Consumer medicine information

Ralovista

Raloxifene hydrochloride

BRAND INFORMATION

Brand name

Ralovista

Active ingredient

Raloxifene hydrochloride

Schedule

SUMMARY CMI

RALOVISTA

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 RALOVISTA?

RALOVISTA contains the active ingredient raloxifene hydrochloride. RALOVISTA is used to prevent and treat osteoporosis in women after menopause. RALOVISTA is also used to reduce the risk of invasive breast cancer in women with osteoporosis after menopause and reduce the risk of invasive breast cancer in women at high risk of invasive breast cancer after menopause.

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

2. What should I know before I use RALOVISTA?

Do not use if you have ever had an allergic reaction to raloxifene hydrochloride 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 RALOVISTA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with RALOVISTA 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 RALOVISTA?

The usual dose is one tablet per day, which can be taken at any time of the day

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

5. What should I know while using RALOVISTA?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using RALOVISTA. It is important that you remember to take RALOVISTA daily and at the dose prescribed by your doctor.
Things you should not do	Do not take RALOVISTA if you have not been through menopause. Do not stop using this medicine without first checking with your doctor. Do not give RALOVISTA to anyone else, your doctor has prescribed it to you.
Driving or using machines	RALOVISTA has no know effect on driving on the ability to use machinery.
Looking after your medicine	Keep your tablets in the blister pack until it is time to take them. Keep your tablets in a cool, dry place where the temperature stays below 25 degrees C. Keep your medicine where young children cannot reach it.

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

6. Are there any side effects?

There are a number of side effects associated with this medicine. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking RALOVISTA, even if you do not think it is connected with this medicine.

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

RALOVISTA

Active ingredient(s): raloxifene hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using RALOVISTA. 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 RALOVISTA.

Where to find information in this leaflet:

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

1. Why am I using RALOVISTA?

RALOVISTA contains the active ingredient raloxifene hydrochloride. RALOVISTA belongs to a group of non-hormonal medicines called Selective Estrogen Receptor Modulators (SERMs). When a woman reaches menopause, the level of the female sex hormone, oestrogen, goes down. RALOVISTA mimics some of the beneficial effects of oestrogen after menopause.

RALOVISTA is used to prevent and treat osteoporosis in women after menopause. It is also used to reduce the risk of invasive breast cancer in women with osteoporosis after menopause and reduce the risk of invasive breast cancer in women at high risk of invasive breast cancer after menopause.

2. What should I know before I use RALOVISTA?

Warnings

Do not use RALOVISTA if:

you are allergic to raloxifene hydrochloride, or any of the ingredients listed at the end of this leaflet
always check the ingredients to make sure you can use this medicine.
you have not been through menopause. RALOVISTA is only for use by women after menopause and must not be taken by women who could still have a baby
if you are being treated or have been treated for blood clots
you are male. RALOVISTA is not intended for use in men.

Check with your doctor if you:

have any unexplained vaginal bleeding.
are at risk of blood clots.
are, or know you will be immobilised for some time, e.g., being wheel-chair bound or having to stay in bed while recovering from an operation or illness.
have liver disease
are intolerant of lactose. RALOVISTA contains a small amount of lactose (about 150 mg) which is unlikely to affect you
have menopausal symptoms, such as hot flushes. RALOVISTA does not treat hot flushes
are on oestrogen or hormone replacement therapy (HRT)
have or have had high blood fats (triglycerides) caused by oestrogen
have previously had a stroke, or if you have ever had other risk factors for stroke such as a mini-stroke (transient ischaemic attack) or a type of irregular heartbeat called atrial fibrillation
have had breast cancer. RALOVISTA has not been fully studied in women who have a history of breast cancer.
Before starting and while taking RALOVISTA you should have breast examinations and mammograms, as directed by your Doctor.
RALOVISTA does not eliminate the chance of developing breast cancers, you need these examinations to find any breast cancers as early as possible.

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

RALOVISTA is only for use by women after menopause and must not be taken by women who could still have a baby.

Check with your doctor is you are pregnant or intended to become pregnant.

You must tell your doctor if you are breastfeeding or intend to breastfeed.

Impaired liver function

The use of RALOVISTA is not recommended in this patient population.

Use in men

RALOVISTA is not intended for use in men.

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 and RALOVISTA may interfere with each other. These include:

medicines for your heart such as digitalis drugs (e.g. digoxin) or blood thinning drugs such as warfarin. Your doctor may need to adjust the dose of these medicines.
hormone replacement therapy (HRT) or oestrogens.
lipid-lowering drugs including cholestyramine.

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

4. How do I take RALOVISTA?

How much to take

The usual dose of RALOVISTA is one tablet per day.
For maximum benefit, RALOVISTA is intended for long-term use.
Follow the instructions provided and use RALOVISTA until your do.
You may take RALOVISTA with or without food.

When to take RALOVISTA

It does not matter what time of day you take your tablet. However, it is best to take it at the same time each day as this will help you remember to take it.

How to take RALOVISTA

RALOVISTA tablets should be swallowed whole with a glass of water.

When prescribed for the treatment or prevention of osteoporosis, RALOVISTA should be taken in conjunction with supplementary calcium if daily calcium intake is inadequate.

How long to take RALOVISTA

For maximum benefit, RALOVISTA is intended for long-term use.

Do not stop taking RALOVISTA without first talking to your doctor.

If you forget to use RALOVISTA

RALOVISTA should be used regularly at the same time each day.

If you miss your dose at the usual time, and it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, then go back to taking RALOVISTA as you would normally.

If you use too much RALOVISTA

If you think that you have used too much RALOVISTA, 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.

5. What should I know while using RALOVISTA?

Things you should do

It is important that you remember to take RALOVISTA daily and at the dose prescribed by your doctor.
If you become pregnant while taking RALOVISTA, tell your doctor.

Tell your doctor if you are immobilised for some time, e.g., being wheel-chair bound or having to stay in bed while recovering from an operation or illness.

If you are going on a long plane or car trip, you should move about periodically.

Tell your doctor if you have any vaginal bleeding.

Call your doctor straight away if you:

have severe pain or swelling in your legs
have severe stomach pain
have shortness of breath or pain or breathing
have problems with your eyesight.

Remind any doctor, dentist or pharmacist you visit that you are using RALOVISTA.

Things you should not do

Do not stop taking RALOVISTA without first checking with your doctor.
Do not give RALOVISTA to anyone else, your doctor has prescribed it specifically for you

Driving or using machines

Be careful before you drive or use any machines or tools until you know how RALOVISTA affects you. RALOVISTA has no known effect on driving or the ability to use machinery.

Looking after your medicine

Keep your tablets in the blister pack until it is time to take them.
Keep your tablets in a cool, dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

There will be an expiry date (month, year) on your RALOVISTA pack.

The medicine should not be taken after this date because it may have lost some of its strength.

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 effects

What to do

General symptoms:

Leg cramps
Swelling of hands, feet and legs
Flu-like symptoms
Infection
Headache
Chest pain
Breast pain

Cardiovascular:

Hot flushes
Migraine
Passing out
Twisted or enlarged veins

Digestive system:

Nausea
Diarrhoea
Upset stomach
Vomiting
Flatulence

Metabolic and nutritional:

Weight gain

Musculoskeletal:

Muscle ache
Muscle spasms
Joint pain and/or swelling
Inflammation or irritation of tendon

Nervous system:

Depression
Difficulty sleeping
Vertigo
Severe pain anywhere in body
Reduced sensibility to touch

Respiratory system:

Congested nose, runny nose, sneezing and itching
Sore throat, wheezing and wet cough
Hoarseness

Skin and appendages:

Rash
Sweating

Eye-related:

Eye inflammation (including redness, swelling and itching)

Urinary system:

Inflammation of the vagina
Urinary tract infection (UTI)
Bladder infection
Yellowish/greenish discharge from vagina
Pain while urinating or passing stool
Uterine disorder
Vaginal bleeding

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

General symptoms:

Severe pain or swelling in your legs
Severe stomach pain
Problems with your eyesight
Shortness of breath or pain on breathing

Cardiovascular:

Blood clots

Digestive systems:

Gall stones

Eye-related:

Problems with your eyesight
Pain or redness of the eyes

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.

In clinical trials of RALOVISTA, some women experienced blood clots in the veins (venous thromboembolic events). This occurred in less than 1% of RALOVISTA patients. This is a serious side effect. You may need urgent medical attention or hospitalisation.

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 RALOVISTA contains

Active ingredient (main ingredient)	Raloxifene hydrochloride
Other ingredients (inactive ingredients)	Povidone Polysorbate 80 Crospovidone Microcrystalline cellulose Colloidal anhydrous silica Magnesium stearate Opadry white 12B580000 (ARTG 108743).

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

What RALOVISTA looks like

RALOVISTA is white to off-white, oval, biconvex, film coated tablets with ‘C’ on one side and ‘12’ on the other side. (Aust R 207898).

Who distributes RALOVISTA

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne, VIC 3121 Australia

This leaflet was prepared in August 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Ralovista

Active ingredient

Raloxifene hydrochloride

Schedule

1 Name of Medicine

Raloxifene hydrochloride.

