Alendronate Sodium

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Overview

What is Alendronate Sodium?

Alendronate sodium is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.

Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.

The empirical formula of alendronate sodium is CHNNaOP•3HO and its formula weight is 325.12. The structural formula is:

Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform.

Each tablet, for oral administration, contains 45.68 mg, 52.21 mg or 91.37 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 35 mg, 40 mg and 70 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.

What does Alendronate Sodium look like?

What are the available doses of Alendronate Sodium?

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What should I talk to my health care provider before I take Alendronate Sodium?

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How should I use Alendronate Sodium?

Alendronate sodium tablets, USP are indicated for:

Alendronate sodium tablets, USP must be taken one-half hour before the first food, beverage, or medication of the day with plain water only (see ). Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate sodium tablets (see ). Waiting less than 30 minutes, or taking alendronate sodium tablets with food, beverages (other than plain water) or other medications will lessen the effect of alendronate sodium tablets by decreasing its absorption into the body.

Alendronate sodium tablets should only be taken upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, an alendronate sodium tablet should be swallowed with a full glass of water (6 - 8 oz). Patients should not lie down for at least 30 minutes until after their first food of the day. Alendronate sodium tablets should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse experiences (see , ).

Patients should receive supplemental calcium and vitamin D, if dietary intake is inadequate (see ).

No dosage adjustment is necessary for the elderly or for patients with mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). Alendronate sodium tablets are not recommended for patients with more severe renal insufficiency (creatinine clearance <35 mL/min) due to lack of experience.

What interacts with Alendronate Sodium?

Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia

Inability to stand or sit upright for at least 30 minutes

Hypersensitivity to any component of this product

Hypocalcemia (see )

What are the warnings of Alendronate Sodium?

LOT NUMBER_____________________________

Alendronate sodium, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking alendronate sodium and/or who fail to swallow it with the recommended amount of water, and/or who continue to take alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see ). In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should be used under appropriate supervision.

Because of possible irritant effects of alendronate sodium on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when alendronate sodium is given to patients with active upper gastrointestinal problems (such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers).

There have been post-marketing reports of gastric and duodenal ulcers, some severe and with complications, although no increased risk was observed in controlled clinical trials.

What are the precautions of Alendronate Sodium?

General

Causes of osteoporosis other than estrogen deficiency, aging, and glucocorticoid use should be considered.

Hypocalcemia must be corrected before initiating therapy with alendronate sodium (see ). Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate sodium.

Presumably due to the effects of alendronate sodium on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget's disease, in whom the pretreatment rate of bone turnover may be greatly elevated and in patients receiving glucocorticoids, in whom calcium absorption may be decreased.

Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget's disease of bone and in patients receiving glucocorticoids.

Musculoskeletal Pain

In post marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis (see ). This category of drugs includes alendronate sodium. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups.

Dental

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection, often with delayed healing, has been reported in patients taking bisphosphonates. Most reported cases of bisphosphonate-associated osteonecrosis have been in cancer patients treated with intravenous bisphosphonates, but some have occurred in patients with postmenopausal osteoporosis. Known risk factors for osteonecrosis include a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., pre-existing dental disease, anemia, coagulopathy, infection).

Patients who develop osteonecrosis of the jaw (ONJ) while on bisphosphonate therapy should receive care by an oral surgeon. Dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk for ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Renal insufficiency

Alendronate sodium is not recommended for patients with renal insufficiency (creatinine clearance <35 mL/min). (See .)

Glucocorticoid-induced osteoporosis

The risk versus benefit of alendronate sodium for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established (see ). Before initiating treatment, the hormonal status of both men and women should be ascertained and appropriate replacement considered.

A bone mineral density measurement should be made at the initiation of therapy and repeated after 6 to 12 months of combined alendronate sodium and glucocorticoid treatment.

The efficacy of alendronate sodium for the treatment of glucocorticoid-induced osteoporosis has been shown in patients with a median bone mineral density which was 1.2 standard deviations below the mean for healthy young adults.

The efficacy of alendronate sodium has been established in studies of two years' duration. The greatest increase in bone mineral density occurred in the first year with maintenance or smaller gains during the second year. Efficacy of alendronate sodium beyond two years has not been studied.

The efficacy of alendronate sodium in respect to fracture prevention has been demonstrated for vertebral fractures. However, this finding was based on very few fractures that occurred primarily in postmenopausal women. The efficacy for prevention of non-vertebral fractures has not been demonstrated.

Information for Patients

General

Physicians should instruct their patients to read the patient package insert before starting therapy with alendronate sodium and to reread it each time the prescription is renewed.

Patients should be instructed to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.

Dosing Instructions

Patients should be instructed that the expected benefits of alendronate sodium may only be obtained when it is taken with plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage, or medication of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate sodium (see ).

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation patients should be instructed to swallow each tablet of alendronate sodium with a full glass of water (6-8 oz). Patients should be instructed not to lie down for at least 30 minutes until after their first food of the day. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take alendronate sodium at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems. Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate sodium and consult their physician.

Patients should be instructed that if they miss a dose of once weekly alendronate sodium, they should take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.

Drug Interactions

(also see )

Estrogen/hormone replacement therapy (HRT)

Concomitant use of HRT (estrogen ± progestin) and alendronate sodium was assessed in two clinical studies of one or two years' duration in postmenopausal osteoporotic women. In these studies, the safety and tolerability profile of the combination was consistent with those of the individual treatments; however, the degree of suppression of bone turnover (as assessed by mineralizing surface) was significantly greater with the combination than with either component alone. The long-term effects of combined alendronate sodium and HRT on fracture occurrence have not been studied (see and ).

Calcium Supplements/Antacids

It is likely that calcium supplements, antacids, and some oral medications will interfere with absorption of alendronate sodium. Therefore, patients must wait at least one-half hour after taking alendronate sodium before taking any other oral medications.

Aspirin

In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate sodium greater than 10 mg and aspirin-containing products.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Alendronate sodium may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate sodium 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate sodium.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to 0.12 to 1.2 times a maximum recommended daily dose of 40 mg (Paget's disease) based on surface area, mg/m. The relevance of this finding to humans is unknown.

Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to 0.26 and 1 times a 40 mg human daily dose based on surface area, mg/m. The relevance of this finding to humans is unknown.

Alendronate was not genotoxic in the microbial mutagenesis assay with and without metabolic activation, in an mammalian cell mutagenesis assay, in an alkaline elution assay in rat hepatocytes, and in an chromosomal aberration assay in mice. In an chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results.

Alendronate had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (1.3 times a 40 mg human daily dose based on surface area, mg/m).

Pregnancy

Pregnancy Category C:

Reproduction studies in rats showed decreased postimplantation survival at 2 mg/kg/day and decreased body weight gain in normal pups at 1 mg/kg/day. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at 10 mg/kg/day in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. The above doses ranged from 0.26 times (1 mg/kg) to 2.6 times (10 mg/kg) a maximum recommended daily dose of 40 mg (Paget's disease) based on surface area, mg/m. No similar fetal effects were seen when pregnant rabbits were treated at doses up to 35 mg/kg/day (10.3 times a 40 mg human daily dose based on surface area, mg/m).

Both total and ionized calcium decreased in pregnant rats at 15 mg/kg/day (3.9 times a 40 mg human daily dose based on surface area, mg/m) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as 0.5 mg/kg/day (0.13 times a 40 mg human daily dose based on surface area, mg/m) when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) occurred in the female rats treated with 15 mg/kg/day for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; calcium supplementation IV prevented maternal, but not fetal deaths.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.

There are no studies in pregnant women. Alendronate sodium should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers

It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alendronate sodium is administered to nursing women.

Pediatric Use

The efficacy and safety of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfecta. One-hundred-and-nine patients were randomized to 5 mg alendronate sodium daily (weight < 40 kg) or 10 mg alendronate sodium daily (weight ≥ 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate sodium-treated patients and 0.1 in the placebo-treated patients. Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate sodium patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate sodium-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects. There were no statistically significant differences between the alendronate sodium and placebo groups in reduction of bone pain.

Alendronate sodium is not indicated for use in children.

(For clinical adverse experiences in children, see .)

Geriatric Use

Of the patients receiving alendronate sodium in the Fracture Intervention Trial (FIT), 71% (n=2302) were ≥65 years of age and 17% (n=550) were ≥75 years of age. Of the patients receiving alendronate sodium in the United States and Multinational osteoporosis treatment studies in women, osteoporosis studies in men, glucocorticoid-induced osteoporosis studies, and Paget's disease studies (see ), 45%, 54%, 37%, and 70%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

What are the side effects of Alendronate Sodium?

Clinical Studies

In clinical studies of up to five years in duration adverse experiences associated with alendronate sodium usually were mild, and generally did not require discontinuation of therapy.

Alendronate sodium has been evaluated for safety in approximately 8000 postmenopausal women in clinical studies.

Treatment of osteoporosis

Postmenopausal women

In two identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational; n=994), discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with alendronate sodium 10 mg/day and 6.0% of 397 patients treated with placebo. In the Fracture Intervention Trial (n=6459), discontinuation of therapy due to any clinical adverse experience occurred in 9.1% of 3236 patients treated with alendronate sodium 5 mg/day for 2 years and 10 mg/day for either one or two additional years and 10.1% of 3223 patients treated with placebo. Discontinuations due to upper gastrointestinal adverse experiences were: alendronate sodium, 3.2%; placebo, 2.7%. In these study populations, 49 - 54% had a history of gastrointestinal disorders at baseline and 54 - 89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies. Adverse experiences from these studies considered by the investigators as possibly, probably, or definitely drug related in ≥1% of patients treated with either alendronate sodium or placebo are presented in the following table.

Rarely, rash and erythema have occurred.

One patient treated with alendronate sodium (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant aspirin developed an anastomotic ulcer with mild hemorrhage, which was considered drug related. Aspirin and alendronate sodium were discontinued and the patient recovered.

The adverse experience profile was similar for the 401 patients treated with either 5 or 20 mg doses of alendronate sodium in the United States and Multinational studies. The adverse experience profile for the 296 patients who received continued treatment with either 5 or 10 mg doses of alendronate sodium in the two-year extension of these studies (treatment years 4 and 5) was similar to that observed during the three-year placebo-controlled period. During the extension period, of the 151 patients treated with alendronate sodium 10 mg/day, the proportion of patients who discontinued therapy due to any clinical adverse experience was similar to that during the first three years of the study.

In a one-year, double-blind, multicenter study, the overall safety and tolerability profiles of once weekly alendronate sodium 70 mg and alendronate sodium 10 mg daily were similar. The adverse experiences considered by the investigators as possibly, probably, or definitely drug related in ≥1% of patients in either treatment group are presented in the following table.

**Osteoporosis Treatment Studies in Postmenopausal Women: Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in ≥1% of Patients**
	United States/Multinational Studies	Fracture Intervention Trial
	Alendronate Sodium %(n=196)	Placebo%(n=397)	Alendronate Sodium %(n=3236)	Placebo%(n=3223)
Gastrointestinal
Musculoskeletal	4.10.0	2.51.0	0.40.2	0.30.1
Nervous System/Psychiatric	2.60.0	1.51.0	0.20.0	0.20.1
Special Senses	0.5	1.0	0.1	0.0
	Once Weekly Alendronate Sodium70 mg %(n=519)	AlendronateSodium 10 mg/day%(n=370)
Gastrointestinal
Musculoskeletal

Men

In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of alendronate sodium 10 mg/day and a one-year study of once weekly alendronate sodium 70 mg) the rates of discontinuation of therapy due to any clinical adverse experience were 2.7% for alendronate sodium 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate sodium 70 mg vs. 8.6% for placebo. The adverse experiences considered by the investigators as possibly, probably, or definitely drug related in ≥2% of patients treated with either alendronate sodium or placebo are presented in the following table.

**Osteoporosis Studies in Men: Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in ≥2% of Patients**
	Two-year Study	One-year Study
	Alendronate Sodium10 mg/day%(n=146)	Once Weekly Alendronate Sodium 70 mg%(n=109)
Gastrointestinal

Prevention of osteoporosis in postmenopausal women

The safety of alendronate sodium 5 mg/day in postmenopausal women 40 to 60 years of age has been evaluated in three double-blind, placebo-controlled studies involving over 1,400 patients randomized to receive alendronate sodium for either two or three years. In these studies the overall safety profiles of alendronate sodium 5 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 7.5% of 642 patients treated with alendronate sodium 5 mg/day and 5.7% of 648 patients treated with placebo.

In a one-year, double-blind, multicenter study, the overall safety and tolerability profiles of once weekly alendronate sodium 35 mg and alendronate sodium 5 mg daily were similar.

The adverse experiences from these studies considered by the investigators as possibly, probably, or definitely drug related in ≥1% of patients treated with either once weekly alendronate sodium 35 mg, alendronate sodium 5 mg/day or placebo are presented in the following table.

**Osteoporosis Prevention Studies in Postmenopausal Women: Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in ≥1% of Patients**
	Two/Three-Year Studies	One-Year Study
	(n=361)	Once Weekly Alendronate Sodium35 mg%
Gastrointestinal
Musculoskeletal

Concomitant use with estrogen/hormone replacement therapy

In two studies (of one and two years' duration) of postmenopausal osteoporotic women (total: n=853), the safety and tolerability profile of combined treatment with alendronate sodium 10 mg once daily and estrogen ± progestin (n=354) was consistent with those of the individual treatments.

Treatment of glucocorticoid-induced osteoporosis

In two, one-year, placebo-controlled, double-blind, multicenter studies in patients receiving glucocorticoid treatment, the overall safety and tolerability profiles of alendronate sodium 5 and 10 mg/day were generally similar to that of placebo. The adverse experiences considered by the investigators as possibly, probably, or definitely drug related in ≥1% of patients treated with either alendronate sodium 5 or 10 mg/day or placebo are presented in the following table.

The overall safety and tolerability profile in the glucocorticoid-induced osteoporosis population that continued therapy for the second year of the studies (alendronate sodium: n=147) was consistent with that observed in the first year.

**One-Year Studies in Glucocorticoid-Treated Patients: Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in ≥1% of Patients**
	Alendronate Sodium10 mg/day%	Alendronate Sodium5 mg/day%	Placebo %

Paget's disease of bone

In clinical studies (osteoporosis and Paget's disease), adverse experiences reported in 175 patients taking alendronate sodium 40 mg/day for 3 - 12 months were similar to those in postmenopausal women treated with alendronate sodium 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse experiences in patients taking alendronate sodium 40 mg/day (17.7% alendronate sodium vs. 10.2% placebo). One case of esophagitis and two cases of gastritis resulted in discontinuation of treatment.

Additionally, musculoskeletal (bone, muscle or joint) pain, which has been described in patients with Paget's disease treated with other bisphosphonates, was considered by the investigators as possibly, probably, or definitely drug related in approximately 6% of patients treated with alendronate sodium 40 mg/day versus approximately 1% of patients treated with placebo, but rarely resulted in discontinuation of therapy. Discontinuation of therapy due to any clinical adverse experience occurred in 6.4% of patients with Paget's disease treated with alendronate sodium 40 mg/day and 2.4% of patients treated with placebo.

Osteogenesis Imperfecta

Alendronate sodium is not indicated for use in children.

The overall safety profile of alendronate sodium in OI patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate sodium. However, there was an increased occurrence of vomiting in OI patients treated with alendronate sodium compared to placebo. During the 24-month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate sodium and 3 of 30 (10%) patients treated with placebo.

In a pharmacokinetic study, 6 of 24 pediatric OI patients who received a single oral dose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration. These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate sodium. See .

Laboratory Test Findings

In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate sodium versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to <8.0 mg/dL (2.0 mM) and serum phosphate to ≤2.0 mg/dL (0.65 mM) were similar in both treatment groups.

Post-Marketing Experience

The following adverse reactions have been reported in post-marketing use:

Body as a Whole:

Gastrointestinal:

Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection, often with delayed healing, has been reported rarely (see ).

Musculoskeletal:

Nervous system:

Skin:

Special Senses:

What should I look out for while using Alendronate Sodium?

Alendronate sodium, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking alendronate sodium and/or who fail to swallow it with the recommended amount of water, and/or who continue to take alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see ). In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should be used under appropriate supervision.

Because of possible irritant effects of alendronate sodium on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when alendronate sodium is given to patients with active upper gastrointestinal problems (such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers).

There have been post-marketing reports of gastric and duodenal ulcers, some severe and with complications, although no increased risk was observed in controlled clinical trials.

What might happen if I take too much Alendronate Sodium?

Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m) and 966 mg/kg (2898 mg/m), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m).

No specific information is available on the treatment of overdosage with alendronate sodium. Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.

Dialysis would not be beneficial.

How should I store and handle Alendronate Sodium?

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.Alendronate sodium tablets, USP for oral administration, are available as:35 mg - white to off-white oval tablet embossed with “AN35" on one side and “>”on the other side. 40 mg - white to off-white round tablet embossed with “AN" over “40”on one side and “>” on the other side. 70 mg - white to off-white oval tablet embossed with “AN70" on one side and “>” on the other side. They are supplied by as follows:This product was Manufactured By: Arrow Pharm (Malta) Ltd., Birzebbugia, BBG06, Malta And Relabeled By:Dispensing Solutions Inc.

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

Non-Clinical Toxicology

Alendronate sodium, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking alendronate sodium and/or who fail to swallow it with the recommended amount of water, and/or who continue to take alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see ). In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should be used under appropriate supervision.

Because of possible irritant effects of alendronate sodium on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when alendronate sodium is given to patients with active upper gastrointestinal problems (such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers).

There have been post-marketing reports of gastric and duodenal ulcers, some severe and with complications, although no increased risk was observed in controlled clinical trials.

(also see )

Causes of osteoporosis other than estrogen deficiency, aging, and glucocorticoid use should be considered.

Hypocalcemia must be corrected before initiating therapy with alendronate sodium (see ). Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate sodium.

Presumably due to the effects of alendronate sodium on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget's disease, in whom the pretreatment rate of bone turnover may be greatly elevated and in patients receiving glucocorticoids, in whom calcium absorption may be decreased.

Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget's disease of bone and in patients receiving glucocorticoids.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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