Consumer medicine information

Nolvadex

Tamoxifen

BRAND INFORMATION

Brand name

Nolvadex, Nolvadex-D

Active ingredient

Tamoxifen

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nolvadex.

What is in this leaflet

In this leaflet, NOLVADEX means Nolvadex or Nolvadex-D tablets.

This leaflet answers some of the common questions people ask about NOLVADEX. It does not contain all the information that is known about NOLVADEX.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you taking NOLVADEX against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What NOLVADEX is for

NOLVADEX is used to either treat breast cancer or reduce the risk of breast cancer occurring if you are at increased risk of breast cancer.

If you and your healthcare professional are considering using NOLVADEX for reducing the risk of breast cancer occurring, your knowledge of treatment risks becomes more important because you don't currently have breast cancer. NOLVADEX therapy may be uncommonly associated with serious side effects such as deep vein thrombosis (DVT - blood clots in veins of your leg), pulmonary embolus (blood clots in your lungs) and uterine cancer. In some women, these events were fatal. Less serious side effects such as hot flushes, vaginal discharge, menstrual irregularities and gynaecological conditions may also occur. Whether the benefits of treatment outweigh the risks depends on your age, health history, your level of breast cancer risk and on your personal judgement. NOLVADEX therapy to reduce the risk of breast cancer may not be appropriate for all women at increased risk for breast cancer. An assessment with your healthcare professional of the potential benefits and risks prior to starting therapy for reduction in breast cancer risk is essential. You should understand that NOLVADEX reduces, but does not eliminate, the risk of breast cancer.

NOLVADEX blocks the actions of oestrogen. Oestrogen is a natural female sex hormone. In some types of breast cancer, oestrogen can help cancer cells to grow.

Your doctor will have explained why you are being treated with NOLVADEX and told you what dose to take.

Follow all directions given to you by your doctor. They may differ from the information contained in this leaflet.

Your doctor may prescribe this medicine for another use. Ask your doctor if you want more information.

NOLVADEX is not addictive.

Before you use NOLVADEX

When you must not use it

Do not use NOLVADEX if you are pregnant, trying to become pregnant or are breastfeeding. We do not know if it is safe for you to take it while you are pregnant. It may affect your baby if you take it at any time during pregnancy. Your baby may take in NOLVADEX from breast milk if you are breastfeeding.

Do not use NOLVADEX if you are allergic to tamoxifen or any of the other ingredients in NOLVADEX.

Do not use NOLVADEX for reducing the risk of breast cancer occurrence if:

  • you are taking medicines used to prevent blood clots such as warfarin
  • you have had deep vein thrombosis (DVT - blood clots in veins of your leg) or pulmonary embolus (blood clots in your lungs).

Do not give NOLVADEX to children. There is no experience of its use in children.

Do not take after the use by (expiry) date printed on the pack. It may have no effect at all, or worse, an entirely unexpected effect if you take it after the expiry date.

Do not take NOLVADEX if the packaging is torn or shows signs of tampering.

Do not use it to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Before you start to use it

You must tell your doctor if:

  1. you have any allergies to:
  • tamoxifen, the active ingredient in NOLVADEX
  • any of the other ingredients in NOLVADEX listed at the end of this leaflet
  • other anti-oestrogen medicines
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
If you have an allergic reaction, you may experience a skin rash, hay fever, difficulty breathing or feel faint.
  1. you have or have ever had any of these medical conditions:
  • a history of hereditary angioedema (as NOLVADEX may cause or worsen symptoms of hereditary angioedema).
  • any unexplained vaginal bleeding
  • problems with your blood
  • liver problems
  • deep vein thrombosis (DVT - blood clots in veins of your leg) or pulmonary embolus (blood clots in your lungs).

It may not be safe for you to take NOLVADEX if you have any of these conditions.

Taking other medicines

Tell your doctor if you are taking any other medicines, including:

  • oral contraceptives ('the pill')
  • hormone replacement therapy
  • medicines used to thin your blood e.g. warfarin
  • rifampicin
  • chemotherapy
  • any medicines that you buy at the chemist, supermarket or health food shop.

NOLVADEX should not be taken with aromatase inhibitors such as anastrozole, letrozole or exemestane.

These medicines may affect the way NOLVADEX works or may not work as well. They could also cause side effects if you take them with NOLVADEX.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

If you have not told your doctor about any of these things, tell them before you take any NOLVADEX.

Taking NOLVADEX

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

Your doctor or pharmacist will tell you how many tablets you will need to take each day.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will decide how much NOLVADEX you need to take.

The usual dose is 20 mg of NOLVADEX each day.

This is two 10 mg Nolvadex tablets taken together or one 20 mg Nolvadex-D tablet taken once a day.

Some people need to take 40 mg once a day. Your doctor will tell you if this is necessary.

Swallow your NOLVADEX whole, with a full glass of water. Do not chew or crush the tablets.

When to take it

Take NOLVADEX at about the same time each day.

It does not matter if you take NOLVADEX before, with or after food.

How long to take it

Continue taking NOLVADEX for as long as your doctor or pharmacist tells you to.

If you forget to take it

If you miss a dose, take it as soon as you remember, as long as it is 12 hours before the next dose is due.

If it is less than 12 hours to the next dose, do not take the dose you have missed.

Do not double the dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

Overdose

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital immediately if you think that you or anyone else may have taken too much NOLVADEX. Do this even if there are no signs of discomfort or poisoning.

If you take too much NOLVADEX you may experience problems with the rhythm of your heart.

While you are using it

Things you must do

Be sure to keep all your appointments with your doctor so your progress can be checked.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking NOLVADEX.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking NOLVADEX.

If you go into hospital, please let the medical staff know that you are taking NOLVADEX.

Things you must not do

Do not get pregnant while you are taking NOLVADEX and for nine months after you stop taking NOLVADEX. Ask your doctor about reliable methods of contraception.

Do not breastfeed while you are taking NOLVADEX.

Do not take NOLVADEX to treat any other complaints unless your doctor tells you to.

Do not stop taking NOLVADEX, or lower the dosage, unless you have discussed this with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how NOLVADEX affects you. Some patients may experience dizziness, fatigue or light headedness.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking NOLVADEX.

NOLVADEX helps most people with breast cancer, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor immediately if you notice any of the following:

  • unusual pain or pressure around your pelvis, in your bones or anywhere in your body
  • excessive thirst
  • swelling of the hands, ankles and feet
  • any changes in your vision
  • pain and reddening around the tumour
  • lumps anywhere in the body
  • unusual tiredness, shortness of breath and dizziness when exercising, and looking pale
  • frequent infection, fever, severe chills, sore throat or mouth ulcers
  • unexplained bruising
  • yellowing of the skin or eyes, dark coloured urine
  • disturbances of vision.

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

If you have any unusual vaginal bleeding or other gynaecological symptoms (such as pelvic pain or pressure) when you are taking NOLVADEX or anytime afterwards, tell your doctor. This is because a number of changes to the lining of the womb (endometrium) may occur, some of which may be serious and could include cancer.

NOLVADEX may decrease bone density in premenopausal women. It is not known if this increases the risk of fractures. Ask your doctor for advice about ways to maintain your bone health.

NOLVADEX may cause or worsen symptoms of hereditary angioedema.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if any of the following happen.

  • Skin rash, itching, hives or peeling skin
  • swelling of the face, lips, tongue and/or throat, difficulty in swallowing or breathing (angioedema).
  • wheezing with difficulty breathing.
  • sudden onset of weakness or paralysis of the arms or legs, sudden difficulty with speaking, walking, difficulty in holding things or difficulty in thinking, any of which may occur because the blood supply in the blood vessels of the brain is reduced. These symptoms could be signs of a stroke.

Increased risk of blood clots and ovarian cysts (in premenopausal women) have been seen with NOLVADEX.

These are serious side effects. You may need urgent medical treatment.

Serious side effects are rare.

Tell your doctor if you notice any of the following and they worry you:

  • depression
  • hot flushes
  • nausea and vomiting
  • unusual vaginal discharge
  • any change in your periods
  • itching around the vagina
  • diarrhoea or constipation
  • headache, dizziness or light headedness
  • hair thinning or hair loss
  • leg cramps

These are all mild side effects of NOLVADEX.

