Raloxifene

Raloxifene is an antineoplastic agent belonging to the pharmacological class of second-generation Selective estrogen receptor modulators (SERM).

Raloxifene is FDA-approved to treat postmenopausal osteoporosis and the risk reduction of invasive breast cancer in postmenopausal women.

Raloxifene is absorbed rapidly from the gastrointestinal tract, with an approximate 2% bioavailability, and it undergoes 60% absorption. The drug is mainly protein-bound, exceeding 95% in distribution. The liver metabolizes Raloxifene, predominantly excreted through the faeces (more than 93%) and urine (less than 0.2%).

Raloxifene's most common side effects are hot flashes, leg cramps, peripheral oedema, flu-like symptoms, joint pain, and sweating.

Raloxifene is available as an oral tablet.

The molecule is available in India, the United Kingdom, the United States, Canada, France, Italy, Japan, Australia, Germany and Brazil.

Raloxifene is an antineoplastic agent belonging to the pharmacological class of second-generation Selective estrogen receptor modulators.

Raloxifene exerts its mechanism of action by binding to estrogen receptors, activating estrogenic pathways (agonistic effect) and blocking them (antagonistic effect) in tissues expressing estrogen receptors, including alpha and beta isoforms. These receptor expressions modify cellular and tissue responses to estrogens. Postmenopausal osteoporosis is characterized by increased bone turnover and elevated fracture risk, Raloxifene inhibits accelerated bone resorption, enhancing bone mineral density and strength. Unlike tamoxifen, it has an estrogen-antagonistic effect in the uterus and breast. Raloxifene also alters cardiovascular risk markers, decreasing LDL-C, fibrinogen, and lipoprotein A while increasing HDL2-C. However, its use in BRCA1 and BRCA2 mutations lacks recommendations, and it is not intended for treating established breast cancer diagnoses.

The onset of action of Raloxifene is eight weeks.

Raloxifene is available as an oral tablet.

Tablet: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, with or without food.

• Treatment and prevention of Postmenopausal osteoporosis.
• Minimizing of postmenopausal women's risk of invasive breast cancer.

• Treatment and prevention of Postmenopausal osteoporosis: Women are frequently affected by postmenopausal osteoporosis, a common disorder that weakens bones and increases the risk of fractures after menopause. By acting as an estrogen agonist, Raloxifene increases bone mineral density and reduces bone resorption. This helps to keep strong, healthy bones and lowers the risk of osteoporosis at the same time. Raloxifene plays a proactive role in maintaining bone health and minimizing the consequences of postmenopausal osteoporosis by helping preserve bone density and reducing the risk of fractures.
• Minimizing of postmenopausal women's risk of invasive breast cancer: In postmenopausal women, Raloxifene significantly lowers the risk of invasive breast cancer, especially for those with a family history or specific biopsy results. A high risk of breast cancer can be identified by a breast biopsy that reveals lobular carcinoma in situ (LCIS) or atypical hyperplasia, by one or more first-degree relatives who have breast cancer, or by a 5-year estimated risk of breast cancer more than 1.66%. Raloxifene is distinctive in its ability to reduce the risk factors linked to breast cancer in this population, rendering it an excellent preventive measure.

It is indicated in the following conditions:

• FDA approves Raloxifene, a second-generation SERM, exerting estrogen-agonistic effects to enhance bone mineral density and reduce bone resorption in postmenopausal osteoporosis treatment and prevention.
• Indicated for minimising the risk of invasive breast cancer in postmenopausal women with high-risk factors, including family history or biopsy findings like LCIS or atypical hyperplasia.

Orally: Patients receive Raloxifene orally through tablets, typically once a day. The prescribed dosage is usually taken with water and can be administered with or without food. Ensuring strict compliance with prescribed guidelines allows for the best possible management of the condition while minimizing the risk of complications.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 60mg

Raloxifene is available as an oral tablet.

