iodine-containing contrast media (certain agents used in X-ray diagnosis) can - due to their high iodine content - trigger both overactive and underactive thyroid function. Particular caution should be exercised in the case of nodular goitres (struma), where there may be as-yet undetected areas in the thyroid gland producing uncontrolled amounts of thyroid hormone (autonomies). Amiodarone blocks the conversion of levothyroxine to
liothyronine, the more active form, and may thereby affect the effect of <[Invented name]> 88 µg. Your doctor may adjust the dose of <[Invented name]> 88 µg. Tyrosine kinase inhibitors (for the treatment of cancer): If you are using levothyroxine at the same time as tyrosine kinase inhibitors (e.g. imatinib, sunitinib, sorafenib, motesanib), your doctor should carefully observe your symptoms and monitor your thyroid function. There may be some loss in the effect of levothyroxine. Your doctor may adjust the dose of <[Invented name]> 88 µg. The following medicines may influence the effect of <[Invented name]> 88 µg: salicylates, specifically at doses greater than 2.0 g/day (fever-reducing medications and painkillers), dicumarol (an anticoagulant agent), high doses (250 mg) of furosemide (used to increase urine output), clofibrate (used to reduce high blood fat levels), Contraceptive medicines or medicines for HRT (hormone replacement therapy): If you are taking hormonal contraceptives containing oestrogen (the “Pill”) or receiving hormone replacement therapy after the menopause, there may be an increased need for levothyroxine. Sertraline; chloroquine/proguanil: Sertraline (an antidepressant) and chloroquine/proguanil (used in malaria and rheumatic disease) make levothyroxine less effective. Barbiturates, rRifampicin, carbamazepine, phenytoin, barbiturates, products containing St John’s wort: Barbiturates (used in seizures, for anaesthesia; certain sleeping pills), rRifampicin (an antibiotic), carbamazepine (used to treat seizures), and phenytoin (used to treat seizures and heart rhythm disorders), barbiturates (used in seizures, for anaesthesia; certain sleeping pills), and products containing St John’s wort (used to treat depression, anxiety, sleep disorders) can weaken the effect of levothyroxine. Protease inhibitors (used to treat HIV infections): If you are using levothyroxine at the same time as protease inhibitors (lopinavir, ritonavir), your doctor should carefully observe your symptoms and monitor your thyroid function. There may be some loss in the effect of levothyroxine when used at the same time as lopinavir/ritonavir.
<[Invented name]> 88 µg with food and drink If your diet contains soya, your doctor will monitor your blood levels of thyroid hormone more frequently. Your doctor may have to adjust the dose of <[Invented name]> 88 µg during and upon discontinuation of such a diet (unusually high doses may be required), as products containing soya may impair the absorption of levothyroxine from the intestine and thereby make it less effective.
Pregnancy, breast-feeding and fertility If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Correct treatment with thyroid hormones is particularly important during pregnancy and breast- feeding to ensure optimal health of the mother and the unborn child. It must therefore be continued consistently and under the supervision of the treating doctor. Despite its widespread use during pregnancy, there have so far been no undesirable effects on pregnancy or the health of the unborn or newborn infant for levothyroxine.
Have your thyroid function checked both during and after pregnancy. Your doctor may have to adjust the dose, as the need for thyroid hormone may increase due to increased blood levels of oestrogen (a female sex hormone) during pregnancy.
During pregnancy, you must not take <[Invented name]> 88 µg at the same time as antithyroid medications (so-called thyrostatic agents), as this will result in the need for a higher thyrostatic dosage. Thyrostatic agents (unlike levothyroxine) can enter the child’s blood circulation via the placenta and are capable of causing underactive thyroid function in the unborn child. If you suffer from an overactive
thyroid, your doctor should treat this during pregnancy only with low-dose thyrostatic agents.
If you are breast-feeding, continue taking levothyroxine as advised by your doctor. Even in high-dose levothyroxine therapy, the amount of levothyroxine passing into breast milk during lactation is very low and therefore harmless.
Hypothyroidism or hyperthyroidism are likely to have an effect on fertility. When treating patients with hypothyroidism the <[Invented name]> 88 µg dose must be adjusted based on laboratory test results because an insufficient dose may not improve the hypothyroidism and an overdose can cause hyperthyroidism.
