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Alendronate tablets

Product description
Approval date: August 19, 2009
 
Modified date: November 30, 2015
 
Alendronate tablets instructions
 
Please read the instructions carefully and use them under the guidance of a physician.
 
 
 
【Drug Name】
 
Common name: Alendronate tablets
 
English name: Alendronate Sodium Tablets
 
Chinese Pinyin: Alunlinsuanna Pian
 
[Ingredients] The main ingredient of this product is: alendronate sodium. Its chemical name is: (4-amino-1-hydroxybutylidene)-1,1-diphosphonic acid monosodium salt trihydrate.
 
Chemical Structure:
 
                 
 
Molecular formula: C4H12NNaO7P2·3H2O
 
Molecular weight: 325.12
 
【Properties】 This product is white or off-white.
 
[indications]
 
1. It is suitable for the treatment of osteoporosis in postmenopausal women to prevent hip and spinal fractures (vertebral compression fractures).
 
2, suitable for the treatment of male osteoporosis to prevent fractures.
 
[Specification] 10mg according to C4H13NO7P2
 
【Dosage】
 
This product must be taken with white water for at least half an hour before eating, drinking or applying other medications for the first time each day, as other beverages (including mineral water), food and some medications may reduce the absorption of this product ( See [drug interaction]).
 
In order to send the medicine to the stomach as soon as possible, to reduce the irritation to the esophagus, this product should be served with a full glass of white water in the morning, and the patient should avoid lying before at least 30 minutes after taking the medicine and before the first time of the day. . This product should not be taken at bedtime and before getting up early in the morning. Otherwise, it will increase the risk of adverse reactions to the esophagus (see [Precautions]).
 
If there is insufficient intake in food, all patients with osteoporosis should be supplemented with calcium and vitamin D (see [Precautions]).
 
Older patients or patients with mild to moderate renal insufficiency (creatinine clearance of 35 to 60 ml/min) do not need to adjust the dose. Due to lack of relevant medication experience, this product is not recommended for patients with more severe renal insufficiency (creatinine clearance <35ml/min).
 
Treatment of osteoporosis in postmenopausal women: The recommended dose is: once a day, once 10mg (1 tablet).
 
Treatment of male osteoporosis: The recommended dose is: once a day, once 10mg (1 tablet).
 
【Adverse reactions】
 
According to foreign literature reports:
 
Clinical research
 
In clinical studies, this product is generally well tolerated. In some years of research, the adverse reactions were usually mild and generally did not require treatment.
 
Treatment of postmenopausal women with osteoporosis
 
Applying 10 mg of this product daily, the results showed that the overall safety was similar to that of the placebo group. ≥1% of patients reported to receive 10 mg of this product per day, the possible upper-gastrointestinal adverse reactions that may occur, are likely or necessarily related to the drug and have a higher incidence than the placebo group include: abdominal pain (6.6% of this product) , placebo 4.8%), dyspepsia (3.6%, 3.5%), esophageal ulcer (1.5%, 0.0%), difficulty swallowing (1.0%, 0.0%), and bloating (1.0%, 0.8%).
 
Rash and erythema rarely occur.
 
In addition, ≥1% of patients receiving 10mg of this product per day, may occur, are likely or necessarily related to drugs, and the incidence is higher than the placebo group: musculoskeletal pain (this product 4.1 %, placebo 2.5%), constipation (3.1%, 1.8%), diarrhea (3.1%, 1.8%), flatulence (2.6%, 0.5%) and headache (2.6%, 1.5%).
 
Treatment of male osteoporosis
 
The safety data of male patients taking 10 mg of this product is consistent with that of postmenopausal women.
 
Clinical experience after product launch
 
The adverse reactions reported after the drug was put on the market were as follows:
 
Systemic reactions: Allergic reactions, including urticaria and rare angioedema. As with other bisphosphonates, a transient acute phase reaction (myalgia, malaise, and rare fever) occurs when you start taking this product. In the presence of incentive conditions, rare hypocalcemia can occur.
 
