Alendronate sodium tablets are a bisphosphonate indicated for: Treatment and prevention of osteoporosis in postmenopausal women ( 1.1 , 1.2 ) Treatment to increase bone mass in men with osteoporosis ( 1.3 ) Treatment of glucocorticoid-induced osteoporosis ( 1.4 ) Treatment of Paget's disease of bone ( 1.5 ) Limitations of use: Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use.
( 1.6 )
1.1Treatment of Osteoporosis in Postmenopausal Women
Alendronate sodium tablets are indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, alendronate sodium tablets increase bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures) [s ee Clinical Studies (14.1) ].
1.2Prevention of Osteoporosis in Postmenopausal Women
Alendronate sodium tablets are indicated for the prevention of postmenopausal osteoporosis [ see Clinical Studies (14.2) ].
1.3Treatment to Increase Bone Mass in Men with Osteoporosis
Alendronate sodium tablets are indicated for treatment to increase bone mass in men with osteoporosis [ see Clinical Studies (14.3) ].
1.4Treatment of Glucocorticoid-Induced Osteoporosis
Alendronate sodium tablets are indicated for the treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density [ see Clinical Studies (14.4) ].
1.5Treatment of Paget's Disease of Bone
Alendronate sodium tablets are indicated for the treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget's disease of bone who have alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease [ see Clinical Studies (14.5) ].
1.6Important Limitations of Use
The optimal duration of use has not been determined. The safety and effectiveness of alendronate sodium tablets for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.
Alendronate sodium tablets are contraindicated in patients with the following conditions: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [ see Warnings and Precautions (5.1) ] Inability to stand or sit upright for at least 30 minutes [ see Dosage and Administration (2.6) ; Warnings and Precautions (5.1) ] Hypocalcemia [ see Warnings and Precautions (5.2) ] Hypersensitivity to any component of this product.
Hypersensitivity reactions including urticaria and angioedema have been reported [ see Adverse Reactions (6.2) ]. Abnormalities of the esophagus which delay emptying such as stricture or achalasia ( 4 , 5.1 ) Inability to stand/sit upright for at least 30 minutes ( 2.6 , 4 , 5.1 ) Hypocalcemia ( 4 , 5.2 ) Hypersensitivity to any component of this product ( 4 , 6.2 )
Warnings and precautions
Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue if new or worsening symptoms occur. ( 5.1 ) Hypocalcemia can worsen and must be corrected prior to use. ( 5.2 ) Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop. ( 5.3 ) Osteonecrosis of the Jaw has been reported. ( 5.4 ) Atypical Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out an incomplete femoral fracture.
( 5.5 )
5.1Upper Gastrointestinal Adverse Reactions
Alendronate sodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects 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 known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers).
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 oral bisphosphonates including 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 oral bisphosphonates including alendronate sodium and/or who fail to swallow oral bisphosphonates including alendronate sodium with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates including 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 Dosage and Administration (2.6) ]. In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should be used under appropriate supervision. There have been postmarketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials [ see Adverse Reactions (6.2) ].
5.2Mineral Metabolism
Hypocalcemia must be corrected before initiating therapy with alendronate sodium [ see Contraindications (4) ] . 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.
5.3Musculoskeletal Pain
In postmarketing 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 Adverse Reactions (6.2) ] . 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.
5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).
The risk of ONJ may increase with duration of exposure to bisphosphonates. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon.
In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.
5.5Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture.
Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
5.6Renal Impairment
Alendronate sodium is not recommended for patients with creatinine clearance less than 35 mL/min .
5.7Glucocorticoid-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 Indications and Usage (1.4) ] . Before initiating treatment, the gonadal 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.
Interactions
Calcium supplements, antacids, or oral medications containing multivalent cations interfere with absorption of alendronate. ( 2.6 , 7.1 ) Use caution when co-prescribing aspirin/nonsteroidal anti-inflammatory drugs that may worsen gastrointestinal irritation. ( 7.2 , 7.3 )
7.1Calcium Supplements/Antacids Co-administration
of alendronate sodium and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of alendronate sodium. Therefore, instruct patients to wait at least one-half hour after taking alendronate sodium before taking any other oral medications.
7.2Aspirin
In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate, the free acid greater than 10 mg and aspirin-containing products.
7.3Non-Steroidal Anti-Inflammatory Drugs
Alendronate sodium may be administered to patients taking non-steroidal anti-inflammatory drugs (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, the free acid 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.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Available data on the use of alendronate sodium in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue alendronate sodium when pregnancy is recognized. In animal reproduction studies, daily oral administration of alendronate to rats from before mating through the end of gestation or lactation showed decreased postimplantation survival and decreased pup body weight gain starting at doses equivalent to less than half of the highest recommended 40 mg clinical daily dose (based on body surface area, mg/m 2 ).
Oral administration of alendronate to rats during organogenesis resulted in reduced fetal ossification starting at doses 3 times the 40 mg clinical daily dose. No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at doses equivalent to approximately 10 times the 40 mg clinical daily dose. Delayed or failed delivery of offspring, protracted parturition, and late pregnancy maternal and fetal deaths due to maternal hypocalcemia occurred in rats at oral doses as low as one tenth the 40 mg clinical daily dose (see Data) .
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 available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential 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. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Reproduction studies in rats dosed orally from before mating to the end of gestation or lactation showed decreased postimplantation survival starting at 2 mg/kg/day and decreased body weight gain starting at 1 mg/kg/day, doses equivalent to less than half the 40 mg clinical daily dose based on body surface area, mg/m 2 .