Rarely an increased level of triglycerides (increased levels of fats in the blood) sometimes with pancreatitis (pain or tenderness in the upper abdomen) has been seen with NOLVADEX.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Some people may get other effects while taking NOLVADEX.

After using it

Storage

Keep your NOLVADEX tablets in the blister pack until it is time to take them. If you take NOLVADEX out of the blister pack it will not keep well.

Keep it in a cool dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom or near a sink.

Keep it where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not leave it on a window sill or in the car on hot days. Heat and dampness can destroy some medicines.

Disposal

Ask your pharmacist what to do with any tablets you have left over if your doctor tells you to stop taking them, or you find that the expiry date has passed.

Product description

What NOLVADEX looks like

Nolvadex 10 mg tablets are white to off-white, round film-coated tablets marked Nolvadex 10 on one side.

Nolvadex-D 20 mg tablets are white to off-white, octagonal (eight sided) film-coated tablets marked Nolvadex-D on one side.

Ingredients

NOLVADEX contains tamoxifen as the active ingredient.

Nolvadex 10 mg tablets each contain 10 mg tamoxifen and Nolvadex-D 20 mg tablets each contain 20 mg of tamoxifen,

plus:

  • maize starch
  • lactose monohydrate
  • croscarmellose sodium
  • gelatin
  • magnesium stearate (572)
  • hypromellose (464)
  • macrogol 300
  • titanium dioxide (171)

Each pack of NOLVADEX tablets contains 30 tablets in blister strips.

NOLVADEX does not contain added sucrose, gluten, tartrazine or any other azo dyes.

Distributor

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805342

This leaflet was prepared on 27 August 2021.

Australian Registration Numbers

Nolvadex 10 mg tablets
AUST R 11233

Nolvadex-D 20 mg tablets
AUST R 11232

Doc ID-002078905 v7.0

Published by MIMS November 2021

BRAND INFORMATION

Brand name

Nolvadex, Nolvadex-D

Active ingredient

Tamoxifen

Schedule

S4

 

1 Name of Medicine

Tamoxifen citrate.

2 Qualitative and Quantitative Composition

Nolvadex tablets each contain tamoxifen citrate (15.2 mg) equivalent to 10 mg of tamoxifen.
Nolvadex-D tablets each contain tamoxifen citrate (30.4 mg) equivalent to 20 mg of tamoxifen.

Both Nolvadex and Nolvadex-D also contain an excipient with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nolvadex is presented as white to off-white, round, biconvex film coated tablets, impressed with "NOLVADEX 10" on one face, and plain on the reverse face.
Nolvadex-D is presented as white to off-white, octagonal shaped, biconvex film coated tablets, impressed with "NOLVADEX-D" on one face, and plain on the reverse face.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of breast cancer.

Nolvadex is indicated for the treatment of breast cancer.

Primary reduction of breast cancer risk.

Nolvadex is indicated for the primary reduction of breast cancer risk in women either at moderately increased risk (lifetime breast cancer risk 1.5 to 3 times the population average) or high risk (lifetime breast cancer risk greater than 3 times the population average).

4.2 Dose and Method of Administration

Adults.

Treatment of breast cancer.

The initial dose is 20 mg once daily. In advanced breast cancer, if no response is seen, dosage may be increased to 40 mg once daily.

Primary reduction of breast cancer risk.

The recommended maximum dose is 20 mg daily for 5 years. There are insufficient data to support a higher dose or longer period of use.
An assessment of the potential benefits and risks prior to starting therapy for reduction in breast cancer risk is essential. Validated algorithms are available that calculate breast cancer risk based on features such as age, family history, genetic factors, reproductive factors, and history of breast disease.
Nolvadex reduces, but does not eliminate, the risk of breast cancer. In clinical trials, Nolvadex decreased the incidence of oestrogen receptor positive tumours, but did not alter the incidence of oestrogen receptor negative tumours. The use of Nolvadex should be as part of a program including regular breast surveillance tailored to the individual woman, taking into account her risk of breast cancer.

Paediatric use.

Nolvadex is not indicated for use in children.

