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1. Nolvadex D
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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nolvadex D

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Tamoxifen Citrate Ph.Eur. 30.4 mg (equivalent to 20 mg tamoxifen)

3    PHARMACEUTICAL FORM

Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

'Nolvadex' is indicated for:

1.    The treatment of breast cancer.

2.    The treatment of anovulatory infertility.

4.2    Posology and method of administration

Route of administration: Oral

1.    Breast Cancer Adults

The recommended daily dose of tamoxifen is normally 20mg. 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 30-40mg per day is not available, although these doses have been used in some patients with advanced disease.

Elderly patients

Similar dosing regimens of Nolvadex have been used in elderly patients with breast cancer and in some of these patients it has been used as sole therapy.

2.    Anovulatory Infertility

Before commencing any course of treatment, whether initial or subsequent, the possibility of pregnancy must be excluded. In women who are menstruating regularly, but with anovular cycles, the initial course of treatment consists of 20mg given daily on the second, third, fourth and fifth days of the menstrual cycle. If unsatisfactory basal temperature records or poor pre-ovulatory cervical mucus indicate that this initial course of treatment has been unsuccessful, further courses may be given during subsequent menstrual periods, increasing the dosage to 40mg and then to 80mg daily.

In women who are not menstruating regularly, the initial course may begin on any day. If no signs of ovulation are demonstrable, then a subsequent course of treatment may start 45 days later, with dosage increased as above. If a patient responds with menstruation, then the next course of treatment is commenced on the second day of the cycle.

Use in children

The use of Nolvadex is not recommended in children, as safety and efficacy have not been established (see sections 5.1 and 5.2).

4.3 Contraindications

Nolvadex must not be given during pregnancy. Premenopausal patients must be carefully examined before treatment for breast cancer or infertility to exclude the possibility of pregnancy (see also section 4.6).

Nolvadex should not be given to patients who have experienced hypersensitivity to the product or any of its ingredients.

Concurrent anastrozole therapy (see section 4.5).

Treatment for infertility: Patients with a personal or family history of confirmed idiopathic venous thromboembolic events or a known genetic defect.

4.4 Special warnings and precautions for use

Menstruation is suppressed in a proportion of premenopausal women receiving Nolvadex 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 treatment. The underlying mechanism is unknown but may be related to the oestrogen-like effect of Nolvadex. Any patient receiving or having previously received Nolvadex who report abnormal gynaecological symptoms, especially vaginal bleeding, or who presents with menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure should be promptly investigated.

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 section 4.8).

•    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 anti coagulation may be justified (cross-reference section 4.5).

•    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 section 4.5). 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 being treated for infertility, tamoxifen should be stopped at least 6 weeks before surgery or long-term immobility (when possible) and re-started only when the patient is fully mobile. 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 being treated for infertility, tamoxifen should not be re-started unless there is a compelling alternative explanation for their thrombotic event. 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 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 20mg 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).

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).

4.5 Interaction with other medicinal products and other forms of interaction

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

When Nolvadex is used in combination with cytotoxic agents for the treatment of breast cancer, there is increased risk of thromboembolic events occurring. (See also sections 4.4 and 4.8). 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 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 section 4.4 and 5.2).

4.6 Fertility, pregnancy and lactation

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 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.

Women should be advised not to become pregnant whilst taking 'Nolvadex' and should use barrier or other non-hormonal contraceptive methods if

sexually active. Pre-menopausal 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' or within two months of cessation of therapy.