2 Qualitative and Quantitative Composition

Each film coated tablet contains 60 mg raloxifene hydrochloride, which is equivalent to 56 mg raloxifene free base.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ralovista.

Raloxifene hydrochloride 60 mg tablets; white to off-white, oval, biconvex, film coated tablets with 'C' on one side and '12' on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Ralovista is indicated for the prevention and treatment of osteoporosis in postmenopausal women.
Ralovista is indicated for the reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis.
Ralovista is indicated for the reduction in the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer.
High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer > 1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty.

4.2 Dose and Method of Administration

The recommended dosage is one 60 mg raloxifene hydrochloride tablet per day orally, which may be taken at any time of day without regard to meals. No dose adjustment is necessary for the elderly.
Supplemental calcium should be added to the diet if daily intake is inadequate.
There are no data on the discontinuation effects of raloxifene. Raloxifene exerts its effect through the estrogen receptor and does not accumulate in any target tissue. Therefore, continuous daily treatment with raloxifene is required to maintain the effect of the drug.

Concomitant use of estrogens.

See Section 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

Ralovista is contraindicated in women who are or may become pregnant. Raloxifene may cause foetal harm when administered to a pregnant woman. Ralovista is not indicated for premenopausal women. Safety of raloxifene in premenopausal women has not been established and its use is not recommended.
Ralovista is contraindicated in women with active or a past history of venous thromboembolic events (VTE), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.
Ralovista is also contraindicated in women with hypersensitivity to raloxifene or other ingredients in the tablet.
Ralovista is contraindicated for use in males. It is only for use in postmenopausal women.

4.4 Special Warnings and Precautions for Use

Identified precautions.

1. In a multicentre double-blind, placebo-controlled, randomised, parallel study of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events followed for a median of 5.6 years, there was an increased risk of mortality due to stroke in the group taking raloxifene, although the incidence of stroke, myocardial infarction, hospitalised acute coronary syndrome, cardiovascular mortality, or overall mortality was comparable to placebo. The incidence of stroke mortality was 1.5 per 1000 women per year for placebo versus 2.2 per 1000 women per year for raloxifene. The risk-benefit balance of raloxifene for treatment or prevention of osteoporosis, or reduction in risk of invasive breast cancer, in postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischaemic attack or atrial fibrillation, should be considered when prescribing raloxifene.
2. Raloxifene is associated with an increased risk for venous thromboembolic events that appears to be similar to the reported risk associated with current use of hormone replacement therapy. The risk-benefit balance should be considered in patients at risk of VTEs (venous thromboembolic events) of any aetiology. Raloxifene should be discontinued in the event of a condition or illness leading to a prolonged period of immobilisation. Discontinuation should happen as soon as possible with illness, or from three days before prolonged immobilisation is likely. Therapy should not be restarted until the initiating condition has resolved and the patient is fully mobile. In addition, women taking raloxifene should be advised to move about periodically during prolonged travel.
3. Raloxifene is not effective in reducing vasodilatation (hot flushes) associated with estrogen deficiency.
4. Raloxifene is metabolised primarily in the liver. Single doses of raloxifene given to patients with cirrhosis produced plasma concentrations of raloxifene which were approximately 2.5 times the controls. The increase correlated with total bilirubin concentrations. Until safety and efficacy have been evaluated further in patients with hepatic insufficiency, the use of raloxifene is not recommended in this patient population.
5. The concurrent use of raloxifene and systemic estrogen for hormone replacement therapy (HRT) has not been studied systematically. Therefore, raloxifene should not be used concomitantly with systemic estrogens.
6. Raloxifene has not been associated with endometrial proliferation (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Effects on the endometrium). Unexplained uterine bleeding should be considered abnormal and investigated as clinically indicated.
7. In patients with a history of oral estrogen-induced hypertriglyceridaemia (> 5.6 mmol/L), raloxifene may be associated with a marked increase in serum triglycerides. Patients with this medical history should have serum triglycerides monitored when taking raloxifene.
8. Raloxifene does not eliminate the risk of breast cancer. Patients should have breast examinations and mammograms before starting raloxifene and should continue regular breast examinations and mammograms in keeping with good medical practice after beginning treatment with raloxifene.
There are no data available regarding the effect of raloxifene on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of raloxifene. Raloxifene is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence. It has not been studied adequately in women with a prior history of breast cancer. It is not indicated for the reduction in risk of non-invasive breast cancer.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Colestyramine.

Raloxifene should not be co-administered with colestyramine or other anion exchange resins. The absorption and enterohepatic cycling of raloxifene is significantly reduced by colestyramine.

Ampicillin and other oral antimicrobials.

