Approval date: 09/01/2007 Modification date: 11/11/2013
Modification date: 24 December 2007 Modification date: 19 January 2015
Modification date: October 01, 2010 Modification date: December 01, 2015
Date Modified.
Tamoxifen Citrate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warning: This product package contains desiccant, please do not eat by mistake.
Drug Name]
Generic name: Tamoxifen Citrate Tablets
English name: Tamoxifen Citrate Tablets
Hanyu Pinyin: Juyuansuan Tamoxifen Pian
Ingredients
The main ingredient of this product is Tamoxifen Citrate.
Chemical name: (Z)-N,N-dimethyl-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]ethylamine citrate
Chemical structure formula.
Molecular formula: C26H29NO-C6H8O7
Molecular weight: 563.64
Excipients: lactose, corn starch, cross-linked sodium carboxymethyl cellulose, gelatin, magnesium stearate and film-coated premix (gastric soluble type).
Characteristic】
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
1.Recurrent or metastatic breast cancer.
2.For adjuvant treatment of early breast cancer after surgery.
Specification
10mg (based on tamoxifen)
Dosage
Take 10mg (1 tablet) orally twice a day, or 20mg (2 tablets) twice a day.
Adverse reactions]
The adverse reactions of this product can be divided into two categories, one is caused by the pharmacological effects of the drug, such as hot flashes, vaginal bleeding, increased vaginal discharge, vulvar itching and combustion tumor reaction, and the other is general adverse reactions, such as gastrointestinal discomfort, headache, dizziness, and occasionally fluid retention and hair loss.
When adverse reactions are severe, they can be reduced by lowering the dose (to no less than 20 mg/day) without losing control of the disease. If the dose is reduced and the adverse reaction profile does not improve, treatment with this product should be discontinued.
Adverse reactions in clinical trials
The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100, <1/10); occasional (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); unclear (cannot be estimated based on available data).
The following frequency categories are summarized from data on adverse events from a large clinical phase III study conducted abroad that included a total of 9366 postmenopausal female breast cancer patients who had received 5 years of operable treatment.
Table 1 Adverse drug reactions by systemic organ classification and frequency
Systemic organ classification (SOC) Frequency of adverse reactions (ADRs) Benign tumors.
malignant tumors and not otherwise specified
(including cysts and polyps) Common uterine fibroids Occasional endometrial carcinoma Rare uterine sarcoma (mostly malignant mixed Mullerian duct tumors)a
Tumor flarea Blood and lymphatic system disorders common anemia occasional thrombocytopenia
Leukopenia Rare neutropenia
Granulocyte deficiency immune system disorders common hypersensitivity reactions metabolic and nutritional disorders very common fluid retention occasionally hypercalcemia (patients with bone metastases) neurological disorders common ischemic cerebrovascular events
Headache
Dizziness
Sensory disorders (including sensory and taste disorders) Rare optic neuritis Ocular disorders common cataracts
Retinopathy Occasional visual disturbances Rare corneal abnormalities
Optic neuropathya vascular disease very common hot flashes common thromboembolic events (including deep vein thrombosis, microvascular thrombosis and pulmonary embolism)
Microvascular thrombosis and pulmonary embolism) Respiratory, thoracic, and mediastinal disorders Occasionally interstitial pneumonia Gastrointestinal disorders Very common Nausea Common vomiting
diarrhea
constipation occasionally pancreatitis hepatobiliary disease common liver enzyme abnormalities
Fatty liver occasionally cirrhosis rare hepatitis
Cholestasisa
Liver failurea
Hepatocellular injurya
Hepatic necrosisa Skin and subcutaneous tissue disorders very common rash common alopecia rare angioedema
Steven Johnsons syndromea
Cutaneous vasculitisa
Herpetic aspergillomaa
Erythema multiformea Very rare cutaneous lupus erythematosusb Musculoskeletal and connective tissue disorders Common leg spasms
Myalgia genital and breast disorders very common vaginal bleeding
Increased vaginal discharge common pruritus valgus
Endometrial changes (including hyperplasia and polyps) Rare endometriosisa
Cystic ovarian swellinga
Vaginal polyps Congenital, familial, and hereditary disorders Very rare Delayed cutaneous porphyriab General disorders and drug site conditions Very common Fatigue Laboratory tests Common elevated triglycerides Injury, toxicity, and surgical complications Very rare Radiotherapy memory reaction ba This adverse reaction was not reported in the tamoxifen-treated group in this study (n = 3094), but has been reported in other trials or by other routes . Frequencies were calculated using the upper 95% confidence interval of the valuation point (based on 3/X, where X represents the clinical study sample size, e.g. 3094). The result is 3/3094, which corresponds to the “rare” frequency category.
b The event was not observed in other major clinical studies. The frequency was calculated using the upper 95% confidence interval of the valuation point (based on 3/X, X representing a sample size of 13,357 patients in the primary clinical study). The result is 3/13,357, which corresponds to the “very rare” frequency category.
