Adverse reactions : תופעות לוואי

4.8 Undesirable Effects
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
System organ class           Adverse reaction                        Frequency Immune system disorders      Hypersensitivity including              Not known anaphylactoid reaction
Endocrine disorders          Permanent hypothyroidism,               Very common hypothyroidism

Transient hyperthyroidism               Common

Thyreotoxic crisis, thyroiditis,        Not known hypoparathyroidism (blood calcium decreased, tetany)

Eye disorders                Endocrine ophthalmopathy (in            Very common Graves’ disease)


Sicca syndrome                          Not known
Respiratory, thoracic and mediastinal              Vocal cord paralysis                    Very rare disorders
Gastrointestinal disorders   Sialoadenitis                           Common Skin and subcutaneous        Iodide induced acne                     Not known tissue disorders
Congenital, familial         Congenital hypothyroidism               Not known and genetic disorders
General disorders            Local swelling                          Not known and administration site conditions

Adverse reactions after treatment of malignant disease
System organ class           Adverse reaction                        Frequency Neoplasms benign,            Leukaemia                               Uncommon malignant and unspecified
(including cysts and polyps)                      Solid cancers, bladder cancer, colon    Not known cancer, gastric cancer, breast cancer
Blood and the lymphatic      Erythrocytopenia, bone marrow failure   Very common system disorders
Leukopenia, thrombocytopenia,           Common


Not known
Aplastic anemia, permanent or severe bone marrow suppression
Immune system disorders      Hypersensitivity including anaphylactoid    Not known reaction

Endocrine disorders          Thyreotoxic crisis, transient               Rare hyperthyroidism

Thyroiditis (transient leukocytosis),       Not known hypoparathyroidism (blood calcium decreased, tetany), hypothyroidism,
hyperparathyroidism

Nervous system disorders     Parosmia, anosmia                           Very common 
Brain oedema                                Not known
Eye disorders                Sicca syndrome (conjunctivitis, dry         Very common eyes, nasal dryness)

Nasolacrimal duct obstruction               Common
(lacrimation increased)

Respiratory, thoracic and    Dyspnoea                                    Common mediastinal disorders
Throat constriction*, Pulmonary fibrosis,   Not known respiratory distress, obstructive airways disorder, pneumonia, tracheitis, vocal cord dysfunction (vocal cord paralysis,
dysphonia, hoarseness), oropharyngeal pain, stridor

Gastrointestinal disorders   Sialoadenitis (dry mouth, salivary gland    Very common pain, salivary gland enlargement,
dental caries, tooth loss), radiation sickness syndrome, nausea, ageusia,
anosmia, dysgeusia, decreased appetite

Vomiting                                    Common

Gastritis, dysphagia                        Not known
Hepatobiliary disorders      Hepatic function abnormal                   Frequency not known**
Renal and urinary            Radiation cystitis                          Not known disorders
Reproductive system and        Ovarian failure, menstrual disorder          Very common breast disorders

Azoospermia, oligospermia, decreased         Not known fertility male

Congenital, familial and       Congenital hypothyroidism                     Not known genetic disorders
General disorders and          Flu-like illness, headache, fatigue, neck     Very common administration site            pain conditions
Local swelling                            Common
*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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com