Lactation

It is not known if 'Nolvadex' is excreted in human milk and therefore the drug is not recommended during lactation. The decision either to discontinue nursing or discontinue 'Nolvadex' should take into account the importance of the drug to the mother.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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) seen with Nolvadex

Frequency	System Organ Class (SOC)	ADR
Very common	Gastrointestinal disorders	•	Nausea
(>10%)	Metabolism and nutrition	•	Fluid retention
	Reproductive system and breast	•	Vaginal bleeding
		•	Vaginal discharge
	Skin and subcutaneous tissue	•	Skin Rash
	Vascular	•	Hot flushes
	General disorders and administration site conditions	•	Fatigue
Common	Blood and lymphatic system	•	Anaemia
(>1% and <10%)	Eye disorders	•	Cataracts
		•	Retinopathy
	Immune system disorders	•	Hypersensitivity reactions
	Investigations	•	Elevated triglycerides

<0.1%)

	Eye disorders	•    Corneal changes •    Optic neuropathya
	Neoplasms benign, malignant and	• Uterine Sarcoma (mostly
	unspecified (incl cysts and polyps)	malignant mixed Mullerian tumours)a • Tumour Flarea
	Nervous system	• Optic neuritis
	Hepatobiliary disorders	•    Hepatitis •    Cholestasisa •    Hepatic failurea •    Hepatocellular injurya •    Hepatic necrosisa
	Skin and subcutaneous tissue	•    Angioedema •    Steven-Johnsons syndromea •    Cutaneous vasculitisa •    Bullous pemphigoida •    Erythema multiformea
	Reproductive system and breast	• Endometriosisa
	disorders	•    Cystic ovarian swellinga •    Vaginal polyps
Very Rare	Skin and subcutaneous tissue	• Cutaneous lupus
(<0.01%)		erythematosusb
	Congenital, familial and genetic disorders	• Porphyria cutanea tardab

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’.

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, cutaneous vasculitis, and bullous pemphigoid) and commonly hypersensitivity reactions including angioedema have been reported.

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 therapy. Cataracts have been reported commonly in association with the administration of Nolvadex.

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.

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, 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 Nolvadex 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.

Uncommonly, cases of interstitial pneumonitis have been reported.

Nolvadex 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.

Cystic ovarian swellings have rarely been observed in women receiving Nolvadex.

Vaginal polyps have rarely been observed in women receiving Nolvadex.

Cutaneous lupus erythematosus has been observed very-rarely in patients receiving Nolvadex.

Porphyria cutanea tarda has been observed very-rarely in patients receiving Nolvadex.

Fatigue has been reported very commonly in patients taking Nolvadex.

Uncommonly incidences of endometrial cancer and rare instances of uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with Nolvadex treatment.

4.9 Overdose

On theoretical grounds, an overdosage would be expected to cause enhancement of the pharmacological side effects mentioned above. 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’ 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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Nolvadex (tamoxifen) is a non-steroidal, triphenylethylene-based drug which displays a complex spectrum of oestrogen antagonist and oestrogen agonistlike 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.

An uncontrolled trial was undertaken in a heterogenous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20mg 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 section 4.4). 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 sections 4.4, 4.5 and 5.2).

CYP2D6 genotype

Available clinical data suggest that patients, who are homozygote for nonfunctional 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 sections 4.4 and 5.2).

5.2 Pharmacokinetic properties

After oral administration, tamoxifen is absorbed rapidly with maximum serum concentrations attained within 4-7 hours. Steady state concentrations (about 300ng/ml) are achieved after four weeks treatment with 40mg 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 20mg 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.

5.3 Preclinical 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 Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Croscarmellose Sodium USNF Gelatin BP

Lactose Monohydrate Ph. Eur Macrogol 300 B.P.

Magnesium Stearate Ph. Eur Maize Starch Ph. Eur Hydroxypropylmethylcellulose USP Titanium Dioxide Ph. Eur (E171)

6.2    Incompatibilities

None known

6.3    Shelf life

5 years

6.4    Special precautions for storage

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

6.5    Nature and contents of container

Aluminium blister pack containing 30 or 250 tablets. HDPE bottles containing 30 or 250 tablets.

6.6    Special precautions for disposal

Use as directed by the prescriber.

7    MARKETING AUTHORISATION HOLDER

AstraZeneca UK Limited,

600 Capability Green,

Luton,

LU1 3LU,

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17901/0034

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

11/06/2000

DATE OF REVISION OF THE TEXT

04/09/2013