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Fosamax Plus D

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Fosamax Plus D

Fosamax Plus D

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 [see DOSAGE AND ADMINISTRATION]. 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 [see ADVERSE REACTIONS].

Mineral Metabolism

Alendronate Sodium

Hypocalcemia must be corrected before initiating therapy with FOSAMAX PLUS D [see CONTRAINDICATIONS]. 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 [see DOSAGE AND ADMINISTRATION]. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.

Vitamin D3 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 [see ADVERSE REACTIONS]. 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), 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 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.

Renal Impairment

FOSAMAX PLUS D is not recommended for patients with creatinine clearance less than 35 mL/min.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Instruct patients to read the Medication Guide before starting therapy with FOSAMAX PLUS D and to reread it each time the prescription is renewed.

Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium if 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) should take additional vitamin D if needed [see DOSAGE AND ADMINISTRATION]. Patients with gastrointestinal malabsorption syndromes may require additional vitamin D supplementation. 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

Instruct patients that the expected benefits of FOSAMAX PLUS D 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 [see CLINICAL PHARMACOLOGY].

Instruct patients not to chew or suck on the tablet because of a potential for oropharyngeal ulceration.

Instruct patients to swallow each tablet of FOSAMAX PLUS D with a full glass of water (6-8 ounces) and not to lie down for at least 30 minutes and until after their first food of the day to facilitate delivery to the stomach and thus reduce the potential for esophageal irritation.

Instruct patients not to take FOSAMAX PLUS D 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.

Instruct patients 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 FOSAMAX PLUS D and consult their physician.

If patients miss a dose of FOSAMAX PLUS D, 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

The following data are based on findings for the individual components of FOSAMAX PLUS D.

Alendronate Sodium

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 0.5 to 4 times a maximum recommended daily dose of 10 mg based on surface area, mg/m². 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 1 and 4 times a 10-mg human daily dose based on surface area, mg/m². The relevance of this finding to humans is unknown.

Alendronate was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro 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 (4 times a 10-mg human daily dose based on surface area, mg/m²).

Cholecalciferol

The carcinogenic potential of cholecalciferol (vitamin D3) has not been studied in rodents. Calcitriol, the hormonal metabolite of cholecalciferol, was not genotoxic in the Ames microbial mutagenesis assay with or without metabolic activation, and in an in vivo micronucleus assay in mice.

Ergocalciferol (vitamin D2) at high doses (150,000 to 200,000 international units/kg/day) administered prior to mating resulted in altered estrous cycle and inhibition of pregnancy in rats. The potential effect of cholecalciferol on male fertility is unknown in rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

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

Alendronate Sodium

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.

Reproduction studies in rats showed decreased postimplantation survival and decreased body weight gain in normal pups at doses less than half of the recommended clinical dose. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at approximately 3 times the clinical dose in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. No similar fetal effects were seen when pregnant rabbits were treated with doses approximately 10 times the clinical dose.

Both total and ionized calcium decreased in pregnant rats at approximately 4 times the clinical dose resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as one tenth the clinical dose when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) also occurred in the female rats treated at approximately 4 times the clinical dose for varying periods of time ranging from treatment only during premating 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; intravenous calcium supplementation prevented maternal, but not fetal deaths.

Cholecalciferol

No data are available for cholecalciferol (vitamin D3). Administration of high doses (greater than or equal to 10,000 international units/every other day) of ergocalciferol (vitamin D2) to pregnant rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of vitamin D2 (40,000 international units/day) to pregnant rats resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally.

Nursing Mothers

Cholecalciferol and some of its active metabolites pass into breast milk. It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FOSAMAX PLUS D is administered to nursing women.

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, placebocontrolled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfect (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 Zscore from baseline to Month 24 was 1.3 in the alendronate-treated patients and 0.1 in the placebotreated 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.

Geriatric Use

Of the patients receiving FOSAMAX in the Fracture Intervention Trial (FIT), 71% (n=2302) were greater than or equal to 65 years of age and 17% (n=550) were greater than or equal to 75 years of age. Of the patients receiving FOSAMAX in the United States and Multinational osteoporosis treatment studies in women, and osteoporosis studies in men [see Clinical Studies], 45% and 54%, 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. Dietary requirements of vitamin D3 are increased in the elderly.

Renal Impairment

FOSAMAX PLUS D is not recommended for patients with creatinine clearance less than 35 mL/min. No dosage adjustment is necessary in patients with creatinine clearance values between 35-60 mL/min [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

Alendronate Sodium

As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary [see CLINICAL PHARMACOLOGY].

Cholecalciferol

Vitamin D3 may not be adequately absorbed in patients who have malabsorption due to inadequate bile production.

Last reviewed on RxList: 11/22/2013
This monograph has been modified to include the generic and brand name in many instances.

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