Consumer medicine information

Tamoxifen Lupin Tablets

Tamoxifen

BRAND INFORMATION

Brand name

Tamoxifen Lupin

Active ingredient

Tamoxifen

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tamoxifen Lupin Tablets.

SUMMARY CMI

Tamoxifen Lupin Tablets

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Tamoxifen Lupin?

Tamoxifen Lupin contains the active ingredient Tamoxifen. Tamoxifen Lupin is used to treat breast cancer or reduce the risk of breast cancer occurring if you are at increased risk of breast cancer.

For more information, see Section 1. Why am I using Tamoxifen Lupin? in the full CMI.

2. What should I know before I use Tamoxifen Lupin?

Do not use if you have ever had an allergic reaction to Tamoxifen Lupin or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Tamoxifen Lupin? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tamoxifen Lupin and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take Tamoxifen Lupin?

  • The usual starting dose is 20 mg once a day. Your doctor may increase this dose to 40 mg a day, depending on your condition and how you respond to the medicine. Swallow the tablets with a glass of water. Do not chew or crush the tablets.

More instructions can be found in Section 4. How do I take Tamoxifen Lupin? in the full CMI.

5. What should I know while using Tamoxifen Lupin?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Tamoxifen Lupin.
  • Use effective contraception (birth control) to avoid becoming pregnant.
Things you should not do
  • Do not take Tamoxifen Lupin to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • You must not get pregnant while you are taking Tamoxifen Lupin tablets.
Driving or using machines
  • Be careful driving or operating machinery until you know how Tamoxifen Lupin affects you.
Drinking alcohol
  • Not relevant
Looking after your medicine
  • Store in a cool dry place where the temperature stays below 25°C.
  • Keep the tablets away from moisture, heat or sunlight

For more information, see Section 5. What should I know while using Tamoxifen Lupin? in the full CMI.

6. Are there any side effects?

More common side effects include hot flushes, night sweats, nausea, vomiting, unusual vaginal discharge or dryness and menstrual irregularities or for premenopausal women, periods stopping, any changes in your period, itching around the genital area, diarrhoea, stomach pain or constipation, headache, dizziness or light headedness, fluid retention, numbness or pins and needles sensation in the hands or feet, changes in taste, tiredness, depression, hair thinning or hair loss, leg cramps, aching muscles, sudden onset of weakness or paralysis of the arms or legs.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Tamoxifen Lupin Tablets

Active ingredient(s): Tamoxifen

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tamoxifen Lupin. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Tamoxifen Lupin.

Where to find information in this leaflet:

1. Why am I using Tamoxifen Lupin?
2. What should I know before I use Tamoxifen Lupin?
3. What if I am taking other medicines?
4. How do I take Tamoxifen Lupin?
5. What should I know while using Tamoxifen Lupin?
6. Are there any side effects?
7. Product details

1. Why am I using Tamoxifen Lupin?

Tamoxifen Lupin contains the active ingredient Tamoxifen. Tamoxifen belongs to a class of medicines commonly known as anti-oestrogen. It works by blocking the actions of oestrogen. Oestrogen is a natural female sex hormone. In some types of breast cancer, oestrogen can help cancer cells to grow.

Tamoxifen Lupin is used to 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 Tamoxifen Lupin for reducing the risk of breast cancer occurring, your knowledge of treatment risks becomes more important because you don't currently have breast cancer. Tamoxifen Lupin 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. Tamoxifen Lupin 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 Tamoxifen Lupin reduces, but does not eliminate, the risk of breast cancer.

2. What should I know before I use Tamoxifen Lupin?

Warnings

Do not take Tamoxifen Lupin if:

  • you are allergic to tamoxifen, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • if you are pregnant or plan to become pregnant.
  • the expiry date printed on the packaging has passed.
  • the packaging is torn or shows signs of tampering

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take Tamoxifen Lupin 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).

Check with your doctor if you:

  • are taking any other anti-oestrogen medicines. Their use is not recommended
  • if you have allergies to any other medicines, foods, preservatives or dyes.
  • take any medicines for any other condition
  • have not been through menopause
  • smoke. It may increase your risk of serious side effects.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Tamoxifen Lupin should not be used during pregnancy or breastfeeding. A small number of unwanted complications, such as birth defects, have been reported in the unborn baby of women who have taken this medicine. However, it has not been shown whether these were due to Tamoxifen Lupin.

Birth Control

If sexually active, your doctor may suggest you use a nonhormonal form of contraception while you are taking Tamoxifen Lupin and for two months after you have stopped treatment with it.

Tell your doctor if you have or have had any of the following medical conditions

  • Liver problems
  • any blood disorder or problems such as thrombocytopenia or leucopenia
  • unusual or unexplained vaginal bleeding or discharge
  • deep vein thrombosis (DVT - blood clots in veins of your leg) or pulmonary embolus (blood clots in your legs)

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Tamoxifen Lupin and affect how it works. These include:

  • oral contraceptives ('the pill')
  • hormone replacement therapy
  • other medicines used to treat cancer, including chemotherapy
  • medicines used to prevent blood clots such as warfarin and heparin
  • rifampicin, an antibiotic
  • antidepressants such as paroxetine or fluoxetine
  • aromatase inhibitors (hormone therapy) such as anastrozole, letrozole or exemestane.

These medicines may be affected by Tamoxifen Lupin or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

If you are taking any other anti-coagulant medicines, you may require further monitoring by your doctor.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Tamoxifen Lupin.

Your doctor may consider your treatment carefully if you are taking any of these medicines.

4. How do I take Tamoxifen Lupin?

How much to take

  • Your doctor will decide how much Tamoxifen Lupin you need to take.
  • The usual starting dose is 20 mg once a day. Your doctor may increase this dose to 40 mg a day, depending on your condition and how you respond to the medicine.

How to take Tamoxifen Lupin

  • Swallow the tablets with a glass of water. Do not crush or chew the tablets.
  • Tamoxifen Lupin can be taken with or without food.
  • Keep taking Tamoxifen Lupin for as long as your doctor recommends.

When to take Tamoxifen Lupin

Take your medicine at about the same time each day.

If you forget to take Tamoxifen Lupin

If you miss your dose at the usual time 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 take a double 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.

If you take too much Tamoxifen Lupin

If you think that you have used too much Tamoxifen Lupin, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

There have been reports of heart rhythm problems associated with an overdose of this medicine.

5. What should I know while using Tamoxifen Lupin?

Things you should do

  • Remind any doctor, dentist or pharmacist you visit that you are using Tamoxifen Lupin.
  • Visit your doctor regularly and keep all of your appointments, so that your progress can be checked.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
  • Use birth control to avoid becoming pregnant.

Tamoxifen Lupin should be stopped 3 weeks before undergoing surgery to reduce the risk of blood clots or other complications.

If you go into hospital, let the medical staff know that you are taking Tamoxifen Lupin.

Tell your doctor immediately if you become pregnant while taking Tamoxifen Lupin, or within two months of stopping treatment.

Tell your doctor immediately if you notice any unusual gynaecological symptoms, especially vaginal bleeding or discharge, even if it occurs after treatment with Tamoxifen Lupin has stopped.

Unusual bleeding or discharge from the vagina are possible side effects of Tamoxifen Lupin but they may also be symptoms of uterine or endometrial cancer. These along with other changes to the uterus lining (endometrium) have been reported in association with the use of this medicine.

You will need to have regular gynaecological check-ups while you are taking Tamoxifen Lupin. Your doctor may also order regular blood tests to check your calcium levels, white blood cell and platelet counts.

Things you should not do

  • Do not take Tamoxifen Lupin to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.
  • You must not get pregnant while you are taking Tamoxifen Lupin tablets. Ask your doctor about reliable methods of contraception while you are taking this medication.

Things to be careful of

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Tamoxifen Lupin affects you.

Tamoxifen Lupin may cause dizziness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your tablets in the pack until it is time to take them.
  • Follow the instructions in the carton on how to take care of your medicine properly.

Keep your tablets in a cool dry place where the temperature stays below 25°C. Keep the tablets away from light.

Do not store Tamoxifen Lupin or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

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.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Skin/soft tissue problems:
  • lumps anywhere in the body
  • yellowing of the skin or eyes, dark coloured urine
  • sensitivity to the sun
  • unexplained bruising
General well-being:
  • excessive thirst
Visual problems:
  • any changes or disturbances in your vision
Bone problems
  • unusual pain or pressure around your pelvis, in your bones or anywhere in your body
  • pain and reddening around the tumour or bone pain
Infections
  • frequent infection, fever, severe chills, sore throat or mouth ulcers
Blood or circulation problems
  • swelling of the hands, ankles and feet
  • unusual tiredness, shortness of breath and dizziness when exercising, and looking pale
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of an allergic reaction:
  • swelling of the face, lips, tongue and/or throat
  • wheezing with difficulty breathing.
  • rash, itching or hives
Tummy problems:
  • severe abdominal pain, loss of appetite, nausea, vomiting, and fever
Vision problems:
  • Cases of cataracts have been observed in some patients. Optic nerve diseases have been reported in patients receiving tamoxifen and, in a small number of cases, blindness has occurred.
Blood or circulation problems:
  • Increased risk of blood clots or blockages in the arteries and cardiovascular events with chest pain. Ovarian cysts (in premenopausal women) have also occurred with tamoxifen.
Infections:
  • Cough and shortness of breath due to a condition known as interstitial pneumonitis have also been reported.
Bone problems:
  • Tamoxifen Lupin 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.
Vaginal problems:
  • If you have any unusual vaginal bleeding or other gynaecological symptoms (such as pelvic pain or pressure) when you are taking Tamoxifen Lupin 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.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Tamoxifen Lupin contains

Active ingredient
(main ingredient)		20 mg of tamoxifen (as citrate)
Other ingredients
(inactive ingredients)		maize starch
lactose monohydrate
povidone (K30)
magnesium stearate
brilliant scarlet 4R.
Potential allergensSugars as lactose monohydrate

Do not take this medicine if you are allergic to any of these ingredients.

What Tamoxifen Lupin looks like

Tamoxifen Lupin tablets are pink, round and biconvex.

Each pack contains 30 or 60 tablets.

Who distributes Tamoxifen Lupin

Southern Cross Pharma Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, Vic 3128
Email: [email protected]
Phone: +61 3 9809 7900
Website: www.generichealth.com.au

This leaflet was prepared in August 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Tamoxifen Lupin

Active ingredient

Tamoxifen

Schedule

S4

 

1 Name of Medicine

Tamoxifen (as citrate).

2 Qualitative and Quantitative Composition

Tamoxifen Lupin tablets contain 20 mg tamoxifen (as citrate).

Excipients with known effect.

Contains sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tamoxifen (as citrate) 20 mg tablets are pink, round and biconvex.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of breast cancer.

Tamoxifen Lupin is indicated for the treatment of breast cancer.

Primary reduction of breast cancer risk.

Tamoxifen Lupin 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.
Tamoxifen Lupin reduces, but does not eliminate, the risk of breast cancer. In clinical trials, tamoxifen decreased the incidence of oestrogen receptor-positive tumours, but did not alter the incidence of oestrogen receptor-negative tumours. The use of tamoxifen should be as part of a program including regular breast surveillance tailored to the individual woman, taking into account her risk of breast cancer.

Children.

Tamoxifen Lupin is not indicated for use in children.