Incidence of incomplete fetal ossification in vertebral, skull, and sternebral bones were increased in rats dosed orally during organogenesis starting at 10 mg/kg/day (approximately 3 times the 40 mg clinical daily dose). No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at up to 35 mg/kg/day (equivalent to approximately 10 times the 40 mg clinical daily dose). Both total and ionized calcium decreased in pregnant rats dosed orally with 15 mg/kg/day alendronate (approximately 4 times the 40 mg clinical daily dose) resulting in delays and failures of delivery.
Protracted parturition due to maternal hypocalcemia was observed when rats were treated from before mating through gestation starting at 0.5 mg/kg/day (approximately one tenth the 40 mg clinical daily dose). Maternotoxicity (late pregnancy deaths) also occurred in female rats treated orally with 15 mg/kg/day (approximately 4 times the 40 mg clinical daily dose) for varying gestational time periods. These maternal deaths were lessened but not eliminated by cessation of treatment.
Calcium supplementation in the drinking water or by subcutaneous minipump to rats dosed orally with 15 mg/kg/day alendronate could not ameliorate the hypocalcemia or prevent the dystocia-related maternal and neonatal deaths. However, intravenous calcium supplementation prevented maternal, but not neonatal deaths.
Adverse reactions
Most common adverse reactions (greater than or equal to 3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Impax Laboratories, Inc. at 1-800-934-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The safety of alendronate sodium in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44 to 84 years.
Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational n = 994); Study 3 was the three-year vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n = 2027) and Study 4 was the four-year clinical fracture cohort of FIT (n = 4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to alendronate sodium.
Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 international units Vitamin D per day. Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the alendronate sodium group.
The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the alendronate sodium group. The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the alendronate sodium group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate sodium or placebo are presented in Table 1.
Table 1: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients United States/Multinational Studies Fracture Intervention Trial Alendronate Sodium 1 % (n = 196) Placebo % (n = 397) Alendronate Sodium 2 % (n = 3236) Placebo % (n = 3223) Gastrointestinal abdominal pain 6.6 4.8 1.5 1.5 nausea 3.6 4.0 1.1 1.5 dyspepsia 3.6 3.5 1.1 1.2 constipation 3.1 1.8 0.0 0.2 diarrhea 3.1 1.8 0.6 0.3 flatulence 2.6 0.5 0.2 0.3 acid regurgitation 2.0 4.3 1.1 0.9 esophageal ulcer 1.5 0.0 0.1 0.1 vomiting 1.0 1.5 0.2 0.3 dysphagia 1.0 0.0 0.1 0.1 abdominal distention 1.0 0.8 0.0 0.0 gastritis 0.5 1.3 0.6
Senses taste perversion 0.5 1.0 0.1 0.0 1. 10 mg/day for three years 2. 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years Rash and erythema have occurred. Gastrointestinal Adverse Reactions: One patient treated with alendronate, the free acid (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. In the Study 1 and Study 2 populations, 49 to 54% had a history of gastrointestinal disorders at baseline and 54 to 89% used non-steroidal anti-inflammatory drugs or aspirin at some time during the studies [s ee Warnings and Precautions (5.1) ]. 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 less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65 mM) were similar in both treatment groups. Weekly Dosing The safety of alendronate, the free acid 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing alendronate, the free acid 70 mg once weekly and alendronate, the free acid 10 mg daily.
The overall safety and tolerability profiles of once weekly alendronate, the free acid 70 mg and alendronate, the free acid 10 mg daily were similar. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients in either treatment group are presented in Table 2. Table 2: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients Once Weekly Alendronate, the free acid 70 mg % (n=519) Alendronate, the free acid 10 mg/day % (n=370) Gastrointestinal abdominal pain 3.7 3.0 dyspepsia 2.7 2.2 acid regurgitation 1.9 2.4 nausea 1.9 2.4 abdominal distention 1.0 1.4 constipation 0.8 1.6 flatulence 0.4 1.6 gastritis 0.2 1.1 gastric ulcer 0.0
1.1Prevention of Osteoporosis in Postmenopausal Women Daily Dosing
The safety of alendronate, the free acid 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, the free acid 5 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse event occurred in 7.5% of 642 patients treated with alendronate, the free acid 5 mg/day and 5.7% of 648 patients treated with placebo.
Weekly Dosing The safety of alendronate, the free acid 35 mg once weekly compared to alendronate, the free acid 5 mg daily was evaluated in a one-year, double-blind, multicenter study of 723 patients. The overall safety and tolerability profiles of once weekly alendronate, the free acid 35 mg and alendronate, the free acid 5 mg daily were similar. The adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either once weekly alendronate, the free acid 35 mg, alendronate, the free acid 5 mg/day or placebo are presented in Table 3.
Table 3: Osteoporosis Prevention Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients Two/Three Year Studies One Year Study Alendronate, the free acid 5mg/day % (n=642) Placebo % (n=648) Alendronate, the free acid 5 mg/day % (n=361) Once Weekly Alendronate, the free acid 35mg % (n=362) Gastronintestinal dyspepsia 1.9 1.4 2.2 1.7 abdominal pain 1.7 3.4 4.2 2.2 acid regurgitation 1.4 2.5 4.2 4.7 nausea 1.4 1.4 2.5 1.4 diarrhea 1.1 1.7 1.1 0.6 constipation 0.9 0.5 1.7 0.3 abdominal distention 0.2 0.3 1.4
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
