Tamoxifen

Tamoxifen is an antineoplastic agent belonging to the pharmacological class of Selective estrogen receptor modulators (SERM).

Tamoxifen is FDA-approved for the treatment of breast cancer in men and women and as a prophylactic agent against breast cancer in women.

Tamoxifen is rapidly absorbed from the gastrointestinal tract, peaking in 4-7 hours. Widely distributed into tissues, primarily those inhibiting estrogen receptors, it exhibits over 99% plasma protein binding. Extensively metabolized in the liver, it undergoes elimination mainly through faeces and urine.

The most common side effects of tamoxifen are hot flashes, mood swings, vaginal discharge, vaginal bleeding, nausea, and fluid retention.

Tamoxifen is available as oral tablets and solutions.

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

Tamoxifen is an antineoplastic agent belonging to the pharmacological class of Selective estrogen receptor modulators.

Tamoxifen competitively blocks the receptor that estrogen binds to, which is essential for estrogen's function in breast cancer cells. Tumor growth factor α and insulin-like growth factor 1 are decreased when tamoxifen is used, whereas sex hormone binding globulin is increased. The rise in sex hormone-binding globulin restricts the quantity of readily available estradiol. These modifications lessen the elements that promote the formation of tumours.

It has also been shown that tamoxifen causes estrogen receptor-positive cells to undergo apoptosis. This activity is believed to stem from the inhibition of protein kinase C, which stops DNA synthesis. Other possible explanations for the apoptotic impact of tamoxifen include the production of tumour growth factor β or the roughly three-fold increase in intracellular and mitochondrial calcium ion levels following treatment.

Tamoxifen is available as oral tablets and solutions.

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

Oral Liquid/solution: Shake the oral liquid or solution before use. Using a measuring cup or dosing syringe, measure the recommended dosage.

• Breast Cancer Prevention
• Ductal Carcinoma in Situ
• Ovulation Induction (Off-label)
• Mastalgia (Off-label)
• Gynecomastia

Tamoxifen effectively treats the metastatic breast cancer in both men and women. It is a pivotal treatment for women who have undergone surgery, radiation, and chemotherapy for breast cancer. Additionally, tamoxifen effectively addresses infertility arising from ovulation failure in women. Obstructing estrogen receptor binding hinders tumour growth, particularly in estrogen receptor-positive breast cancer. Administered as adjuvant therapy, tamoxifen demonstrates efficacy in early and metastatic stages. Beyond its curative role, tamoxifen serves preventively by reducing the likelihood of contralateral breast cancer, solidifying its significance in comprehensive breast cancer management.

It is indicated in the following conditions:

• Treat adults with metastatic breast cancer with estrogen receptor-positive tumours.
• Administer as adjuvant treatment for early-stage estrogen receptor-positive breast cancer, reducing contralateral breast cancer occurrence.
• Prescribe for women with ductal carcinoma in situ (DCIS) post-surgery and radiation to lower the risk of invasive breast cancer.
• Use to decrease breast cancer incidence in women at high risk for the disease.

Orally: Patients receive tamoxifen orally through tablets or solutions. The prescribed dosage is usually taken with water and can be administered with or without food, providing flexibility for incorporation into daily routines. This ease of administration enhances patient convenience and adherence to the treatment regimen. 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.

Tablets: 10mg, 20mg

Oral solution: 10mg/5mL

Tamoxifen is available as oral tablets and solutions.

.Dose Adjustment in Adult Patients:

Breast Cancer

Metastatic breast cancer: doses >20 mg/day should be divided BID (morning and evening); 20–40 mg/day PO

The FDA has approved a dosage range of 20 to 40 mg/day; however, there is no evidence of clinical benefit for doses higher than 20 mg/day.

Adjuvant breast cancer

Taking 20 mg PO qDay for 5–10 years is advised.

There is no extra therapeutic benefit at doses greater than 20 mg/day.