Peak concentrations of raloxifene are reduced by co-administration with ampicillin. This reduction is consistent with decreased enterohepatic cycling associated with antibiotic reduction of enteric bacteria. However, as the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene can be concurrently administered with ampicillin. In the osteoporosis treatment trial, co-administered oral antimicrobial agents (including amoxycillin, cephalexin, ciprofloxacin, macrolide antibiotics, sulfamethoxazole/trimethoprim and tetracycline) had no effect on plasma raloxifene concentration.

Corticosteroids.

The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose.

Digoxin.

Raloxifene has no effect on the pharmacokinetics of digoxin. In the osteoporosis treatment trial, co-administered digoxin had no effect on plasma raloxifene concentration.

Gastrointestinal medications.

Concurrent administration of either calcium carbonate or aluminium and magnesium-hydroxide containing antacids does not alter the initial absorption or systemic exposure (AUC_0-t) of raloxifene. In the osteoporosis treatment trial, co-administered gastrointestinal medications (including bisacodyl, cisapride, docusate, H₂-antagonists, laxatives, loperamide, omeprazole and psyllium) had no effect on plasma raloxifene concentration.

Highly glucuronidated drugs.

The influence of co-administered highly glucuronidated drugs (including paracetamol, ketoprofen, morphine and oxazepam) on raloxifene plasma concentrations was evaluated in the osteoporosis treatment trial. No clinically significant effects of these agents on raloxifene plasma concentrations were identified.

Highly protein-bound drugs.

The influence of co-administered highly protein-bound drugs (including diazepam, gemfibrozil, ibuprofen, naproxen and warfarin) on raloxifene plasma concentrations was evaluated in the osteoporosis treatment trial. No clinically significant effects of these agents on raloxifene plasma concentrations were identified. In vitro, raloxifene did not affect the binding of phenytoin, tamoxifen or warfarin. As small decreases in the prothrombin time have been observed with raloxifene, if raloxifene is given concurrently with warfarin or other coumarin derivatives, the prothrombin time should be monitored.

Hormones.

Raloxifene increases hormone-binding globulin concentrations, including sex steroid binding globulins (SHBG), thyroxine binding globulin (TBG), and corticosteroid binding globulin (CBG), with corresponding increases in total hormone concentrations. These changes do not affect concentrations of free hormones.

Lipid-lowering drugs.

Raloxifene lowers serum total and LDL cholesterol but does not affect serum concentrations of total HDL cholesterol or triglycerides. These effects should be taken into account in therapeutic decisions for patients who may require therapy for hyperlipidaemia. Concurrent use of raloxifene and lipid-lowering agents has not been studied.

Concomitant use of estrogens.

In the clinical trial program, there were no interactions noted with concomitant use of vaginal estrogen preparations and raloxifene (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproductive effects observed in animal studies are consistent with the known pharmacological profile of raloxifene. Oestrous cycling was disrupted in mice given dietary doses ≥ 15 mg/kg/day, and in rats at oral gavage doses ≥ 1 mg/kg/day, with a no-effect dose level of 0.1 mg/kg/day in the latter study. Fertility of female rats was abolished at dietary doses ≥ 5 mg/kg/day (no-effect dose not established). In one study, fertility of female rats dosed by oral gavage at 10 mg/kg/day was almost completely restored immediately after cessation of treatment and was completely restored after a 2-week recovery period.
However, disruption of oestrous cycling and infertility persisted up to 5 weeks in a few rats dosed at 6-63 mg/kg/day in a dietary study. In rats becoming pregnant immediately after cessation of treatment at 10 mg/kg/day by oral gavage, litter size was reduced, gestation length was slightly increased and the timing of events in neonatal development was slightly altered; similar effects were not seen in animals mated after a 2-week recovery period. When given by oral gavage to mated female rats during the preimplantation period at 0.1 to 10 mg/kg/day, raloxifene delayed and disrupted embryo implantation resulting in prolonged gestation, and reduced litter size. Development of offspring to weaning was not affected.
The reproductive effects of raloxifene in animal studies reflect the pharmacological activity of the drug and similar effects may occur if raloxifene is administered to premenopausal women.
Raloxifene is a potent antiestrogen in the rat uterus and prevented growth of estrogen-dependent mammary tumours in rats and mice.
(Category X)
Raloxifene is only for use in postmenopausal women.
Raloxifene must not be taken by women of child bearing potential. Animal studies showed that raloxifene caused foetal malformations in rabbits and abnormalities in the reproductive system and impaired reproductive function in the female offspring of rats. These developmental effects were observed at pharmacologically active dose levels and similar effects on foetal development may occur if raloxifene is administered to a pregnant woman. If this drug is used mistakenly during pregnancy or the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the foetus.
It is not known whether raloxifene is excreted in human or animal milk. In animal studies, oral administration of raloxifene (0.1 to 10 mg/kg/day) during pregnancy and lactation caused suppression of pup growth during lactation and histopathological changes in the reproductive system of female offspring; fertility of female offspring was impaired at the high dose level. Raloxifene's use, therefore, cannot be recommended in lactating women, as it may affect the development of the baby.