Driving and using machines No studies have been performed to investigate whether taking <[Invented name]> 88 µg will affect your ability to drive and use machines.
<[Invented name]> 88 µg contains sodium This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’.
3. How to take <[Invented name]> 88 µg
Always take <[Invented name]> 88 µg exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
Your treating doctor will determine the daily dose you need, based on follow-up examinations.
Dosage For individual treatment, tablets are available with various levels of active substance (25– 200 micrograms of levothyroxine sodium). This means that you will only need to take one tablet daily in most cases.
To start up treatment, to increase the dose in adults and to treat children, your doctor may prescribe you tablets with a lower active substance content.
Depending on the symptoms, your doctor will be guided by the following recommendations: To treat an underactive thyroid, adults start by taking 25–50 micrograms of levothyroxine sodium daily. If instructed by the doctor, this dose can be increased by 25–50 micrograms of levothyroxine sodium at two to four-week intervals, up to a daily dose of 100–200 micrograms of levothyroxine sodium. To prevent new goitres from growing after goitre removal and to treat benign goitres, 75 –200 micrograms of levothyroxine sodium are taken daily. As add-on therapy in the treatment of an overactive thyroid with thyrostatic agents, 50–100 micrograms of levothyroxine sodium are taken daily. After thyroid surgery due to a malignant thyroid tumour, the daily dose is 150–300 micrograms of levothyroxine sodium.
In some cases, a lower dose of thyroid hormone may be sufficient.
Method of administration Take the total daily dose in the morning on an empty stomach, at least half an hour before breakfast. Swallow the tablets whole (without chewing) with plenty of liquid, preferably with a glass of water. The active substance is better absorbed on an empty stomach than before or after a meal.
Children are given the total daily dose at least half an hour before their first meal of the day. They can also have the tablet dissolved in some water (10–15 ml) and the resulting fine dispersion (to be freshly prepared for each dose) administered with some more liquid (5–10 ml).
Children In the long-term treatment of congenital and hereditary hypothyroidism (underactive thyroid), the daily dose is generally 100–150 micrograms of levothyroxine sodium per m2 of body surface area.
In newborn infants and children with congenital hypothyroidism (underactive thyroid), rapid hormone replacement is particularly important to achieve normal mental and physical development. For this form of underactive thyroid, a daily dose of 10–15 micrograms of levothyroxine sodium per kg body weight is recommended in the first 3 months of treatment. Thereafter, the treating doctor will individually adjust the dose required, based on follow-up examinations (including blood levels of thyroid hormone).
In children with acquired hypothyroidism (underactive thyroid), a dose of 12.5–50 micrograms of levothyroxine sodium per day is recommended at the start of treatment. The treating doctor will gradually increase the dose every 2 to 4 weeks until the dose required for long-term treatment is reached. In so doing, the doctor will be guided in particular by blood levels of thyroid hormone.
Elderly patients, patients with coronary heart disease, patients with an underactive thyroid In elderly patients, patients with coronary heart disease and in patients with severe or long-term hypothyroidism (underactive thyroid), particular care must be taken when starting treatment with thyroid hormones (a low starting dose, which is then slowly increased at longer intervals, with frequent monitoring of thyroid hormone).
Patients with a low body weight and patients with a large goitre Experience shows that a lower dose is sufficient even in patients with a low body weight and in patients with a large goitre.
Duration of use - In most cases, <[Invented name]> 88 µg is taken on a life-long basis for an underactive thyroid, after goitre or thyroid removal and to prevent growth of a new goitre after goitre removal. - When used as add-on therapy to treat an overactive thyroid, <[Invented name]> 88 µg is taken for the same amount of time as the thyrostatic agents (antithyroid medications). - To treat benign goitre in patients with normal thyroid function, a treatment period of 6 months up to 2 years is necessary. If treatment with <[Invented name]> 88 µg has failed to achieve the desired success within this time, your doctor will consider other therapeutic options.
If you take more <[Invented name]> 88 µg than you should The signs of overdose are described in section 4. “Possible side effects”. Please consult your doctor if such symptoms occur.
