Nolvadex-D

Tamoxifen.

Nolvadex-D contains Tamoxifen Citrate Ph. Eur. 30.4 mg (equivalent to 20 mg tamoxifen).
Excipient with known effect: Lactose.
Excipients/Inactive Ingredients: Croscarmellose Sodium, Gelatin, Lactose, Macrogol 300, Magnesium Stearate, Maize Starch, Hypromellose, Titanium Dioxide.

Pharmacology: Pharmacodynamics: Nolvadex-D (tamoxifen) is a non-steroidal, triphenylethylene-based drug which displays a complex spectrum of oestrogen antagonist and oestrogen agonist-like pharmacological effects in different tissues. In breast cancer patients, at the tumour level, tamoxifen acts primarily as an antioestrogen, preventing oestrogen binding to the oestrogen receptor. In the clinical situation, it is recognised that tamoxifen leads to reductions in levels of blood total cholesterol and low density lipoproteins in postmenopausal women of the order of 10-20%. Tamoxifen does not adversely affect bone mineral density in postmenopausal women.
An uncontrolled trial was undertaken in a heterogenous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration. Among the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no bleeding for a 6-month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. 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 Precautions). There are no long-term safety data in children. In particular, the long-term effects of tamoxifen on growth, puberty and general development have not been studied.
CYP2D6 polymorphism status may be associated with variability in clinical response to tamoxifen. The poor metaboliser status may be associated with reduced response. The consequences of the findings for the treatment of CYP2D6 poor metabolisers have not been fully elucidated (see Precautions, Interactions and Pharmacokinetics as follows).
CYP2D6 genotype: Available clinical data suggest that patients who are homozygote for non-functional CYP2D6 alleles, may experience reduced effect of tamoxifen in the treatment of breast cancer.
The available studies have mainly been performed in postmenopausal women (see Precautions and Pharmacokinetics as follows).
Pharmacokinetics: After oral administration, tamoxifen is absorbed rapidly with maximum serum concentrations attained within 4-7 hours. Steady state concentrations (about 300 ng/ml) are achieved after four weeks treatment with 40 mg daily. The drug is highly protein bound to serum albumin (>99%). Metabolism is by hydroxylation, demethylation and conjugation, giving rise to several metabolites, which have a similar pharmacological profile to the parent compound and thus contribute to the therapeutic effect. Excretion occurs primarily via the faeces and an elimination half-life of approximately seven days has been calculated for the drug itself, whereas that for N-desmethyltamoxifen, the principal circulating metabolite, is 14 days.
In a clinical study where girls between 2 and 10 years with McCune Albright Syndrome (MAS) received 20 mg tamoxifen once a day for up to 12 months duration, there was an age-dependent decrease in clearance and an increase in exposure (AUC), (with values up to 50% higher in the youngest patients) compared with adults.
Tamoxifen is metabolised mainly via CYP3A4 to N-desmethyl-tamoxifen, which is further metabolised by CYP2D6 to another active metabolite endoxifen. In patients who lack the enzyme CYP2D6 endoxifen concentrations are approximately 75% lower than in patients with normal CYP2D6 activity. Administration of strong CYP2D6 inhibitors reduces endoxifen circulating levels to a similar extent.
Toxicology: Pre-clinical safety data: Tamoxifen was not mutagenic in a range of in-vitro and in-vivo mutagenicity tests. Tamoxifen was genotoxic in some in-vitro and in-vivo genotoxicity tests in rodents. 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.
Tamoxifen is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the packet leaflet text.

Nolvadex-D is indicated for the treatment of breast cancer.