4.7 Effects on Ability to Drive and Use Machines

Raloxifene has no known effect on driving or the ability to use machinery.

4.8 Adverse Effects (Undesirable Effects)

Osteoporosis treatment clinical trial.

Therapy was discontinued due to an adverse event in 10.9% of women treated with raloxifene hydrochloride 60 mg and 8.8% of women treated with placebo. Common adverse reactions considered to be related to raloxifene therapy were hot flushes and leg cramps. Hot flushes were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter.

Osteoporosis prevention clinical trial.

The adverse event most frequently reported as the reason for discontinuation in patients treated with raloxifene was hot flushes. Discontinuation rates due to hot flushes did not differ significantly between raloxifene and placebo groups (1.7% and 2.2%, respectively).

Osteoporosis treatment and prevention clinical trials.

Across all placebo-controlled clinical trials of raloxifene in osteoporosis, venous thromboembolic events, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis occurred in a frequency of approximately 0.7% or 3.25 cases per 1,000 patient years. A relative risk of 2.32 (CI 1.26, 4.26) was observed in raloxifene-treated patients compared to placebo. The risk of a thromboembolic event was greatest in the first four months of therapy. Superficial vein thrombophlebitis occurred in a frequency of less than 1%.
Table 1 lists adverse events occurring in either the osteoporosis treatment or the prevention placebo-controlled clinical trial databases at a frequency ≥ 2.0% in either group and in more raloxifene-treated women than in placebo-treated women. Adverse events are shown without attribution of causality.

Comparison of raloxifene hydrochloride 60 mg and hormone replacement therapy.

Raloxifene hydrochloride 60 mg was compared with estrogen-progestin replacement therapy (HRT) in 3 clinical trials for prevention of osteoporosis. Table 2 shows adverse events occurring more frequently in one treatment group and at an incidence ≥ 2.0% in any group. Adverse events are shown without attribution of causality.

Breast pain.

Across all placebo-controlled trials, raloxifene was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. Raloxifene was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin.

Gynaecologic cancers.

Raloxifene-treated and placebo-treated groups had similar incidences of endometrial cancer and ovarian cancer.

Placebo-controlled trial of postmenopausal women at increased risk for major coronary events (RUTH).

The safety of raloxifene hydrochloride (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55-92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Therapy was discontinued due to an adverse reaction in 25% of 5044 raloxifene-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups.
Adverse reactions reported more frequently in raloxifene-treated women than in placebo-treated women included peripheral oedema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flushes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2.0% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo).

Tamoxifen-controlled trial of postmenopausal women at increased risk for invasive breast cancer (STAR).

The safety of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years was assessed in 19,747 postmenopausal women (age range 35-83 years) in a randomised, double-blind trial. As of 31 December 2005, the median follow-up was 4.3 years. The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials.

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

In clinical trials, no overdose of raloxifene has been reported. In an 8-week study of 63 postmenopausal women, a dose of raloxifene hydrochloride of 600 mg/day was safely tolerated. In clinical trials, more than 2500 postmenopausal women received a daily dose of 120 mg for three years.
In postmarketing spontaneous reports, overdose has been reported very rarely (less than 1 out of 10000 [< 0.01%] patients treated). The highest overdose has been approximately 1.5 grams. No fatalities associated with overdose have been reported. In adults, symptoms reported in patients who took more than 120 mg as a single ingestion included leg cramps and dizziness. In some cases, no adverse events were reported as a result of the overdose.
Raloxifene is not indicated for use in children, however, in accidental overdose in children under 2 years of age, the maximum reported dose has been 180 mg. In children, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhoea, tremor and flushing, as well as elevation in alkaline phosphatase.
No mortality was seen after a single oral dose in rats or mice at 5000 mg/kg (810 times the human dose for rats and 405 times the human dose for mice based on surface area, mg/m²) or in monkeys at 1000 mg/kg (80 times the AUC in humans).
There is no specific antidote for raloxifene.
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.

Long term postmenopausal health and the role of estrogen.

Estrogen exerts agonistic effects on a number of bodily tissues. For example, estrogen affects the structure and integrity of bone.
Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption, accelerated bone loss and increased risk of fracture. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. This imbalance between resorption and formation is related to loss of estrogen, and may also involve age-related impairment of osteoblasts or their precursors. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women. These fractures are associated with substantial morbidity and impairment in quality of life.
Managing postmenopausal changes that are associated with decreased estrogen is a challenge. Other conditions not related to decreased estrogen levels, such as cancers of the breast and uterus, also increase post-menopause.