4.3 Contraindications

Nolvadex must not be given during pregnancy. In premenopausal women, the possibility of pregnancy must be excluded before starting tamoxifen.
Nolvadex should not be given to patients who have experienced hypersensitivity to the product or any of its ingredients.
When considered for primary reduction of breast cancer risk, Nolvadex is contraindicated in women who require concomitant coumarin type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus.

4.4 Special Warnings and Precautions for Use

General precautions.

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 incidence and pattern of this increase suggest that the underlying mechanism is related to the oestrogenic properties of Nolvadex. Any patients receiving or having previously received Nolvadex who report abnormal gynaecological symptoms, especially nonmenstrual vaginal bleeding, should be promptly investigated.
In a large randomized trial in Sweden of adjuvant Nolvadex 40 mg/day for 2-5 years, an increased incidence of uterine cancer was noted. Twenty three of 1,372 patients randomized to receive Nolvadex versus 4 of 1,357 patients randomized to the observation group developed cancer of the uterus [RR = 5.6; (1.9-16.2), p < 0.001].
One of the patients with cancer of the uterus who was randomized to receive Nolvadex never took the drug. After approximately 6.8 years of follow-up in the ongoing NSABP B-141 trial, 15 of 1,419 women randomized to receive Nolvadex 20 mg/day for 5 years developed uterine cancer, and 2 of the 1,424 women randomized to receive placebo, who subsequently had recurrent breast cancer and were treated with Nolvadex, also developed uterine cancer. Most of the uterine cancers were diagnosed at an early stage, but deaths from uterine cancer have been reported. Patients receiving Nolvadex should have routine gynaecological care and report any abnormal vaginal bleeding to their physician.
In patients with hereditary angioedema, Nolvadex may induce or exacerbate symptoms of angioedema.
In an uncontrolled trial in 28 girls aged 2-10 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. Tamoxifen is not approved for treatment of McCune Albright syndrome.
There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during Nolvadex therapy. When Nolvadex is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of Nolvadex should be carefully considered in women with a history of thromboembolic events.
In delayed microsurgical breast reconstruction Nolvadex may increase the risk of microvascular flap complications.
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.
Cases of visual disturbances, including infrequent reports of corneal changes, and common reports of retinopathy have been described in patients receiving Nolvadex therapy. Cataracts have commonly been reported in association with the administration of Nolvadex.
Nolvadex should be used with caution in patients with existing leucopenia or thrombocytopenia. 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 rarely cases of agranulocytosis have been reported. Decreases in platelet counts, usually to 50,000 to 100,000/mm3, infrequently lower, have been occasionally reported in patients taking Nolvadex for breast cancer. Periodic complete blood counts, including platelet counts, may be appropriate.
1 The NSABP (National Surgical Adjuvant Breast and Bowel Project) B-14 trial is undergoing reaudit and information from this study may be subject to change.

Additional precautions relating to primary reduction of breast cancer risk.

Nolvadex therapy for this indication has uncommonly been associated with serious side effects such as pulmonary embolus and uterine cancer (both endometrial adenocarcinoma and uterine sarcoma). In trials comparing tamoxifen to placebo for reduction of the incidence of breast cancer in women at increased risk of breast cancer, the use of tamoxifen was associated with an increased risk of serious and sometimes fatal adverse events including endometrial cancer (approximately 4 cases per 1000 women over 5 years of use) and thromboembolic events (including deep vein thrombosis and pulmonary embolism). Less serious side effects such as hot flushes, vaginal discharge, menstrual irregularities and gynaecological conditions may also occur. Whether the benefits of treatment are considered to outweigh the risks depends on the woman's age, health history, and level of breast cancer risk (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects)).
Benign gynaecological conditions (including endometrial polyps, endometriosis, and ovarian cysts) and gynaecological procedures (including hysteroscopy, dilation and curettage, and hysterectomy) were also found to occur more frequently with tamoxifen use. Nongynaecological conditions such as cataracts were also increased (see Section 4.8 Adverse Effects (Undesirable Effects)).
Any women receiving or having previously received Nolvadex for risk reduction should be promptly investigated if any abnormal gynaecological symptoms develop, especially nonmenstrual vaginal bleeding.
The risks of tamoxifen therapy are generally lower in younger women than in older women. In the primary risk reduction trials, women younger than 50 years did not have an increased risk of endometrial cancer or pulmonary embolism and the increased risk of deep vein thrombosis was small and restricted to the treatment period (see Section 4.8 Adverse Effects (Undesirable Effects)), Women under 50 years old). Women aged less than 30 years old were excluded from primary risk reduction trials so the efficacy and safety of tamoxifen treatment in these younger women is unknown.
When considered for primary reduction of breast cancer risk, Nolvadex is contraindicated in women who require concomitant coumarin type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus (see Section 4.3 Contraindications). In women who do not have a history of thromboembolic events, but who are at increased risk of thromboembolic events, the benefits and risks of tamoxifen for the primary reduction of breast cancer risk should be carefully considered. Risk factors for thromboembolic events include smoking, immobility and a family history of venous thrombosis; an additional risk factor, is concomitant oral contraceptive or hormone replacement therapy, which is not recommended in women taking tamoxifen. In women receiving tamoxifen for primary reduction of breast cancer risk, tamoxifen should be stopped approximately 3 weeks before undergoing elective surgery to reduce the risk of thromboembolic events. Consideration should also be given to discontinuing tamoxifen during periods of immobility.
The use of tamoxifen for reduction of breast cancer risk has been associated with reduced bone density in premenopausal women. Whether this may result in an increased risk of fracture is not known. Premenopausal women taking tamoxifen for this reason should be advised regarding measures to maintain bone health.

