Fosamax Plus D Drug Information
Generic name: ALENDRONATE SODIUM AND CHOLECALCIFEROL
Vitamin D [EPC]
Uses of Fosamax Plus D
Treatment of Osteoporosis in Postmenopausal Women
FOSAMAX ® PLUS D is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, FOSAMAX PLUS D increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures).
Treatment to Increase Bone Mass in Men with Osteoporosis
FOSAMAX PLUS D is indicated for treatment to increase bone mass in men with osteoporosis .
Important Limitations of Use
FOSAMAX PLUS D alone should not be used to treat vitamin D deficiency. The optimal duration of use has not been determined. The safety and effectiveness of FOSAMAX PLUS D 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.
Dosage & Administration of Fosamax Plus D
Treatment of Osteoporosis in Postmenopausal Women
The recommended dosage is one 70 mg alendronate/2800 international units vitamin D 3 or one 70 mg alendronate/5600 international units vitamin D 3 tablet once weekly. For most osteoporotic women, the appropriate dose is FOSAMAX PLUS D (70 mg alendronate/5600 international units vitamin D 3 ) once weekly.
Treatment to Increase Bone Mass in Men with Osteoporosis
The recommended dosage is one 70 mg alendronate/2800 international units vitamin D 3 or one 70 mg alendronate/5600 international units vitamin D 3 tablet once weekly. For most osteoporotic men, the appropriate dose is FOSAMAX PLUS D (70 mg alendronate/5600 international units vitamin D 3 ) once weekly.
Important
Administration Instructions Instruct patients to do the following: Take FOSAMAX PLUS D at least one-half hour before the first food, beverage, or medication of the day with plain water only . Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate . Waiting less than 30 minutes, or taking FOSAMAX PLUS D with food, beverages (other than plain water) or other medications will lessen the effect of alendronate by decreasing its absorption into the body. Take FOSAMAX PLUS D upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, a FOSAMAX PLUS D tablet should be swallowed with a full glass of water (6-8 ounces). Patients should not lie down for at least 30 minutes and until after their first food of the day.
FOSAMAX PLUS D 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 .
Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental
calcium if dietary intake is inadequate . Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. The recommended intake of vitamin D is 400-800 international units daily.
FOSAMAX PLUS D 70 mg/2800 international units and 70 mg/5600 international units are intended to provide seven days' worth of 400 and 800 international units daily vitamin D in a single, once-weekly dose, respectively.
Administration Instructions for Missed Doses
If a once-weekly dose of FOSAMAX PLUS D is missed, instruct patients to take one tablet on the morning after they remember. They should not take two tablets on the same day but should return to taking one tablet once a week, as originally scheduled on their chosen day.
Side Effects of Fosamax Plus D
Clinical 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. FOSAMAX Treatment of Osteoporosis in Postmenopausal Women FOSAMAX Daily The safety of FOSAMAX in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44-84 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 (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 FOSAMAX. 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 FOSAMAX group.
The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the FOSAMAX 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 FOSAMAX 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 FOSAMAX 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 FOSAMAX 10 mg/day for three years % (n=196) Placebo % (n=397) FOSAMAX 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years % (n=3236) Placebo % (n=3223) Gastrointestinal abdominal pain nausea dyspepsia constipation diarrhea flatulence acid regurgitation esophageal ulcer vomiting dysphagia abdominal distention gastritis 6.6 3.6 3.6 3.1 3.1 2.6 2.0 1.5 1.0 1.0 1.0 0.5 4.8 4.0 3.5 1.8 1.8 0.5 4.3 0.0 1.5 0.0 0.8 1.3 1.5 1.1 1.1 0.0 0.6 0.2 1.1 0.1 0.2 0.1 0.0 0.6 1.5 1.5 1.2 0.2 0.3 0.3 0.9 0.1 0.3 0.1 0.0
Musculoskeletal musculoskeletal (bone, muscle or joint) pain muscle cramp 4.1 0.0 2.5
1.0 0.4 0.2 0.3
Nervous System/Psychiatric headache dizziness 2.6 0.0 1.5 1.0 0.2 0.0 0.2 0.1
Special Senses taste perversion 0.5 1.0 0.1
Rash and erythema have occurred. Gastrointestinal Adverse Reactions: One patient treated with
FOSAMAX (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 FOSAMAX were discontinued and the patient recovered. In the Study 1 and Study 2 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.
