Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Tabulated list of adverse reactions
The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: 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).

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women patients with operable breast cancer treated for 5 years and unless specified, no account was taken of the frequency within the comparative treatment group or whether the investigator considered it to be related to study medication.

Table 1    Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency.
SOC                               Frequency       Adverse Drug Reaction 

Neoplasms benign, malignant       Common          Uterine fibroids and unspecified (incl cysts and polyps)                           Uncommon        Endometrial cancer
Rare            Uterine Sarcoma (mostly malignant mixed Mullerian tumours)1
Tumour Flare1
Blood and lymphatic system        Common          Anaemia disorders                         Uncommon        Thrombocytopenia
Leukopenia

Rare            Neutropenia
Agranulocytosis

Immune system disorders           Common          Hypersensitivity reactions Metabolism and nutrition          Very common Fluid retention disorders                         Uncommon        Hypercalcaemia (in patients with bony metastases) 
Nervous system disorders          Common          Ischaemic cerebrovascular events Headache
Light headedness
Sensory disturbances (including paraesthesia and dysgeusia)
Rare          Optic neuritis
Eye disorders                  Common        Cataracts
Retinopathy
Uncommon      Visual disturbances
Rare          Corneal changes
Optic neuropathy1

Vascular disorders             Very Common Hot flushes
Common        Thromboembolic events (including deep vein thrombosis,
microvascular thrombosis and pulmonary embolism)

Respiratory, thoracic and      Uncommon      Interstitial pneumonitis mediastinal disorders

Gastrointestinal disorders     Very common Nausea
Common        Vomiting
Diarrhoea
Constipation

Uncommon      Pancreatitis
Hepatobiliary disorders        Common        Changes in liver enzymes Fatty liver

Uncommon      Cirrhosis of the liver
Rare          Hepatitis
Cholestasis1
Hepatic failure1
Hepatocellular injury1
Hepatic necrosis1
Skin and subcutaneous tissue   Very common Skin Rash disorders
Common        Alopecia
Rare          Angioedema
Steven-Johnsons syndrome1
Cutaneous vasculitis1
Bullous pemphigoid1
Erythema multiforme1
Toxic epidermal necrolysis1

Very rare     Cutaneous lupus erythematosus2
Not known     Exacerbation of hereditary angioedema

Musculoskeletal and            Common        Leg cramp connective tissue disorders                  Myalgia
Reproductive system and        Very common Vaginal bleeding breast disorders
Vaginal discharge

Common           Pruritus valvae
Endometrial changes (including hyperplasia and polyps)
Rare             Endometriosis1
Cystic ovarian swelling1
Vaginal polyps

Congenital, familial and genetic Very rare          Porphyria cutanea tarda2 disorders

General disorders and              Very common Fatigue administration site conditions

Investigations                     Common           Elevated triglycerides 

Injury, poisoning and              Very rare        Radiation Recall2 procedural complications

Psychiatric Disorders              Very             Depression common

1
This adverse drug reaction was not reported in the tamoxifen arm (n= 3094) of the above study; however, it has been reported in other trials or from other sources. The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate (based on 3/X, where X represents the total sample size e.g. 3094). This is calculated as 3/3094 which equates to a frequency category of ‘rare’.
2
The event was not observed in other major clinical studies. The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate (based on 3/X, where X represents the total sample size of 13,357 patients in the major clinical studies). This is calculated as 3/13,357 which equates to a frequency category of ‘very rare’.

Side effects can be classified as either due to the pharmacological action of the drug, e.g. hot flushes, vaginal bleeding, vaginal discharge, pruritus vulvae and tumour flare, or as more general side effects, e.g. gastrointestinal intolerance, headache, light- headedness and occasionally, fluid retention and alopecia.
When side effects are severe, it may be possible to control them by a simple reduction of dosage (to not less than 20 mg/day) without loss of control of the disease. If side effects do not respond to this measure, it may be necessary to stop the treatment.
Skin rashes (including rare reports of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous vasculitis, and bullous pemphigoid) and commonly hypersensitivity reactions including angioedema have been reported.

Cases of exacerbation of angioedema have been reported in patients with hereditary angioedema receiving tamoxifen.
Uncommonly, patients with bony metastases have developed hypercalcaemia on initiation of therapy.
Cases of visual disturbances, including rare reports of corneal changes, and common 
reports of retinopathy have been described in patients receiving tamoxifen therapy.
Cataracts have been reported commonly in association with the administration of tamoxifen.
Cases of optic neuropathy and optic neuritis have been reported in patients receiving tamoxifen and, in a small number of cases, blindness has occurred.
Sensory disturbances (including paraesthesia and dysgeusia) have been reported commonly in patients receiving tamoxifen.
Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported.
Falls in platelet count, usually to 80,000 to 90,000 per cu mm but occasionally lower, have been reported in patients taking tamoxifen for breast cancer.
Leucopenia has been observed following the administration of tamoxifen, sometimes in association with anaemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can sometimes be severe, and very rarely cases of agranulocytosis have been reported.
There is evidence of ischaemic cerebrovascular events and thromboembolic events, including deep vein thrombosis, microvascular thrombosis and pulmonary embolism, occurring commonly during tamoxifen therapy (see sections 4.3, 4.4 and 4.5). When Tamoxifen Teva is used in combination with cytotoxic agents, there is an increased risk of thromboembolic events occurring.
Leg cramps and myalgia have been reported commonly in patients receiving tamoxifen.
Uncommonly, cases of interstitial pneumonitis have been reported.
Tamoxifen has been associated with changes in liver enzyme levels and with a spectrum of more severe liver abnormalities which in some cases were fatal, including fatty liver, cholestasis and hepatitis, liver failure, cirrhosis, and, hepatocellular injury (including hepatic necrosis).
Commonly, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen.

Depression has been reported with frequency very common in association with the use of tamoxifen.
Cystic ovarian swellings have rarely been observed in women receiving tamoxifen.
Vaginal polyps have rarely been observed in women receiving tamoxifen.
Cutaneous lupus erythematosus has been observed very-rarely in patients receiving tamoxifen.
Porphyria cutanea tarda has been observed very-rarely in patients receiving tamoxifen.
Fatigue has been reported very commonly in patients taking tamoxifen.
Radiation Recall has been observed very rarely in patients receiving tamoxifen.
Uncommonly incidences of endometrial cancer and rare instances of uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with tamoxifen treatment.
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