Use in premenopausal women.

Menstruation is suppressed in a proportion of premenopausal women receiving Nolvadex. Ovarian cysts have occasionally been observed in women receiving Nolvadex.

Use in the elderly.

See Section 5.1 Pharmacodynamic Properties, Clinical trials, Effects of age and menopausal status.

Paediatric use.

Nolvadex is not indicated for use in children. See Section 4.2 Dose and Method of Administration, Paediatric use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

When Nolvadex is used in combination with coumarin type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration is initiated for the treatment of breast cancer, careful monitoring of the patient is recommended. In women receiving tamoxifen for the primary reduction of breast cancer risk, the use of coumarin type anticoagulants is contraindicated (see Section 4.3 Contraindications).
When Nolvadex is used in combination with cytotoxic agents, there is increased risk of thromboembolic events occurring.
The use of tamoxifen in combination with an aromatase inhibitor 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, has been reported in the literature.
Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen has been reported in literature. This showed a reduction in plasma level of active tamoxifen metabolite, 4-hydroxy-N-desmethyltamoxifen. Reduced efficacy on tamoxifen has been reported with concomitant usage of some SSRI antidepressants (e.g. paroxetine).
For the primary reduction of breast cancer risk, there is some evidence that hormone replacement therapy may reduce the effectiveness of tamoxifen, and the safety of concomitant use of tamoxifen and hormone replacement therapy or oral contraceptives is unknown. In women with breast cancer, the use of hormone replacement therapy or oral contraceptives to manage tamoxifen side effects is a relative contraindication.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3)
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 (see Section 4.3 Contraindications).
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 informed of the potential risks to the foetus, should they become pregnant whilst taking Nolvadex or within nine months of cessation of therapy.
 It is not known if Nolvadex is excreted in human milk and therefore the drug is not recommended during lactation.

4.7 Effects on Ability to Drive and Use Machines

Fatigue has been reported with the use of Nolvadex. Therefore, caution should be observed when driving or operating machinery while such symptoms persist.