Ductal Carcinoma in Situ: 5 years at 20 mg PO qDay

Prevention of Breast Cancer: 20 mg PO qDay for five years

Off-label Ovulation Induction: 5–40 mg PO every 12 hours for four days

Off-label Mastalgia: 10 mg PO qDay for four months

While taking tamoxifen, specific dietary guidelines should be followed to ensure optimal effectiveness and safety. Consume a fibre-rich diet with healthy carbohydrates from fruits, vegetables, and whole grains. Incorporate fish, soy, tomatoes, Brussels sprouts, kale, broccoli, and omega-3 fatty acid-containing oils like olive oil to reduce prostate cancer risk potentially. Eliminate grilled and red meats, saturated fats from animal products, and dairy. Regular exercise to manage weight is crucial, as obesity is considered a risk factor for prostate cancer.

The dietary restriction should be individualized as per patient requirements.

• Hypersensitivity to tamoxifen or any container component or ingredient in the formulation.
• Pregnancy
• Patients whose condition requires concurrent warfarin therapy or who have a history of deep vein thrombosis or pulmonary embolus if treatment is indicated to reduce the occurrence of breast cancer in high-risk patients or to lower the risk of invasive breast cancer following DCIS treatment.
• Undiagnosed vaginal bleeding

• Liver abnormalities, including liver cancer and enzyme level changes, have been reported with tamoxifen use. Severe conditions like fatty liver, cholestasis, hepatitis, and hepatic necrosis, with occasional fatalities, have also been noted. Regularly monitor liver function.

• Tamoxifen's impact on non-uterine cancers is unknown.

• Hypercalcemia, occurring within weeks in breast cancer patients with bone metastases, requires prompt treatment. Severe cases may necessitate discontinuation.

• CYP2D6 polymorphism may reduce tamoxifen efficacy; monitor for lowered CYP2D6 activity.

• Platelet count decreases, sometimes leading to hemorrhagic episodes; perform periodic blood counts.

• Ocular disturbances, cataracts, and thromboembolic events may occur; seek medical attention for visual disturbances.

• Increased incidence of uterine malignancies, particularly adenocarcinoma and sarcoma, was reported. Assess risks in long-term users.

• Tamoxifen may affect bone mineral density, with varying effects based on menstrual status.

• Hypercholesterolemia and hypertriglyceridemia were reported; monitor lipid levels.

• Perform periodic CBC, including platelet counts and liver function tests during and post-treatment.

It is unsafe to consume alcohol.

Avoid breastfeeding while taking tamoxifen.

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

Consume fibre-rich foods and omega-3 sources; avoid red meat; exercise regularly.

The adverse reactions related to tamoxifen can be categorized as:

• Common Adverse Effects: Hot flashes, vaginal discharge, amenorrhea, and menstrual changes.
• Less Common Adverse Effects: Oligomenorrhea, cataracts, bone pain, nausea, cough, oedema, fatigue, musculoskeletal pain, ovarian cysts, depression, abdominal cramps, and anorexia.
• Rare Adverse Effects: Angioedema, endometrial cancer, corneal changes, loss of libido, pancreatitis, retinal vein thrombosis, stroke, and uterine fibroids.

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

• Drug-Drug Interaction: Tamoxifen may interact with other medications used to treat breast cancer (exemestane, letrozole, anastrozole), blood thinners (warfarin), anti-cancer drugs, antibiotics (rifampin), antidepressants (fluoxetine, paroxetine), anti-ulcer medications (cimetidine), medications related to the heart (quinidine), and medications that treat hyperparathyroidism/overactive parathyroid gland (cinacalcet).
• Drug-Food Interaction: Tamoxifen may interact with grapefruit juice.
• Drug-Disease Interaction: Patients who have a history of stroke or blood clot, are undergoing chemotherapy, have liver or renal problems, heart disease, high blood pressure, diabetes, high cholesterol, or cataracts should use tamoxifen with caution.

The common side effects of Tamoxifen include:

• Hot flushes
• Headache
• Vaginal discharge
• Fluid retention
• Muscle aches
• Tiredness
• Leg cramps
• Vaginal bleeding
• Mood swings
• Nausea
• Thinning of hair
• Numbness or tingling sensation

• Pregnancy

Pregnancy Category D (FDA): Use in situations where there is no safer medication available and life is in danger. Evidence that human fetal risk exists.

When given to a pregnant woman, fetal damage could result.

Tamoxifen was found to be genotoxic in nonhuman studies and to have inconclusive results in human studies, according to the FDA's reevaluation of genotoxicity data, postmarketing reports, and published literature. However, no significant congenital disabilities or adverse maternal or fetal outcomes have been linked to the drug, according to data from published literature and postmarketing reports from women who became pregnant between two and nine months after their last dose of tamoxifen.

Animal studies

In rat and rabbit studies, tamoxifen doses equivalent to or less than human doses increased embryotoxicity, abortions, and altered learning behaviours in offspring. Rodent models demonstrated reproductive tract changes resembling diethylstilbestrol (DES) effects in both male and female offspring. Animal studies suggest tamoxifen may hinder embryo implantation in reproductive females but may not consistently induce infertility. Women should be informed that tamoxifen does not invariably cause infertility, even with menstrual irregularities.

Contraception

Before initiating treatment, conduct a pregnancy test on females of reproductive potential. Advise these females to utilize effective non-hormonal contraception during the treatment period and for two months after the final dose.

Infertility

Tamoxifen may hinder the implantation of embryos in fertile females, according to research on animals, although it may not always result in infertility.

Inform women that even when menstruation irregularities are present, tamoxifen does not necessarily result in infertility.

• Nursing Mothers

Two placebo-controlled trials involving more than 150 women showed that tamoxifen reduces lactation. Tamoxifen dramatically reduces early postpartum milk production when given within 24 hours after delivery and for 5 to 18 days. The effect of tamoxifen on existing milk production is unknown. Data about tamoxifen excretion into human milk need to be included. In rodents, direct newborn exposure caused abnormalities in the male reproductive tract and lesions in the female reproductive tract. Women taking tamoxifen are advised not to breastfeed due to the possibility of significant adverse effects in nursing infants.

• Pediatric Use

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

• Geriatrics (> 65 years old)

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

Insufficient data from Tamoxifen studies involve subjects aged 65 or older. Clinical experience hasn't shown differences between elderly and younger patients. Caution in dose selection for elderly patients is essential, considering potential hepatic, renal, or cardiac function declines and other concurrent medical conditions or medications.

Dose Adjustment in Kidney Impairment Patients:

Patients with impaired renal function or any history of kidney disorders should take caution while administering Tamoxifen tablets.

Dose Adjustment in Hepatic Impairment Patients:

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

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Tamoxifen.

Signs and Symptoms

Overconsumption of Tamoxifen could lead to acute neurotoxicity manifested by tremors, hyperreflexia, unsteady gait, and dizziness.Within three to five days of starting tamoxifen, these symptoms disappeared two to five days after the medication was stopped.

Management

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

Timely medical intervention plays a crucial role in managing Tamoxifen overdose, ensuring careful monitoring and proper care to address symptoms and prevent complications.

Pharmacodynamics

In cancers that have estrogen receptors, tamoxifen suppresses growth and encourages apoptosis. Since the half-life of the active metabolite, N-desmethyl tamoxifen, is about two weeks, it has a lengthy duration of activity. Higher dosages may cause convulsions or trouble breathing, limiting its therapeutic index. The use of tamoxifen is also linked to a higher risk of uterine cancer.

Pharmacokinetics:

• Absorption: Tamoxifen undergoes rapid absorption from the gastrointestinal tract, reaching peak plasma concentration within 4-7 hours after administration.
• Distribution: Widely distributed into most tissues, primarily those inhibiting estrogen receptors. Plasma protein binding is significant, with over 99%, predominantly to albumin.

• Metabolism: Extensive liver metabolism is facilitated by demethylation (via CYP3A4/5) and hydroxylation (via CYP2D6), producing significant metabolites such as N-desmethyltamoxifen and minor metabolites like 4-hydroxytamoxifen, further metabolized to 4-hydroxy-N-desmethyltamoxifen (endoxifen).

• Excretion: Predominantly excreted via faeces (approximately 65% as polar conjugates, less than 30% as unchanged drug and unconjugated metabolites), with a minor contribution through urine (in small amounts).

• Elimination Half-life: Tamoxifen has an elimination half-life of approximately 5-7 days, while N-desmethyltamoxifen exhibits an elimination half-life of around 14 days.

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