Gastrointestinal reactions: nausea, vomiting, esophagitis, esophageal erosion, esophageal ulcer, rare esophageal stricture or perforation, oropharyngeal ulcer; rare stomach and duodenal ulcer. Some are more severe with complications, although their causal relationship with the drug has not been determined (see [Precautions] and [Usage and Dosage]). A rare local osteonecrosis of the mandible occurs when the extraction and/or local infection is delayed.
 
Musculoskeletal: Bone, joint, and/or muscle pain, rare and severe or disabling.
 
Skin: rash (even with light allergy), itching. Rare severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis.
 
Special feeling: rare uveitis, rare scleritis.
 
Laboratory results
 
In a double-blind, multicenter, placebo-controlled clinical study, 18% and 10% of patients in this group had asymptomatic, mild, and transient serum calcium and serum phosphorus, respectively, in the placebo group. 12% and 3%. However, the incidence of serum calcium <8.0 mg/dL (2.0 mmol/L) and serum phosphorus ≤2.0 mgP/dL (0.65 mmol/L) was similar in both groups.
 
[taboo]
 
1. Esophageal abnormalities that cause delayed esophageal emptying, such as esophageal stricture or slowing.
 
2. Can not stand or sit for at least 30 minutes.
 
3. Those who are allergic to any of the ingredients in this product.
 
4. Hypocalcemia (see [Precautions]).
 
【Precautions】
 
Like other bisphosphonates, this product may cause local irritation to the upper digestive tract mucosa.
 
Among the patients taking this product, the reported esophageal adverse reactions were esophagitis, esophageal ulcers, and esophageal erosion, and rare reports of esophageal stricture or perforation. Some of these cases require hospitalization for these serious adverse reactions. Therefore, doctors should be alert to any symptoms and signs of possible esophageal reactions. Patients should be instructed to discontinue this product and seek medical advice if they have difficulty swallowing, swallowing pain, retrosternal pain, or new heartburn or heartburn.
 
Patients who continue to take medication after lying on the product, and/or without a full glass of water, and/or who have symptoms of esophageal irritation, are at greater risk of developing severe esophageal adverse reactions. Therefore, it is important to provide patients with detailed medication guidance so that they are fully understood (see [Usage and Dosage]).
 
Although no increase in the risk of gastric and duodenal ulcers has been observed in large-scale clinical trials abroad, there have been very few reports after marketing, some of which are more severe with complications. However, their causal relationship with drugs has not been determined.
 
Because this product has an irritating effect on the upper digestive tract mucosa and may aggravate the underlying disease, it should be used with active upper digestive tract diseases such as dysphagia, esophageal diseases, gastritis, duodenitis, ulcers or more recently. Patients with a history of gastrointestinal disease (nearly 1 year), such as peptic ulcer or active gastrointestinal bleeding or digestive tract surgery (except pyloric angioplasty).
 
In order to facilitate the delivery of this product to the stomach to reduce irritation to the esophagus, the patient should be instructed to swallow the drug with a full glass of water and not to lie in at least 30 minutes and before eating for the first time on the day. Patients should not chew or suck pills to prevent oropharyngeal ulcers. Patients should be especially advised not to take this product before going to bed or before getting up early in the morning. Patients should be told that if they do not follow the doctor's advice, they may increase the risk of esophageal problems. Patients should be told that if symptoms of esophageal disease (such as difficulty swallowing or pain, pain in the back of the chest, or new heartburn or increased heartburn) should be discontinued, the doctor should be diagnosed.
 
    This product is not recommended for patients with creatinine clearance <35ml/min (see [Usage and Dosage]).
 
In addition to estrogen deficiency and aging, other causes of osteoporosis should also be considered.
 
Hypocalcemia must be corrected before starting the application of this product (see [Contraindications]). Other abnormalities that affect mineral metabolism (such as vitamin D deficiency) should also be treated effectively. For these patients, serum calcium and hypocalcemia should be monitored when using this product.
 
[Pregnant women and lactating women]
 
Not studied in pregnant women, pregnant women should not use.
 
Studies have not been conducted in lactating women and should not be applied to such patients.
 
[Children's medication]
 
Children have not been studied and children should not use them.
 
[Geriatric Use]
 
In clinical studies, this product has not been found to have age-related differences in efficacy and safety, or as directed by a physician.
 
【medicine interactions】
 
If you take calcium supplements, antacids and other oral medications at the same time, it may interfere with the absorption of this product. Therefore, patients must wait at least half an hour before taking this product before taking other drugs.
 
No other clinically significant drug interactions are expected.
 
In the clinical study of osteoporosis, a small number of postmenopausal women were also taking estrogen (vaginal, subcutaneous or oral) while taking this product. No adverse reactions were found in the combination.
 
Specific interaction studies have not been conducted. In the treatment of osteoporosis in men and postmenopausal women, this product has been used with a variety of commonly used prescription drugs, no clear clinical adverse interactions.
 
【Drug overdose】
 
There is currently no information on the overdose of this product. Oral overdose may cause hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events such as stomach upset, heartburn, esophagitis, gastritis or ulcers. Milk or an antacid should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain upright.
 
【Pharmacology and Toxicology】
 
According to foreign literature reports:
 
Mechanism
 
Animal studies have found that this product has the following mode of action. At the cellular level, alendronate has an affinity for sites of bone resorption, particularly osteoclasts. Under normal circumstances, osteoclasts adhere to the bone surface but the edges are not rough, while the rough edges are a sign of active bone resorption. Alendronate does not affect the aggregation or adhesion of osteoclasts, but it does inhibit the activity of osteoclasts. Studies on the site of intraosseous action of [3H] alendronate labeled with radioactivity in mice showed that the uptake of osteoclasts was 10 times greater than that of osteoblasts. The radioactive [3H] alendronate sodium was administered to rats for 6 days and mice for 49 days. After examination of the bone tissue, normal bone was formed on alendronate, which was no longer bound to the matrix. It has pharmacological activity, so alendronate must be continuously administered to inhibit the newly formed absorption surface of osteoclasts. Histomorphometry of sputum and rats showed that alendronate reduced bone turnover (ie, the number of bone remodeling sites), and at these sites, bone formation exceeded bone resorption, resulting in increased bone mass.
 
Animal toxicology
 
Acute toxicity
 
For female rats and mice, the LD50 values ​​for oral alendronate sodium were 552 mg/kg (3256 mg/m2) and 966 mg/kg (2898 mg/m2), respectively (equivalent to human oral doses *27600 and 48300 mg). . For male rats, these values ​​are slightly higher, at 626 mg/kg and 1280 mg/kg, respectively. The dog oral dose of 200mg/kg (4000 mg/m2) still showed no lethal effect (equivalent to human oral dose *10000mg).
 
* Based on the patient's weight of 50 kg.
 
Chronic toxicity
 
Repeated dose-toxicity studies of rats and dogs for 1 year and 3 years, respectively, found that the associated changes in alendronate have the following aspects: the endogenous cartilage bone formation area retains the original pine Bone quality; alkaline phosphatase activity continued to decrease; blood calcium and blood phosphorus concentrations decreased transiently. These are all related to the expected pharmacological activity of alendronate. The dose of nephrotoxicity in species most sensitive to nephrotoxicity, such as dogs, is equivalent to at least 100 mg in humans. Rats require higher doses to exhibit this nephrotoxicity. Gastrointestinal toxicity only occurs in rodents. This may be due to a direct effect on the mucosa and only occurs when the dose exceeds 2.5 mg/kg/day.
 
Carcinogenic effect
 
Oral administration of alendronate sodium to rats at 3.75 mg/kg per day for 105 weeks and oral administration of alendronate sodium at 10 mg/kg/day showed no carcinogenic effects for 92 weeks.
 
Mutagenic effect
 
Regardless of the metabolic activity, the in vitro microbial mutagenicity test did not find that alendronate sodium has mutagenic effects. Similarly, in vitro mammalian cell mutagenicity test, in vitro rat liver cell alkaline elution test, and intravenous administration of alendronate sodium 25 mg/kg (75 mg/m2) in vivo chromosomal aberration test were also found to have mutagenic effects. . However, in vitro chromosomal aberration tests of Chinese hamster egg cells found that albendronate concentrations greater than 5 mM had weak cytotoxicity, which was not relevant for humans. Because the therapeutic dose in the body cannot reach the same concentration. Moreover, four of the five genotoxicity studies were purely negative, including studies most directly related to human carcinogenic potential (in vivo chromosomal aberration tests and microbial mutagenicity tests), as well as carcinogenic studies in rats and mice. Negative results indicate that alendronate is not genetically toxic or carcinogenic to humans.
 
