OPTRUMA Film-coated tablet Ref.[49845] Active ingredients: Raloxifene

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. Optruma 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, hospitalized 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 1000 women per year for raloxifene versus 1.5 per 1000 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 ischemic attack or atrial fibrillation.

There is no evidence of endometrial proliferation. Any uterine bleeding during Optruma 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 Optruma 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 hypertriglyceridemia (>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 Optruma in patients with breast cancer has not been adequately studied. No data are available on the concomitant use of Optruma and agents used in the treatment of early or advanced breast cancer. Therefore, Optruma 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.

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

Optruma contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 Optruma 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 C_max 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 Optruma 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.

Pregnancy

Optruma is only for use in postmenopausal women.

Optruma must not be taken by women of child bearing 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 newborns/infants cannot be excluded. Its clinical use, therefore, cannot be recommended in breastfeeding women. Optruma may affect the development of the baby.

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

a. Summary of the safety profile

The clinically most important adverse reactions reported in postmenopausal women treated with Optruma 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 postmarketing 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 postmarketing 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 Optruma 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 Optruma 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).

^a Term(s) included based on postmarketing experience.

c. Description of selected adverse reactions

Compared with placebo-treated patients the occurrence of vasodilatation (hot flushes) was modestly increased in Optruma patients (clinical trials for the prevention of osteoporosis, 2 to 8 years postmenopausal, 24.3% Optruma and 18.2% placebo; clinical trials for the treatment of osteoporosis, mean age 66, 10.6% for Optruma 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 Optruma 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 in 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 Optruma, 1.9% for placebo in the prevention population and 9.2% for Optruma, 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 Optruma 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 Optruma and 1.9% for placebo; and in the treatment population occurred at an incidence of 7.1% for Optruma 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 placebocontrolled 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 can not 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%).

Optruma (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 via the national reporting system listed in Appendix V.

Not applicable.