4.8 Adverse Effects (Undesirable Effects)

The adverse reactions which have been reported are of two types: those associated specifically with the pharmacological action of the drug, e.g. hot flushes, vaginal bleeding, vaginal discharge, pruritus vulvae, tumour pain and tumour flare and those of a more general nature, e.g. gastrointestinal intolerance, headache, lightheadedness and, occasionally, fluid retention and alopecia. In patients treated with Nolvadex for metastatic breast cancer, the most frequent adverse reactions are hot flushes, nausea and vomiting. These may occur in up to one fourth of patients. Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, alopecia and increased bone and tumour pain. Other adverse reactions which are seen infrequently are hypercalcaemia, peripheral oedema, pruritis vulvae, dizziness and lightheadedness. Infrequent cases of endometrial, ocular and haematological adverse effects have been reported (see Section 4.4 Special Warnings and Precautions for Use). When such adverse reactions 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. If adverse reactions do not respond to this measure, it may be necessary to stop the treatment.
Skin rashes (including isolated 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.
Although hypercalcaemia may occur in patients with advanced breast cancer, uncommonly patients with bony metastases have developed hypercalcaemia on initiation of therapy with Nolvadex.
Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported.
Cystic ovarian swellings have occasionally been observed in premenopausal women receiving Nolvadex. Vaginal polyps have rarely been observed in women receiving Nolvadex.
There is evidence of ischaemic cerebrovascular events and thromboembolic events, including deep vein thrombosis, microvascular thrombosis and pulmonary embolism, occurring commonly during Nolvadex therapy. When Nolvadex is used in combination with cytotoxic agents, there is increased risk of thromboembolic events occurring.
Uncommonly, cases of interstitial pneumonitis have been reported.
Leg cramps and myalgia have been reported commonly in patients receiving Nolvadex.
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.
Depression has been reported with frequency very common in association with the use of Nolvadex.
An increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with Nolvadex treatment.
Cutaneous lupus erythematosus has been observed very rarely in patients receiving Nolvadex.
Porphyria cutanea tarda has been observed very rarely in patients receiving Nolvadex.
Cases of optic neuropathy and optic neuritis have been rarely 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.
Fatigue has been reported very commonly in patients taking Nolvadex.
Radiation recall has been observed very rarely in patients receiving Nolvadex.

Primary reduction of breast cancer risk.

The most common adverse events reported from studies in women at increased risk of breast cancer, and occurring more frequently during treatment with tamoxifen than with placebo, were those associated specifically with the pharmacological action of tamoxifen such as vasomotor symptoms (hot flushes, night sweats), menstrual abnormalities/ irregularities, vaginal discharge, and vaginal dryness.
A summary of the more serious adverse events reported during the primary risk reduction trials is shown in Table 1. Tamoxifen significantly increased the incidence of endometrial cancer, deep vein thrombosis, and pulmonary embolism compared with placebo, but the absolute increase in risk was small. The risk of developing cataracts was also significantly increased with tamoxifen.

Women under 50 years old.

A meta-analysis of risk reduction trials stratified by age (Iqbal 2012) showed that while women over 50 years old at randomisation had a significantly increased risk of endometrial cancer compared with placebo (RR 3.32, 95% CI 1.95-5.67; p < 0.0001), women aged under 50 years did not (RR 1.19, 95% CI 0.53-2.65; p = 0.6). Similarly, women under 50 did not have a significantly increased risk of pulmonary embolism compared with placebo (RR 1.16, 95% CI 0.55-2.43; p = 0.60) and their risk of deep vein thrombosis was only significantly increased during the active treatment phase (RR 2.30, 95% CI 1.23-4.31; p = 0.009) but not after treatment had ended.

Gynaecological conditions and procedures.

In placebo controlled trials of the use of tamoxifen for the primary reduction of breast cancer risk, benign gynaecological conditions and procedures were more commonly reported with tamoxifen. The IBIS-1 trial found that in 3573 women taking tamoxifen compared to 3566 women on placebo, the following gynaecological conditions and procedures were more common in women taking tamoxifen: abnormal bleeding (842 v 678, p < 0.0001); endometrial polyps (130 v 65, p < 0.0001); ovarian cysts (101 v 42, p < 0.0001); hysteroscopy (228 v 138, p < 0.0001); pelvic ultrasound (209 v 132, p < 0.0001); dilation and curettage (178 v 94, p < 0.0001); hysterectomy (154 v 104, p = 0.002) and oophorectomy (103 v 67, p = 0.006).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
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 to 200 times the equivalent of the recommended daily human 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

Mechanism of action.

Nolvadex 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.

Clinical trials.