Reproduction
 
Oral administration of alendronate sodium to rats at 5 mg/kg per day had no effect on the fertility and reproductive capacity of both sexes. The only drug-related effect found in these studies was the difficulty of delivery in rats. This is directly related to drug-mediated hypocalcemia, which can be prevented by supplementing calcium with rats. Moreover, the daily dose of 1.25 mg/kg had no effect.
 
Growth and development
 
In the toxicity study on growth and development, no adverse effects were observed in rats given alendronate 25 mg/kg per day and rabbits 35 mg/kg per day.
 
【Pharmacokinetics】
 
According to foreign literature reports:
 
absorb
 
Taking intravenous dose as a reference, alendronate sodium 5 to 70 mg was given 2 days before fasting and standard breakfast, and the average oral bioavailability was 0.64% in women and 0.6% in male oral 10 mg, both of which were similar. If administered 1 or 1.5 hours before the standard breakfast, its bioavailability has a similar decrease in both sexes (about 40%). Osteoporosis studies have shown that this product is given at least 30 minutes before eating or drinking for the first time each day.
 
If administered 2 hours or more after the standard breakfast, its bioavailability is negligible. Alendronate sodium with coffee or orange juice can reduce its bioavailability by about 60%.
 
For healthy people, oral administration of prednisone (20 mg three times a day for 5 days) had no clinically significant effect on the oral bioavailability of alendronate (an average increase of 20 to 44%).
 
distributed
 
Studies have shown that after intravenous administration of alendronate sodium 1 mg/kg, it is instantaneously distributed in soft tissues, but then rapidly redistributed to bone tissue or excreted through the urine. Its average steady-state volume of distribution in the human body, except for bone tissue, is at least 28L. Oral administration of a therapeutic dose of alendronate sodium is difficult to perform an assay (less than 5 ng/ml) due to its low concentration in plasma. Its plasma protein binding rate is about 78%.
 
metabolism
 
There is no evidence that alendronate is metabolized in animals or humans.
 
Clear
 
A single intravenous administration of C14-labeled alendronate found that about 50% of the radioactivity was excreted by the urine within 72 hours, with little or no radioactivity in the feces. The renal clearance rate was 71 ml/min after a single intravenous administration of 10 mg of alendronate, and the systemic clearance rate did not exceed 200 ml/min. The plasma concentration decreased by more than 95% within 6 hours after intravenous administration. Its terminal half-life in the human body is estimated to be greater than 10 years, suggesting that alendronate is released from the bone.
 
Patient characteristics
 
Preclinical studies have shown that this drug is not deposited in the bone and is rapidly excreted by the urine. Long-term accumulation of intravenous administration of 35 mg/kg in animals showed no evidence of bone resorption saturation. Although there is no clinical data, when renal function is impaired, as with animal studies, alendronate is likely to decline through renal clearance. Therefore, the accumulation of alendronate in the body may increase when kidney function is impaired (see [Usage and Dosage]).
 
[Storage] Sealed (10 ~ 30 ° C) for storage.
 
[Packing] Aluminum-plastic packaging, 6 pieces per box; 7 pieces per box; 12 pieces per box; 14 pieces per box.
 
[Validity Period] 24 months
 
[Executive Standards] "Chinese Pharmacopoeia" 2015 Edition 2
 
[Approval No.] National Drug Standard H20093921
 
【manufacturer】
 
  Company Name: Guangdong Pi Di Pharmaceutical Co., Ltd.
 
  Production address: No. 66, Pidi Avenue, Yueshan Town, Kaiping City, Guangdong Province
 
  Postal code: 529331
 
  Phone number: (0750) 2789348 2783621 National service phone: 400-8899-328
 
  Fax number: (0750) 2789348
 
  Website: http://www.pdpharm.com
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