NOLVADEX

Associations requiring precautions for use

+ Vitamin K antagonists

Increased risk of thrombotic and hemorrhagic events during neoplastic diseases. Moreover, possible interaction between vitamin K antagonists and chemotherapy.

More frequent monitoring of INR.

+ Cytotoxic agents

Risk of increased thromboembolic events.

A pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75 % reduction in plasma levels of endoxifen, one of the most active forms of the drug, has been reported in the literature. A decrease in the efficacy of tamoxifen has been reported in some studies with the concomitant use of certain SSRIs - selective serotonin reuptake inhibitors - (e.g.: paroxetine). As a reduction in the effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (e.g.: paroxetine, fluoxetine, quinidine, cinacalcet, terbinafine or bupropion) should be avoided whenever possible (see sections 4.4 and 5.2).

+ Medicines that may prolong the QT interval

TAMOXIFENE SANDOZ, at the recommended dose, may prolong the QTc interval on electrocardiogram (ECG). Concomitant use of TAMOXIFENE SANDOZ with other medicines known to prolong the QT interval may further potentiate the prolongation of the QT interval. Consequently, particular attention is recommended in the case of such an association, and monitoring of ECG and electrolytes is recommended in these patients (see section 4.4).

Women of childbearing potential / Contraception in men and women

Due to the genotoxic potential of tamoxifen (see section 5.3), women of childbearing potential should use an effective method of contraception during their treatment with TAMOXIFENE SANDOZ and during the 9 months following the discontinuation of treatment.

Men are recommended to use an effective method of contraception and not to conceive a child during their treatment with TAMOXIFENE SANDOZ and during the 6 months following the discontinuation of treatment.

Breastfeeding

Breast cancer contraindicates breastfeeding.

Limited data suggest that tamoxifen and its active metabolites are excreted and accumulate over time in breast milk, therefore, this medicine is not recommended during breastfeeding. The decision to discontinue breastfeeding or to discontinue TAMOXIFENE SANDOZ should take into account the importance of the medicine for the mother.

Drivers or machine users should be drawn to the risks of visual disturbances and fatigue associated with the use of this medicine.

In all treated patients, the following may be observed:

· an increase in the frequency of endometrial abnormalities (pseudo-hyperplastic atrophies, hypertrophies, polyps, cancers) requiring rapid and thorough investigation of any patient reporting metrorrhagia (see section 4.4),

· uncommon incidences of endometrial cancers and rare cases of uterine sarcomas (mainly mixed Müllerian malignant tumors) have been reported,

· frequent ischemic cerebrovascular accidents and thromboembolic accidents, including deep thrombosis, microvascular complications at the level of the reconstruction flap in the case of delayed reconstructive microsurgery (cf: 4.4. "Special warnings and precautions for use") and pulmonary embolism. The thromboembolic risk is increased in case of association with cytotoxic agents,

· visual disturbances including frequent cataracts, rare corneal changes and/or frequent retinopathies, for which ophthalmological follow-up is recommended,

· cases of neuropathies and optic neuritis have been reported in patients receiving tamoxifen which can be complicated by mono or bilateral blindness,

· frequently: paresthesias, dysesthesias, dysgeusias and sensory peripheral neuropathies,

· hot flashes and vulvar pruritus related to the anti-estrogen effect,

· rare nauseous phenomena relieved by fractionation of the therapy,

· minor leucorrhoea,

· cutaneous manifestations: skin rashes, urticaria. Rare cases of severe cutaneous manifestations, such as erythema multiforme, bullous pemphigoid, Stevens-Johnson syndrome, cutaneous vasculitis have been described,

· frequently allergic reactions including angioedemas,

· alopecia,

· headaches,

· at the start of treatment are possible but rare, a transient aggravation of cancer symptoms (pain and/or increase in the apparent volume of the tumor),

· at the start of treatment, infrequently, patients presenting with bone metastases developed hypercalcemia,

· leucopenia sometimes associated with anaemia and/or thrombocytopenia, exceptionally severe neutropenia; rarely cases of agranulocytosis have been reported,

· changes in liver enzymes and more severe hepatic abnormalities, with some having a fatal evolution, of the type of steatosis, cholestasis, hepatitis, hepatic necrosis, cirrhosis and hepatocellular insufficiency,

· rarely pains at the level of the tumor and very rarely a water-sodium retention,

· frequent cases of hypertriglyceridemia or pancreatitis have been reported (see section 4.4),

· interstitial pneumopathies have been reported infrequently,

· frequent cases of arthralgia have been reported,

· cramps of the lower limbs and myalgias have been frequently reported,

· rarely, an increase in the volume of ovarian cysts,

· rarely vaginal polyps have been observed,

· very rarely cases of cutaneous lupus erythematosus have been observed,

· very rarely cases of late cutaneous porphyria have been observed,

· cases of fatigue have been reported very frequently,

· a resurgence of radiation reactions has been very rarely observed in patients on tamoxifen,

· cases of decreased bone density (pre-menopausal women) have been reported,

· cases of QT interval prolongation have been reported.

In non-menopausal women, certain adverse effects are more specifically reported:

· amenorrhea or cycle irregularities,

· an eventually important elevation of circulating estradiol levels, associated with ovarian cysts and/or menometrorrhagia (see section 4.4).

The adverse effects listed below are classified by frequency and by System Organ Class (SOC). The frequencies of occurrence of adverse effects are defined as follows:

Very frequent (≥ 1/10); frequent (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1 000 to < 1/100); rare (from ≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), unknown frequency (cannot be estimated on the basis of available data).

Unless otherwise indicated, frequencies have been calculated from the number of adverse events reported in a large phase III study, conducted in 9366 postmenopausal patients with operable breast cancer treated for 5 years and unless otherwise indicated, the frequency within the comparison treatment groups or the existence, according to the investigator, of a causal link with the drug under study were not taken into account.

a This adverse effect was not reported in the tamoxifen arm (n = 3094) of the above study, but it has been reported in other trials or other sources. The frequency was 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 for example 3094). It is calculated as 3/3094 which corresponds to the frequency category "rare".

b This event was not observed in other major clinical studies. The frequency was 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 major clinical studies). It is calculated as 3/13 357 which corresponds to the frequency category "very rare".

Reporting of suspected adverse effects

Reporting of suspected adverse effects after authorisation of the medicinal product is important. It allows continuous monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr .