Raloxifene

Mechanism of Action

The mechanism of action of raloxifene occurs through binding to estrogen receptors. This binding results in activation of estrogenic pathways (estrogen-agonistic effect) and blockade (estrogen-antagonistic effect) in tissues that express estrogen receptors. These receptors express as two different isoforms, the alpha estrogen receptor (activating effect) and the beta estrogen receptor (inhibiting effect). Therefore, the expression of these receptors will modify cellular and tissue responses to estrogens.

In postmenopausal osteoporosis, bone turnover dramatically increases. The bone resorption develops at a faster rate than bone formation, leading to a progressive loss of bone mass and bone mineral density. This disease represents an elevated risk for developing fractures. Raloxifene can inhibit accelerated bone resorption both short and long-term, increasing bone mineral density (BMD) and enhancing bone strength. Other pharmacologic agents for the management of osteoporosis are estrogen, bisphosphonates, selective estrogen receptor modulators (SERMs), parathyroid hormone (PTH), and calcium and vitamin D.

It has an estrogen-antagonistic effect in the uterus and breast, in contrast with tamoxifen (a first-generation selective estrogen receptor modulator), which has an estrogen-agonistic effect over the uterus. In addition, raloxifene modifies cardiovascular risk markers by decreasing LDL-C, fibrinogen, lipoprotein A and increasing HDL2-C without modifying triglyceride levels. There are no recommendations for raloxifene use in BRCA1 and BRCA2 positive mutations; there are no reports of apparent effectiveness. This drug is not intended for use in treating patients with an established diagnosis of breast cancer.[3][4]

Raloxifene bioavailability is approximately 2%, with an absorption of 60%. The onset of action is eight weeks, and distribution is mainly protein-bound (more than 95%). Metabolism of the drug occurs in the liver, excreted primarily in the feces (more than 93%) and urine (less than 0.2%).

Administration

Raloxifene hydrochloride administration is via the oral route. Raloxifene hydrochloride is available as 60 mg tablets.

• Indications for the drug are the treatment and prevention of postmenopausal osteoporosis. The recommended dose for osteoporosis is 60 mg by mouth daily. [5] Recommendations for Calcium and Vitamin D Supplementation. For osteoporosis prevention or treatment, supplemental calcium and/or vitamin D needs to be added to the diet when daily intake is insufficient. Postmenopausal women need an average of 400-800 IU vitamin D and 1500 mg of elemental calcium daily. Patients at high risk for vitamin D insufficiency (e.g., gastrointestinal malabsorption syndromes, chronically ill, nursing home-bound, over the age of 70 years) may need additional vitamin D supplements.
• It is also prescribed for prevention and risk reduction of invasive breast cancer in postmenopausal women demonstrating a high risk for invasive breast cancer.[1] The recommended dose for breast cancer prevention is 60 mg by mouth daily for five years.[6]
• Clinical trials had reported some beneficial effects of raloxifene during menopause, decreasing LDL levels and reducing the risk of pelvic organ prolapse and breast cancer. No reports exist of an effect on cognitive mood or sleep disturbances.[7]

Special Population

Patients with Renal Impairment: Use with caution; safety and efficacy are not well known in patients with moderate or severe renal impairment.

Patients with Liver Impairment: Safety and efficacy are not well known in patients with hepatic impairment.[3][8]

Pregnancy and Breastfeeding Implications: Raloxifene is a US FDA pregnancy category X medicine. Pregnancy and lactation constitute a contraindication to using raloxifene. Fertile women wishing to become pregnant need to avoid or discontinue this drug. It is not known whether raloxifene is excreted in human milk. Many medicines are excreted in human milk, so exercise caution when administered to a nursing woman.

Adverse Effects

Raloxifene's most common documented adverse effects are hot flashes, flu-like symptoms, muscle spasms, arthralgia, and infection. Less common effects are insomnia, vomiting, sinusitis, deep venous thrombosis (DVT), bronchitis, pharyngitis, breast pain.[9] Raloxifene-treated women reported peripheral edema ( raloxifene 14.1% vs placebo 11.7%), muscle spasms/leg cramps (12.1%  vs 8.3% ), hot flashes (7.8%  vs 4.7% ), cholelithiasis (3.3%  vs 2.6% ), and venous thromboembolic events 2.0%  vs 1.4%).

The most serious adverse reaction related to raloxifene is venous thromboembolism  (pulmonary embolism, deep venous thrombosis,  and retinal vein thrombosis). During the clinical trial, with raloxifene treatment for 2.6 years, venous thromboembolism (VTE) precipitated in about 1 out of 100 patients. A total of 26 raloxifene-exposed women had a VTE compared to 11 placebo-treated women, and the highest risk of VTE was in the initial four months of the treatment phase with raloxifene.

Contraindications

Contraindications to raloxifene include past medical history of deep venous thrombosis, renal vein thrombosis, pulmonary embolism, malignancy, active smoking, or any thrombophilia (factor V Leiden deficiency, prothrombin gene mutation G20210A, antiphospholipid syndrome, deficiency of antithrombin, protein c and s deficiency).

Death due to stroke: Postmenopausal women with coronary heart disease or at increased risk for coronary events are at increased risk of death due to stroke when treated with raloxifene. Perform risk-benefit analysis in women with a risk of strokes, such as women with a history of transient ischemic attack (TIA) or stroke, cigarette smoking habit, hypertension, and atrial fibrillation.

Careful administration is recommended in hospitalized, immobilized, unable to walk, or post-surgical recovery patients, given the high risk of developing deep vein thrombosis and pulmonary embolism.

The safety of raloxifene in premenopausal women is not established, and its use in premenopausal women is not recommended.

Drug Interactions

• There are reports of an ospemifene and raloxifene interaction; it increases the effect of the other by synergism. Therefore, monitor the following drugs (for interaction with raloxifene) closely: apalutamide, cholestyramine, famciclovir, levothyroxine.
• There is a reported minor interaction of raloxifene with warfarin; it increases the effect of warfarin by plasma protein binding competition.[9][10]
• Concomitant administration of raloxifene with amoxicillin,  ampicillin, digoxin, corticosteroids, antacids, cholestyramine, other anion exchange resins, or systemic estrogens is not recommended. 
• It should be used with caution with highly protein-bound drugs such as diazepam, diazoxide, and lidocaine, as it might affect the protein binding of other drugs.

Monitoring

Monitoring is recommended in patients with suggestive deep vein thrombosis (DVT) symptoms, including redness, tenderness, and inflammation of calves and lower limbs. In such instances, patients should proceed immediately to the emergency department. A Doppler ultrasound of lower limbs is needed to rule out deep vein thrombosis in the emergency department. If such testing proves positive, admission to the hospital will be essential. In addition, it is vital to rule out pulmonary embolism in patients exhibiting chest pain, shortness of breath, or hemoptysis.

Reports recommend suspending raloxifene 72 hours before and during an expected immobilization of a patient. When raloxifene is given concomitantly with warfarin or other warfarin derivatives, monitor prothrombin time more closely when starting or stopping the medicine. Supplementation of vitamin D and calcium is also a recommendation in conjunction with raloxifene therapy. In addition, monitor hepatic profile and triglycerides levels, given the agonistic effect of estrogen over triglycerides.

Monitor for any unexpected abnormal uterine bleeding. For patients with abnormal uterine bleeding in using raloxifene, it is recommended to establish a consultation with OB/GYN and initiate further workup to establish the source of the bleeding. An endometrial biopsy is suggested to rule out endometrial cancer.[10]

Investigations and research have been done to establish the effect of raloxifene on the heart, given its estrogen-agonistic effect in the heart estrogen receptors. Reports indicate that raloxifene does not produce myocardial hypertrophy in postmenopausal women after being treated for six months.[11][12]

Toxicity

There is some documentation of increased risk of deep vein thrombosis, embolic cerebrovascular accident, and pulmonary embolism with the usage of this drug. Patients developing new-onset vaginal bleeding will need workup, including endometrial biopsy and OB/GYN consultation. There are some reports of an increased risk of death due to a cerebrovascular accident in trials of postmenopausal women with coronary heart disease or with high-risk factors for coronary arterial disease.[4][12]

In an 8-week clinical study, 63 postmenopausal women safely tolerated 600 mg raloxifene daily. No death associated with raloxifene overdose has been reported in postmarketing spontaneous reports. One patient overdosed with raloxifene 1.5 grams was reported. Adverse reactions (mainly leg cramps and dizziness) were reported in approximately half of the adults who took more than 180 mg raloxifene. Overdose toxicity was reported with 180 mg raloxifene in two 18-month-old children. Reported adverse reactions include vomiting, ataxia, diarrhea, dizziness, rash, flushing, tremor, and elevated alkaline phosphatase. There is no specific antidote for raloxifene.

Enhancing Healthcare Team Outcomes

Raloxifene can be prescribed by primary care clinicians, nurse practitioners, physician assistants, OB/GYNS, and endocrinologists. The drug is useful for the prevention and treatment of osteoporosis and the prevention of breast cancer. However, healthcare workers, including pharmacists, must warn the patient that the drug can cause deep vein thrombosis and how they can detect the symptoms and present them immediately to the emergency department. Also, the drug can cause hot flashes, flu-like symptoms, and muscle spasms. The interprofessional team should work together to monitor the patient closely for deep vein thrombosis, pulmonary embolism, or embolic cerebrovascular accident. Patient education should include immediate provider notification if shortness of breath, chest pain, arm or leg weakness, calf redness, or pain. Nursing staff must be vigilant to ask about these symptoms at every follow-up visit and alert the prescriber with any concerns. The pharmacist will also need to perform medication reconciliation to avoid drug interactions and verify all dosing is appropriate. A provider may want these medications stopped before prolonged bed rest, immobility, or surgery.[12][5]

Prescribing raloxifene and follow-up monitoring requires an interprofessional team approach, including clinicians, specialists, nurses, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results and prevent complications. [Level 5]