Mode of action.

Raloxifene has agonistic effects at some estrogen receptors, antagonistic effects at other estrogen receptors and has been referred to as a selective estrogen receptor modulator (SERM). It exerts the positive effects of estrogen on bone and lipid metabolism, while specifically antagonising some of the potentially negative effects of estrogen on uterine and breast tissues. The agonistic effect of raloxifene on bone and lipid metabolism has been shown to be dose dependent.
Raloxifene decreases resorption of bone and normalises bone turnover to the premenopausal range. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers, decreases in bone resorption, increases in bone mineral density (BMD) and decreases in incidences of fractures.
The biological actions of raloxifene, like those of estrogen, are mediated through binding to estrogen receptors. This binding results in differential expression of multiple estrogen-regulated genes in different tissues. Recent data suggest that the estrogen receptor can regulate gene expression by at least two distinct pathways which are ligand-, tissue-, and/or gene-specific.

Clinical trials.

Clinical data indicate that raloxifene, a selective estrogen receptor modulator (SERM), has estrogen-like effects on bone (increase in BMD) and on lipid (decrease in total and LDL cholesterol levels) metabolism. Preclinical data in rodents suggest that raloxifene is an estrogen antagonist in uterine and breast tissues. Clinical data demonstrate that raloxifene lacks estrogen-like effects on uterus and breast tissue.
Skeletal effects. In postmenopausal women with osteoporosis, raloxifene reduces the risk of vertebral fractures. Raloxifene also increases BMD of the spine, hip and total body. Similarly, in postmenopausal women without osteoporosis, raloxifene preserves bone mass and significantly increases BMD of the hip and spine.

i) Treatment of osteoporosis.

The effects of raloxifene on fracture incidence and BMD in postmenopausal women with osteoporosis were examined at 3 years in a large randomised placebo-controlled, double-blind osteoporosis treatment trial. The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a) low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women) without baseline vertebral fractures, or b) one or more baseline vertebral fractures. Women enrolled in this study had a median age of 67 years (range 31 to 80) and a median time since menopause of 19 years. All women received calcium (500 mg/day) and vitamin D (400-600 IU/day).
Raloxifene hydrochloride, 60 mg administered once daily, increased spine and hip BMD by 2-3% and total body and ultradistal radius BMD by 1-2%, and decreased the incidence of one or more vertebral fractures by as much as 55% (see Table 3) compared to an active therapy of calcium plus vitamin D supplemented placebo. Raloxifene reduced the incidence of vertebral fractures whether or not patients had experienced a previous fracture.

ii) Prevention of osteoporosis.

The effects of raloxifene on BMD in postmenopausal women were examined in three large randomised, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/day). Women enrolled in these studies had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years post-menopause). The majority of the women were Caucasian (93.5%). Women were included if they had spine bone mineral density between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women. The mean T scores (number of standard deviations above or below the mean in healthy young women) ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD.
Raloxifene produced significant increases in bone density of the hip (1.3% to 2.4%) and spine (1.8% to 2.4%) compared to placebo (see Table 4). Raloxifene also increased BMD compared with placebo in the total body by 1.3% to 2.0% and in Ward's Triangle (hip) by 3.1% to 4.0%. The effects of raloxifene on forearm BMD were inconsistent between studies (see Figure 1).

iii) Calcium kinetics.

Raloxifene and estrogen affect bone remodelling and calcium metabolism similarly. In a 31-week open-label radiocalcium kinetics study, 33 early postmenopausal women were randomised to treatment with once-daily raloxifene hydrochloride 60 mg, cyclic estrogen/progestin (HRT) or no treatment. Raloxifene was associated with reduced bone resorption and a mean positive shift in calcium balance of 60 mg per day, due primarily to decreased urinary calcium losses. These findings were similar to those observed with HRT.

iv) Histomorphometry (bone quality).

In the osteoporosis treatment study, bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment with placebo, raloxifene hydrochloride 60 mg or raloxifene hydrochloride 120 mg daily. There were 56 paired biopsies evaluable (24 placebo, 20 raloxifene hydrochloride 60 mg and 12 raloxifene hydrochloride 120 mg). Similarly to placebo-treated patients, in raloxifene-treated patients, normal bone quality was maintained; specifically, there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity or woven bone after 2 years of treatment.
The effects of raloxifene on bone histomorphometry were determined by pre- and post-treatment biopsies in a 6-month study of Caucasian postmenopausal women who received once-daily doses of raloxifene hydrochloride 60 mg or 0.625 mg conjugated estrogens. Ten raloxifene-treated and 8 estrogen-treated women had evaluable bone biopsies at baseline and after 6 months of therapy. Bone in raloxifene-treated and estrogen-treated women showed no evidence of mineralisation defects, woven bone or marrow fibrosis.
Effects on the endometrium. In clinical trials, raloxifene did not stimulate the postmenopausal uterine endometrium. Compared to placebo, raloxifene was not associated with spotting or bleeding or endometrial hyperplasia. Nearly 3,000 transvaginal ultrasound (TVUs) examinations were evaluated from 831 women in all dose groups. Raloxifene-treated women consistently had an endometrial thickness which was indistinguishable from placebo. Furthermore, there were no differences between the raloxifene and placebo groups with respect to the incidence of reported uterine bleeding.
Endometrial biopsies taken after six months of therapy with raloxifene demonstrated nonproliferative endometrium in all patients. In addition, in a study with 2.5 times the recommended daily dose of raloxifene there was no evidence of endometrial proliferation and no increase in uterine volume.
In the osteoporosis treatment trial, endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for three years. Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the raloxifene hydrochloride 60 mg-treated women had a 0.06 mm mean increase (not different from baseline).
After three years, raloxifene did not increase the risk of endometrial or ovarian cancer.
Effects on breast tissue. Preclinical data in rodents suggest that raloxifene is an estrogen antagonist in uterine and breast tissues. Across all placebo-controlled trials, raloxifene was indistinguishable from placebo with regard to frequency and severity of breast symptoms. Raloxifene was associated with significantly fewer breast symptoms (swelling, tenderness, breast pain) than reported by patients receiving estrogens, with or without added progestins.

MORE trial.

The effect of raloxifene on the incidence of breast cancer was assessed as a secondary safety endpoint in a randomised, placebo-controlled, double-blind, multinational osteoporosis treatment trial in postmenopausal women. After 4 years, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of all breast cancers by 62%, compared with placebo (HR 0.38, 95% CI 0.22-0.67). Raloxifene reduced the incidence of invasive breast cancer by 71%, compared with placebo (adjusted relative risk (ARR) 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene group compared with placebo. Table 3 presents efficacy and selected safety outcomes.

CORE trial.

The effect of raloxifene on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE osteoporosis treatment trial. Women were not re-randomised; the treatment assignment from the osteoporosis treatment trial was carried forward to this study. Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 56%, compared with placebo (ARR 3.0 per 1000 women-years); this was primarily due to a 63% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene group compared with placebo. There was no reduction in the incidence of ER-negative breast cancer. In the osteoporosis treatment trial and the follow-up study, there was no difference in incidence of noninvasive breast cancer between the raloxifene and placebo groups. Table 5 presents efficacy and selected safety outcomes.

MORE-CORE combined.

In a subset of postmenopausal women followed for up to 8 years from randomisation in MORE to the end of CORE, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 60% in women assigned raloxifene (n=1355) compared with placebo (n=1286) (HR 0.40, 95% CI 0.21, 0.77; ARR 1.95 per 1000 women-years); this was primarily due to a 65% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene group compared with placebo.

RUTH trial.

The effect of raloxifene on the incidence of invasive breast cancer was assessed in a randomised, placebo-controlled, double-blind, multinational study in 10,101 postmenopausal women at increased risk of coronary events. Women in this study had a median age of 67.6 years (range 55-92) and were followed for a median of 5.6 years (range 0.01-7.1). Eighty four percent were Caucasian, 9.8% of women reported a first-degree relative with a history of breast cancer, and 41.4% of the women had a 5-year predicted risk of invasive breast cancer > 1.66%, based on the modified Gail model.
Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 44% compared with placebo [absolute risk reduction (ARR) 1.2 per 1000 women-years]; this was primarily due to a 55% reduction in estrogen receptor (ER)-positive invasive breast cancer in the raloxifene group compared with placebo (ARR 1.2 per 1000 women-years). There was no reduction in ER-negative invasive breast cancer. Table 6 presents efficacy and selected safety outcomes.

The effect of raloxifene in reducing the incidence of invasive breast cancer was consistent among women above or below age 65 or with a 5-year predicted invasive breast cancer risk, based on the modified Gail model, < 1.66%, or > 1.66%. (The modified Gail model is described in Section 4.1 Therapeutic Indications).

STAR trial.

The effects of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years on reducing the incidence of invasive breast cancer were assessed in 19,747 postmenopausal women in a randomised, double-blind trial conducted in North America by the National Surgical Adjuvant Breast and Bowel Project and sponsored by the National Cancer Institute. Women in this study had a mean age of 58.5 years (range 35-83), a mean 5-year predicted invasive breast cancer risk of 4.03% (range 1.66-23.61%), and 9.1% had a history of lobular carcinoma in situ (LCIS). More than 93% of participants were Caucasian. As of 31 December 2005, the median time of follow-up was 4.3 years (range 0.07-6.50 years).
Raloxifene was not superior to tamoxifen in reducing the incidence of invasive breast cancer. The observed incidence rates of invasive breast cancer were raloxifene 4.4 and tamoxifen 4.3 per 1000 women per year. The effect of each treatment on invasive breast cancer was consistent when women were compared by baseline age, history of LCIS, history of atypical hyperplasia, 5-year predicted risk of breast cancer by the modified Gail model, or the number of relatives with a history of breast cancer. Fewer noninvasive breast cancers occurred in the tamoxifen group compared to the raloxifene group. Table 7 presents efficacy and selected safety outcomes.

5.2 Pharmacokinetic Properties

Absorption.

Raloxifene is absorbed rapidly after oral administration. Although approximately 60% of an oral dose is absorbed, presystemic glucuronide conjugation is extensive and absolute bioavailability is 2.0%. The time to reach average maximum plasma concentration and bioavailability are functions of absorption, systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.

Distribution.

Raloxifene is distributed extensively in the body. The volume of distribution is not dose dependent.

Protein binding.

Approximately 98% to 99% of raloxifene is bound in vitro to plasma proteins, including both albumin and α-1-acid glycoprotein. Raloxifene is not displaced in vitro by its glucuronide conjugates.

Metabolism.

Raloxifene comprises less than 1% of the combined concentrations of raloxifene and the glucuronide metabolites in plasma. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, prolonging raloxifene's plasma elimination half-life to an average of 27.7 hours after oral dosing.
Results from single oral doses of raloxifene predict multiple dose pharmacokinetics, although increasing doses of raloxifene result in slightly less than a proportional increase in the area under the plasma concentration/time curve.

Excretion.

The majority of a dose of raloxifene and its glucuronide metabolites are excreted within 5 days, primarily in the faeces, with less than 6% excreted in the urine.

Special populations.

Renal insufficiency.

Less than 6% of the total dose is eliminated in urine. In the osteoporosis treatment and prevention trials, blood levels of raloxifene and its metabolite were not affected by renal function in women having estimated creatinine clearance as low as 21 mL/min.

Hepatic insufficiency.

The pharmacokinetics of a single dose of raloxifene in patients with hepatic dysfunction have been compared to that in healthy individuals. Plasma raloxifene concentrations were approximately 2.5-fold higher than in controls and correlated with total bilirubin concentrations.

5.3 Preclinical Safety Data

Genotoxicity.

Raloxifene was not genotoxic in assays of gene mutation, chromosomal damage, DNA damage or sister chromatid exchange.

Carcinogenicity.

In a 2-year carcinogenicity study in rats, an increase in ovarian tumours of granulosa/theca cell origin was observed in females given a dietary dose of 279 mg/kg/day (approximately 400 times the AUC in humans). In a 21-month dietary study in mice, there was an increased incidence of testicular interstitial cell tumours and prostatic adenomas and adenocarcinomas in males given 41 to 210 mg/kg/day (comparable to 4.7 to 24 times the AUC in humans) and prostatic leiomyoblastoma in males given 210 mg/kg/day. An increased incidence of ovarian tumours in female mice given dietary doses of 9 to 242 mg/kg/day (comparable to 0.3 to 34 times the AUC in humans) included benign and malignant tumours of granulosa/theca cell origin and benign tumours of epithelial cell origin. The female rodents in these studies were treated during their reproductive lives, when their ovaries were functional and highly responsive to hormonal stimulation.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain povidone, polysorbate 80, glycine, crospovidone, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate and Opadry White 12B580000 (ARTG PI 108743).

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.

6.5 Nature and Contents of Container

Pack of 28 tablets. Aluminium/aluminium blisters.

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

Raloxifene hydrochloride is an off-white to pale-yellow solid that is very slightly soluble in water.

Chemical structure.

Chemically raloxifene hydrochloride is methanone, [6-hydroxy-2-(4-hydroxyphenyl) benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl) ethoxy] phenyl]-, hydrochloride and its empirical formula is C₂₈H₂₇NO₄S.HCl which corresponds to a molecular weight of 510.05.

CAS number.

The CAS number for raloxifene HCl is 82640-04-8. The CAS number for raloxifene free base is 84449-90-1.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicines - S4.

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Ralovista

Raloxifene hydrochloride

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Ralovista 60 mg Tablets