Consumer medicine information

Fixta 60

Raloxifene hydrochloride

BRAND INFORMATION

Brand name

Fixta 60 Tablets

Active ingredient

Raloxifene hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fixta 60.

What is in this leaflet

This leaflet is designed to provide you with answers to some common questions about this medicine. It does not contain all the available information and does not take the place of talking with your doctor.

All medicines have risks and benefits. Your doctor has more information about this medicine than is contained in this leaflet. Also, your doctor has had the benefit of taking a full and detailed history from you and is in the best position to make an expert judgement to meet your individual needs.

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

Keep this leaflet with this medicine.

You may need to read it again.

What FIXTA is used for

FIXTA belongs to a group of nonhormonal medicines called Selective Estrogen Receptor Modulators (SERMs). When a woman reaches menopause, the level of the female sex hormone, oestrogen, goes down. FIXTA mimics some of the beneficial effects of oestrogen after menopause.

FIXTA is used to prevent and treat osteoporosis in women after menopause.

Osteoporosis causes your bones to become thin and fragile - it is especially common in women after menopause. While osteoporosis may have no symptoms at first, it makes your bones more likely to break, especially in your spine, hips and wrists. Osteoporosis may also cause back pain, loss of height and a curved back.

Fractures may occur during normal, everyday activity, such as lifting, or from minor injury that would not ordinarily fracture normal bone.

Your doctor may have prescribed FIXTA for another reason.

Ask your doctor if you have any questions about why FIXTA has been prescribed for you.

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

Before you take FIXTA

Tell your doctor if you have any of the following conditions or if you have ever experienced any of these conditions.

When you must not take FIXTA

Do not take FIXTA:

  • if you have not been through menopause. FIXTA is only for use by women after menopause and must not be taken by women who could still have a baby.
  • if you have had an allergic reaction to FIXTA or any of the ingredients listed at the end of this leaflet (see 'Product Description'). Signs of an allergic reaction may include a skin rash, itching, shortness of breath or swelling of the face, lips or tongue.
  • if you are being treated or have been treated for blood clots.
  • if the packaging is torn or shows signs of tampering, or if the tablets do not look quite right.
  • if the expiry date on the pack has passed. If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure whether you should start taking FIXTA, talk to your doctor or pharmacist.

Before you start taking FIXTA

You must tell your doctor:

  • if you have any unexplained vaginal bleeding.
  • if you are at risk of blood clots.
  • if you 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.
  • if you have liver disease.
  • if you have menopausal symptoms, such as hot flushes. FIXTA does not treat hot flushes.
  • if you are breastfeeding.
  • if you are on oestrogen or hormone replacement therapy (HRT).
  • if you have or have had high blood fats (triglycerides) caused by oestrogen.
  • if you 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.
  • if you have had breast cancer. FIXTA has not been fully studied in women who have a history of breast cancer.

Before starting and while taking FIXTA you should have breast examinations and mammograms, as directed by your Doctor. FIXTA does not eliminate the chance of developing breast cancers, you need these examinations to find any breast cancers as early as possible.

FIXTA is not intended to be taken by men. FIXTA has no known effect on driving or the ability to use machinery.

Taking other medicines

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

Some medicines and FIXTA 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.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking FIXTA.

Tell your doctor about these things before taking FIXTA.

How to take FIXTA

Carefully follow all directions given to you by your doctor or pharmacist.

These may differ from the information contained in this leaflet.

How much to take

The usual dose of FIXTA is one tablet per day.

How to take it

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

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

When to take it

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.

You may take FIXTA with or without food.

How long do I take it

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

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

If you forget to take it

If it is almost time for your next dose, skip the tablet 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 your medicine as you would normally.

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 take too much

Immediately telephone your doctor or the Australian Poisons Information Centre (13 11 26), or the New Zealand National Poisons Information Centre (0800 POISON or 0800 764 766), or go to the Accident and Emergency Department at your nearest hospital, if you think that you or anyone else has taken too much FIXTA.

Do this even if there are no signs of discomfort or poisoning.

In adults, symptoms of an overdose may include leg cramps and dizziness.

In children, symptoms of an overdose may include coordination problems, dizziness, vomiting, rash, diarrhoea, repetitive shaking, and flushing.

While you are taking FIXTA

Things you must do

It is important that you remember to take FIXTA daily and at the dose prescribed by your doctor.

Tell all doctors and pharmacists who are treating you that you are taking FIXTA.

While you are taking FIXTA, tell your doctor or pharmacist before you start any new medicine.

If you become pregnant while taking FIXTA, 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.

Things you must not do

Do not stop taking FIXTA without first checking with your doctor.

Do not give FIXTA to anyone else, your doctor has prescribed it specifically for you.

Side Effects

Tell your doctor or pharmacist as soon as possible if you experience any undesirable effect or feel unwell while you are taking FIXTA.

Like other medicines, FIXTA may cause some unwanted side effects. These are likely to vary from patient to patient.

The majority of side effects seen with FIXTA have been mild.

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

  • hot flushes
  • leg cramps
  • muscle spasms
  • swelling of hands, feet and legs
  • flu-like symptoms

These are the more common side effects of FIXTA.

Tell your doctor immediately or go to the Accident and Emergency Department at your nearest hospital if you notice any of the following:

  • severe pain or swelling in your legs
  • severe stomach pain
  • problems with your eyesight
  • shortness of breath or pain on breathing

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

Tell your doctor if you notice anything unusual or if you are concerned about any aspect of your health, even if you think the problems are not associated with this medicine and are not referred to in this leaflet.

Clinical trials using raloxifene have shown that:

  • Women taking raloxifene have less swelling, tenderness and pain in their breasts than women receiving oestrogen.
  • Unlike oestrogen, raloxifene has no effect on the uterus and is unlikely to cause vaginal bleeding or spotting.

After using FIXTA

Storage

Keep your tablets in the original pack until it is time to take them.

Keep your tablets in a cool, dry place where the temperature stays below 25 degrees C.

All medicines should be kept where young children cannot reach them.

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

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

Disposal

If your doctor tells you to stop taking FIXTA or you find that the tablets have passed their expiry date, please return any left over tablets to your pharmacist.

Product Description

What it looks like

FIXTA 60 (60 mg raloxifene as hydrochloride) are presented in pack size of 7 & 28 tablets in blister and 30 & 100 tablets in bottle pack.

FIXTA 60
White to off-white, elliptical, film-coated tablets debossed with 'X' on one side and '57' on other side.

Ingredients

Active ingredient

Raloxifene Hydrochloride

Inactive ingredients

  • microcrystalline cellulose
  • Povidone
  • polysorbate 80
  • crospovidone
  • magnesium stearate
  • hypromellose
  • macrogol 400
  • citric acid monohydrate
  • titanium dioxide

Name and Address of the Sponsor

Aurobindo Pharma Australia Pty Ltd
Unit 3, North Rydelink
Business Park
277-283 Lane Cove Road
Macquarie Park
NSW 2113
Australia

Date of Approval
26 September 2013

BRAND INFORMATION

Brand name

Fixta 60 Tablets

Active ingredient

Raloxifene hydrochloride

Schedule

S4

 

Name of the medicine

Raloxifene hydrochloride.

Excipients.

Microcrystalline cellulose, povidone, polysorbate 80, crospovidone, magnesium stearate, hypromellose, macrogol 400, citric acid monohydrate and titanium dioxide.

Description

Chemical name: methanone, [6-hydroxy-2-(4-hydroxyphenyl) benzo[b]thien-3-yl]- [4-[2-(1-piperidinyl)ethoxy]phenyl], hydrochloride. Molecular Formula: C28H27NO4S.HCl. Molecular Weight: 510.05.
The CAS number for raloxifene hydrochloride is 82640-04-8. The CAS number for raloxifene free base is 84449-90-1.
Raloxifene hydrochloride is an off-white to pale-yellow solid that is very slightly soluble or practically insoluble in water and in acetone.
Each Fixta film coated tablet contains 60 mg raloxifene hydrochloride, which is equivalent to 56 mg raloxifene free base.
Fixta tablets contain following inactive ingredients: microcrystalline cellulose, povidone, polysorbate 80, crospovidone, magnesium stearate, hypromellose, macrogol 400, citric acid monohydrate and titanium dioxide.

Pharmacology

Longterm post-menopausal health and the role of oestrogen.

Oestrogen exerts agonistic effects on a number of bodily tissues. For example, oestrogen affects the structure and integrity of bone.
Decreases in oestrogen 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 oestrogen, and may also involve age-related impairment of osteoblasts or their precursors. Vertebral fractures are the most common type of osteoporotic fracture in post-menopausal women. These fractures are associated with substantial morbidity and impairment in quality of life.
Managing post-menopausal changes that are associated with decreased oestrogen is a challenge. Other conditions not related to decreased oestrogen levels, such as cancers of the breast and uterus, also increase post-menopause.