Posology: Adults: The recommended daily dose of tamoxifen is normally 20 mg. No additional benefit, in terms of delayed recurrence or improved survival in patients, has been demonstrated with higher doses. Substantive evidence supporting the use of treatment with 30-40 mg per day is not available, although these doses have been used in some patients with advanced disease.
Elderly people: Similar dosing regimens of Nolvadex-D have been used in the elderly with breast cancer and in some of these patients it has been used as sole therapy.
Paediatric population: The use of Nolvadex-D is not recommended in children. The safety and efficacy of Nolvadex-D in children has not yet been established (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
Method of administration: For administration by the oral route.

On theoretical grounds, an overdosage would be expected to cause enhancement of the pharmacological side effects mentioned under Adverse Reactions. Observations in animals show that extreme overdosage (100-200 times recommended daily dose) may produce oestrogenic effects.
There have been reports in the literature that Nolvadex-D given at several times the standard dose may be associated with prolongation of the QT interval of the ECG.
There is no specific antidote to overdosage, and treatment must be symptomatic.

General contraindications: Nolvadex-D should not be used in the following: Pregnancy. Premenopausal patients must be carefully examined before treatment for all indications to exclude the possibility of pregnancy (see also Use in Pregnancy & Lactation).
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Concurrent anastrozole therapy (see Interactions).

Menstruation is suppressed in a proportion of premenopausal women receiving Nolvadex-D for the treatment of breast cancer.
An increased incidence of endometrial changes including hyperplasia, polyps, cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours), has been reported in association with Nolvadex-D treatment. The underlying mechanism is unknown but may be related to the oestrogen-like effect of Nolvadex-D.
There are several factors that influence the risk of developing endometrial cancer, with the majority of risk factors affecting oestrogen levels.
Therefore, Nolvadex-D treatment may increase the incidence of endometrial cancer. In addition, other risk factors include obesity, nulliparity, diabetes mellitus, polycystic ovary syndrome and oestrogen-only HRT. There is also the general risk for endometrial cancer with increasing age.
Any patient receiving or having previously received Nolvadex-D who report abnormal gynaecological symptoms, especially non-menstrual vaginal bleeding, or who presents with menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure should be promptly investigated.
In patients with hereditary angioedema, Nolvadex-D may induce or exacerbate symptoms of angioedema.
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.
Venous thromboembolism: A 2- 3-fold increase in the risk for VTE has been demonstrated in healthy tamoxifen-treated women (see Adverse Reactions).
In patients with breast cancer, prescribers should obtain careful histories with respect to the patient's personal and family history of VTE. If suggestive of a prothrombotic risk, patients should be screened for thrombophilic factors. Patients who test positive should be counselled regarding their thrombotic risk. The decision to use tamoxifen in these patients should be based on the overall risk to the patient. In selected patients, the use of tamoxifen with prophylactic anticoagulation may be justified (cross-reference Interactions).
The risk of VTE is further increased by severe obesity, increasing age and all other risk factors for VTE. The risks and benefits should be carefully considered for all patients before treatment with tamoxifen. In patients with breast cancer, this risk is also increased by concomitant chemotherapy (see Interactions). Long-term anticoagulant prophylaxis may be justified for some patients with breast cancer who have multiple risk factors for VTE.
Surgery and immobility: For patients with breast cancer, tamoxifen treatment should only be stopped if the risk of tamoxifen-induced thrombosis clearly outweighs the risks associated with interrupting treatment. All patients should receive appropriate thrombosis prophylactic measures and should include graduated compression stockings for the period of hospitalisation, early ambulation, if possible, and anticoagulant treatment.
If any patient presents with VTE, tamoxifen should be stopped immediately and appropriate anti-thrombosis measures initiated. In patients receiving tamoxifen for breast cancer, the decision to re-start tamoxifen should be made with respect to the overall risk for the patient. In selected patients with breast cancer, the continued use of tamoxifen with prophylactic anticoagulation may be justified.
All patients should be advised to contact their doctors immediately if they become aware of any symptoms of VTE.
In delayed microsurgical breast reconstruction Nolvadex-D 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 Pharmacology: Pharmacodynamics under Actions).
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 Pharmacology: Pharmacokinetics under Actions).
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 Interactions and Pharmacology: Pharmacokinetics under Actions).
Radiation recall has been reported very rarely in patients on Nolvadex-D who have received prior radiotherapy. The reaction is usually reversible upon temporary cessation of therapy and re-challenge may result in a milder reaction. Treatment with Nolvadex-D was continued in most cases.
Nolvadex-D contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Toxic epidermal necrolysis: 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-D 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-D 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-D, treatment with Nolvadex-D must not be restarted in this patient at any time.
Exacerbation of hereditary angioedema: In patients with hereditary angioedema, tamoxifen may induce or exacerbate symptoms of angioedema.
Effects on ability to drive and use machines: Nolavdex-D is unlikely to impair the ability of patients to drive or operate machinery. However, fatigue has been reported with the use of Nolvadex-D and caution should be observed when driving or using machinery while such symptoms persist.

Women of childbearing potential: Women should be advised not to become pregnant whilst taking Nolvadex-D 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 informed of the potential risks to the foetus, should they become pregnant whilst taking Nolvadex-D or within nine months of cessation of therapy.
Pregnancy: Nolvadex-D 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-D, 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 estradiol, ethinylestradiol, 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.
Breast-feeding: Limited data suggest that Nolvadex-D 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-D should take into account the importance of the drug to the mother.

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. (See table.)

Click on icon to see table/diagram/image

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 Nolvadex-D.
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 Nolvadex-D therapy. Cataracts have been reported commonly in association with the administration of Nolvadex-D.
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 Nolvadex-D.
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 Nolvadex-D, sometimes in association with anaemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can sometimes be severe and 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 Contraindications, Precautions and Interactions). When Nolvadex-D 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 Nolvadex-D.
Uncommonly, cases of interstitial pneumonitis have been reported.
Nolvadex-D 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 Nolvadex-D.
Depression has been reported with frequency very common in association with the use of Nolvadex-D.
Cystic ovarian swellings have rarely been observed in women receiving Nolvadex-D.
Vaginal polyps have rarely been observed in women receiving Nolvadex-D.
Cutaneous lupus erythematosus has been observed very-rarely in patients receiving Nolvadex-D.
Porphyria cutanea tarda has been observed very-rarely in patients receiving Nolvadex-D.
Fatigue has been reported very commonly in patients taking Nolvadex-D.
Radiation Recall has been observed very rarely in patients receiving Nolvadex-D.
Uncommonly incidences of endometrial cancer and rare instances of uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with Nolvadex-D 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. Healthcare professionals are asked to report any suspected adverse reactions via local reporting system.

When Nolvadex-D is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such co-administration is initiated for the treatment of breast cancer, careful monitoring of the patient is recommended.
When Nolvadex-D is used in combination with cytotoxic agents for the treatment of breast cancer, there is increased risk of thromboembolic events occurring (see also Precautions and Adverse Reactions). Because of this increase in risk of VTE, thrombosis prophylaxis should be considered for these patients for the period of concomitant chemotherapy.
The use of tamoxifen in combination with anastrozole as adjuvant therapy has not shown improved efficacy compared with tamoxifen alone.
As Nolvadex-D is metabolised by cytochrome P450 3A4, care is required when co-administering with drugs, such as rifampicin, known to induce this enzyme as tamoxifen levels may be reduced. The clinical relevance of this reduction is unknown.
Pharmacokinetic interaction with CYP2D6 inhibitors, showing a reduction in plasma level of an active tamoxifen metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen), has been reported in the literature.
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 Precautions and Pharmacology: Pharmacokinetics under Actions).

Special precautions for disposal: No specifical requirement for disposal.
Incompatibilities: Not applicable.

Do not store above 30°C. Store in original container.

Cancer Hormone Therapy

L02BA01 - tamoxifen ; Belongs to the class of anti-estrogens. Used in treatment of neoplastic diseases.

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