Primary reduction of breast cancer risk. The breast cancer primary risk reduction trials include the International Breast Cancer Intervention Study (IBIS-1), the National Surgical Adjuvant Breast and Bowel Project P1 study (NSABP P1), and the Royal Marsden Hospital chemoprevention trial (Royal Marsden). All trials were double blind placebo controlled randomised trials of oral tamoxifen (20 mg per day) for the primary reduction of breast cancer risk in women at increased risk of breast cancer. Women were treated for 5 years (IBIS-1 and NSABP P1) or 8 years (Royal Marsden) and followed for up to 20 years.
The IBIS-1, NSABP P1, and Royal Marsden trials all defined breast cancer risk differently, and recruited women with both moderate or high lifetime risk: IBIS-I included women with a two-fold relative risk if they were aged 45 to 70 years, a four-fold relative risk if they were aged 40 to 44 years, or a ten-fold relative risk if they were aged 35 to 39 years; NSABP P1 included women aged ≥ 60 years or aged 35 to 59 years with a 5 year predicted risk for breast cancer of at least 1.66% as determined using a modified Gail's model or a history of lobular carcinoma in situ (LCIS) or atypical hyperplasia; and Royal Marsden included healthy women aged 30 to 70 years old with an increased risk of developing breast cancer based on family history.
All trials excluded women with breast cancer (apart from Lobular Carcinoma In Situ (LCIS)), a history of invasive cancer, pregnancy, and current or past deep vein thrombosis or pulmonary embolism. Other relevant exclusion criteria included the current use of oral contraceptives (NSABP P1, Royal Marsden), recent or current hormone replacement therapy (NSABP P1), and current anticoagulant use (IBIS-I).
The majority of women in all trials were aged 59 years or below. NSABP P1 included the largest proportion of women aged 60 years or over (30%). In NSABP P1, the majority of women were white (96%); race was not reported in the other trials. A substantial proportion of women in all trials were premenopausal (46% in IBIS-I and 65% in Royal Marsden) or younger than 50 years old (37% NSABP P1).
Efficacy results from the trials are shown in Tables 2 and 3. Table 2 includes results of a meta-analysis of individual participant data from over 28,000 women who were treated with tamoxifen or placebo for the primary reduction of breast cancer risk. The results of the individual trials were generally consistent with the findings in the meta-analysis and the risk reduction effects of tamoxifen lasted for more than 10 years after treatment ended. Table 3 shows the number needed to treat (NNT) to prevent a diagnosis of breast cancer based on the same data.
In the health related quality of life component of the NSABP-1 trial, which included 11,064 of the 13,388 women enrolled in the trial, vasomotor and gynaecological symptoms were reported more frequently in the tamoxifen group, consistent with the known safety profile of tamoxifen. Some sexual functioning symptoms were reported significantly more frequently in the tamoxifen group, but the differences were very small (mean differences between the treatment groups ranged from 0.54% to 1.24%). Tamoxifen did not increase the rate of depression or mental health problems in general, nor significantly increase the frequency of reported changes in body weight.
Mortality was a secondary outcome measure for the IBIS-1, NSABP P1 and Royal Marsden trials. In comparing the tamoxifen and placebo arms, no significant difference was found for mortality in each trial. This outcome may be due to confounding factors in these trials such as low event rates, underpowering, close screening leading to early detection of events and subsequent breast cancer treatments.

Concomitant use of hormone replacement therapy.

The IBIS-I trial found that tamoxifen was effective in reducing the risk of breast cancer in women who were not taking hormone replacement therapy. For women who did use hormone replacement therapy, there was no significant reduction in the risk of developing invasive breast cancers: 110 vs 124 (HR 0.88, 95% CI 0.68-1.13, p = 0.31). These findings were consistent over the 20 year study period. In the NSABP P1 trial, women who were taking hormone replacement therapy were excluded from the trial. The Royal Marsden trial was not powered to demonstrate an effect.

Effects of age and menopausal status.

No age related effects of tamoxifen on breast cancer incidence were reported in the primary risk reduction trials. Analyses according to age were performed in the final analyses of the IBIS-1 and the NSABP P1 trials. In the IBIS-I trial, breast cancer incidence was significantly decreased in the tamoxifen vs the placebo group in women aged ≤ 50 years and > 50 years. In the NSABP P1 trial, invasive breast cancer incidence was significantly decreased in the tamoxifen vs the placebo group in women aged ≤ 49 years, 50 to 59 years, and ≥ 60 years. Thus, no age related effects of tamoxifen on breast cancer incidence were reported in the trials.
Analyses according to menopausal status were performed in the 96 month analysis of the IBIS-1 trial. In the IBIS-I trial, tamoxifen significantly reduced the risk of breast cancer in premenopausal women compared with placebo. It should be noted that the IBIS-1 trial was not sufficiently powered to detect a difference specifically in postmenopausal women. In the NSABP P1 trial, the incidence of invasive breast cancer was significantly lower in the tamoxifen vs placebo group in women aged ≥ 60 years, who would have been postmenopausal (40 vs 80, RR 0.49, 95% CI 0.33-0.73).

Lobular carcinoma in situ and atypical hyperplasia.

In NSABP P1, there was a 75% breast cancer risk reduction in women with a history of atypical hyperplasia compared with a 37% risk reduction in women with no history of atypical hyperplasia (RR 0.63, 95% CI 0.50-0.78). The risk reductions for women with and without lobular carcinoma in situ were similar.

5.2 Pharmacokinetic Properties

Absorption.

Tamoxifen is absorbed from the gastrointestinal tract. However, the site and extent of absorption is not known. Peak serum levels of 15 to 25 nanogram/mL were observed three to six hours after administration of a single oral dose of 10 mg tamoxifen. Steady-state serum levels are achieved after approximately 4 weeks therapy. Mean steady-state values after dosing at 20 mg twice daily were 285 ± 19 nanogram/mL and 477 ± 35 nanogram/mL for tamoxifen and N-desmethyltamoxifen, respectively.

Distribution.

Little information is available in humans. It has been found in the uterus and ovary, particularly in the endometrium and corpus luteum. Radioactivity studies in animals show high levels in the liver, lung, ovary and spleen. Low levels have been found in the pituitary, eyes and brain.

Protein binding.

The drug appears to be bound to an unknown degree to cytoplasmic protein receptors in all oestrogen target tissues, and is highly protein bound to serum albumin (> 99%).

Metabolism.

Tamoxifen undergoes extensive metabolism in the liver by hydroxylation, demethylation and conjugation, giving rise to several metabolites. The major circulating metabolite of tamoxifen in humans is N-desmethyltamoxifen which has a pharmacological profile very similar to that of tamoxifen and thus contributes to the therapeutic effect. Other minor metabolites are formed, some of which also have antioestrogenic activity.

Half-life.

The elimination half-life of tamoxifen is estimated to be 5 to 7 days and 10 to 14 days for N-desmethyltamoxifen.

Excretion.

The elimination of tamoxifen and its major metabolite N-desmethyltamoxifen is slow. This leads to extensive accumulation of both compounds in serum during chronic administration. Tamoxifen is mainly excreted via the faeces, with only small amounts appearing in the urine. The drug is excreted mainly as its conjugates. In one patient studied for 13 days after dosing, approximately 50% of the dose had been excreted in the faeces, and 13% in the urine. In animals, tamoxifen undergoes enterohepatic circulation, and is thought to do so in humans.
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.

Clinical implications of pharmacokinetic data.

As the main site of metabolism is the liver, and accumulation of the drug and its active metabolites is possible with prolonged treatment, dose and dosing interval may need adjustment in patients with liver disease.

5.3 Preclinical Safety Data

Genotoxicity.

Tamoxifen was genotoxic in some in vitro tests 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.

Carcinogenicity.

Tamoxifen was not mutagenic in a range of in vitro and in vivo mutagenicity tests.

6 Pharmaceutical Particulars

6.1 List of Excipients

Both Nolvadex and Nolvadex-D include the following excipients: maize starch, lactose monohydrate, croscarmellose sodium, gelatin, magnesium stearate, hypromellose, macrogol 300, titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of the medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Nolvadex and Nolvadex-D tablets should be protected from light. Store below 30°C.

6.5 Nature and Contents of Container

Nolvadex (10 mg): blister-packed in strips of 10, in containers of 30.*
Nolvadex-D (20 mg): blister-packed in strips of 10, in containers of 30.
*Not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Tamoxifen is the trans-isomer of 1-[4-(2-dimethylaminoethoxy) phenyl]-1,2-diphenyl-1-butene.

Molecular formula.

C26H29NO, C6H8O7.

MW.

563.6.

CAS number.

54965-24-1.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes