NOLVADEX D Film-coated tablet Ref.[51030] Active ingredients: Tamoxifen

Menstruation is suppressed in a proportion of premenopausal women receiving Nolvadex for the treatment of breast cancer. An increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with Nolvadex treatment. The underlying mechanism is unknown, but may be related to the oestrogen‑like effect of Nolvadex. Any patients receiving or having previously received Nolvadex, who report abnormal gynaecological symptoms, especially vaginal bleeding, should be promptly investigated.

Nonetheless, the possibility that Nolvadex may affect the development of endometrial pathology, including neoplasia, should be kept in mind when designing treatment regimens.

Investigations in different in vivo and in vitro systems have shown that tamoxifen has a genotoxic potential following hepatic activation. Gonadal tumours in mice and liver tumours in rats receiving tamoxifen have been reported in long-term studies. The clinical relevance of these findings has not been established.

A number of second primary tumours, occurring at sites other than the endometrium and the opposite breast, have been reported in clinical trials, following the treatment of breast cancer patients with tamoxifen. No causal link has been established and the clinical significance of these observations remains unclear.

In delayed microsurgical breast reconstruction Nolvadex may increase the risk of microvascular flap complications.

In an uncontrolled trial in 28 girls aged 2–10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration, mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of tamoxifen, a causal relationship has not been established(see section 5.1).

Nolvadex contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. In the literature it has been shown that CYP2D6 poor metabolisers have a lowered plasma level of endoxifen, one of the most important active metabolites of tamoxifen (see section 5.2).

Concomitant medications that inhibit CYP2D6 may lead to reduced concentrations of the active metabolite endoxifen. Therefore, potent inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided during tamoxifen treatment (see section 4.5 and 5.2).

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with Nolvadex treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Nolvadex should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or TEN with the use of Nolvadex, treatment with Nolvadex must not be restarted in this patient at any time.

In patients with hereditary angioedema, tamoxifen may induce or exacerbate symptoms of angioedema.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

When ‘Nolvadex’ is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such co-administration is initiated, careful monitoring of the patient is recommended.

When ‘Nolvadex’ is used in combination with cytotoxic agents, there is increased risk of thromboembolic events occurring (see also section 4.8).

The use of tamoxifen in combination with anastrozole as adjuvant therapy has not shown improved efficacy compared with tamoxifen alone.

The known principal pathway for tamoxifen metabolism in humans is demethylation, catalysed by CYP3A4 enzymes.

Pharmacokinetic interaction with the CYP3A4 inducing agent rifampicin, showing a reduction in tamoxifen plasma levels have been reported in the literature. The relevance of this finding is not known. Pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75% reduction in plasma levels of one of the more active forms of the drug, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants (e.g. paroxetine) in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided (see section 4.4 and 5.2).

Pregnancy

Nolvadex must not be administered during pregnancy. There have been a small number of reports of spontaneous abortions, birth defects and foetal deaths after women have taken Nolvadex, although no causal relationship has been established. Reproductive toxicology studies in rats, rabbits and monkeys have shown no teratogenic potential.

In rodent models of foetal reproductive tract development, tamoxifen was associated with changes similar to those caused by oestradiol, ethynyloestradiol, clomiphene and diethylstilboestrol (DES). Although the clinical relevance of these changes is unknown, some of them, especially vaginal adenosis, are similar to those seen in young women who were exposed to DES in utero and who have a 1 in 1000 risk of developing clear-cell carcinoma of the vagina or cervix. Only a small number of pregnant women have been exposed to tamoxifen. Such exposure has not been reported to cause subsequent vaginal adenosis or clear-cell carcinoma of the vagina or cervix in young women exposed in utero to tamoxifen.

Women should be advised not to become pregnant whilst taking Nolvadex and for nine months following the cessation of therapy and should use barrier or other non-hormonal contraceptive methods if sexually active. Premenopausal patients must be carefully examined before treatment to exclude pregnancy. Women should be appraised of the potential risks to the foetus, should they become pregnant whilst taking Nolvadex or within nine months of cessation of therapy.

Breast-feeding

Limited data suggest that Nolvadex and its active metabolites are excreted and accumulate over time in human milk, therefore the drug is not recommended during breast-feeding. The decision either to discontinue nursing or discontinue Nolvadex should take into account the importance of the drug to the mother.

Nolvadex is unlikely to impair the ability of patients to drive or use machinery. However, fatigue has been reported with the use of Nolvadex and caution should be observed when driving or using machinery while such symptoms persist.

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.

Adverse drug reactions (ADRs) can be classified as either due to the pharmacological action of the drug, e.g. hot flushes, vaginal bleeding, vaginal discharge and pruritus vulvae, or as more general ADRs e.g. nausea, fluid retention and skin rash. When such side effects are severe, it may be possible to control them by a simple reduction of dosage (within the recommended dose range) without loss of control of the disease.

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

^a 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’.
^b 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’.

Cases of optic neuropathy and optic neuritis have been reported in patients receiving tamoxifen and, in a small number of cases, blindness has occurred.

Falls in platelet count, usually only to 80,000-90,000 per cu mm but occasionally lower, have been reported in patients taking Nolvadex for breast cancer.

When Nolvadex is used in combination with cytotoxic agents, there is increased risk of thromboembolic events occurring.

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: HPRA Pharmacovigilance Website: www.hpra.ie.

Not applicable.