Post-marketing experience
Less frequently reported adverse reactions include vaginal bleeding, increased vaginal discharge, menstrual disorders, rash, and headache. These are usually not sufficient to require dose reduction or discontinuation of therapy. Very rare cases of erythema multiforme, Stevens-Johnson syndrome, herpetic aspergillosis, interstitial pneumonia, and rare hypersensitivity reactions, including angioedema, have been reported in the treatment of this product. In some cases, more than one year has elapsed since the onset of the attack. Rarely, elevated serum triglyceride levels may be associated with the use of this product, and some cases have been associated with pancreatitis.
[Contraindications
1. Contraindicated in pregnant women or women with pregnancy plans (refer to [Pregnancy and Lactation] and [Precautions] items). All premenopausal patients to be treated with this product must be carefully examined prior to treatment to exclude the possibility of pregnancy.
2. Contraindicated in patients who are hypersensitive to this product or any of its components.
3. Contraindicated in patients with fundus lesions (refer to item [Caution]).
4. Combined use with anastrozole is prohibited.
Precautions
Warnings and Important Precautions
1. As with other add-on hormone therapies (estrogen and androgen), hypercalcemia has been reported in some patients with bone metastatic breast cancer within a few weeks of starting treatment with this product. If bone metastases occur, blood calcium needs to be checked regularly during the initial treatment period; if hypercalcemia does occur, appropriate therapeutic measures should be taken; if severe, the product should be discontinued.
2. Menstrual disorders or amenorrhea occur in a certain percentage of premenopausal women receiving this product for breast cancer. There is an increased incidence of disease associated with endometrial changes associated with tamoxifen treatment, including hyperplasia, polyps, endometrial cancer, and uterine sarcomas (mainly malignant mixed mullerian duct tumors). The mechanisms involved are unclear and may be related to the estrogenic effects of tamoxifen.
3. The risk of endometrial cancer is associated with several factors, most of which can affect estrogen levels. Therefore, this product may increase the risk of endometrial cancer. In addition, other risk factors include obesity, never having had children, diabetes, polycystic ovary syndrome, and hormone replacement therapy with estrogen alone. There is also a general risk of endometrial cancer with advancing age. Any patient receiving or previously treated with this product who develops abnormal gynecological symptoms, especially non-menstrual vaginal bleeding, or symptoms such as irregular menstruation, increased vaginal discharge and pelvic pain or pressure, should seek prompt medical attention.
4. In clinical studies, there have been reports of second primary tumors (including hepatocellular carcinoma; in the Swedish trial of adjuvant treatment with 40 mg/day for 2-5 years, three cases of hepatocellular carcinoma were reported in the treatment group and one case of hepatocellular carcinoma was reported in the observation group) in patients with breast cancer treated with this product. The relationship between this product and the above-mentioned second primary tumor has not been clarified, and the clinical significance of the above observations is unclear.
5. This product has been associated with changes in liver enzyme levels and, in rare cases, a range of more serious liver abnormalities, including fatty liver, cholestasis, hepatitis, and hepatic necrosis. A few of these serious events ended in death. In the majority of reported events, the relationship with this product is unclear. However, some positive re-dosing and discontinuation of the drug have been reported. This product should be used with caution in patients with abnormal liver function.
6. Risk of venous thromboembolism
-This product may increase the risk of venous thromboembolism by 2-3 times in healthy women.
-In patients with breast cancer, a careful assessment of the patient’s personal and family history of venous thromboembolism should be made when prescribing this product. If a pre-thrombotic risk is indicated, the patient’s risk factors for thromboembolism should be further evaluated. Patients with a positive thromboembolic risk test should be accounted for. The decision to prescribe this product for these patients is based on the combined benefit and risk assessment, and it may be prescribed in combination with anticoagulants.
-Severe obesity, increased age, and all other risk factors for venous thromboembolism may further increase the risk of venous thromboembolism. Physicians should decide whether to prescribe this product for patients based on a combined benefit and risk assessment. Concomitant chemotherapy also increases the risk of venous thromboembolism in breast cancer patients, so long-term anticoagulation prophylaxis is reasonable for breast cancer patients with multiple risk factors for venous thromboembolism.
-Surgery and prolonged bed rest: In breast cancer patients, treatment with this product should be discontinued only if the risk of tamoxifen-induced thrombosis is significantly greater than the risk of interrupting therapy. All patients should receive appropriate thrombosis prophylaxis, which should include the use of graduated compression stockings during hospitalization, early voluntary activity (if possible), and anticoagulation therapy.
-If a patient develops venous thromboembolism, tamoxifen therapy should be discontinued immediately and appropriate antithrombotic measures should be instituted. For breast cancer patients treated with this product, a comprehensive assessment of patient benefit and risk should be made on the basis of which a decision to continue treatment with this product should be made, and when treatment with this product is continued, reasonable prophylactic anticoagulation measures should be taken concurrently.
-Patients are advised to contact their physicians for immediate management of any symptoms of venous thromboembolism.
7. This product may increase the risk of microvascular complications in patients undergoing microsurgical breast reconstruction.
8. Ocular symptoms including corneal abnormalities, decreased visual perception of color, retinal vein thrombosis and retinopathy have been reported in subjects receiving this product. Increased incidence of cataracts and the need for cataract surgery have been reported in subjects treated with this product. This product is contraindicated in patients with fundus disease.
Other General Precautions
1. This product contains lactose in the prescription. This product should not be used in patients with the rare genetic disorder galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
2. Effects on the ability to drive and use machinery: Tamoxifen is unlikely to impair the ability of patients to drive or operate machinery. However, the use of this product has been reported to cause fatigue and caution should be exercised when driving or using machinery.
3. Use with caution in athletes.
Pregnant women and nursing mothers
1. Women of childbearing potential are advised to avoid pregnancy during the use of this product and to use condom contraception or other suitable non-hormonal contraceptive measures if sexually active. Premenopausal patients must be carefully examined to rule out pregnancy prior to treatment. Patients should be informed of the potential risks to the fetus if they become pregnant while taking this product, or if they become pregnant within two months of stopping treatment.
2. The use of this product is contraindicated during pregnancy. Although no studies have been conducted, there have been a few reports of spontaneous abortion, birth defects, and fetal death in women following use of this product.
3. It is not known whether tamoxifen can be secreted through breast milk; therefore, the use of this product is not recommended during breastfeeding.
Pediatric Use]
The efficacy and safety of tamoxifen in the pediatric population is not known and its use in children is not recommended.
Geriatric use]
Two overseas clinical studies suggest that no overall differences in tolerability were observed between elderly patients and younger patients.
Drug Interactions]
Estrogen may affect the therapeutic effect of this product.
When used in combination with coumarin-based anticoagulants, the anticoagulant effect may be significantly increased. If this product is used in combination with coumarin anticoagulants for the treatment of breast cancer, careful monitoring of the patient at the beginning of treatment is recommended.
There is an increased risk of thromboembolic events when this product is used in combination with cytotoxic agents for the treatment of breast cancer; therefore, necessary prophylactic measures should be taken for patients during chemotherapy.
The combination of tamoxifen with anastrozole for the adjuvant treatment of breast cancer has not shown better efficacy compared to tamoxifen alone.
Tamoxifen reduced letrozole plasma concentrations by 37%. Whether tamoxifen has an effect on the metabolism and excretion of other antitumor agents (e.g., cyclophosphamide) and other drugs requiring mixed-function oxidase activation is unclear.
Tamoxifen is metabolized via cytochrome CYP3A4-mediated metabolism. Combination with known CYP3A4 inducers such as rifampicin decreases tamoxifen blood levels, and although the clinical relevance is unknown, tamoxifen should be combined with CYP3A4 inducers with caution.
Co-administration with bromocriptine increased serum levels of tamoxifen and N-desmethyltamoxifen.
Data from pharmacokinetic interaction studies show that CYP2D6 inhibitors reduce plasma concentrations of the main active metabolite of tamoxifen, 4-hydroxy-N-desmethyltamoxifen, by 65-75%. In addition, the combination of this product with SSRI antidepressants (e.g., paroxetine) may reduce the efficacy of tamoxifen. Therefore, combination with known CYP2D6 inhibitors (such as paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should be avoided if possible.
[Drug Overdose].
Theoretically, overdose of this product can lead to enhanced drug side effects. In acute toxicity studies in animals (100-200 times the recommended daily dose), the manifestations of toxicity observed at the highest dose were respiratory distress and convulsions.
