A selective estrogen receptor modulator, tamoxifen (Nolvadex) (SERM). It binds to estrogen receptors found on tumor cells and other tissues, such as breast tissue, that compete with estrogen. As a result, it blocks estrogen's actions by creating a nuclear complex that prevents DNA synthesis. Patients with the following conditions are treated with it:

• To reduce the risk of breast cancer in adult females at a high risk of breast cancer:

• For the treatment of breast cancer:

  • Ductal carcinoma in situ:

    • Following breast surgery and radiation, it is used to reduce the risk of invasive breast cancer in adult females with ductal carcinoma in situ.

  • Adjuvant treatment:

    • adult patients receiving adjuvant therapy for breast cancer that has early-stage estrogen receptor positivity.
    • to lower adult patients' risk of developing contralateral breast cancer.

  • Metastatic breast cancer:

    • For the treatment of patients with metastatic breast cancer who are estrogen receptor-positive.
• Off-Label Use of Tamoxifen in Adults:
  • Progressive or recurrent Desmoid tumors.
  • Idiopathic male infertility
  • For the induction of ovulation in breast cancer patients
  • Recurrent, metastatic, or high-risk endometrial carcinoma.
  • Gynecomastia
  • Severe mastalgia
  • Advanced or recurrent ovarian cancer.

Tamoxifen dose in Adults

Note: Patients who are being treated for breast cancer should receive tamoxifen followed by chemotherapy.

Tamoxifen dose in the treatment of risk reduction of Breast cancer in premenopausal and postmenopausal high-risk females:

• 20 mg orally once a day for 5 years.

Tamoxifen dose in the treatment of Breast cancer:

Adjuvant therapy:

• • 20 mg once a day

• Duration of therapy:

  • For Adjuvant Endocrine Therapy of Hormone-Receptor Positive Breast Cancer, the American Society of Clinical Oncology (ASCO) guidelines recommend the following durations of therapy. Note treatment is based on the menopausal status):

    • Premenopausal or perimenopausal at therapy initiation:

      • Tamoxifen should be used during the first five years.
      • Tamoxifen may be maintained for a total of 10 years if the menopausal status cannot be identified, after 5 years of medication, or if the patient is perimenopausal or premenopausal.
      • After five years of tamoxifen medication, if the patient is postmenopausal, tamoxifen may be maintained for a total of ten years, or it may be changed to an aromatase inhibitor for a maximum of ten years.

    • Postmenopausal at endocrine therapy initiation:

      • Treatment may be given for a total duration of 10 years or
      • For 5 years followed by an aromatase inhibitor or
      • for 2 - 3 years followed by an aromatase inhibitor for 5 years ( total duration of treatment of 7 - 8 years) or
      • Aromatase inhibitor for 5 years.

• To reduce the risk of invasive breast cancer in patients with ductal carcinoma in situ (DCIS) (females):

  • 20 mg once a day for 5 years.

  • Metastatic:

    • 20 mg once a day.

  • Guideline recommendations:

    •  For Hormone-Receptor Positive Metastatic Breast Cancer, The American Society of Clinical Oncology (ASCO) guidelines recommend the following based on the menopausal status of the patient:

      • Premenopausal:

        • In individuals who have not previously had endocrine treatment or ovarian suppression, tamoxifen may be used as first-line therapy.
        • An aromatase inhibitor may be prescribed if the patient has already taken ovarian suppression therapy.
        • It may also be used as a second-line treatment for ongoing ovarian suppression.
        • Although tamoxifen monotherapy is an option, combined treatment is recommended.

      • Postmenopausal:

        • It may be used as a second-line treatment for individuals who have not had endocrine therapy.
        • In patients who have previously had endocrine therapy with tamoxifen but had a delayed response, it may be given as either the first or second line of treatment. (defined as more than 12 months of adjuvant therapy).
        • Tamoxifen may be used as first- or second-line therapy for individuals who have already had endocrine therapy with an aromatase inhibitor.

      • Duration of therapy:

        • Tamoxifen treatment should be continued until disease progression is documented by imaging, clinical examination, or disease-related symptoms.

Dose in the treatment of recurrent, metastatic, or high-risk endometrial carcinoma (Off-label use):

• Monotherapy:

  • 20 mg two times a day until toxicity develops or the disease progresses.

• Combination therapy:

  • 20 mg two times a day for 3 weeks alternating with megestrol acetate every 3 weeks.
  • until unacceptable toxicity develops or the disease progresses.

Dose in the treatment of Gynecomastia (off-label):

• 20 mg once a day for up to 12 months.

Dose in the treatment of Idiopathic male infertility (off-label):

• 20 to 30 mg once a day for 3 - 6 months.
• This is followed by assisted reproductive therapy if tamoxifen treatment fails.

Dose in the treatment of Induction of ovulation in patients with breast cancer (off-label):

• In conjunction with low-dose follicle-stimulating hormone [FSH], 60 mg once a day commencing on the second or third day of the menstrual cycle).

• The course of treatment should last right up until hCG injection day.

Dose in the treatment of Mastalgia, severe (off-label):

• 10 mg once a day for 3 months.
• Further treatment may be considered if relapse occurs.

Dose in the treatment of advanced or recurrent ovarian cancer (off-label)

• 20 mg two times a day.

Tamoxifen dose in Children

Dose in the treatment of precocious puberty in patients with McCune-Albright syndrome:

• Children 2 - 10 years:
  • 20 mg once a day.

Tamoxifen (Nolvadex) Pregnancy Risk Category: D

• It may harm the developing fetus, according to theory.
• However, the data available are not sufficient to make a conclusion.
• Reports of vaginal bleeding, birth defects, and spontaneous abortions, as well as fetal deaths, have been made following the use of this medication in pregnancy.
• There is a risk that the fetus may develop a syndrome similar to diethylstilbestrol, (DES).
• A negative pregnancy test must be done before you start treatment.
• Tamoxifen therapy should be continued for 2 months, and then a non-hormonal contraceptive should be used.

Tamoxifen use during breastfeeding:

• It is unknown if the drug will be excreted into breast milk.
• It could also decrease milk production after birth.
• The manufacturer recommends that breastfeeding be stopped for at least three months following the last dose of Tamoxifen.

Tamoxifen dose in Renal Disease:

Dose adjustment in patients with kidney disease including those on hemodialysis has not been recommended by the manufacturer.

Tamoxifen dose in Liver Disease:

Dose adjustment in patients with liver disease has not been recommended by the manufacturer.

Common Side Effects of Nolvadex (Tamoxifen) Include:

• Hematologic & Oncologic:

  • Lymphedema

• Cardiovascular:

  • Vasodilatation
  • Flushing
  • Hypertension
  • Peripheral Edema

• Dermatologic:

  • Skin Changes
  • Skin Rash

• Central Nervous System:

  • Mood Changes
  • Pain
  • Depression

• Endocrine & Metabolic:

  • Hot Flash
  • Fluid Retention
  • Menstrual Disease
  • Weight Loss
  • Amenorrhea

• Gastrointestinal:

  • Nausea
  • Vomiting

• Genitourinary:

  • Vaginal Discharge
  • Vaginal Hemorrhage

• Neuromuscular & Skeletal:

  • Weakness
  • Arthritis
  • Arthralgia

• Respiratory:

  • Pharyngitis

Less Common Side Effects of Tamoxifen (Nolvadex) include:

• Cardiovascular:

  • Ischemic Heart Disease
  • Angina Pectoris
  • Chest Pain
  • Venous Thrombosis
  • Edema
  • Deep Vein Thrombosis
  • Myocardial Infarction

• Central Nervous System:

  • Headache
  • Anxiety
  • Insomnia
  • Dizziness
  • Paresthesia
  • Fatigue

• Dermatologic:

  • Diaphoresis
  • Alopecia

• Endocrine & Metabolic:

  • Oligomenorrhea
  • Weight Gain
  • Hypercholesterolemia
  • Ovarian Cyst

• Genitourinary:

  • Urinary Tract Infection
  • Leukorrhea
  • Mastalgia
  • Vaginitis
  • Vulvovaginitis

• Gastrointestinal:

  • Abdominal Pain
  • Constipation
  • Diarrhea
  • Dyspepsia
  • Abdominal Cramps
  • Anorexia

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Anemia
  • Breast Neoplasm
  • Neoplasm

• Hepatic:

  • Increased Serum AST
  • Increased Serum Bilirubin

• Hypersensitivity:

  • Hypersensitivity Reaction

• Infection:

  • Infection
  • Sepsis

• Neuromuscular & Skeletal:

  • Back Pain
  • Ostealgia
  • Arthropathy
  • Myalgia
  • Bone Fracture
  • Osteoporosis
  • Musculoskeletal Pain

• Ophthalmic:

  • Cataract

• Respiratory:

  • Cough
  • Bronchitis
  • Sinusitis
  • Dyspnea
  • Flu-Like Symptoms
  • Throat Irritation

• Renal:

  • Increased Serum Creatinine

• Miscellaneous:

  • Cyst

Rare side effects of Tamoxifen:

• Dermatologic:

  • Pruritus Vulvae

• Cardiovascular:

  • Cerebrovascular Accident
  • Phlebitis
  • Pulmonary Embolism
  • Thrombosis (especially the retinal Vein)

• Central Nervous System:

  • Tumor Pain may occur during the treatment Of Metastatic Breast Cancer which generally resolves with continuation)

• Endocrine & Metabolic:

  • Hypercalcemia
  • Hyperlipidemia

• Gastrointestinal:

  • Cholestasis
  • Dysgeusia

• Genitourinary:

  • Endometrial Polyps
  • Endometriosis
  • Endometrial Hyperplasia
  • Vaginal Dryness

• Hepatic:

  • Hepatic Necrosis
  • Hepatitis
  • Liver Steatosis

• Hematologic & Oncologic:

  • Endometrial Carcinoma
  • Tumor Flare (During Treatment Of Metastatic Breast Cancer; It usually resolves With Continuation)
  • Uterine Fibroids

• Ophthalmic:

  • Corneal Changes
  • Retinopathy

Contraindications to Tamoxifen Include:

• Severe allergic reactions such as angioedema or severe skin reactions to tamoxifen and any component of it can result in serious reactions.
• Patients on warfarin and those with a history of deep vein thrombosis or pulmonary embolism (when used for risk reduction and reduction of invasive malignancy in patients with ductal carcinoma in situ)

Warnings and precautions

• Metastatic breast cancer
  • Patients may experience worsening symptoms, increased bone pains, or tumor pains.
  • These symptoms usually appear within a few hours of treatment beginning and are associated with a positive response to treatment.
  • Patients with bony metastasis can develop hypercalcemia. In severe hypercalcemia, treatment may need to be stopped.
• Suppression of bone marrow
  • It can cause thrombocytopenia and leukopenia as well as neutropenia and pancytopenia.
  • Selten occurs bleeding diathesis due to significant thrombocytopenia. It is important to monitor blood counts regularly.
• Gynecologic effects/malignancies: [US-Boxed Warning]
  • It has been linked to serious and fatal uterine malignancies.
  • A National Surgical Adjuvant Breast and Bowel Project P-1 Trial was conducted on females at high risk of breast cancer.
  • It reported an incidence rate of 1.1% per 1000 women years.
• For endometrial carcinoma:
  • 2.20 for Tamoxifen versus 0.71 placebo
• Ocular effects
  • It has been associated with retinopathy, retinopathy, and corneal changes. There have also been reports of increased incidence of cataracts. It is important to evaluate the patient promptly
• For uterine Sarcoma:
  • Tamoxifen 0.17 versus placebo 0.04.
  • Most patients with uterine malignancies that result from tamoxifen are considered to be endometrial carcinomas. 
  • However, uterine cancers have been reported.
  • Uterine Sarcoma is usually associated with higher FIGO stages (III/IV) after diagnosis and poor prognosis.
  • It can also be short-lived. Uterine sarcomas can also develop after 2 years or more of tamoxifen treatment.
  • There have been reports of endometrial hyperplasia and endometriosis as well as polyps, uterine fibroids, and ovarian cysts.
  • It is possible to have irregular menstrual cycles and amenorrhea.
  • Tamoxifen therapy patients should undergo an annual gynecological examination.
  • Any abnormal vaginal bleeding or irregular menstrual cycles, pelvic pain, pressure or changes in vaginal discharge should be reported promptly.
• Hepatotoxicity:
  • Adjuvant tamoxifen 40 mg twice daily has been shown to increase the incidence of hepatocellular cancer in patients who have received it.
  • After its use, transaminitis and fatty liver may develop. It is important to monitor liver functions regularly.
• Thromboembolic Events: [US Boxed Warning]
  • There have been many life-threatening strokes and pulmonary embolisms, some of them fatal.
  • According to the National Surgical Adjuvant Breast and Bowel Project P-1 trial, the incidence rates for women at high risk of breast cancer are estimated to be per 1,000 women years
• To be exact:
  • 1.43 for Tamoxifen versus 1.00 for the placebo
• For pulmonary embolism
  • Tamoxifen 0.75 vs placebo 0.25
  • Tamoxifen's benefits outweigh the risks for patients with breast cancer.
  • However, benefits and risks should always be evaluated before treatment begins.
  • Pulmonary embolism can occur in an average of 27 to 60 months after treatment initiation.
  • DVT can occur after 19 to 30 months, while strokes may occur after about 30 months.
  • Tamoxifen should not be used in women with ductal carcinoma in situ and for the risk reduction of breast cancer in women who have had a history of pulmonary embolism or DVT and those who require warfarin.
  • Concomitant chemotherapy can increase the risk of thromboembolism.
  • Patients must be advised to notify their doctor if they experience symptoms of thromboembolism.
• Bone mineral density:
  • Tamoxifen protects bone mineral density (BMD) It prevents osteoporosis (in postmenopausal women) that lasts the 5-year treatment period.
  • Premenopausal women who had continued to have periods were able to observe a decrease in BMD.
• Hyperlipidemia:
  • Reports of hypercholesterolemia and cases of hyperlipidemia have been made.
  • Patients with hyperlipidemia should have their cholesterol and triglycerides checked regularly. 

Tamoxifen: Drug Interaction

Monitor:

• CBC with platelets,
• serum calcium,
• liver function tests;
• triglycerides and cholesterol in patients with hyperlipidemias;
• INR and prothrombin time (in patients on vitamin K antagonists like warfarin);
• pregnancy test before initiating the treatment in females of reproductive potential;
• monitor the patient for abnormal vaginal bleeding, irregular menstrual cycles, pelvic pain, and pelvic pressure;
• breast and gynecologic exams should be performed at baseline and as a routine,
• a mammogram should be done at baseline and as a routine
• Clinical features of DVT and pulmonary embolism such as leg swelling, tenderness, and shortness of breath;
• ophthalmic examination if vision problem or cataracts;
• bone mineral density in premenopausal women.
• Monitor adherence to the treatment.

How to administer Tamoxifen (Nolvadex)?

• Administer the tablets or oral solution orally with or without food.
• The supplied dosing cup should be used for the oral solution.

Mechanism of action of Tamoxifen (Nolvadex):

• Tamoxifen (Nolvadex), is a selective estrogen receptor modator (SERM). 
• It binds with the estrogen receptors found on breast cancer cells and other tissues, such as breasts, competing with estrogen.
• The nuclear complex it produces interferes with DNA synthesis and inhibits estrogen's effects.
• It is non-steroidal and has powerful anti-estrogenic qualities. It is cytostatic because it stops the cell cycle at the G phase.

Absorption: Well absorbed Distribution: It is distributed widely in the body, particularly to tissues with estrogen receptors.

Protein binding: It is highly protein-bound.

Metabolism is via the Hepatic route. It is metabolized via CYP2D6 to 4-hydroxy-tamoxifen and via CYP3A4/5 to N-desmethyl-tamoxifen. Each is then further converted into endoxifen. The metabolites are 30 - 100 times more potent than tamoxifen

Bioavailability: The oral solution is bioequivalent to the tablets

Half-life elimination: The half-life of tamoxifen is about 5 to 7 days and that of N-desmethyl tamoxifen is about 14 days.

Time to reach the peak serum concentration is: Children 2 - 10 years (female): about 8 hours Adults: about 5 hours

Excretion: About 65% of the drug is excreted primarily via feces and less than 30% is excreted as unchanged drug and unconjugated metabolites.

Clearance: It is higher about 2.3-fold in female pediatric patients (2 - 10 years) compared to adult patients with breast cancer. Within the pediatric population, clearance is faster in children 2 - 6 years compared to older children.

International Brands of Tamoxifen:

• Bilem
• Citofen
• Crisafeno
• Cytotam
• Cytotam-10
• Diemon
• Fenahex
• Genox
• Ginarsan
• Ginarsan Forte
• Gynatam
• Gyraxen
• Kessar
• Mamofen
• Medtax
• Moxafen
• Neophedan
• Neophedan-10
• Nolvadex
• Nolvadex D
• Nolvadex-D
• Novofen
• Novofen Forte
• Novofen-D
• Oncotamox
• Retaxim
• Soltamox
• Tadex
• Tamec
• Tamifen
• Tamifine
• Tamizam
• Tamodex
• Tamofen
• Tamofon
• Tamona
• Tamophar
• Tamoplex
• Tamorex
• Tamosin
• Tamox
• Tamoxen
• Tamoxifen-Eurogenerics
• Tamoxifen-Hexal
• Tamoxifenratioparm
• Tamoxifen-Teva
• Tamoxifen-Zeneca
• Tamoxin
• Tamoxis
• Tamoxit
• Taxus
• Tecnofen
• Temolex
• Xifen
• Zitazonium
• APO-Tamox
• DOM-Tamoxifen
• MYLAN-Tamoxifen
• Nolvadex D
• PMS-Tamoxifen
• TEVA-Tamoxifen

Tamoxifen Brands in Pakistan: