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LEVOTHYROXINE Levothyroxine Tablets 50 micrograms and 100 micrograms
New Zealand Data Sheet
1 PRODUCT NAME
LEVOTHYROXINE 50 microgram and 100 microgram tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Levothyroxine sodium (anhydrous) 50 microgram and 100 microgram. Each tablet contains 50 micrograms (0.05 mg) or 100 micrograms (0.1 mg) anhydrous levothyroxine sodium, which is the monosodium salt of the levorotary isomer of thyroxine. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Levothyroxine 50 microgram (0.05 mg) tablets are white, uncoated, biconvex tablets, engraved on one face with โLTโ and โ50โ on the other. Levothyroxine 100 microgram (0.1 mg) tablets are white, uncoated, biconvex tablets, engraved on one face with โLTโ and โ100โ on the other. The tablets must be swallowed whole. Do not halve the tablets. Dose equivalence when the tablet is divided has not been established.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications Levothyroxine is indicated for the treatment of hypothyroidism. This product should only be prescribed to patients already taking this product who are known to be intolerant to all other levothyroxine containing products. This product may also be prescribed to patients already taking this product who are not known to be intolerant to all other levothyroxine containing products, but for whom changing to another levothyroxine containing product is not clinically appropriate.
LEVOTHYROXINE Levothyroxine Tablets 50 micrograms and 100 micrograms 4.2 Dose and method of administration Thyroxine has a narrow therapeutic index. Appropriate thyroxine dosage is based upon clinical assessment and laboratory monitoring of thyroid function tests. During the initial titration period, careful dosage titration and monitoring is necessary to avoid the consequences of under- or over-treatment. The symptoms of excessive thyroxine dosage are the same as many features of endogenous thyrotoxicosis. A pre-therapy ECG is valuable, as changes induced by hypothyroidism may be confused with ECG evidence of ischaemia. If the increase in metabolism is too rapid (causing diarrhoea, nervousness, rapid pulse, insomnia, tremors and sometimes anginal pain where there is latent myocardial ischaemia), dosage must be reduced or withheld for a day or two, then restarted at a lower level. In younger patients, and in the absence of heart disease, a serum levothyroxine (T4) level of about 70 to 160 nanomols per litre, or a serum thyrotrophin level of less than 5 milliunits per litre, should be aimed at. In those aged over 50, and/or in the presence of heart disease, clinical response is probably a more acceptable criterion of dosage than serum levels. In patients whose medications include levothyroxine and known interfering agents, administration should be separated by at least 4 hours (see Section 4.5 Interactions with other medicines and other forms of interactions). Dose Adults Initially 50 to 100 micrograms daily and adjust at 4 to 6 week intervals by 50 micrograms until normal metabolism is steadily maintained. This may require doses of 100 to 200 micrograms daily. Patients over 50 years, elderly, or with diabetes or cardiac symptoms With patients aged over 50 years, it is not advisable to exceed 50 micrograms a day initially. Where there is cardiac disease 25 micrograms, given as 50 micrograms on alternate days, is more suitable. In this condition the daily dosage may be slowly increased by 25 micrograms increments (given as 50 micrograms on alternate days) at intervals of perhaps four weeks. This dosing regimen is illustrated in Table 1 below. Table 1 โ Recommended dosage regimen for levothyroxine tablets DAILY DOSE DOSING REGIMEN 25 micrograms One 50 microgram tablet on alternate days 50 micrograms One 50 microgram tablet daily 75 micrograms One 50 microgram tablet daily and one 50 microgram tablet on alternate days 100 micrograms One 100 microgram tablet daily 125 micrograms One 100 microgram tablet daily and one 50 microgram tablet on alternate days
LEVOTHYROXINE Levothyroxine Tablets 50 micrograms and 100 micrograms Diabetes Special care is needed in patients with diabetes mellitus or insipidus. Levothyroxine raises blood sugar levels and this may upset the stability of patients receiving antidiabetic agents. Patients should be monitored carefully to ensure the correct dose is prescribed. Potential for bone loss Subclinical hyperthyroidism may be associated with bone loss. In women, long-term levothyroxine sodium therapy has been associated with increased bone resorption, thereby decreasing bone mineral density, especially in post-menopausal women on greater than replacement doses or in women who are receiving suppressive doses of levothyroxine sodium. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorus, elevations in bone alkaline phosphate and suppressed serum parathyroid hormone levels. To minimise the risk of osteoporosis, dosage of levothyroxine should be titrated to the lowest possible effective level. Elderly Special care is needed in the elderly. Paediatric population Parents of children receiving levothyroxine should be advised that partial loss of hair may occur during the first few months of therapy, but this effect is usually transient and subsequent regrowth usually occurs. Thyroxine should not be used for the treatment of obesity or weight loss In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life- threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for anorectic effects. Malabsorption syndromes Thyroxine absorption is decreased in patients with malabsorption syndromes. It is advised to treat the malabsorption condition to ensure effective thyroxine treatment with regular thyroxine dose. Myxoedema Patients with myxoedema have an increased sensitivity for thyroid hormones; in these patients the starting dose should be low with slow dosing increments. Pregnancy During pregnancy, serum thyroxine levels may decrease with a concomitant increase in serum TSH level to values outside the normal range. Patients taking levothyroxine should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of levothyroxine. Since postpartum TSH serum levels are similar to preconception values, levothyroxine dosage can be reduced to the pre-pregnancy dose.