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 FOSAMAX 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. FOSAMAX Once-Weekly The safety of FOSAMAX 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing FOSAMAX 70 mg once weekly and FOSAMAX 10 mg daily.
The overall safety and tolerability profiles of once weekly FOSAMAX 70 mg and FOSAMAX 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 FOSAMAX 70 mg % (n=519) FOSAMAX 10 mg/day % (n=370) Gastrointestinal abdominal pain dyspepsia acid regurgitation nausea abdominal distention constipation flatulence gastritis gastric ulcer 3.7 2.7 1.9 1.9 1.0 0.8 0.4 0.2 0.0 3.0 2.2 2.4 2.4 1.4 1.6 1.6 1.1
Musculoskeletal musculoskeletal (bone, muscle, joint) pain muscle cramp 2.9 0.2 3.2 1.1
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 FOSAMAX 10 mg once daily and estrogen ± progestin (n=354) was consistent with those of the individual treatments. Osteoporosis in Men In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of FOSAMAX 10 mg/day and a one-year study of once weekly FOSAMAX 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for FOSAMAX 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly FOSAMAX 70 mg vs. 8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 2% of patients treated with either FOSAMAX or placebo are presented in Table 3. Table 3: Osteoporosis Studies in Men Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 2% of Patients Two-year Study One-year Study FOSAMAX 10 mg/day % (n=146) Placebo % (n=95) Once Weekly FOSAMAX 70 mg % (n=109) Placebo % (n=58) Gastrointestinal acid regurgitation flatulence gastroesophageal reflux disease dyspepsia diarrhea abdominal pain nausea 4.1 4.1 0.7 3.4 1.4 2.1 2.1 3.2 1.1 3.2 0.0 1.1 1.1 0.0 0.0 0.0 2.8 2.8 2.8 0.9 0.0 0.0 0.0 0.0 1.7 0.0 3.4
FOSAMAX
PLUS D In a fifteen-week double-blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile of FOSAMAX PLUS D (70 mg/2800 international units) was similar to that of FOSAMAX once weekly 70 mg. In the 24-week double-blind extension study in women (n=619) and men (n=33), the safety profile of FOSAMAX PLUS D (70 mg/2800 international units) administered with an additional 2800 international units vitamin D 3 was similar to that of FOSAMAX PLUS D (70 mg/2800 international units).
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of FOSAMAX, FOSAMAX PLUS D, or bisphosphonate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: hypersensitivity reactions including urticaria and angioedema.
Transient symptoms of myalgia, malaise, asthenia and rarely, fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema.
Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications have also been reported . Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported . Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and incapacitating ; joint swelling; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones . Nervous System: dizziness and vertigo. Pulmonary: acute asthma exacerbations.
Skin: rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Special Senses: uveitis, scleritis or episcleritis. Cholesteatoma of the external auditory canal (focal osteonecrosis).
Warnings & Cautions for Fosamax Plus D
Upper Gastrointestinal Adverse Reactions
FOSAMAX PLUS D, 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 FOSAMAX PLUS D 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 FOSAMAX PLUS D. 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 FOSAMAX PLUS D 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 FOSAMAX PLUS D and/or who fail to swallow oral bisphosphonates including FOSAMAX PLUS D with the recommended full glass (6-8 ounces) of water, and/or who continue to take oral bisphosphonates including FOSAMAX PLUS D 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 . In patients who cannot comply with dosing instructions due to mental disability, therapy with FOSAMAX PLUS D should be used under appropriate supervision. There have been post-marketing 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 .
Mineral Metabolism Alendronate Sodium Hypocalcemia must be corrected before initiating therapy with
FOSAMAX PLUS D . 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 FOSAMAX PLUS D. Presumably due to the effects of alendronate on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur. Cholecalciferol FOSAMAX PLUS D alone should not be used to treat vitamin D deficiency (commonly defined as 25-hydroxyvitamin D level below 9 ng/mL). Patients at increased risk for vitamin D insufficiency may require higher doses of vitamin D supplementation . Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.
Vitamin D 3 supplementation may worsen hypercalcemia and/or hypercalciuria when administered to patients with diseases associated with unregulated overproduction of 1,25 dihydroxyvitamin D (e.g., leukemia, lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.
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 . This category of drugs includes alendronate. 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 FOSAMAX, the percentages of patients with these symptoms were similar in the FOSAMAX and placebo groups.
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 FOSAMAX PLUS D. 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.
Atypical Fractures Including Femoral Fractures Atypical, low-energy, or low trauma fractures of
the femoral shaft have been reported during treatment with bisphosphonates, including alendronate, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred 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.
Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates.
Concomitant treatment with glucocorticoid may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs was reported by patients. 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.
Bony pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered.
Renal Impairment
FOSAMAX PLUS D is not recommended for patients with creatinine clearance less than 35 mL/min.
Drug Interactions with Fosamax Plus D
Calcium Supplements/Antacids Co-administration of
FOSAMAX PLUS D and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of alendronate. Therefore, instruct patients to wait at least one-half hour after taking FOSAMAX PLUS D 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 FOSAMAX greater than 10 mg and aspirin-containing products.
Nonsteroidal Anti-Inflammatory Drugs
FOSAMAX PLUS D may be administered to patients taking nonsteroidal 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 FOSAMAX 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 FOSAMAX PLUS D.
Drugs that May Impair the Absorption of Cholecalciferol Olestra, mineral oils, orlistat
and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D. Additional vitamin D supplementation should be considered .
Drugs that May Increase the Catabolism of Cholecalciferol Anticonvulsants, cimetidine, and thiazides
may increase the catabolism of vitamin D. Additional vitamin D supplementation should be considered .
Pregnancy Safety for Fosamax Plus D
Pregnancy Risk Summary Available data on the use of FOSAMAX plus vitamin D use in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue FOSAMAX PLUS D when pregnancy is recognized. Alendronate Sodium 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. Cholecalciferol No data are available for cholecalciferol (vitamin D 3 ) in animals.
However, administration of high doses of vitamin D 2 to pregnant rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of high doses of vitamin D 2 to pregnant rats resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally. (See Data.) 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 2-4% and 15-20%, respectively. Data Animal Data Alendronate Sodium 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.
Cholecalciferol Administration of high doses (greater than or equal to 10,000 international units/every other day during pregnancy) of ergocalciferol (vitamin D 2 ) to pregnant rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of vitamin D 2 (40,000 international units/day) to pregnant rats from gestation day 10 to 21 (organogenesis) resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally.
Pediatric Use of Fosamax Plus D
Pediatric Use FOSAMAX PLUS D is not indicated for use in pediatric patients. The safety and efficacy of alendronate were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate daily (weight less than 40 kg) or 10 mg alendronate daily (weight greater than or equal to 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-treated patients and 0.1 in the placebo-treated patients.
Treatment with alendronate did not reduce the risk of fracture. Sixteen percent of the alendronate 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-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 and placebo groups in reduction of bone pain. The oral bioavailability of alendronate in children was similar to that observed in adults.
Contraindications for Fosamax Plus D
D is contraindicated in patients with the following conditions: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia Inability to stand or sit upright for at least 30 minutes Hypocalcemia Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported . Abnormalities of the esophagus which delay emptying such as stricture or achalasia Inability to stand/sit upright for at least 30 minutes Hypocalcemia Hypersensitivity to any component of this product
Overdosage Information for Fosamax Plus D
Alendronate Sodium Significant lethality after single oral doses with alendronate was seen in female rats and mice at 552 mg/kg (3256 mg/m 2 ) and 966 mg/kg (2898 mg/m 2 ), 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 2 ). No specific information is available on the treatment of overdosage with alendronate.
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. Cholecalciferol Significant lethality occurred in mice treated with a single high oral dose of calcitriol (4 mg/kg), the hormonal metabolite of cholecalciferol. There is limited information regarding doses of cholecalciferol associated with acute toxicity, although intermittent (yearly or twice yearly) single doses of ergocalciferol (vitamin D 2 ) as high as 600,000 international units have been given without reports of toxicity.
Signs and symptoms of vitamin D toxicity include hypercalcemia, hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia, weakness, and lethargy. Serum and urine calcium levels should be monitored in patients with suspected vitamin D toxicity. Standard therapy includes restriction of dietary calcium, hydration, and systemic glucocorticoids in patients with severe hypercalcemia.
Dialysis to remove vitamin D would not be beneficial.
Clinical Studies of Fosamax Plus D
Treatment of Osteoporosis in Postmenopausal Women
FOSAMAX Daily The efficacy of FOSAMAX 10 mg daily was assessed in four clinical trials. Study 1, a three-year, multicenter, double-blind, placebo-controlled, US clinical study enrolled 478 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 2, a three-year, multicenter, double-blind, placebo-controlled, Multinational clinical study enrolled 516 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 3, the Three-Year Study of the Fracture Intervention Trial (FIT), a study which enrolled 2027 postmenopausal patients with at least one baseline vertebral fracture; and Study 4, the Four-Year Study of FIT, a study which enrolled 4432 postmenopausal patients with low bone mass but without a baseline vertebral fracture. Effect on Fracture Incidence To assess the effects of FOSAMAX on the incidence of vertebral fractures (detected by digitized radiography; approximately one third of these were clinically symptomatic), the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of FOSAMAX (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a statistically significant reduction in the proportion of patients treated with FOSAMAX experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk reduction). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed.
In the pooled analysis, patients who received FOSAMAX had a loss in stature that was statistically significantly less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm). The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone mass but without a baseline vertebral fracture. In both studies of FIT, 96% of randomized patients completed the studies (i.e., had a closeout visit at the scheduled end of the study); approximately 80% of patients were still taking study medication upon completion. Fracture Intervention Trial: Three-Year Study (patients with at least one baseline radiographic vertebral fracture) This randomized, double-blind, placebo-controlled, 2027-patient study (FOSAMAX, n=1022; placebo, n=1005) demonstrated that treatment with FOSAMAX resulted in statistically significant reductions in fracture incidence at three years as shown in Table 6. Table 6: Effect of FOSAMAX on Fracture Incidence in the Three-Year Study of FIT (patients with vertebral fracture at baseline) Percent of Patients FOSAMAX (n=1022) Placebo (n=1005) Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk % Patients with: Vertebral fractures (diagnosed by X-ray) Number evaluable for vertebral fractures: FOSAMAX, n=984; placebo, n=966 ≥1 new vertebral fracture 7.9 15.0 7.1 47 p<0.001 ≥2 new vertebral fractures 0.5 4.9 4.4 90 Clinical (symptomatic) fractures Any clinical (symptomatic) fracture 13.8 18.1 4.3 26 p=0.007 ≥1 clinical (symptomatic) vertebral fracture 2.3 5.0 2.7 54 p<0.01 Hip fracture 1.1 2.2 1.1 51 p<0.05 Wrist (forearm) fracture 2.2 4.1 1.9 48 Furthermore, in this population of patients with baseline vertebral fracture, treatment with FOSAMAX significantly reduced the incidence of hospitalizations (25.0% vs. 30.7%). In the Three-Year Study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on FOSAMAX, p=0.047. Figure 1 displays the cumulative incidence of hip fractures in this study.
Figure 1: Cumulative Incidence of Hip Fractures in the Three-Year Study of FIT (patients with radiographic vertebral fracture at baseline) Fracture Intervention Trial: Four-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture) This randomized, double-blind, placebo-controlled, 4432-patient study (FOSAMAX, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to FOSAMAX. The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and non-osteoporotic women. The results are shown in Table 7 below for the patients with osteoporosis.
Table 7: Effect of FOSAMAX on Fracture Incidence in Osteoporotic Baseline femoral neck BMD at least 2 SD below the mean for young adult women Patients in the Four-Year Study of FIT (patients without vertebral fracture at baseline) Percent of Patients FOSAMAX (n=1545) Placebo (n=1521) Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk (%) Patients with: Vertebral fractures (diagnosed by X-ray) Number evaluable for vertebral fractures: FOSAMAX, n=1426; placebo, n=1428 ≥1 new vertebral fracture 2.5 4.8 2.3 48 p<0.001 ≥2 new vertebral fractures 0.1 0.6 0.5 78 p=0.035 Clinical (symptomatic) fractures Any clinical (symptomatic) fracture 12.9 16.2 3.3 22 p=0.01 ≥1 clinical (symptomatic) vertebral fracture 1.0 1.6 0.6 41 (NS) Not significant. This study was not powered to detect differences at these sites. Hip fracture 1.0 1.4 0.4 29 (NS) Wrist (forearm) fracture 3.9 3.8 -
NS Fracture Results Across Studies
In the Three-Year Study of FIT, FOSAMAX reduced the percentage of women experiencing at least one new radiographic vertebral fracture from 15.0% to 7.9% (47% relative risk reduction, p<0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1% (44% relative risk reduction, p=0.001); and in the combined U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction, p=0.034). FOSAMAX reduced the percentage of women experiencing multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk reduction, p<0.001) in the combined U.S./Multinational studies and from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in the Three-Year Study of FIT. In the Four-Year Study of FIT, FOSAMAX reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035). Thus, FOSAMAX reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture. Effect on Bone Mineral Density The bone mineral density efficacy of FOSAMAX 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years' duration. Figure 2 shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving FOSAMAX 10 mg/day relative to placebo-treated patients at three years for each of these studies.
Figure 2: At three years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received FOSAMAX 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as three months and continued throughout the three years of treatment. (See figure 3 for lumbar spine results.) In the two-year extension of these studies, treatment of 147 patients with FOSAMAX 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm and total body were maintained.
FOSAMAX was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean). Figure 3: In patients with postmenopausal osteoporosis treated with FOSAMAX 10 mg/day for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups. Bone Histology Bone histology in 270 postmenopausal patients with osteoporosis treated with FOSAMAX at doses ranging from 1 to 20 mg/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo.
These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with FOSAMAX is of normal quality. Effect on Height FOSAMAX, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. placebo in patients with and without baseline radiographic vertebral fractures. At the end of the FIT studies, the between-treatment group differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.
FOSAMAX Once-Weekly The therapeutic equivalence of once-weekly FOSAMAX 70 mg (n=519) and FOSAMAX 10 mg daily (n=370) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70-mg once-weekly group (n=440) and 5.4% (5.0, 5.8%; 95% CI) in the 10-mg daily group (n=330). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.
Concomitant Use with Estrogen Hormone Replacement Therapy The effects on BMD of treatment with FOSAMAX 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two-year, double-blind, placebo-controlled study of hysterectomized postmenopausal osteoporotic women (n=425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or FOSAMAX alone (both 6.0%). The effects on BMD when FOSAMAX was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one-year, double-blind, placebo-controlled study in postmenopausal osteoporotic women (n=428). The addition of FOSAMAX 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%). In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD. Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture.
Compared to placebo there was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with FOSAMAX and HRT, 94% on FOSAMAX alone, and 78% on HRT alone. The long-term effects of combined FOSAMAX and HRT on fracture occurrence and fracture healing have not been studied.
Treatment to Increase Bone Mass in Men with Osteoporosis
The efficacy of FOSAMAX in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies. FOSAMAX Daily A two-year, double-blind, placebo-controlled, multicenter study of FOSAMAX 10 mg once daily enrolled a total of 241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving FOSAMAX 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatment with FOSAMAX also reduced height loss (FOSAMAX, -0.6 mm vs. placebo, -2.4 mm). FOSAMAX Once-Weekly A one-year, double-blind, placebo-controlled, multicenter study of once weekly FOSAMAX 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or a BMD T-score less than or equal to -2 at the lumbar spine and less than or equal to -1 at the femoral neck, or a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck.
At one year, the mean increases relative to placebo in BMD in men receiving FOSAMAX 70 mg once weekly were significant at the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in BMD were similar to those seen at one year in the 10 mg once-daily study. In both studies, BMD responses were similar regardless of age (greater than or equal to 65 years vs. less than 65 years), gonadal function (baseline testosterone less than 9 ng/dL vs. greater than or equal to 9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score less than or equal to -2.5 vs. greater than -2.5). image of Figure 1 image of Figure 2 image of Figure 3
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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