4.3 Contraindications

Tamoxifen must not be given during pregnancy. In premenopausal women, the possibility of pregnancy must be excluded before starting tamoxifen.
Tamoxifen Lupin 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, Tamoxifen Lupin 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 tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the oestrogenic properties of tamoxifen. Any patients receiving or having previously received tamoxifen, who report abnormal gynaecological symptoms, especially non-menstrual vaginal bleeding, should be promptly investigated.
In a large randomized trial in Sweden of adjuvant tamoxifen 40 mg/day for 2-5 years, an increased incidence of uterine cancer was noted. Twenty three of 1,372 patients randomized to receive tamoxifen 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 tamoxifen never took the drug. After approximately 6.8 years of follow-up in the ongoing NSABP B-1411 trial, 15 of 1,419 women randomized to receive tamoxifen 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 tamoxifen, 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 tamoxifen should have routine gynaecological care and report any abnormal vaginal bleeding to their physician.
In patients with hereditary angioedema, tamoxifen 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 tamoxifen therapy.
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.
When tamoxifen 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 tamoxifen should be carefully considered in women with a history of thromboembolic events.
In delayed microsurgical breast reconstruction tamoxifen may increase the risk of microvascular flap complications.
Tamoxifen was not mutagenic in a range of in vitro and in vivo mutagenicity tests. 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.
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 tamoxifen therapy. Cataracts have commonly been reported in association with the administration of tamoxifen.
Tamoxifen should be used with caution in patients with existing leucopenia or thrombocytopenia. Leucopenia has been observed following the administration of tamoxifen 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 tamoxifen for breast cancer. Periodic complete blood counts, including platelet counts, may be appropriate.

Additional precautions relating to primary reduction of breast cancer risk.

Tamoxifen 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 4.4 Special Warnings and Precautions for Use; 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. Non-gynaecological conditions such as cataracts were also increased (see Section 4.8 Adverse Effects (Undesirable Effects)).
Any women receiving or having previously received tamoxifen for risk reduction should be promptly investigated if any abnormal gynaecological symptoms develop, especially non-menstrual 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, tamoxifen 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 tamoxifen. Ovarian cysts have occasionally been observed in women receiving tamoxifen.

Use in the elderly.

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

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

When tamoxifen 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 tamoxifen 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)
Tamoxifen 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 tamoxifen, 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, ethinyloestradiol, 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 Tamoxifen Lupin 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 tamoxifen or within nine months of cessation of therapy.
 It is not known if tamoxifen 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 tamoxifen. 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;
those of a more general nature, e.g. gastrointestinal intolerance, headache, light-headedness and, occasionally, fluid retention and alopecia.
In patients treated with tamoxifen 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, pruritus vulvae, dizziness and light-headedness. 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 tamoxifen.
Although hypercalcaemia may occur in patients with advanced breast cancer, uncommonly patients with bony metastases have developed hypercalcaemia on initiation of therapy with tamoxifen.
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 tamoxifen. Vaginal polyps have rarely been observed in women receiving tamoxifen.
There is evidence of ischaemic cerebrovascular events and thromboembolic events, including deep vein thrombosis, microvascular thrombosis and pulmonary embolism, occurring commonly during tamoxifen therapy. When tamoxifen 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 tamoxifen.
Tamoxifen 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 tamoxifen.
Depression has been reported with frequency very common in association with the use of Tamoxifen Lupin.
An increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with tamoxifen treatment.
Cutaneous lupus erythematosus has been observed very rarely in patients receiving tamoxifen. Porphyria cutanea tarda has been observed very rarely in patients receiving tamoxifen.
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 tamoxifen.
Fatigue has been reported very commonly in patients taking tamoxifen. Radiation recall has been observed very rarely in patients receiving tamoxifen.

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

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 tamoxifen 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

No data available.

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.

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.

Half-life.

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

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.

Bioavailability.

No information available.

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

Maize starch, lactose monohydrate, povidone (K30), magnesium stearate, and Brilliant Scarlet 4R.

6.2 Incompatibilities

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

Store below 25°C and protect from light.

6.5 Nature and Contents of Container

Tamoxifen (as citrate) 20 mg tablets are presented in PA/Al/PVC/Al blister packs of 30 and 60.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: 2-[4-[(Z)-1,2-Diphenylbut-1-en-1-yl]phenoxy]-N,N-dimethylethan-1-amine dihydrogen 2-hydroxypropane-1,2,3-tricarboxylate.
Molecular formula: C26H29NO.C6H8O7.
Molecular weight: 563.6.

CAS number.

54965-24-1.
Tamoxifen Lupin (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.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes