THERACAP131 37 MBq-5.55 GBq capsules, hard

Radioiodine thyroid therapy is indicated in adults and children for:

• Hyperthyroidism: Treatment of Graves' disease, toxic multinodular goitre or autonomous nodules.

• Treatment of papillary and follicular thyroid carcinoma including metastatic disease.

Sodium iodide (¹³¹I) therapy is often combined with surgical intervention and with antithyroid medicinal products.

Posology

This medicinal product should be administered only by authorized healthcare professionals in designated clinical settings (see section 6.6).

Posology

The activity to be administered is a matter of clinical judgement. The therapeutic effect is only achieved after several weeks. The activity of the capsule should be determined before use.

Adults

Treatment of hyperthyroidism

In case of failure or impossibility to pursue the medical treatment, radioactive iodide may be administered to treat the hyperthyroidism.

Patients should be rendered euthyroid medically whenever possible before giving radioiodine treatment for hyperthyroidism.

The activity to be administered depends on the diagnosis, the size of the gland, thyroid uptake and iodine clearance. It is usually in the range of 200-800 MBq for a patient of average weight (70 kg) but repeated treatment up to a cumulative dose of 5000 MBq may be necessary. Re-treatment after 6-12 months is indicated for persisting hyperthyroidism.

The activity to be administered may be defined by fixed dose protocols or may be calculated according to the following equation:

under the following conditions

The following target organ doses may be used:

In the case of Graves' disease, multifocal or disseminated autonomy, the above mentioned target organ doses are related to the overall volume of the thyroid gland mass, however in the case of unifocal autonomy, the target organ dose is only related to the volume of the adenoma. For recommended doses to target organs, see section 11.

Other dosimetric procedures may also be used including sodium pertechnetate (99mTc) thyroid uptake tests to determine the appropriate target organ dose (Gy).

Thyroid ablation and treatment of metastases

The activities to be administered following total or sub total thyroidectomy to ablate remaining thyroid tissue are in the range of 1850-3700 MBq. It depends on the remnant size and radioiodine uptake. For treatment for metastases, administered activity is in the range 3700-11100 MBq.

Special populations

Renal impairment

Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in patients with reduced renal function. The therapeutic use of sodium iodide (¹³¹I) in patients with significant renal impairment requires special attention (see section 4.4).

Paediatric population

The use of sodium iodide (¹³¹I) in children and adolescents has to be considered carefully, based upon clinical needs and assessing the benefit/risk ratio in this patient group.

In certain cases the activity to be administered in children and adolescents should be determined after performing an individual dosimetry (see section 4.4).

In children and adolescents, treatment of benign thyroid defects with radioactive iodide is possible in justified cases, in particular in case of relapse after the use of antithyroid medicinal products or in case of severe adverse reaction to antithyroid medicinal products (see section 4.4).

Method of administration

Theracap is for oral use. The capsule should be taken on an empty stomach. They should be swallowed whole with abundant drink to ensure clear passage into the stomach and upper small intestine.

In case of administration to children, especially to younger children, it must be ensured that the capsule can be swallowed whole without chewing. It is recommended to give the capsule with mashed food.

For patient preparation, see section 4.4.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Pregnancy and breast-feeding (see section 4.6).

• Patients with dysphagia, oesophageal stricture, oesophagal stenosis, oesophagus diverticulum, active gastritis, gastric erosions and peptic ulcer.

• Patients with suspected reduced gastrointestinal motility.

Potential for hypersensitivity or anaphylactic reactions

If hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product mustbe discontinued immediately and intravenous treatment initiated, if necessary. To enable immediate action in emergencies, the necessary medicinal products and equipment such as endotracheal tube and ventilator must be immediately available.

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit. The activity to beadministered should in every case be as low as reasonably achievable to obtain the required therapeutic effect.

There is little evidence of an increased incidence of cancer, leukaemia or mutations in patients after treatment with radioiodine for benign thyroid diseases, despite its extensive use. In the treatment of malignant thyroid diseases, in a study conducted on patients with doses of sodium iodide (131I) higher than 3700 MBq a higher incidence of bladder cancer was reported. Another study reported a slight increase in leukaemia in patients receiving very high doses. Therefore, total cumulative dosesgreater than 26000 MBq are not recommended.

Gonadal function in males

The use of the sperm bank could be considered to compensate a potential reversible damage of gonadal function in males due to the high therapeutic dose of radioiodine, in the cases of patientswith extensive disease.

Patients with renal impairment

Careful consideration of the benefit/risk balance in these patients is required since an increasedradiation exposure is possible. In these patients it may be necessary to adjust the posology.

Paediatric population

Careful consideration of the indication is required since the effective dose per MBq is higher than in adults (see section 11). When treating children and young adults, account must be taken of the greater sensitivity of child tissue and the greater life expectancy of such patients. The risks should beweighed against those of other possible treatments (see sections 4.2 and 11).

The radioiodine treatment of benign thyroid diseases of children and adolescents may be performedonly in justified cases, especially in relapse after use of antithyroid medicinal products or in case of serious adverse reactions to antithyroid medicinal products. There is no evidence of an increased incidence of cancer, leukemia or mutations in humans with respect to patients treated for benign thyroid disease with radioiodine, despite extensive use.

Persons who have received radiotherapy of the thyroid as children and adolescents, should be re-examined once a year.

Patient preparation

Patients should be encouraged to increase oral fluids and urged to void as often as possible to reducebladder radiation, especially after high activities e.g. for the treatment of thyroid carcinoma. Patientswith bladder voiding problems should be catheterised after administration of high activities of radioiodine.

To reduce colon radiation exposure, mild laxatives (but not stool softeners which do not stimulatethe bowel) may be necessary in patients having less than one bowel movement a day.

To avoid sialoadenitis that may occur after high dose radioiodine administration, the patient should be advised to take sweets or drinks containing citric acid (lemon juice, vitamin C) to stimulate salivaexcretion before therapy. Other pharmacological protection measures may be used additionally.

Iodide overload from food or medicinal treatment should be investigated before administration of iodide (see section 4.5). A low iodine diet prior to therapy is recommended to enhance uptake intofunctioning thyroid tissue.

Thyroid replacement should be stopped prior to radioiodine administration for thyroid carcinoma to ensure adequate uptake. It is recommended to stop triiodothyronine treatment for a period of 14 daysand to stop thyroxine treatment for a period of 4 weeks. They should be restarted two days after treatment.

Carbimazole and propylthiouracil should be stopped 1 week prior to treatment of hyperthyroidismand restarted several days after treatment.

Hyponatraemia: Serious manifestations of hyponatraemia have been reported after sodium iodide (¹³¹I) therapy in elderly patients who have undergone total thyroidectomy. Risk factors include olderage, female sex, use of thiazide diuretics and hyponatraemia at the start of sodium iodide (¹³¹I) therapy. Regular serum electrolytes measurements shall be considered for these patients.

The radioiodine treatment of Graves' disease should be performed under concomitant treatment ofcorticosteroids, particularly when endocrine ophthalmopathy is present.

In patients with suspected gastrointestinal disease, great care should be taken when administeringsodium iodide (¹³¹I) capsules. Concomitant use of H2- antagonists or proton pump inhibitors is advised.

After the procedure

Close contact with infants and pregnant women should be restricted for at least one week aftertherapeutic doses.

In case of vomiting, the risk of contamination has to be considered.

Patients receiving therapy of the thyroid should be re-examined at appropriate intervals.

Specific warnings

This medicinal product contains 50 mg of sodium per capsule., equivalent to 2.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

For precautions with respect to environmental hazard see section 6.6.

Many pharmacologically active substances interact with radioiodide. Various interaction mechanisms exist which can affect the protein binding, the pharmacokinetics or the dynamic effects of labelled iodide. As a consequence, it should be considered that the thyroid uptake might be reduced. Therefore, a full drug history should be taken and relevant medicinal products are required to be withheld prior to the administration of sodium iodide (¹³¹I).

For example, the treatment with the following substances should be discontinued:

* Due to the long half-life of amiodarone, iodine uptake in the thyroid tissue can be decreased for several months.

Women of childbearing potential

When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient. Women receiving sodium [¹³¹I] iodide should be advised not to become pregnant within 6-12 months of administration.

Contraception in males and females

Contraception for a period of 6 months (for patients with benign thyroid conditions) or 12 months (for patients with thyroid cancer) is recommended for both sexes after therapeutic administration of sodium iodide (¹³¹I).

Men should not father a child for a time period of 6 months after radioiodine treatment to allow the replacement of irradiated by non-irradiated spermatozoa. Sperm banking should be considered for men who have extensive disease and therefore may need high sodium iodide (¹³¹I) therapeutic doses.

Pregnancy

The use of sodium iodide (¹³¹I) is contraindicated during established or suspected pregnancy or when pregnancy has not been excluded because transplacental passage of sodium iodine (¹³¹I) can cause severe and possibly irreversible hypothyroidism in neonates (the absorbed dose to the uterus for this medicinal product is likely to be in the range 11-511 mGy, and the foetal thyroid gland avidly concentrates iodine during the second and third trimesters (see section 4.3).

If a differentiated thyroid carcinoma is diagnosed during pregnancy, sodium iodide (¹³¹I) treatment should be postponed until after the childbirth.

Breastfeeding

Before administering radiopharmaceuticals to a mother who is breast-feeding, consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breast-feeding, and what is the most appropriate choice of radiopharmaceuticals, bearing in mind the secretion of activity in breast milk.

If the administration is considered necessary, breast-feeding must be discontinued at least 8 weeks before sodium iodide (¹³¹I) administration and should not be resumed (see section 4.3).

For radioprotection reasons following therapeutic doses, it is recommended to avoid close contact between mother and infants for at least one week.

Fertility

After radioiodine therapy of thyroid carcinoma, a dose dependent impairment of fertility may occur in men and women. Depending on the activity dose, a reversible impairment of the spermatogenesis could occur in doses above 1,850 MBq. Clinical relevant effects including oligospermia and azoospermia and elevated serum FSH serum levels have been described after administration greater than 3,700 MBq.

No studies on the effect on the ability to drive or use machines have been performed.

Summary of the safety profile

The frequencies of reported adverse reactions were derived from the medical literature. The safety profile of sodium iodide (¹³¹I) differs widely according to the doses administered, while the doses to be administered are dependent on the type of treatment (i.e. treatment of benign or malignant disease). Moreover, the safety profile depends on the cumulative doses administered and the dosing intervals which are used. Therefore, the reported adverse reactions were grouped by their occurrence in treatment of benign or malignant disease.

Frequently occurring adverse reactions are: hypothyroidism, transient hyperthyroidism, salivary and lacrimal gland disorders, and radiation local effects. In cancer treatment additionally, gastro-intestinal adverse reactions and bone marrow suppression may frequently occur.

Tabulated list of adverse reactions

The following tables include reported adverse reactions sorted by system organ classes. Symptoms, which are rather secondary to a group-syndrome (e.g. sicca syndrome) are subsumed in parenthesis behind the respective syndrome.

The following table presents how the frequencies are reflected in this section:

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) and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions after treatment of benign disease

Adverse reactions after treatment of malignant disease

*especially in existing tracheal stenosis

** this effect may be seen with other similar products but has not been observed with Theracap I-131

Description of selected adverse reactions

General advice

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and mutations. In all cases it is necessary to ensure that the risks of the radiation are less than from the disease itself.

For therapeutic use, radiation dose to specific organs, which may not be the target organ of therapy, can be influenced significantly by pathophysiological changes induced by the disease process. As part of the risk-benefit assessment it is advised that the Effective Dose and likely radiation doses to individual target organ(s) be calculated prior to administration. The activity might then be adjusted according to thyroid mass, biological half-life and the “ re-cycling” factor which takes into account the physiological status of the patient (including iodine depletion) and the underlying physiology.

Thyroid and parathyroid glands disorders

Hypothyroidism may occur, depending on the dose, as a delayed result of treatment for hyperthyroidism with radioiodine.

In the treatment of malignant disease, hypothyroidism is often reported as an adverse reaction; however the treatment of malignant diseases with radioiodine generally follows thyroidectomy.

The destruction of thyroid follicles caused by the radiation exposure of sodium iodide (¹³¹I) may lead to exacerbation of an already existing hyperthyroidism within 2 – 10 days or may cause a thyrotoxic crisis. Occasionally, an immune hyperthyroidism may appear after initial normalisation (latency period is 2--10 months). After 1-3 days of administration of high dose radioiodine, the patient may experience transient inflammatory thyroiditis and tracheitis, with a possibility of severe tracheal constriction, especially where there is existing tracheal stenosis.

In rare cases, a temporary hyperthyroidism could be observed even after treatment of a functional thyroid carcinoma.

Cases of transient hypoparathyroidism have been observed after radioiodine administration which should be appropriately monitored and treated with replacement therapy.

Late consequences

Dose dependent hypothyroidism may occur as a delayed result of radioiodine treatment of hyperthyroidism. This hypothyroidism may manifest itself weeks or years after the treatment, and monitoring of thyroid function and appropriate hormone replacement therapy are required. Hypothyroidism does not generally appear until 6 - 12 weeks after radioiodine administration.

Eye disorders

Endocrine ophthalmopathy may progress or new ophthalmopathy may occur after radioiodine therapy of hyperthyroidism or Graves` disease. Radioiodine treatment of Graves' disease should be associated with corticosteroids.

Local irradiation effects

Dysfunction and paralysis of vocal cords have been reported after administration of sodium iodide (¹³¹I), however, in some cases it cannot be decided whether the dysfunction of the vocal cords was caused by radiation or by surgical treatment.

High tissue uptake of radioiodine can be associated with local pain, discomfort and local oedema, e.g. in case of radioiodine treatment of the remnant thyroid gland, a diffuse and severe soft tissue pain may occur in the head and neck region.

Radiation induced pneumonia and pulmonary fibrosis have been observed in patients with diffuse pulmonary metastases from differentiated thyroid carcinoma, due to destruction of metastatic tissue. This occurs mainly after high dose radioiodine therapy.

In the treatment of metastasing thyroid carcinomas with central nervous system (CNS) involvement, the possibility of local cerebral oedema and/or aggravation of existing cerebral oedema should also be considered.

Gastrointestinal disorders

High levels of radioactivity may also lead to gastrointestinal disturbance, usually within the first hours or days after administration. For prevention of gastrointestinal disorders, see section 4.4.

Salivary and lacrimal gland disorders

Sialoadenitis may occur, with swelling and pain in the salivary glands, partial loss of taste and dry mouth. Sialoadenitis is usually reversible spontaneously or with anti-inflammatory treatment but cases of dose-dependent persistent ageusia and dry mouth have occasionally been described. The lack of saliva may lead to infections, e.g. caries and this may result in loss of teeth. For prevention of salivary disorders, see section 4.4.

Malfunction of the salivary and/or lacrimal glands with resulting sicca syndrome may also appear with a delay of several months and up to two years after radioiodine therapy. Although sicca syndrome is a transient effect in most cases, the symptom may persist for years in some patients.

Bone marrow depression

As a late consequence, reversible bone marrow depression may develop, presenting with isolated thrombocytopenia or erythrocytopenia which may be fatal. Bone marrow depression is more likely to occur after one single administration of more than 5000 MBq, or after repeat administration in intervals below 6 months.

Secondary malignancies

After higher activities, typically those used in the treatment of thyroid malignancies, an increased incidence of leukaemia has been observed. There is evidence of an increased frequency of solid cancers induced by administration of high activities (above 7.4 GBq).

Paediatric population

The type of undesirable effects expected in children are identical to the one in adults. Based on greater radiation sensitivity of child tissues (see section 11) and the greater life expectancy frequency and severity may be different.

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:

Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/

This product must be used by authorised personnel in a hospital setting. The risk of overdose is therefore theoretical. In the event of administration of a radiation overdose, the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by frequent micturition and by forced diuresis and frequent bladder voiding. Additionally, the blockade of the thyroid gland should be recommended (e.g. with potassium perchlorate) in order to reduce the radiation exposure of the thyroid gland. To reduce the uptake of sodium iodide (¹³¹I), emetics can be given.

Pharmacotherapeutic group: Therapeutic radiopharmaceuticals, Iodine (¹³¹I) compounds, ATC code: V10XA01.

The pharmacological active substance is sodium iodide (¹³¹I) in the form of sodium iodide that is taken up by the thyroid. The physical decay takes place essentially in the thyroid gland, where sodium iodide (¹³¹I) has a long residence time, delivering a selective irradiation to this organ. In the amount used for therapeutic indications, no pharmacodynamic effects of sodium iodide (¹³¹I) are to be expected.

More than 90% of the radiation effects result from emitted β radiation which has a mean range of 0.5 mm. The β irradiation will dose dependently decrease cell function and cell division leading to cell destruction. The short range and almost absence of uptake of sodium iodide (¹³¹I) outside the thyroid lead to a negligible amount of irradiation exposure outside the thyroid gland.

Absorption

After oral administration, sodium iodide (¹³¹I) is absorbed rapidly from the upper gastrointestinal tract (90% in 60 minutes). The absorption is influenced by gastric emptying. It is increased by hyperthyroidism and decreased by hypothyroidism.

Studies on the serum activities levels showed that after a fast increase, over 10 to 20 minutes, an equilibrium is reached after about 40 minutes. After oral administration of sodium iodide (¹³¹I) solution an equilibrium is reached at the same time.

Distribution and organ uptake

The pharmacokinetics follows that of unlabelled iodide. After entering the blood stream it is distributed in the extra thyroidal compartment. From here it is predominantly taken up by the thyroid that extracts approximately 20% of the iodide in one pass or excreted renally. The iodide uptake in the thyroid reaches a maximum after 24-48 hours, 50% of the maximum peak is reached after 5 hours. The uptake is influenced by several factors: patient age, thyroid gland volume, renal clearance, plasmatic concentration of iodide and other drugs (see section 4.5). The iodide clearance by the thyroid gland is usually 5-50 mL/min. In case of iodine deficiency the clearance is increased to 100 mL/min and in case of hyperthyroidism can be up to 1,000 mL/min. In case of iodide overload the clearance can decrease to 2-5 ml/min. Iodide also accumulates in the kidneys.

Small amounts of sodium iodide (¹³¹I) are taken up by salivary glands, gastric mucosa and they would also be localised in breast milk, the placenta and choroid plexus.

The iodide fixed by the thyroid enters the known metabolic path of thyroid hormones and is incorporated in the organic substances entering in the synthesis of thyroid hormones.

Biotransformation

The iodide that has been taken up by the thyroid follows the known metabolism of the thyroid hormones and is incorporated in the organic compounds from which the thyroid hormones are synthesised.

Elimination

Urinary excretion is 37-75%, faecal excretion is about 10%, with almost negligible excretion in sweat.

Urinary excretion is characterised by the renal clearance, which constitutes about 3% of the renal flow and is relatively constant from one person to another. The clearance is lower in hypothyroidism and in impaired renal function and higher in hyperthyroidism. In euthyroidic patients with normal renal function 50-75% of the administered activity is excreted in urine within 48 hours.

Half-life

The effective half-life of radioiodine in plasma is about 12 hours in blood plasma and about 6 days in the thyroid gland. Thus after administration of sodium iodide (¹³¹I) about 40% of the activity has an effective half-life of 6 hours and the remaining 60% of 8 days.

Renal impairment

Patients with renal impairment may have a decrease in the radioiodine clearance, resulting in increased radiation exposure of sodium iodide (¹³¹I) administered. One study showed, for example, that patients with impaired renal function undergoing continuous ambulatory peritoneal dialysis (CAPD) have a clearance of radioiodine 5 times lower than patients with normal kidney function.

Because of the small quantities of administered substance compared with the normal intake of iodine with food (40-500 µ g/day), no acute toxicity is expected or observed.

There are no data available on the toxicity of repeated doses of sodium iodide nor on its effects on reproduction in animals or its mutagenic or carcinogenic potential.

Sodium thiosulphate, pentahydrate

Disodium phosphate anhydrous

Silica, colloidal anhydrous

Maize starch

Sodium hydroxide

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

The shelf life for this product is 14 days from the activity reference date stated on the label.

Store below 25° C. Do not freeze.

Store in the original package to prevent from external radiation exposure.

Storage of radiopharmaceuticals should be in accordance with national regulations on radioactive materials.

Each capsule is contained within a polycarbonate cup with a charcoal disc to absorb iodine-131. This cup is enclosed within a lead shield.

Pack sizes: 37 - 740 MBq in 37 MBq steps, 50 – 1000 MBq in 50 MBq steps, 0.925 - 5.55 GBq in 185 MBq steps and 1000 – 5500 MBq in 100 MBq steps. Each pack contains a single capsule.

Not all pack sizes may be marketed.

General warning

Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the local competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements.

Precautions to be taken before handling or administration of the medicinal product

The administration of sodium iodide (131I) for therapy is likely to result in a relatively high radiation dose to most patients and may result in significant environmental hazard and creates risks for other persons from external radiation or contamination from spill of urine, vomiting, etc. This may be of concern to the immediate family of those individuals undergoing treatment or the general public depending on the level of activity administered. Suitable precautions in accordance with national regulations should therefore be taken concerning the activity eliminated by the patients in order to avoid any contaminations.

Administration procedures should be carried out in a way to minimize risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

When opening the container personnel should be aware that free radioactivity may be registered on monitors. This activity is due to Xe-131m which is formed for 1.17 % in the decay of I-131. Though visible on monitors this does not pose a relevant risk for personnel.

The effective dose rate by inhalation of the Xe-131m formed is 0.1% of the dose rate at 1 m from a lead-shielded capsule.

Precautions and activity data

1.3% of iodine (¹³¹I) decays via xenon (^131mXe) (half-life 12 days) and a small amount of xenon (^131mXe) activity may be present in the packaging as a result of diffusion. It is therefore recommended that the transport container be opened in a ventilated enclosure and that, after removal of the capsule, the packaging materials are allowed to stand overnight before disposal to permit the release of absorbed xenon (^131mXe).

In addition, there can be limited leakage of volatile iodine-131 activity from the capsule.

The activity of a capsule at 12h00 GMT from calibration date can be calculated from the table 1.

Table 1

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