Dose Adjustment in Adult Patients:

Postmenopausal Women's Osteoporosis: 60 mg PO qDay

Breast cancer prevention: 60 mg PO every day for five years

Dosing Considerations

• Calcium and vitamin D supplementation

For postmenopausal patients with insufficient dietary intake, it is advisable to supplement calcium and vitamin D. Postmenopausal women should aim for an average of 1500 mg/day of elemental calcium. No additional bone benefits have been observed, with total daily calcium intake surpassing 1500 mg. Intake exceeding 2000 mg daily has been linked to heightened risks of adverse effects, such as hypercalcemia and kidney stones. The prescribed daily dose of vitamin D is 400-800 IU.

• Use restrictions for lowering the risk of breast cancer

No data exist on the impact of Raloxifene on the incidence of invasive breast cancer in women with inherited mutations (BRCA1, BRCA2), preventing specific recommendations on its effectiveness. Raloxifene is not approved for treating invasive breast cancer, reducing recurrence risk, or lowering the risk of noninvasive breast cancer.

• Severe hepatic impairment
• Pregnancy, lactation
• Women who could become pregnant
• Active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.

• Cardiovascular Disease: Raloxifene is contraindicated for the primary or secondary prevention of cardiovascular disease. Use caution and assess the risk-benefit balance in patients with documented coronary heart disease or those at increased risk for major coronary events. There is an increased risk of death due to stroke in postmenopausal women with coronary heart disease.

• Venous Thromboembolism: Raloxifene is associated with an elevated risk of venous thromboembolism, including pulmonary embolism, deep vein thrombosis, and retinal vein thrombosis. Discontinue its use 72 hours before and during prolonged immobilization.

• Premenopausal Women: Raloxifene is not recommended for use in premenopausal women.

• Hepatic Impairment: Exercise caution when using Raloxifene in patients with hepatic impairment.

• Concomitant Use with Systemic Estrogens: The concurrent use of Raloxifene with the systemic estrogens is not recommended.

• Hypertriglyceridemia: Monitor serum triglycerides in individuals with a history of hypertriglyceridemia following previous estrogen treatment.

It is unsafe to consume alcohol.

Avoid breastfeeding while taking Raloxifene.

Due to clear evidence of risk to the developing fetus, it is not safe to use during pregnancy.

Consume fibre-rich foods and avoid tobacco; exercise regularly.

The adverse reactions related to Raloxifene can be categorized as:

•Common Adverse Effects: Hot flashes, flu syndrome, muscle cramps/spasms, joint pain, and infections.

•Less Common Adverse Effects: Insomnia, vomiting, sinusitis, venous thromboembolism, bronchitis, pharyngitis, breast pain, gastroenteritis, and diaphoresis.

•Rare Adverse Effects: Retinal vein occlusion, stroke, and death associated with venous thromboembolism (VTE).

The clinically relevant drug interactions of Raloxifene are briefly summarized here.

• Ospemifene and Raloxifene have been shown to interact, increasing each other's effects through synergism. As a result, cautiously monitor how the following medications interact with Raloxifene: levothyroxine, cholestyramine, famciclovir, and apalutamide.
• Raloxifene and warfarin have been shown to have a minor interaction that boosts the medication's effectiveness by competing for plasma protein binding.
• Taking Raloxifene concurrently with digoxin, ampicillin, amoxicillin, corticosteroids, antacids, cholestyramine, other anion exchange resins, or systemic estrogens is not advised.
• Strongly protein-bound drugs, such as lidocaine, diazepam, and diazoxide, should be used cautiously since they may alter the way other medications bind to proteins.

The common side effects of Raloxifene include:

• Leg cramps
• Peripheral edema
• Flu-like symptoms
• Joint pain
• Breast Tenderness
• Sweating
• Breast pain
• Hot flashes

• Pregnancy

Pregnancy Category X (FDA): Avoid using while pregnant. The risks are more significant than the potential benefits. There are safer options available.

Pregnant women should not take Raloxifene as it may harm the developing fetus. It is also not recommended for usage in women who may become pregnant. Patients should be informed of the possible risks to the developing fetus if they use this medication while pregnant or if they fall pregnant while taking it.

Animal data

A low rate of fetal heart malformations (ventricular septal defects) and abortion were observed in rabbit experiments at doses ≥0.1 mg/kg (≥0.04 times the human dosage based on surface area, mg/m2). In contrast, fetuses exposed to doses ≥10 mg/kg (≥4 times the human dose based on the surface area, mg/m2) developed hydrocephaly. In rat studies, doses ≥1 mg/kg (≥0.2 times the human dose based on the surface area, mg/m2) caused retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation). Maternal treatment at doses of 0.1 to 10 mg/kg during gestation and lactation produced various adverse effects in offspring, including disrupted parturition, decreased neonatal survival, altered physical development, and growth reductions. At 10 mg/kg, Raloxifene disrupted parturition, leading to maternal and progeny mortality and morbidity. The effects extended to adult offspring, exhibiting uterine hypoplasia, reduced fertility, and age-specific reductions in growth, pituitary hormone content, and lymphoid compartment size.

• Nursing Mothers

Women who are breastfeeding shouldn't use Raloxifene. The medication may or may not be eliminated in human milk, which is unknown. One should use caution while giving Raloxifene to a breastfeeding woman because a lot of medications are excreted in human milk.

• Pediatric Use

As per FDA, the safety and efficacy of Raloxifene in Pediatric population have not been established.

• Geriatrics (> 65 years old)

As per the FDA, the safety and efficacy of Raloxifene in elderly patients above 65 have not been extensively studied or established.

In the Raloxifene placebo-controlled clinical trials, 61% of patients were 65 or older, and 15.5% were 75 or older. Other reported clinical experience has not found differences in responses between elderly and the younger patients. Still, it cannot be ruled out that some older patients may be more sensitive than others. Overall, no differences were observed in safety or effectiveness between the elderly subjects and younger adult subjects.

Clinical research shows that elderly patients don't require dose modification.

Dose Adjustment in Kidney Impairment Patients:

When administering raloxifene tablets to individuals who have moderate to severe renal impairment, caution should be exercised. It is unknown if this medication is safe and effective for people with moderate or severe renal impairment.

Dose Adjustment in Hepatic Impairment Patients:

Patients with liver function disorders should take caution while administering Raloxifene tablets because the drug is extensively metabolized in the liver.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Raloxifene.

Signs and Symptoms

Raloxifene overdose has been documented in postmarketing spontaneous reports extremely rarely (less than 1 in 10,000 cases). However, leg cramps and lightheadedness may result from consuming too much Raloxifene.

Management

There is no specific antidote or treatment for overdosage of Raloxifene, so treatment typically involves symptomatic measures, supportive measures and monitoring for potential complications. Activated charcoal may be administered to limit further absorption of Raloxifene from the gastrointestinal tract, and hemodialysis is unlikely to be beneficial.

Due to the low systemic bioavailability of Raloxifene, the potential for significant overdosage is limited.

Pharmacodynamics

Raloxifene therapy regularly and significantly inhibited bone resorption and formation in trials on the prevention and treatment of osteoporosis. This suppression is reflected in changes in bone turnover markers found in serum and urine, including collagen breakdown products, osteocalcin, and bone-specific alkaline phosphatase. The effect on markers of bone turnover was evident at three months and continued for the entire 36-month and 24-month monitoring periods. Thirty-three early postmenopausal women were randomly assigned to receive either no therapy, cyclic estrogen/progestin, or 60 mg of Raloxifene once a day in an open-label, thirty-one-week radiocalcium kinetics research. Hormone treatment and Raloxifene decreased bone resorption, leading to a favourable calcium balance change. Similar to the effects of estrogen therapy, there were slight declines in serum calcium, inorganic phosphate, total protein, albumin, and platelet count.

Pharmacokinetics:

• Absorption: Raloxifene is absorbed from the gastrointestinal tract with a bioavailability of approximately 2%.

• Distribution: It undergoes extensive distribution throughout the body, with a large volume of distribution of 2,348 L/kg. The drug predominantly binds to plasma proteins, with over 95% binding, mainly to albumin and α1-acid glycoprotein.

• Metabolism: Raloxifene undergoes extensive first-pass hepatic metabolism, leading to the formation of glucuronide conjugates. Additionally, it participates in enterohepatic recycling, contributing to its metabolic processes.

• Excretion: The primary route of excretion is through the faeces, with more than 93% of the drug eliminated in this manner. In the urine, less than 0.2% is excreted as the unchanged drug, and less than 6% is glucuronide conjugates.
• Raloxifene exhibits a half-life of approximately 27 hours.

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