If you forget to take <[Invented name]> 88 µg If you happen to have taken too little, or if you have missed a dose, do not make up for the forgotten dose. Continue to take your tablets according to your regular schedule.
If you stop taking <[Invented name]> 88 µg For your treatment to be successful, you must take <[Invented name]> 88 µg regularly at the dosage prescribed by your doctor. You must never take it upon yourself to change, suspend or stop treatment with <[Invented name]> 88 µg too early, as your symptoms may otherwise return.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Hypersensitivity to the active substance or the other ingredients of <[Invented name]> In case of hypersensitivity to levothyroxine or any of the other ingredients of <[Invented name]>, allergic reactions of the skin and respiratory tract may occur (either immediately or within several days of drug administration), that may be life-threatening. Symptoms may include rash, itching, difficulty breathing, shortness of breath, swelling of the face, lips, throat or tongue. Contact your doctor or healthcare professional immediately or go to the nearest hospital emergency room right away.
Intolerance to the dosage strength, overdose If the dosage strength is not tolerated in individual cases, or in the case of an overdose, symptoms typical of an overactive thyroid (hyperthyroidism) may occur, especially if the dose is increased too quickly at the start of treatment.
Very common side effects (may affect more than 1 in 10 people) palpitations insomnia headache
Common side effects (may affect up to 1 in 10 people) racing heart (tachycardia) nervousness
Rare side effects (may affect up to 1 in 1,000 people) increased brain pressure (especially in children)
Other side effects frequency not known (cannot be estimated from the available data) hypersensitivity heart rhythm disorders pain with chest tightness (symptoms of angina pectoris) allergic reactions of the skin (e.g. angioedema [difficulty breathing, or swelling of the face, lips, throat or tongue], rash, urticaria) inner restlessness muscle weakness and muscle cramps brittle bones (Osteoporosis) at high doses of levothyroxine, especially in postmenopausal women, mainly when treated for a long period feeling hot menstrual disorders diarrhoea vomiting nausea weight loss trembling (tremor) excessive sweating fever circulatory collapse in low birth weight preterm neonates (see section 2. “Warnings and precautions”)
Hypersensitivity to the active substance or the other ingredients of <[Invented name]> 88 µg In case of hypersensitivity to levothyroxine or any of the other ingredients of<[Invented name]> 88 µg, allergic reactions of the skin (e.g. angioedema [difficulty breathing, or swelling of the face, lips, throat or tongue], rash, urticaria) and respiratory tract may occur.
Tell your doctor if side effects occur. They will decide whether the daily dose should be reduced or whether you should stop medication for a few days. As soon as the side effect has worn off, treatment can be started again at a cautious dosage.
Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system <[to be completed nationally]>. By reporting side effects you can help provide more information on the safety of this medicine.
5. How to store <[Invented name]> 88 µg
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after “EXP”. The expiry date refers to the last day of that month.
Do not store above 25 °C.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What <[Invented name]> 88 µg contains The active substance is levothyroxine sodium. 1 tablet contains 88 micrograms of levothyroxine sodium.
The other ingredients are: Maize starch, pregelatinised starch (maize), microcrystalline cellulose, sodium carbonate, sodium thiosulphate, colloidal anhydrous silica, hydrogenated castor oil.
What <[Invented name]> 88 µg looks like and contents of the pack <[Invented name]> 88 µg are round, white tablets, scored on one side and marked “3.5L” on both sides. The tablets can be divided into equal halves.
<[Invented name]> 88 µg is available in packs of 28 (calendar pack), 50, 84 (calendar pack), 98 (calendar pack),100 tablets and 500 tablets (10 x 50 tablets). Not all pack sizes may be marketed.
Marketing Authorisation Holder <[To be completed nationally]>
Co-distributor <[To be completed nationally]>
Manufacturer <[To be completed nationally]>
This medicinal product is authorised in the Member States of the EEA under the following names: Germany: L-Thyroxin Winthrop 88 µg Tabletten France: L-Thyroxin Henning 88 microgrammes comprimé sécable
This leaflet was last revised in <{MM/YYYY}>.
<[To be completed nationally]>