[Adverse Reactions]

Adverse reactions of this product can be divided into two categories. One is caused by the pharmacological action of the drug. These include hot flashes, vaginal bleeding, increased vaginal discharge, genital itching and flaming reactions, and general adverse reactions such as gastrointestinal discomfort, headache, dizziness, and occasionally fluid retention and hair loss.

When adverse reactions are severe, they can be mitigated by lowering the dose (to no less than 20mg/ day) without losing control of the disease. If the dose is reduced and the adverse effect does not improve, the treatment of this product should be discontinued.

Adverse reactions in clinical trials

The frequency of ADR was defined as follows: very common (≥1/10); Common (≥1/100, <1/10); Occasionally (≥1/1000, <1/100); Rare (≥1/10000, <1/1000); Very rare (<1/10000); Not clear (impossible to estimate based on available data).

The following frequency categories were summarized based on adverse event data from a large, overseas phase II clinical study of 9,366 postmenopausal women with breast cancer who received 5 years of operable treatment.

Table 1 Adverse drug reactions by system organ classification and frequency

No such adverse effects were reported in the tamoxifen-treated group (n=3094) in this study. But it has been reported in other trials and in other ways. The frequencies were calculated using the upper 95% confidence interval of the valuation points (based on 3/X, where X represents the clinical study sample size, for example, 3094) and the result was 3/3094, equivalent to the "rare" frequency category.

B This event has not been observed in other major clinical studies. The frequencies were calculated using the upper 95% confidence interval of the valuation points (based on 3/X, where X represents the main clinical study sample size of 13,357 patients). The result is 3/13,357. Equivalent to the "Very Rare" frequency category.

Post-marketing application experience

Less frequently reported adverse events were vaginal bleeding, increased vaginal discharge, menstrual disorders, rashes, and headaches. Often these are not enough to warrant a dose reduction or a cessation of treatment. Very rare erythema pleomorphic, Stevens-Johnson syndrome, bullous pemphigus, interstitial pneumonia, and rare hypersensitivity reactions, including angioedema, have been reported during treatment with this product. In some cases, more than a year has elapsed since the onset. In rare cases, elevated serum triglyceride levels may be associated with the use of this product, with pancreatitis in some cases.

【 taboo 】

1. It is forbidden for pregnant women or women who plan to become pregnant (refer to [Drug use for pregnant women and lactating women] and [Precautions]). Before treatment, all premenopausal patients to be treated with this product must be carefully examined to rule out the possibility of pregnancy;

2. It is prohibited for patients who are allergic to this product or any of its ingredients;

3. It is forbidden for those with fundus lesions (refer to [Precautions]);

4. It is forbidden to use in combination with anastrozole.

[Precautions]

Warning and important points to note

1. As with other supplemental hormone therapies (estrogen and androgen), hypercalcemia has been reported in some patients with breast cancer with bone metastases within weeks of initiation of treatment with this product. If bone metastasis occurs, regular blood calcium examination is required at the beginning of treatment. If hypercalcemia does occur. Appropriate treatment should be taken: if it is serious, the product should be discontinued.

2. Premenopausal women receiving this product for the treatment of breast cancer. A certain proportion of patients have menstrual disorders or amenorrhea. There is an increased incidence of diseases associated with endometrial changes associated with tamoxifen treatment, including hyperplasia, polyps, endometrial cancers, and uterine sarcomas (mainly malignant Muller's duct mixed tumors). The mechanism is still unclear, but it may be related to the estrogen effect of tamoxifen.

3. The risk of endometrial cancer is associated with several factors, most of which affect estrogen levels. Therefore, this product may increase the risk of endometrial cancer. In addition. Other risk factors include obesity, never having given birth, diabetes, polycystic ovary syndrome, and hormone replacement therapy with only one of these hormones. In addition, the risk of endometrial cancer is more common with increasing age. Abnormal gynecological symptoms occur in any patient who has received or has been treated with this product. Especially non-menstrual vaginal bleeding, or menstrual irregularity, increased vaginal discharge and pelvic pain or a sense of pressure and other symptoms. Seek medical attention promptly.

4. In clinical studies, breast cancer patients treated with this product developed a second primary tumor outside the endometrium and contralateral breast (including liver cancer). In the Swedish trial of 40mg/ day adjuvant therapy for 2 to 5 years, 3 cases of liver cancer were reported in the treatment group. And 1 case of liver cancer in the observation group). It is not clear that this product is related to. The relationship between these secondary primary tumors and the clinical significance of these observations is unclear.

5. This product is associated with changes in liver enzyme levels and, in rare cases, with a range of more serious liver abnormalities, including fatty liver, cholestasis, hepatitis, and liver necrosis. A few of these serious incidents end in death. In most of the reported incidents, the relationship to the product is unclear. However, some positive remedication and discontinuation of medication have been reported. This product should be used with caution in patients with abnormal liver function.

6. Risk of venous thromboembolism

• This product can increase the risk of venous thromboembolism in healthy women by two to three times.

• In patients with breast cancer, physicians should carefully evaluate the patient's personal and family history of VTE before prescribing this product. If there is a prethrombotic risk. Patients should be further assessed for thromboembolism risk factors. Patients who test positive for thromboembolism risk should be explained. Based on the comprehensive assessment of benefits and risks, a prescription of this product can be issued in combination with anticoagulants in these patients.

• Severe obesity, increasing age, and all other VTE risk factors can further increase the risk of VTE. The physician should decide whether to prescribe the product based on a comprehensive assessment of the benefits and risks. Concomitant chemotherapy also increases the risk of VTE in breast cancer patients, so long-term anticoagulant prophylaxis is reasonable for breast cancer patients with multiple VTE risk factors.

• Surgery and long-term bed rest: for breast cancer patients. Treatment with tamoxifen-induced thrombosis should be discontinued only when the risk of tamoxifen-induced thrombosis is significantly greater than the risk of discontinuation of treatment. All patients should receive appropriate measures to prevent thrombosis. Preventive measures should include the use of graded pressure stockings during hospitalization. Start autonomic activity (if possible) and anticoagulation therapy as early as possible.

• If a patient develops VTE, treatment with tamoxifen should be discontinued immediately and appropriate antithrombotic measures taken. For breast cancer patients treated with this product, the patient benefits and risks should be evaluated in a comprehensive manner. On the basis of this decision whether to continue to receive this product treatment, when continue to receive this product treatment. Reasonable preventive anticoagulation measures should be taken at the same time.

• Patients are advised to contact a doctor immediately if they develop any symptoms of VTE.

7. This product may increase the risk of microvascular complications in patients with microsurgical breast reconstruction.

8. Ocular symptoms have been reported in subjects receiving this product, including corneal abnormalities, decreased visual perception of color, retinal venous thrombosis, and retinopathy. An increase in the incidence of cataracts and the need for cataract surgery has been reported in subjects treated with this product. People with fundus diseases should not use this product.

Other general precautions

1. This product contains lactose in the prescription. This product should not be used in patients with the rare genetic disorder lactose intolerance, Lapp lactase deficiency, or malabsorption of glucose-galactose.

2. Effects on driving and using machine ability: tamoxifen is unlikely to impair the patient's ability to drive or operate the machine. However, it is reported that. Use of this product may cause fatigue and caution should be exercised when driving or using machinery.

3. Athletes should use it with caution.

[Medication for pregnant and lactating women]

1. It is recommended that women with fertility potential avoid pregnancy during the use of this product. If you are sexually active, use condoms or other appropriate non-hormonal contraception. Premenopausal patients must be carefully examined before treatment to rule out pregnancy. If the patient is pregnant while taking this product. Or pregnant within two months after the cessation of treatment, they should be informed of the potential harm to the fetus.

2. Do not use this product during pregnancy. Although no studies have been conducted, there have been a small number of reports of spontaneous abortions, birth defects and fetal deaths among women using the product.

3. It is not known whether tamoxifen can be secreted through breast milk, so its use is not recommended during breastfeeding.

[Children's medicine]

The efficacy and safety of tamoxifen in the pediatric population is not yet clear, and tamoxifen is not recommended for use in children.

[Medication for the elderly]

Two foreign clinical studies suggest that. No overall differences in tolerance were observed between older and younger patients.

[Drug interactions]

Estrogen may affect the therapeutic effect of this product.

When used in combination with coumarin anticoagulants, the anticoagulant effect may be significantly increased. If this product is used in combination with coumarin anticoagulants in the treatment of breast cancer, careful monitoring of patients is recommended at the beginning of treatment.

This product and cytotoxic drugs combined with the treatment of breast cancer. There is an increased risk of thromboembolic events, so patients should take the necessary preventive measures during chemotherapy.

Tamoxifen in combination with anastrozole in adjuvant treatment of breast cancer has not been shown to be more effective than tamoxifen alone.

Tamoxifen reduced the plasma concentration of letrozole by 37%. It is not clear whether tamoxifen affects the metabolism and excretion of other anti-tumor drugs (such as cyclophosphamide) and other drugs that require mixed functional oxidase activation.

Tamoxifen is metabolized by CYP3A4 mediated by the cytochrome, and the combination of tamoxifen with the known CYP3A4 inducer of rifamequan can reduce the blood concentration of tamoxifen. Although the clinical correlation is unclear, the combination of tamoxifen and CYP3A4 inducer should be used with caution.

In combination with bromocryptotine, serum levels of tamoxifen and N-methyltamoxifen were increased.

Data from pharmacokinetic interaction studies have shown that CYP2D6 inhibitors can reduce plasma concentrations of 4-hydroxy-N-demethyltamoxifen, the main active metabolite of tamoxifen. Their plasma concentrations were reduced by 65-75%. In addition, combination with SSRI antidepressants such as paroxetine may reduce the efficacy of tamoxifen. Therefore, use of known CYP2D6 inhibitors (such as paroxetine, fluoxetine, and quinidine) should be avoided as far as possible. Sinacase or bupropion).

[Drug overdose]

From the theory. Speaking. Excessive use of this product can lead to increased side effects of the drug. In animal acute toxicity studies (100-200 times the recommended daily dose). The signs of toxicity observed at the highest doses were dyspnea and convulsions.

There have been no reports of acute drug overdoses in humans. In a study of patients with advanced metastatic cancer. In evaluating the use of very high doses to reverse multidrug resistance. The maximum tolerated dose of this product was determined and acute neurotoxic symptoms were observed. The performance is tremor, hyperreflexia, unsteady gait and dizziness. These symptoms occurred within 3-5 days of the initiation of treatment and resolved within 2-5 days of discontinuation of treatment, with no permanent neurotoxicity observed. One patient had an epileptic seizure a few days after discontinuation of the product and relief of neurotoxic symptoms. The causal relationship between seizures and treatment with this product is not clear. All of these patients received doses greater than 400mg/m2 loading dose. The maintenance dose was 150mg/m2 twice daily.

In the same study, patients were given a load dose greater than 250mg/m2. The maintenance dose was 80mg/m2 twice daily. EKG QT interval prolongation was observed. For women with a body surface area of 1.5m2, the minimum load dose and maintenance dose for neurological symptoms and changes in QT were at least 6 times higher than the maximum recommended dose.

There is no specific treatment for drug overdose: treatment must be symptomatic.

2. Pharmacological toxicology

Pharmacological effects Tamoxifen citrate is an anti-estrogen nonsteroidal drug. The antiestrogen effect of tamoxifen is related to its ability to compete with estrogen binding target tissues such as the binding sites on the breast. Tamoxifen can inhibit the occurrence of 7, 12-dimethylbenzanthracene (DMBA) -induced breast cancer in rats and induce tumor atrophy induced by DMBA. In a rat model, tamoxifen exerts anti-tumor effects by binding to estrogen receptors.

In the cytoplasm of cells derived from human breast cancer cells. Tamoxifen competes with estradiol for estrogen receptor protein.

Toxicology research

Genotoxicity: Tamoxifen has not shown genotoxicity in classical in vitro and in vivo prokaryotic or true nuclear test systems with drug metabolic systems. Tamoxifen induced increased levels of DNA adducts (3P - markers) in rat liver tissue and cultured human lymphocytes. Tamoxifen can increase the micronucleus level of human lymphoblast cell line (MCL-5). Based on these findings, tamoxifen is genotoxic to rodent cells and human MCL--5 cells.

Reproductive toxicity: Female rats were given tamoxifen 0.04mg/kg/d(in mg/m2) from 2 weeks before mating to 7 days of gestation. About 0.01 times the maximum daily recommended dose for humans). It can cause damage to the fertility and conception of female rats, significantly reduce the fertility and fertility index, and all embryos die.

Female rats were given tamoxifen 0.16mg/kg/d(mg/m2) from day 7 to 17 of pregnancy. About 0.03 times the maximum daily recommended human dose) and increased embryonic mortality. Rabbitswere given ≥0.125mg/kg/d(mg/ m2). About 0.05 times the maximum daily recommended dose for humans). Can cause fetal absorption, premature delivery, embryo death. No teratogenic changes were observed in rats and rabbits.

Reproductive research. Rats treated with tamoxifen at or below the human dose showed reversible, non-teratogenic changes in bone development. In studies of rat fertility and teratogenicity in rabbits, tamoxifen at or below human doses resulted in reduced embryo implantation rates and increased embryo mortality. Intrauterine growth retardation, and some rat pups showed lower learning behavior than historical data. Marmosets were given tamoxifen 10mg/kg/d(mg/m2) during organ formation or late pregnancy. About twice the maximum daily recommended dose for humans). No teratogenic changes were observed in animals with termination of pregnancy (this dose caused cessation of pregnancy in some animals) or in animals with continuation of pregnancy.

In rodent models, tamoxifen (mg/m2) was used to measure the efficacy of tamoxifen (mg/m2). About 0.002-2.4 times the maximum daily recommended dose for humans) caused changes in embryonic reproductive system development (similar to those caused by estradiol, acetylenestradiol, and diethylstilbestrol) in both sexes, although their clinical relevance is not known. But some of these changes, particularly vaginal adenosis, are similar to those seen in young women exposed to diethylstradiol, which causes progressive clear cell adenocarcinoma of the vagina or cervix with a 1 in 1,000 risk.

There is no data to suggest that tamoxifen can be secreted by human breast milk, if at all. There is no data on the effects of tamoxifen in breast milk on infants or animals that are lactating. Direct maternal (non-lactational) exposure to tamoxifen in newborn mice or rats is seen in: 1) reproductive system damage in female rodents (similar to that caused by human uterine exposure to diethylstilbestrol) and 2) reproductive system dysfunction in male rodents, such as testicular atrophy and impaired spermatogenesis.

Carcinogenicity: In the classic carcinogenicity study, rats were given 5, 20, and 35mg/kg/d(mg/m2) orally for 2 consecutive years. About 1, 3, and 7 times the maximum daily recommended dose for humans). Hepatocellular carcinoma was significantly increased in all dose groups, and the incidence of this tumor in 20 and 35mg/kg/d groups (69%) was significantly higher than that in 5mg/kg/d group (14%). In a separate study, rats were given tamoxifen 45mg/kg/d(measured in mg/m2). About nine times the maximum daily recommended dose for humans). Hepatocellular neoplasms can be seen at 3 to 6 months.

In two separate mouse studies. Mice were treated with 5, 20, and 50mg/kg/d(mg/m2) of trans racemic tamoxifen for 13 to 15 months. About 0.5, 2, and 5 times the recommended daily dose for humans). Here are granulosa cell tumors of the ovary and mesenchymal cell tumors of the testis.

[Pharmacokinetics]

The following are the data of clinical pharmacokinetic studies carried out abroad:

Absorption and distribution

A single dose of tamoxifen 20mg was taken orally. A mean plasma peak concentration of 40ng/mL(range) was reached approximately 5 h after administration