4.1. Therapeutic indications

This medicine is indicated for the treatment and prevention of osteoporosis in postmenopausal women. A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated.

When determining the choice of Raloxifene hydrochloride or other therapies, including oestrogens, for an individual postmenopausal woman, consideration should be given to: menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5.1).

4.2. Posology and method of administration

Posology

The recommended dose is one tablet daily by oral administration, which may be taken at any time of the day without regard to meals. Due to the nature of the disease process, this medicine is intended for long-term use.

Generally, calcium and vitamin D supplements are advised in women with a low dietary intake.

Elderly:

No dose adjustment is necessary for the elderly.

Renal impairment:

Raloxifene hydrochloride should not be used in patients with severe renal impairment (see section 4.3). In patients with moderate and mild renal impairment, this medicine should be used with caution.

Hepatic impairment:

This medicine should not be used in patients with hepatic impairment (see section 4.3 and 4.4).

Paediatric population:

Raloxifene hydrochloride should not be used in children of any age. There is no relevant use of this medicine in the paediatric population.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Must not be used in women with childbearing potential (see section 4.6).

• Active or past history of venous thromboembolic events (VTE), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.

• Hepatic impairment, including cholestasis.

• Severe renal impairment.

• Unexplained uterine bleeding.

This medicine should not be used in patients with signs or symptoms of endometrial cancer, as safety in this patient group has not been adequately studied.

4.4. Special warnings and precautions for use

Raloxifene is associated with an increased risk for venous thromboembolic events that is 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 venous thromboembolic events of any aetiology. This medicine should be discontinued in the event of an illness or a condition leading to a prolonged period of immobilisation. Discontinuation should happen as soon as possible in case of the illness, or from 3 days before the immobilisation occurs. Therapy should not be restarted until the initiating condition has resolved and the patient is fully mobile.

In a study of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, raloxifene did not affect the incidence of myocardial infarction, hospitalised acute coronary syndrome, overall mortality, including overall cardiovascular mortality, or stroke, compared to placebo. However, there was an increase in death due to stroke in women assigned to raloxifene. The incidence of stroke mortality was 2.2 per 1,000 women per year for raloxifene versus 1.5 per 1,000 women per year for placebo (see section 4.8). This finding should be considered when prescribing raloxifene for postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischaemic attack or atrial fibrillation.

There is no evidence of endometrial proliferation. Any uterine bleeding during Raloxifene hydrochloride therapy is unexpected and should be fully investigated by a specialist. The two most frequent diagnoses associated with uterine bleeding during raloxifene treatment were endometrial atrophy and benign endometrial polyps. In postmenopausal women who received raloxifene treatment for 4 years, benign endometrial polyps were reported in 0.9% compared to 0.3% in women who received placebo treatment.

Raloxifene is metabolised primarily in the liver. Single doses of raloxifene given to patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) produced plasma concentrations of raloxifene which were approximately 2.5-times the controls. The increase correlated with total bilirubin concentrations. Therefore, this medicine is not recommended to be used in patients with hepatic insufficiency. Serum total bilirubin, gamma-glutamyl transferase, alkaline phosphatase, ALT and AST should be closely monitored during treatment if elevated values are observed.

Limited clinical data suggest that 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.

The safety of raloxifene in patients with breast cancer has not been adequately studied. No data are available on the concomitant use of raloxifene and agents used in the treatment of early or advanced breast cancer. Therefore, this medicine should be used for osteoporosis treatment and prevention only after the treatment of breast cancer, including adjuvant therapy, has been completed.

As safety information regarding co-administration of raloxifene with systemic oestrogens is limited, such use is not recommended.

This medicine is not effective in reducing vasodilatation (hot flushes), or other symptoms of the menopause associated with oestrogen deficiency.

Raloxifene hydrochloride contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Raloxifene hydrochloride contains sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Concurrent administration of either calcium carbonate or aluminium and magnesium-hydroxide containing antacids do not affect the systemic exposure of raloxifene.

Co-administration of raloxifene and warfarin does not alter the pharmacokinetics of either compound. However, modest decreases in the prothrombin time have been observed, and if raloxifene is given concurrently with warfarin or other coumarin derivatives, the prothrombin time should be monitored. Effects on prothrombin time may develop over several weeks if raloxifene treatment is started in patients who are already on coumarin anticoagulant therapy.

Raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a single dose.

Raloxifene does not affect the steady-state AUC of digoxin. The Cmax of digoxin increased by less than 5%.

The influence of concomitant medication on raloxifene plasma concentrations was evaluated in the prevention and treatment trials. Frequently co-administered medicinal products included: paracetamol, non-steroidal anti-inflammatory drugs (such as acetylsalicylic acid, ibuprofen, and naproxen), oral antibiotics, H1-antagonists, H2-antagonists, and benzodiazepines. No clinically relevant effects of the co-administration of the agents on raloxifene plasma concentrations were identified.

Concomitant use of vaginal oestrogen preparations was allowed in the clinical trial programme, if necessary to treat atrophic vaginal symptoms. Compared to placebo there was no increased use in raloxifene-treated patients.

In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen.

Raloxifene should not be co-administered with cholestyramine (or other anion exchange resins), which significantly reduces the absorption and enterohepatic cycling of raloxifene.

Peak concentrations of raloxifene are reduced with co-administration with ampicillin. However, since the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene can be concurrently administered with ampicillin.

Raloxifene modestly 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

Raloxifene hydrochloride is only for use in postmenopausal women.

This medicine must not be taken by women of childbearing potential. Raloxifene may cause foetal harm when administered to a pregnant woman. If this medicinal product is used mistakenly during pregnancy or the patient becomes pregnant while taking it, the patient should be informed of the potential hazard to the foetus (see section 5.3).

Breast-feeding

It is unknown whether raloxifene/raloxifene metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. Its clinical use, therefore, cannot be recommended in breast-feeding women. This medicine may affect the development of the baby.

4.7. Effects on ability to drive and use machines

Raloxifene has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

a. Summary of the safety profile

The clinically most important adverse reactions reported in postmenopausal women treated with raloxifene were venous thromboembolic events (see section 4.4), which occurred in less than 1% of treated patients.

b. Tabulated summary of adverse reactions

The table below gives the adverse reactions and frequencies observed in treatment and prevention studies involving over 13,000 postmenopausal women, along with adverse reactions arising from post marketing reports. The duration of treatment in these studies ranged from 6 to 60 months. The majority of adverse reactions have not usually required cessation of therapy.

The frequencies for post marketing reports were calculated from placebo-controlled clinical trials (comprising a total of 15,234 patients, 7,601 on raloxifene 60 mg and 7,633 on placebo) in postmenopausal women with osteoporosis or established coronary heart disease (CHD) or increased risk for CHD, without comparison to the frequencies of adverse events in the placebo assignment groups.

In the prevention population, discontinuations of therapy due to any adverse reaction occurred in 10.7% of 581 raloxifene -treated patients and 11.1% of 584 placebo-treated patients. In the treatment population, discontinuations of therapy due to any clinical adverse event occurred in 12.8% of 2,557 raloxifene-treated patients and 11.1% of 2,576 placebo-treated patients.

The following convention has been used for the classification of the adverse reactions: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥ 1/10,000 to <1/1,000), very rare (<1/10,000).

Blood and lymphatic system disorders

Uncommon: Thrombocytopenia a

Nervous system disorders

Common: Headache, including migraine a

Uncommon: Fatal strokes

Vascular disorders

Very common: Vasodilatation (hot flushes)

Uncommon: Venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, retinal vein thrombosis, superficial vein thrombophlebitis, arterial thromboembolic reactions a

Gastrointestinal disorders

Very common: Gastrointestinal symptoms a such as nausea, vomiting, abdominal pain, dyspepsia

Skin and subcutaneous tissue disorders

Common: Rash a

Musculoskeletal and connective tissue disorders

Common: Leg cramps

Reproductive system and breast disorders

Common: Mild breast symptoms a such as pain, enlargement and tenderness

General disorders and administration site conditions

Very common: Flu syndrome

Common: Peripheral oedema

Investigations

Very common: Increased blood pressure a

a Term(s) included based on post marketing experience.

c. Description of selected adverse reactions

Compared with placebo-treated patients, the occurrence of vasodilatation (hot flushes) was modestly increased in raloxifene patients (clinical trials for the prevention of osteoporosis, 2 to 8 years postmenopausal, 24.3% raloxifene and 18.2% placebo; clinical trials for the treatment of osteoporosis, mean age 66, 10.6% for raloxifene and 7.1% placebo). This adverse reaction was most common in the first 6 months of treatment, and seldom occurred de novo after that time.

In a study of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events (RUTH), the occurrence of vasodilatation (hot flushes) was 7.8% in the raloxifene-treated patients and 4.7% in the placebo-treated patients.

Across all placebo-controlled clinical trials of raloxifene in osteoporosis, venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis occurred at a frequency of approximately 0.8% or 3.22 cases per 1,000 patient-years. A relative risk of 1.60 (CI 0.95, 2.71) 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%.

In the RUTH study, venous thromboembolic events occurred at a frequency of approximately 2.0% or 3.88 cases per 1,000 patient-years in the raloxifene group and 1.4% or 2.70 cases per 1,000 patient-years in the placebo group. The hazard ratio for all VTE events in the RUTH study was HR = 1.44 (1.06 – 1.95). Superficial vein thrombophlebitis occurred at a frequency of 1% in the raloxifene group and 0.6% in the placebo group.

In the RUTH study, raloxifene did not affect the incidence of stroke, compared to placebo. However, there was an increase in death due to stroke in women assigned to raloxifene. The incidence of stroke mortality was 2.2 per 1,000 women per year for raloxifene versus 1.5 per 1,000 women per year for placebo (see section 4.4). During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women.

Another adverse reaction observed was leg cramps (5.5% for raloxifene, 1.9% for placebo in the prevention population; and 9.2% for raloxifene, 6.0% for placebo in the treatment population).

In the RUTH study, leg cramps were observed in 12.1% of raloxifene-treated patients and 8.3% of placebo-treated patients.

Flu syndrome was reported by 16.2% of raloxifene-treated patients and 14.0% of placebo-treated patients.

One further change was seen which was not statistically significant (p>0.05), but which did show a significant dose trend. This was peripheral oedema, which occurred in the prevention population at an incidence of 3.1% for raloxifene and 1.9% for placebo; and in the treatment population occurred at an incidence of 7.1% for raloxifene and 6.1% for placebo.

In the RUTH study, peripheral oedema occurred in 14.1% of the raloxifene-treated patients and 11.7% of the placebo-treated patients, which was statistically significant.

Slightly decreased (6-10%) platelet counts have been reported during raloxifene treatment in placebo-controlled clinical trials of raloxifene in osteoporosis.

Rare cases of moderate increases in AST and/or ALT have been reported where a causal relationship to raloxifene cannot be excluded. A similar frequency of increases was noted among placebo patients. In a study (RUTH) of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an additional adverse reaction of cholelithiasis occurred in 3.3% of patients treated with raloxifene and 2.6% of patients treated with placebo. Cholecystectomy rates for raloxifene (2.3%) were not statistically significantly different from placebo (2.0%).

Raloxifene (n=317) was compared with continuous combined (n = 110) hormone replacement therapy (HRT) or cyclic (n = 205) HRT patients in some clinical trials. The incidence of breast symptoms and uterine bleeding in raloxifene treated women was significantly lower than in women treated with either form of HRT.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 the Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store).

4.9. Overdose

In some clinical trials, daily doses were given up to 600mg for 8 weeks and 120mg for 3 years. No cases of raloxifene overdose were reported during clinical trials.

In adults, symptoms of leg cramps and dizziness have been reported in patients who took more than 120mg as a single ingestion.

In accidental overdose in children younger than 2 years of age, the maximum reported dose has been 180mg. In children, symptoms of accidental overdose included ataxia, dizziness, vomiting, rash, diarrhoea, tremor, flushing and elevation in alkaline phosphatase.

The highest overdose has been approximately 1.5 grams. No fatalities associated with overdose have been reported.

There is no specific antidote for raloxifene hydrochloride.