[Approval Date
Year Month Day
Toremifene Citrate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name: Toremifene Citrate Tablets
Trade name: Faloton
English name: Toremifene Citrate Tablets
Hanyu Pinyin: Juyuansuan Tuoruimifen Pian
Ingredients
The main ingredient of this product is Toremifene Citrate.
Chemical name: (Z)-4-chloro-1,2-diphenyl-1-[4-(2-(N,N)-dimethylamino)ethoxy]phenyl-1-butene citrate
Chemical structure formula.
Molecular formula: C26H28CINO-C6H8O7
Molecular weight: 598.09
Properties
This product is a white or off-white, round, flat, beveled edge tablet with the word TO60 printed on one side.
Indications
It is indicated for the treatment of estrogen receptor positive/ or unknown metastatic breast cancer in postmenopausal women.
Specification
60mg
Dosage]
The recommended dose is 1 tablet (60mg) once daily.
Patients with renal insufficiency: No dose adjustment is required.
Hepatic impairment: Toremifene should be taken with caution (see [Pharmacokinetics] for details).
Adverse Reactions
Common adverse reactions are hot flashes, excessive sweating, uterine bleeding, leukorrhea, fatigue, nausea, rash, pruritus, dizziness, and depression. These adverse reactions are generally mild.
Organ System Classification Most Common* Common* Uncommon* Rare* Very Rare* Unknown Neoplasms: benign, malignant and of unknown nature (including cysts and polyps) Endometrial cancer Blood and lymphatic system disorders Thrombocytopenia, anemia and leukopenia Metabolic and nutritional disorders Loss of appetite Mental disorders Depression Insomnia Nervous system disorders Dizziness Headache Eye disorders Transient corneal clouding Ear and vagus disorders Vertigo Vascular Diseases Hot flashes Thromboembolic events Respiratory, thoracic, and mediastinal disorders Dyspnea Gastrointestinal disorders Nausea, vomiting Constipation Hepatobiliary disorders Elevated transaminases Hepatitis jaundice Skin and subcutaneous tissue disorders Hyperhidrosis Rash, pruritus Hair loss Reproductive and breast disorders Uterine bleeding and leukorrhea Endometrial hypertrophy Endometrial polyps Endometrial hyperplasia General symptoms and site conditions Fatigue Edema Weight gain * The incidence of adverse reactions is categorized as follows.
Very common ( ≥ 1/10).
Common ( ≥ 1/100, < 1/10 ).
Uncommon ( ≥ 1/1,000,< 1/100 ).
Rare ( ≥ 1/10,000,< 1/1,000 ).
Very rare ( < 1/10,000 ).
Not known (not predictable with the available information).
Thromboembolic events include deep vein embolism, thrombophlebitis, and pulmonary embolism (see [Precautions] for details).
Treatment with toremifene is associated with altered liver enzyme levels (elevated transaminases) but more severe liver function abnormalities (jaundice) are very rare.
Several cases have been reported of hypercalcemia at the start of toremifene treatment in patients with bone metastases.
Endometrial thickening may occur during treatment due to some of the estrogen-like effects of toremifene. There is an increased risk of endometrial changes including hyperplasia, polyps and endometrial cancer. This may be related to the underlying mechanism/estrogen-like stimulation (see [Precautions] for details).
Toremifene prolongs the QT interval in a dose-related manner.
Contraindications]
Prolonged administration of toremifene is contraindicated in patients with endometrial hyperplasia or severe hepatic failure.
Contraindicated in patients with known hypersensitivity to toremifene and any of the excipients in the tablets.
Preclinical and human trials have shown cardiac electrophysiological changes in the form of prolonged QT interval upon exposure to toremifene.
For drug safety reasons, toremifene is contraindicated in
– persons with congenital or acquired proven prolongation of the QT interval
– electrolyte disturbances, particularly intractable hypokalemia
– Clinically relevant bradycardia
– clinically relevant heart failure with reduced left ventricular ejection fraction
– with previous symptoms of arrhythmia
Toremifene should not be used in combination with other drugs that prolong the QT interval. (See [Drug Interactions] for details)
Precautions]
Toremifene has been shown to prolong the ECG QTc interval in a dose-related manner in some patients. The following information is particularly important regarding QT interval prolongation (see [Contraindications] for details). A parallel randomized double-blind clinical trial in 250 men in 5 arms (placebo, moxifloxacin 400 mg, toremifene 20 mg, toremifene 80 mg, toremifene 300 mg) was conducted to assess the effect of toremifene on the QTc interval. The results of the trial showed a mean prolongation of 21-26 ms with toremifene 80 mg, which strongly suggests an important dose-related effect. Women tend to have longer baseline QTc intervals than men and may be more sensitive to QTc interval prolonging drugs than men. Older patients may also be more susceptible to the effects of drug-related QT intervals. Toremifene should be used with caution in patients with ongoing arrhythmias such as acute myocardial ischemia or prolonged QT interval (especially in elderly patients) due to the possible increased risk of ventricular arrhythmias (including TdP) and even cardiac arrest (see [Contraindications] for more information).
If signs or symptoms of arrhythmia develop during toremifene treatment, stop the drug and review the ECG. If the QTc interval is greater than 500 ms, toremifene should not be used.
A gynecological examination is performed before treatment to rigorously check for endometrial abnormalities. Subsequent gynecologic exams should be performed at least every year. Patients at risk for endometrial cancer, such as those with hypertension or diabetes, or high body mass index (>30), or those with previous use of estrogen replacement therapy should be monitored closely (see [Adverse Reactions] for details).
Anemia, leukopenia and thrombocytopenia have been reported. Red blood cell, white blood cell, or platelet counts should be monitored with the use of phalloidin.
Hepatic injury has been reported with toremifene, including elevated liver enzymes (> 10 times the upper limit of normal), hepatitis, and jaundice. Most cases occurred during the first month of treatment. The pattern of liver injury was predominantly hepatocellular in nature.
Patients with a prior history of thrombotic disease are generally not treated with toremifene (see [Adverse Reactions] for details).
Patients with non-compensated cardiac insufficiency and severe angina pectoris should be closely monitored.
Patients with bone metastases may develop hypercalcemia at the beginning of treatment and should be monitored closely in these patients.
Systematic data are not available for patients with unstable diabetes mellitus, altered severe functional status or heart failure.
Effect on driving and ability to operate machinery: No effect.
Use with caution in athletes.
Faradone tablets contain 30 mg of lactose per tablet. This product should not be taken by persons with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
[For pregnant and lactating women].
Toremifene is recommended for postmenopausal women. There is a lack of sufficient data on the administration of phalloctone in humans during pregnancy. Animal studies have shown reproductive toxicity (see [Pharmacology and Toxicology] for details). The potential risk to humans is unclear.
This product is contraindicated during pregnancy.
In rats, administration during lactation may cause weight loss in their offspring.
This product is contraindicated during lactation.
For children]
Not applicable.
For elderly patients
Same as adults.
Drug Interactions]
The additive effect of QTc interval prolongation cannot be excluded when toremifene is used concomitantly with the following QTc interval prolongation drugs. This may increase the risk of ventricular arrhythmias (including torsional ventricular tachycardia TdP). Therefore, concomitant use of toremifene with
– Class IA antiarrhythmics (e.g., quinidine, hydroquinidine, dasuprenyl) or
– Class III antiarrhythmics (e.g., amiodarone, methylsulfamethoxydine, dofetilide, ibrit)
– neuroleptics (e.g., phenothiazines, permethrin, Schlitzel, haloperidol, sutropil)
– Certain antimicrobials (moxifloxacin, erythromycin IV, pentoxifylline, especially the antimalarial halofantrine)
– Certain antihistamines (terfenadine, astemizole, imipramine)
– Others (cisapride, vincristine IV, bepridil, diphenhydramine)
Drugs that reduce renal excretion of calcium e.g. thiazide diuretics can increase hypercalcemia
Enzyme inducers such as phenytoin sodium, phenobarbital and carbamazepine can accelerate the excretion of toremifene and decrease steady-state serum concentrations. Daily doses may have to be doubled when this occurs.
It is well established that anti-estrogenic drugs have a synergistic effect with favalin-based anticoagulants causing a severe increase in bleeding time. Therefore, concomitant administration with such drugs should be avoided.
The main metabolic pathway of toremifene is the CYP3A enzyme system, and the metabolism of toremifene can be inhibited by drugs that theoretically inhibit this enzyme system, such as the antifungal imidazole ketoconazole; other antifungal drugs (itraconazole, voriconazole, posaconazole); protease inhibitors (ritonavir, nelfinavir), macrolides (clarithromycin, erythromycin, telithromycin). Therefore, the simultaneous application with these drugs should be considered carefully.
Drug overdose]
Vertigo, headache and dizziness were observed in healthy volunteers with 680mg per day. The potential of toremifene to prolong the QTc interval in a dose-related manner should be taken into account in case of overdose. Symptomatic treatment with special antidotes is not required.
Pharmacology and Toxicology
Pharmacological effects
Toremifene is a non-steroidal tristephine derivative. Toremifene binds to estrogen receptors and may produce estrogenic activity or anti-estrogenic activity, or both of these activities, depending on the duration of administration, animal species, sex, target organ, or endpoint of choice. In general, non-steroidal tristephine derivatives produce mainly anti-estrogenic effects in rats and humans, and mainly estrogenic effects in mice. In rats, toremifene causes regression of dimethylbenzanthracene (DMBA)-induced mammary tumors. It is believed that the antitumor effect of toremifene in breast cancer is mainly due to its anti-estrogenic effect, which blocks estrogen-stimulated growth in tumors by competing with estrogen for binding sites.
Toxicological studies
Genotoxicity: Negative results in the Ames test for toremifene; positive results in the in vitro chromosomal aberration test, the human lymphoblastoid cell MCL-5 micronucleus test, and the in vivo rat hepatocyte chromosomal aberration test.
Reproductive toxicity: Impaired fertility and conception were observed in male and female rats given toremifene at doses ≥25.0 mg/kg/day and 0.14 mg/kg/day (approximately 4 times and 1/50th of the recommended maximum daily human dose of 60 mg based on body surface area), respectively. At these doses, male rats showed atrophy of the seminal vesicles and prostate gland and decreased sperm count, fertility index and fertilization rate; female rats showed significantly decreased fertility and fertility index and increased loss before and after implantation; the offspring of rats in the administered group showed decreased fertility index. Ovarian atrophy was observed in dogs given toremifene at a dose of ≥3 mg/kg/day (approximately 1.4 times the maximum recommended human daily dose of 60 mg based on body surface area) for 16 weeks, and ovarian cysts and endometrial stromal cells were observed in monkeys given toremifene at a dose of ≥1 mg/kg/day (approximately 1/3 the maximum recommended human daily dose of 60 mg based on body surface area) for 52 weeks. Structure reduction.
Maternal toxicity, increased loss before implantation, increased absorption, decreased fetal weight and fetal anomalies were seen in pregnant rats given to toremifene at approximately 6% of the maximum recommended human daily dose of 60 mg (based on body surface area) during organogenesis. Foetal anomalies include limb deformities, incomplete ossification, skeletal deformities, rib/vertebral anomalies, ureteral effusion, hydronephrosis, testicular displacement, and subcutaneous edema. Adverse embryo-fetus effects may be related to maternal toxicity. Similar embryo-fetal toxicity was seen in rabbits given to toremifene when the administered dose was approximately 40% of the maximum recommended daily human dose of 60 mg (based on body surface area), including increased preimplantation loss, increased absorption, incomplete ossification, and anencephaly.
Embryo-fetal toxicity was seen in rats and rabbits given to toremifene at doses ≥1.0 mg/kg/day and ≥1.25 mg/kg/day, respectively. In a rodent model of fetal litter development, toremifene inhibited female fetal uterine development, similar to that observed with hexestrol (DES) and tamoxifen administration. The clinical relevance of these changes is unclear. Whether toremifene has potential DES-like effects in the offspring (e.g., vaginal adenopathy) has not been evaluated in neonatal rodents. Administration of the same drug can lead to vaginal adenopathy in animals, and vaginal adenopathy has been observed in females exposed to hexenestrol in utero.
Animal studies have found that toremifene crosses the placenta and accumulates in rodent fetuses.
Carcinogenicity: A 2-year carcinogenicity test in rats showed that toremifene was not carcinogenic at doses ranging from 0.12 mg/kg/day to 12 mg/kg/day (approximately 1/50 to 2 times the maximum recommended daily human dose of 60 mg based on body surface area).
Results of a 2-year carcinogenicity test in mice showed an increased incidence of ovarian tumors, testicular tumors, bone tumors, and osteosarcomas at doses ranging from 1.0 mg/kg/day to 30.0 mg/kg/day (approximately 1/15 to 2 times the maximum recommended daily human dose of 60 mg on a body surface area basis). The clinical significance of the results of the mouse test is uncertain because the effects of estrogen in mice and the estrogen-like effects of toremifene in mice differ from those in humans. Other human estrogen receptor agonists/antagonists that have primarily estrogenic activity in mice can also lead to an increased incidence of ovarian and testicular tumors in mice. Endometrial hyperplasia was seen in monkeys given toremifene ≥1 mg/kg for 52 weeks and dogs given toremifene ≥3 mg/kg for 16 weeks (approximately 1/3 and 1.4 times the maximum recommended daily human dose of 60 mg, respectively, based on body surface area).
Pharmacokinetics]
General properties
Absorption
Toremifene is rapidly absorbed after oral administration and reaches peak serum concentration within 3 hours (between 2 and 5 hours). Food intake has no effect on absorption but delays the peak concentration by 1.5-2 hours. Changes due to feeding are not clinically significant.
Distribution
Phase I (distribution) half-life is 4 (between 2-12) hours and phase II (excretion) half-life is 5 (between 2-10) days. Basic distribution data (systemic clearance CL and volume of distribution V) cannot be estimated due to the lack of studies of intravenous administration. Toremifene binds heavily (> 99.5%) to serum proteins (mainly albumin). Serum toremifene pharmacokinetics are linear within 11-680 mg daily oral toremifene dose. The mean steady-state toremifene serum concentration at the recommended dose of 60 mg daily is 0.9 (between 0.6-1.3) µg/ml.
Metabolism
Toremifene is extensively metabolized. The major metabolite in human serum is N-desmethyltoremifene, with a mean half-life of 11 (between 4-20) days. Its steady-state concentration is approximately two times that of the parent drug. It has similar anti-estrogenic effects, but is not as potent as the parent drug’s antitumor effects. Its binding to serum proteins is more extensive than that of toremifene (> 99.9%). Three minor metabolites were detected in human serum: desaminohydroxytoremifene, 4-hydroxytoremifene, and N,N-desmethyltoremifene, but are not biologically important because of their low concentrations.
Excretion
Toremifene is excreted mainly as metabolites in the feces. There may be hepatic-intestinal circulation. Approximately 10% of the oral dose is excreted as metabolites in the urine. Due to slow excretion, steady-state concentrations in serum take 4 to 6 weeks to reach.
b) Patient characteristics
There is no positive correlation between clinical antitumor efficacy and serum concentrations at the recommended dose of 60 mg daily.
No data are available on the metabolism of multiple styles. The complex enzyme family known to metabolize toremifene in humans is cytochrome P450-dependent hepatic mixed function oxidase. The main metabolic pathway is CYP3A enzyme-induced demethylation.
In an open study on the pharmacokinetics of toremifene, patients were divided into four parallel groups (10 in each group): normal, hepatic impairment (median AST 57 U/L, median ALT 76 U/L, median r-GT 329 U/L) or hepatic activation (median AST 25 U/L, median ALT 30 U/L, median r-GT 91 U/L – patients in this group treated with antiepileptic drugs) and renal function impairment group (Cr 176 μmol/L). The results of the study showed no significant changes in toremifene pharmacokinetics in the renal impairment group compared to normal subjects. The excretion of toremifene and its metabolites increased significantly in the hepatic activation group, while it decreased in the hepatic impairment group.
Storage
Store at room temperature (15℃~25℃).
Package】
Aluminum foil green PVC plastic film packaging, 10 tablets per plate, 3 plates per box, 30 tablets/box.
Expiration date
60 months
Executive Standard
JX20130130
Approval number
H20130705
Manufacturer
Company Name ：Orion Corporation
Production Address: Tengstrominkatu 8, 20360, Turku , Finland
Packing Address: Joensuunkatu 7, Salo 24100,Finland
Postal Code: 02200
Tel: 358-10-4261
Fax: 358-10-4263815
Website: www.orion.fi