Mode of action.

Raloxifene has agonistic effects at some oestrogen receptors, antagonistic effects at other oestrogen receptors and has been referred to as a selective oestrogen receptor modulator (SERM). It exerts the positive effects of oestrogen on bone and lipid metabolism, while specifically antagonising some of the potentially negative effects of oestrogen 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 pre-menopausal 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 oestrogen, are mediated through binding to oestrogen receptors. This binding results in differential expression of multiple oestrogen-regulated genes in different tissues. Recent data suggest that the oestrogen receptor can regulate gene expression by at least two distinct pathways which are ligand-, tissue-, and/or gene-specific.

Pharmacokinetics.

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. 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.

Clinical Trials

Clinical data indicate that raloxifene, a selective oestrogen receptor modulator (SERM), has oestrogen-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 oestrogen antagonist in uterine and breast tissues. Clinical data demonstrate that raloxifene lacks oestrogen-like effects on uterus and breast tissue.

Skeletal effects.

In post-menopausal women with osteoporosis, raloxifene reduces the risk of vertebral fractures. Raloxifene also increases BMD of the spine, hip and total body. Similarly, in post-menopausal 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 post-menopausal 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 post-menopausal 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% (Table 1) 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 post-menopausal 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 (Table 2). 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 oestrogen 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 oestrogen/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 post-menopausal women who received once-daily doses of raloxifene hydrochloride 60 mg or 0.625 mg conjugated oestrogens. Ten raloxifene treated and 8 oestrogen-treated women had evaluable bone biopsies at baseline and after 6 months of therapy. Bone in raloxifene-treated and oestrogen-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 post-menopausal 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 oestrogen 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 oestrogens, 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. Table 3 presents 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. 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 3 presents outcomes.

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. See Table 4.

Indications

Raloxifene is indicated for the prevention and treatment of osteoporosis in post-menopausal women.

Contraindications

Raloxifene is contraindicated in women who are or may become pregnant. Raloxifene may cause foetal harm when administered to a pregnant woman. Raloxifene is not indicated for premenopausal women. Safety of raloxifene in premenopausal women has not been established and its use is not recommended.
Raloxifene 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.
Raloxifene is also contraindicated in women with hypersensitivity to raloxifene or other ingredients in the tablet.
Raloxifene is contraindicated for use in males. It is only for use in post-menopausal women.

Precautions

General.

1. In a multi-centre 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, 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 oestrogen 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 oestrogen for hormone replacement therapy (HRT) has not been studied systematically. Therefore, raloxifene should not be used concomitantly with systemic oestrogens.
6. Raloxifene has not been associated with endometrial proliferation (see 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 oestrogen-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 has no known effect on driving or the ability to use machinery.
9. 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.

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 pre-menopausal women.
Raloxifene is a potent antioestrogen in the rat uterus and prevented growth of oestrogen-dependent mammary tumours in rats and mice.

Use in pregnancy.

(Category X)
Raloxifene is only for use in post-menopausal 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.
Australian categorisation definition of Category X: Drugs which have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy.

Use in lactation.

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.

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.

Interactions

Cholestyramine.

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

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 post-menopausal 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 (AUC0-t) of raloxifene. In the osteoporosis treatment trial, coadministered 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 oestrogens.

In the clinical trial program, there were no interactions noted with concomitant use of vaginal oestrogen preparations and raloxifene (see Precautions).

Adverse 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 5 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 oestrogen-progestin replacement therapy (HRT) in 3 clinical trials for prevention of osteoporosis. Table 6 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 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 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.

Dosage and 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 oestrogen 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 oestrogens - see Precautions.

Overdosage

In clinical trials, no overdose of raloxifene has been reported. In an 8-week study of 63 post-menopausal women, a dose of raloxifene hydrochloride of 600 mg/day was safely tolerated. In clinical trials, more than 2500 post-menopausal 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 10,000 [<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.

Presentation

Fixta 60 tablets containing 60 mg raloxifene hydrochloride (equivalent to 56 mg raloxifene) are available in PA/Alu/PVC-Aluminium blister packs of 7 and 28 tablets.
Fixta 60 tablets are also supplied in HDPE bottle packs containing 30 and 100 tablets.
Fixta 60 (Blister Pack: AUST R 203699 and Bottle: AUST R 203695).
White to off-white, elliptical, film-coated tablets debossed with 'X' on one side and '57' on other side.

Storage

Store below 25°C.

Poison Schedule

S4.