LEVOTHYROXINE Levothyroxine Tablets 50 micrograms and 100 micrograms 4.5 Interaction with other medicines and other forms of interaction Anticoagulants Levothyroxine increases the effect of anticoagulants and it may be necessary to reduce the dose of anticoagulant if excessive hypoprothrombinaemia and bleeding are to be avoided. Phenytoin Phenytoin levels may be increased by levothyroxine. Enzyme inducers Anticonvulsants such as carbamazepine and phenytoin enhance the metabolism of thyroid hormones and may displace them from plasma proteins. Initiation or discontinuation of anticonvulsant therapy may alter levothyroxine sodium dose requirements. Enzyme inducers like rifampicin and barbiturates increase the metabolism and excretion of thyroxine, resulting in increased thyroxine requirements. Propylthiouracil, glucocorticoids, amiodarone and iodine containing contrast media Medicines that (partially) inhibit the peripheral transformation of T4 or T3 โ like propranolol, amiodarone, lithium, iodine, oral contrast agents, propylthiouracil and glucocorticoids โ lower the T3 level and therefore also the therapeutic effect. Cardiac glycosides If co-administered with cardiac glycosides, adjustment of dosage of cardiac glycoside may be necessary. Sympathomimetic agents The effects of sympathomimetic agents are also enhanced. Tricyclic antidepressants Levothyroxine increases receptor sensitivity to catecholamines thus accelerating the response to tricyclic antidepressants. Cholestyramine Cholestyramine, calcium-, aluminium-, magnesium-, iron supplements, polystyrene sulfonates, sucralfate, lanthanum, bile acid sequestrants (e.g. colestipol), anion/cation exchange resins (e.g. kayexalate, sevelamer), and proton pump inhibitors concurrently reduces the gastrointestinal absorption of levothyroxine. Separate the dosages of thyroxine and the above-mentioned medicines as much as possible to avoid interaction in the stomach or the small bowel. Soy supplements Soy-containing compounds and high-fibre diets can decrease the intestinal absorption of thyroxine. Therefore, a dosage adjustment of thyroxine may be necessary, in particular at the beginning or after termination of nutrition with soy supplements. Weight loss drugs Orlistat may decrease levothyroxine absorption which may result in
LEVOTHYROXINE Levothyroxine Tablets 50 micrograms and 100 micrograms should be monitored in patients treated with levothyroxine at least the first month after starting and/or ending ritonavir treatment. Ciprofloxacin There are limited case reports that oral ciprofloxacin may decrease the absorption of levothyroxine. An interval of six hours between the administration of the two medications is recommended and monitoring to changes in thyroid function should be carried out. Thyroid function tests A number of drugs may affect thyroid function tests and this should be borne in mind when monitoring a patient on levothyroxine sodium therapy. 4.6 Pregnancy and lactation Pregnancy Levothyroxine has been taken by a large number of pregnant women and women of childbearing age without any form of definite disturbances in the reproductive process having been observed so far. Thyroid hypo- or hyperactivity in the mother may, however, unfavourably influence the foetal outcome or well-being. Breastfeeding Levothyroxine is excreted in breast milk in low concentrations and this may be sufficient to interfere with neonatal screening for hypothyroidism. Fertility No information held by the sponsor. 4.7 Effects on ability to drive and use machines Levothyroxine is not expected to interfere with the ability to drive or operate machinery based on the pharmacokinetic and pharmacodynamic properties. 4.8 Undesirable effects The following effects are indicative of excessive dosage and usually disappear on reduction of dosage or withdrawal of treatment for a few days. Immune system disorders Hypersensitivity reactions such as skin rash, pruritus and anaphylactic reactions have been reported. Metabolism and nutrition disorders Increased appetite, excessive loss of weight. Gastrointestinal disorders Abdominal cramps, nausea, vomiting, diarrhoea.
