LARFEN Tablet

- Treatment and Prevention of Osteoporosis in Postmenopausal Women

(See the package insert about the details below.)

- Reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis

- Reduction in the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer.

Important limitations of use for breast cancer risk reduction

- 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 or raloxifene.

- Raloxifene is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.

- Raloxifene is not indicated for the reduction in the risk of noninvasive breast cancer.

Dosage and Administration

Recommended dosing

60mg daily, which may be administered any time of day without regard to meals.

No dose adjustment is necessary for the elderly.

Due to the nature of this disease process, raloxifene is intended for long-term use.

For the indications in risk of invasive breast cancer the optimum duration of treatment is not known.

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

- Hypersensitivity to the active substance or to any of the excipients.

- Must not be used in women with childbearing potential.

- 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.

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

See the package insert about the details.

Vascular disorders

Very common: Vasodilation(hot flushes)

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

Musculoskeletal and connective tissue disorders

Common: Leg cramps

General disorders and administration site conditions

Very common: Flu syndrome

Common: Peripheral edema

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 dioxin.

The influence of concomitant medication on raloxifene plasma concentrations was evaluated in the prevention and treatment trials.

Frequently co-administered medicinal products included: paracetamol, NSAIDs (such as acetylsalicylic acid, ibuprofen, and naproxen), and 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 estrogen 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, 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, thyroxine binding globulin, and corticosteroid binding globulin, with corresponding increases in total hormone concentrations. These changes do not affect concentrations of free hormones.

Raloxifene is only for use in postmenopausal women.

Pregnancy

Raloxifene must not be taken by women of childbearing potential. Raloxifene may cause fetal farm 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 fetus.

Lactation

It is not known whether raloxifene is excreted in human milk. Its clinical use, therefore, cannot be recommended in lactating women. Raloxifene may affect the development of the body.

See the package insert about the details below:

- Cardiovascular disease

- Venous thromboembolism

- Death due to stroke

- Premenopausal use

- History of breast cancer

- Use in men

- Unexplained uterine bleeding

- Breast abnormalities

- History of hypertriglyceridemia when treated with estrogens

- Hepatic dysfunction

Use in specific populations

- Pediatric use

- Geriatric use

- Use in renal impairment

- Use in hepatic impairment

- Effects on ability to drive and use machines

Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors. In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women.

The biological actions of raloxifene are largely mediated though binding to estrogen receptors. This binding results in activation of estrogenic pathways in certain tissues and blockade of estrogenic pathways in others. Thus, raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM).

These effects on bone are manifested as reductions in the serum and urine levels of bone tumover markers, decreases in bone resorption based on radio calcium kinetics studies, increases in bone mineral density, and decreases in incidence of fractures.