There have been no reports of acute drug overdose in humans with this product. In a study in patients with advanced metastatic cancer, the maximum tolerated dose of this product was determined when evaluating the use of very high doses to reverse multidrug resistance, and acute neurotoxic symptoms were observed in the form of tremor, hyperreflexia, gait instability, and dizziness. These symptoms occurred within 3-5 days of treatment initiation and resolved within 2-5 days after discontinuation of treatment, and no permanent neurotoxicity was observed. One patient experienced seizures a few days after discontinuation of the product and resolution of neurotoxic symptoms. The causal relationship between seizures and treatment with this product is unclear. All of these patients were given a dose greater than the loading dose of 400 mg/m2 and a maintenance dose of 150 mg/m2 twice daily.
In the same study, prolongation of the ECG QT interval was observed in patients given a loading dose greater than 250 mg/m2 and a maintenance dose of 80 mg/m2 twice daily. For women with a body surface area of 1.5 m2, the minimum loading dose and maintenance dose at the onset of neurological symptoms and QT changes were at least six times higher compared to the maximum recommended dose.
There is no specific treatment for drug overdose; symptomatic treatment is necessary.
Pharmacology and Toxicology
Pharmacological effects
Tamoxifen citrate is a non-steroidal drug with anti-estrogenic effects. The anti-estrogenic effect of tamoxifen is related to its ability to compete with estrogen for binding sites on target tissues such as the breast. Tamoxifen inhibits 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis in rats and causes DMBA-induced tumor shrinkage. In a rat model, tamoxifen exerts antitumor effects by binding to estrogen receptors.
In the cytoplasm of cells derived from human breast cancer cells, tamoxifen competes with estradiol for estrogen receptor proteins.
Toxicological studies
Genotoxicity: Tamoxifen has not been shown to be genotoxic in classical ex vivo prokaryotic or eukaryotic test systems containing drug metabolism systems. Tamoxifen caused increased levels of DNA adducts (32P-labeled) in rat liver tissue and in cultured human lymphocytes. Tamoxifen increased micronuclei levels in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic to rodent cells and human MCL-5 cells.
Reproductive toxicity:
Administration of tamoxifen 0.04 mg/kg/d (at mg/m2, approximately 0.01 times the maximum recommended daily human dose) to female rats from 2 weeks prior to mating to day 7 of gestation caused impairment of fertility and conception in female rats, with a significant reduction in fertility and fertility index and total embryonic death.
Administration of tamoxifen 0.16 mg/kg/d (at mg/m2, approximately 0.03 times the maximum recommended daily human dose) to female rats on days 7 to 17 of gestation increased embryonic mortality. Rabbits given ≥0.125 mg/kg/d (at mg/m2, approximately 0.05 times the maximum recommended daily dose in humans) caused fetal resorption, preterm delivery, and embryonic death. No teratogenic changes were observed in rats and rabbits.
In reproductive studies, rats given tamoxifen at or below the human dose showed reversible, non-teratogenic alterations in skeletal development. In rat fertility and rabbit teratogenicity studies, tamoxifen at doses equivalent to or lower than human doses caused reduced embryonic fertility, increased embryonic mortality, delayed intrauterine development, and lower than historical data in the learning behavior of some rat pups. Tamoxifen given at 10 mg/kg/d (at mg/m2, approximately twice the maximum recommended daily dose in humans) during organogenesis or late gestation in marmoset monkeys, and no teratogenic changes were seen in animals that terminated their pregnancies (this dose caused some animals to stop) or continued their pregnancies.
In rodent models, tamoxifen (at mg/m2, approximately 0.002-2.4 times the maximum recommended daily dose in humans) caused alterations in embryonic reproductive development in both sexes (changes similar to those caused by estradiol, ethinyl estradiol, and ethylene estradiol), and although the clinical relevance of these changes is not known, some of them, particularly vaginal adenopathy, were associated with young women exposed to ethylene estradiol, and the risk of such changes causing progressive clear cell adenocarcinoma of the vagina or cervix is 1 in 1000.
There are no data to suggest that tamoxifen is secreted through human milk, and even if it is, there are no data to suggest that tamoxifen in milk has effects in nursing infants or animals. In mice or rats, direct exposure of newborn pups to tamoxifen via the maternal (non-lactal route) has been seen to cause 1) reproductive damage in female rodents (similar to that produced by human uterine exposure to ethylene estradiol) and 2) reproductive defects in male rodents, such as testicular atrophy and impaired spermatogenesis.
Carcinogenicity:In classical carcinogenicity studies, rats given tamoxifen 5, 20, and 35 mg/kg/d (approximately 1, 3, and 7 times the maximum recommended daily human dose in mg/m2) orally for 2 consecutive years showed a significant increase in hepatocellular carcinoma in all dose groups, and the incidence of this tumor was significantly higher in the 20 and 35 mg/kg/d groups (69%) than in the 5 mg/kg/d group (14%) ). In an independent study, hepatocellular tumors were seen in rats given tamoxifen 45 mg/kg/d (at mg/m2, approximately 9 times the maximum recommended daily dose in humans) at 3-6 months.
In two independent mouse studies, ovarian granulosa cell tumors and testicular mesenchymal stromal cell tumors were seen in mice given tamoxifen trans-exosomes 5, 20, and 50 mg/kg/d (at mg/m2, approximately 0.5, 2, and 5 times the recommended daily human dose) for 13 to 15 consecutive months.
Pharmacokinetics]
The following is information on clinical pharmacokinetic studies conducted abroad.
Absorption and distribution
A single oral dose of tamoxifen 20 mg reached a mean peak plasma concentration of 40 ng/mL (range 35-45 ng/mL) approximately 5 hours after administration. The plasma concentration of tamoxifen is biphasically reduced with a terminal elimination half-life of approximately 5-7 days. the mean peak plasma concentration of N-desmethyltamoxifen is 15 ng/mL (range 10-20 ng/mL). The mean steady-state plasma concentration of tamoxifen was 120 ng/mL (range 67-183 ng/mL) and N-desmethyltamoxifen was 336 ng/mL (range 148-654 ng/mL) when patients received tamoxifen 10 mg orally twice daily for 3 months. Mean steady-state plasma concentrations of tamoxifen and N-desmethyltamoxifen were 122 ng/mL (range 71 to 183 ng/mL) and 353 ng/mL (range 152 to 706 ng/mL), respectively, after once-daily tamoxifen 20 mg and 3 months of continuous dosing. Steady-state blood concentrations of tamoxifen were reached within approximately 4 weeks after treatment initiation and N-desmethyltamoxifen within approximately 8 weeks, indicating a half-life of approximately 14 days for this metabolite. A steady-state crossover equivalence study between twice daily doses of 10 mg of this product and once daily doses of 20 mg of this product showed bioequivalence between 20 mg and 10 mg of this product. Serum albumin binding of this product was high (>99%).
Metabolism
Tamoxifen is metabolized by hydroxylation, demethylation and binding reactions to yield several metabolites with similar pharmacological activity to the parent compound and exert therapeutic effects. n-Desmethyltamoxifen is the major metabolite found in patient plasma and the biological activity of n-desmethyltamoxifen is similar to that of tamoxifen. 4-hydroxytamoxifen and side chain primary alcohol derivatives of tamoxifen have been identified as plasma secondary metabolites. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6 and an inhibitor of P-glycoprotein. In patients lacking the CYP2D6 enzyme, 4-hydroxy-
N-desmethyltamoxifen plasma concentrations are approximately 75% lower than in patients with normal CYP2D6 enzyme activity. Combination with potent CYP2D6 inhibitors reduced 4-hydroxy-
N-desmethyltamoxifen circulating levels.
Excretion
Studies in female subjects given 14C-tamoxifen 20 mg showed that approximately 65% of the administered dose was excreted via the body within 2 weeks, indicating that the primary route of elimination of this product is via fecal excretion. The drug is excreted primarily as a polar conjugate, with the prototype drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.
Special Populations
The effect of age, gender and race on the pharmacokinetics of tamoxifen has not been determined. However, in a clinical study conducted abroad, girls aged 2 to 10 years with McCune Albright syndrome who were given 20 mg of tamoxifen daily for 12 months showed age-dependent reductions in clearance and increases in exposure (AUC) compared to adults (up to 50% increase in AUC in the youngest patients).
The effect of reduced hepatic function on the pharmacokinetics of tamoxifen has not been determined.
Storage】Store under light and seal.
Package]: 60 tablets/bottle in high-density polyethylene bottle.
Expiration date】 18 months
Execution Standard
Approval number】 State Drug Administration H32021472
Manufacturer
Company Name: Yangtze River Pharmaceutical Group Co.
Address: No. 1, Yangzijiang South Road, Taizhou City, Jiangsu Province
Postal Code: 225321
Telephone number: 400-988-1999
Fax number: (0523)86976161
Web
Address: www.yangzijiang.com