LEVOTHYROXINE Levothyroxine Tablets 50 micrograms and 100 micrograms Nervous system disorders Headache, tremors, seizure. Rare cases of pseudotumour cerebri (benign intracranial hypertension) have been reported especially in children. Psychiatric disorders Anxiety, emotional lability, nervousness, excitability, insomnia, restlessness, psychotic depression. Cardiac disorders Anginal pain, cardiac arrhythmias, palpitation, tachycardia, increased blood pressure, heart failure, myocardial infarction. Endocrine disorders Hyperthyroidism Respiratory, thoracic and mediastinal disorders Dysponea Musculoskeletal, connective tissue and bone disorders Cramps in skeletal muscle, muscular weakness. Excessive dose may result in craniosynostosis in infants and premature closure of epiphyses in children with compromised adult height. Skin and subcutaneous tissue disorders Sweating, hair loss. Vascular disorders Flushing. Investigations Decreased bone mineral density. Reproductive system and breast disorders Menstrual irregularity, impaired fertility. General disorders and administration site conditions Fatigue, heat intolerance, fever. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/ 4.9 Overdose Symptoms In addition to exaggeration of side effects the following symptoms may be seen:
LEVOTHYROXINE Levothyroxine Tablets 50 micrograms and 100 micrograms precise signals controlling the conversion of T4 to T3 within the cell are not known. The thyroid hormones are required for normal growth and development, particularly of the nervous system. They increase the resting or basal metabolic rate of the whole organism and have stimulatory effects on the heart, skeletal muscle, liver and kidney. Thyroid hormones enhance lipolysis and the utilization of carbohydrate. 100 microgram levothyroxine is equivalent in activity to 20 to 30 microgram liothyronine/triiodothyronine or 60 mg Thyroid BP and/or local pharmacopoeia specification. This medicine has been given a provisional consent under Section 23 of the Act. This means that further evidence on this medicine is awaited or that there are specific conditions of use. Provisional consent is valid until 11 November 202 2. 5.2 Pharmacokinetic properties Absorption Following oral administration the absorption of levothyroxine is incomplete and variable, especially when taken with food. The amount absorbed increases during fasting conditions. Levothyroxine is nearly totally bound to serum protein. Metabolism The main pathway for the metabolism of levothyroxine (T4) is its conversion, by deiodination, to the active metabolite triiodothyronine (T3). Further deiodination of T and T3 leads to production of inactive products. Elimination Levothyroxine is eliminated slowly from the body with a half-life of approximately 7 days in a normal person. This may be reduced in hyperthyroid states or increased in hypothyroid patients. Renal or hepatic diseases do not appear to have any significant effect on the disposition of levothyroxine. In man, approximately 20 โ 40% of levothyroxine is eliminated in the faeces and approximately 30 โ 55% of a dose of levothyroxine is excreted in the urine. 5.3 Preclinical safety data No further data of relevance.
LEVOTHYROXINE Levothyroxine Tablets 50 micrograms and 100 micrograms
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients Sodium citrate Maize starch Lactose Acacia powdered Magnesium stearate Purified water 6.2 Incompatibilities None known. 6.3 Shelf life 24 months for Levothyroxine 100 microgram tablets 18 months for Levothyroxine 50 microgram tablets 6.4 Special precautions for storage Store below 25ยฐC. Protect from light. 6.5 Nature and contents of container 50 microgram tablets in blister packaging with PVC/PVdC film (heat treated foil/heat seal lacquer) containing 28 tablets per pack. 100 microgram tablets in blister packaging with PVC/PVdC film (heat treated foil/heat seal lacquer) containing 28 tablets per pack. 6.6 Special precautions for disposal and other handling No special requirements
7 MEDICINE SCHEDULE
Prescription Medicine
