Thyrozol 10

Thyrozol 20.

2. Qualitative and quantitative composition
Medically active ingredient: thiamazole.

Each tablet Thyrozol 5 contains 5 mg thiamazole.

Each tablet Thyrozol 10 contains 10 mg thiamazole.

Each tablet Thyrozol 20 contains 20 mg thiamazole.

Other ingredients: lactose 1 H2O, corn starch, cellulose powder, talc, methyl-hydroxypropyl cellulose, magnesium stearate, poly (O-carboxymethyl) starch sodium salt, silicon dioxide, Macrogol 400, dimethicone 100, colorings E 171 and E 172.

3. Pharmaceutical form
Film-coated tablets.

4. Clinical particulars
4.1 Therapeutic indications

- Conservative treatment of hyperthyroidism (Graves' disease or thyroid autonomy)

- Preoperative therapy of hyperthyroidism

- Prior to radioiodine therapy of hyperthyroidism

- Intermediate therapy of hyperthyroidism after treatment with radioiodine up to the onset of the radioiodine effect

- Antithyroid maintenance therapy of hyperthyroidism where definitive therapeutic measures may not be applied

- Prophylactic treatment of latent hyperthyroidism, autonomy of the thyroid or in cases with a history of hyperthyroidism prior to exposure to iodine (e.g. iodine-containing X-ray contrast media)

4.2 Posology and method of administration

Depending on the degree of severity of the hyperthyroidism the initial dose is 20 - 40 mg thiamazole/day for a period of 3 - 6 weeks. After this the dose can be reduced to a maintenance dose of 20 to 10 - 5 mg thiamazole/day. From this point on concomitant therapy with thyroid hormone is recommended.

Alternative:

Monotherapy with 2.5 - 10 mg thiamazole/day.

In pregnancy:

Thiamazole should be given in as low a dose as possible, e.g. 2.5 - 10 mg thiamazole/day without concomitant therapy with thyroid hormones.

Preoperative administration:

20 - 40 mg thiamazole/day until the hyperthyroidism has been eliminated. To shorten the period of time before surgery is performed Thyrozol 5 can be given in combination with a beta-blocker and/or iodine preparation.

Radioiodine therapy:

Before radioiodine therapy: 20 - 40 mg thiamazole/day.

After radioiodine therapy: 20 - 10 to 5 mg thiamazole/day depending on the symptoms up to onset of the radioiodine effect.

Antithyroid maintenance therapy:

2.5 - 10 mg thiamazole/day with or without the addition of a low levothyroxine dose.

Prophylactic treatment in latent hyperthyroidism before exposure to iodine:

20 - 40 mg thiamazole/day in combination with levothyroxine.

Ingestion: the tablets should be swallowed whole after meals, preferably with a little liquid.

The daily dose can be divided up into 2 - 3 single doses or it can be administered in one dose. Therapy is usually given over a period of 6 months to 2 years.

In preoperative preparation Thyrozol is given up to the time of the operation.

When used in preparation for radioiodine therapy Thyrozol is given up to about 7 days before the administration of radioiodine and is continued 10 days after the therapy for a further period of 2 - 4 months as intermediate therapy up to the onset of the effect of the radioiodine therapy.

In prophylactic treatment prior to exposure to iodine the duration depends on the retention time of the iodine-containing substance in the organism.

4.3 Contraindications

Known hypersensitivity to thiamazole or thionamides. Previous bone marrow damage after carbimazole or thiamazole is an absolute contra-indication.

Earlier allergic skin reactions to thionamides constitute a relative contra-indication. Large goiters which constrict the trachea should only be treated with thiamazole for a short period (in combination with levothyroxine).

4.4 Special warnings and special precautions for use

In hepatic insufficiency plasma clearance of thiamazole is reduced. The selected dose should be as low as possible here.

4.5 Interaction with other medicaments and other forms of interaction

Iodine deficiency increases the response to thiamazole, iodine excess lowers the response. There is no information available on the influence of other drugs on the pharmacokinetics and pharmacodynamics of thiamazole.

4.6 Pregnancy and lactation

Thyrozol should be given in as low dose as possible in pregnancy without the addition of levothyroxine since only thiamazole but not levothyroxine crosses the placental barrier. There have been no indications of teratogenic effects due to thiamazole. If the dose of thiamazole is too high it may occasionally cause formation of goitre and hypothyroidism in the fetus.

Thiamazole enters breast milk and should therefore be lowdosed in the lactation period (up to 10 mg thiamazole/day).

4.7 Effects on ability to drive to to use machines

There are no indications that thiamazole interferes with driving a vehicle, operating machinery, or working without a firm hold.

4.8 Undesirable effects

Allergic skin symptoms (pruritus, exanthem, urticaria) are occasionally observed.

Drug fever, hypogeusia and agranulocytosis are rarely seen. These may become manifest even weeks to months after commencement of therapy and may make discontinuation of treatment necessary. The following have also been reported in isolated cases: arthritis, cholestatic jaundice or toxic hepatitis, generalized lymphadenopathy, acute swelling of the salivary glands, thrombopenia, pancytopenia, neuritis and polyneuropathies as well as drug-induced lupus erythematosus.

Before commencement of treatment patients should be advised of the symptoms of agranulocytosis (stomatitis, pharyngitis, fever). In the event of their occurrence the treatment must be stopped immediately and blood count must be made.

Overdosage may precipitate subclinical or clinical hypothyroidism and goitre growth due to TSH increase. Consequently the thiamazole dose should be reduced after the patient becomes euthyroid. Levothyroxine can then be given additionally. Goitre growth during thiamazole therapy where TSH is suppressed is a consequence of the basic disease and cannot be prevented by additional treatment with levothyroxine.

The occurrence of or a deterioration in an endocrine ophthalmopathy is largely independent of the course taken by the thyroid disease and is not to be regarded as a side effect of thiamazole therapy correctly carried out.

In rare cases late hypothyroidism can occur after antithyroid therapy. It is to be regarded as a consequence of inflammatory and destructive processes in the parenchyma of the thyroid occurring alongside the basic disease.

4.9 Overdose

Overdosage causes goitre growth and hypothyroidism. It necessitates an immediate reduction of the thiamazole dose and additional substitution with levothyroxine.

5. Pharmacological properties
5.1.- Pharmacodynamic properties

Thiamazole interferes dose-dependently with the incorporation of iodine into tyrosine and with the new synthesis of thyroid hormones. This allows symptomatic therapy of hyperthyroidism regardless of its cause. The release of previously synthesized thyroid hormones from the thyroid is not affected.

5.2. Pharmacokinetic properties

Thiamazole is almost completely absorbed after oral administration. Maximum serum concentrations are reached within 0.4 - 1.2 hours. Pharmacokinetics of thiamazole can be described by a one-compartment model with a half-life of approx. 3 hours. The half-life is prolonged in case of hepatic insufficiency. Thiamazole is accumulated in the thyroid where it is metabolized slowly. This leads to a duration of action of almost 24 hours for the single dose. The thiamazole levels in serum do therefore not reflect its therapeutic effectiveness. The pharmacokinetics of thiamazole is not measurably influenced by disturbances in thyroid function. Thiamazole is eliminated via the kidneys and the bile; only 7 - 12 % are excreted in unchanged form, the remainder in the form of metabolites.

Thiamazole is rapidly and completely absorbed and undergoes practically no protein binding. The maximum serum concentrations are reached after 0.4 - 1.2 hours.

5.3. Preclinical safety data

Acute toxicity

In mice the LD50 after oral administration is about 800 mg/kg of bodyweight, in rats the LD50 after oral administration is 1250 mg/kg of bodyweight.

Chronic toxicity

See point 4.8. undesirable effects.-

Mutagenicity

No information is available on mutagenicity. So far no indications of any kind have become known suggesting damage to the progeny due to damages in the genous caused by thiamazole.

Cancerogenicity

No long-term animal studies on carcinogenicity have been carried out with thiamazole.

6. Pharmaceutical particulars
6.1. List of excipients

Excipients: lactose 1 H2O, corn starch, cellulose powder, talc, methyl-hydroxypropyl cellulose, magnesium stearate, poly (O-carboxymethyl) starch sodium salt, silicon dioxide, Macrogol 400, dimethicone 100, colorings E 171 and E 172.

6.2. Incompatibilities

Unknown.

6.3. Shelf life

3 years.

6.4. Special precautions for storage

Store this product in a dry place below 25 C.

7. Marketing authorization holder
Merck KGaA

D - 64271 Darmstadt

8. Marketing authorization number
Varies from country to country

9. Date of first authorization/renewal of authorization
Varies from country to country

10. Date of revision of the text
May 1996