Fosamax Plus D

(Alendronate Sodium And Cholecalciferol)

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Fosamax Plus D Prescribing Information

70 mg alendronate/2800 international units vitamin D₃or 70 mg alendronate/5600 international units vitamin D₃ tablet once weekly. (
2.1 Treatment of Osteoporosis in Postmenopausal Women
The recommended dosage is one 70 mg alendronate/2800 international units vitamin D₃or one 70 mg alendronate/5600 international units vitamin D₃tablet once weekly. For most osteoporotic women, the appropriate dose is FOSAMAX PLUS D (70 mg alendronate/5600 international units vitamin D₃) once weekly.
,
2.2 Treatment to Increase Bone Mass in Men with Osteoporosis
The recommended dosage is one 70 mg alendronate/2800 international units vitamin D₃or one 70 mg alendronate/5600 international units vitamin D₃tablet once weekly. For most osteoporotic men, the appropriate dose is FOSAMAX PLUS D (70 mg alendronate/5600 international units vitamin D₃) once weekly.
)
Instruct patients to: (
2.3 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
  [see Patient Counseling Information (17.2)]
  . Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate
  [see Drug Interactions (7.1)]
  . 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
  [see Warnings and Precautions (5.1)and Patient Counseling Information (17.2)]
  .
)
- Swallow tablets whole with 6-8 ounces plain water at least 30 minutes before the first food, drink, or medication of the day.
- Not lie down for at least 30 minutes after taking FOSAMAX PLUS D and until after food.

Pregnancy: Discontinue when pregnancy is recognized. (
8.1 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/m²). 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 D₃) in animals. However, administration of high doses of vitamin D₂to pregnant rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of high doses of vitamin D₂to 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/m². 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 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 from gestation day 10 to 21 (organogenesis) resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally.
)
FOSAMAX PLUS D is not indicated for use in pediatric patients. (
8.4 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.
)
FOSAMAX PLUS D is not recommended in patients with severe renal impairment (creatinine clearance less than 35 mL/min). (
5.6 Renal Impairment
FOSAMAX PLUS D is not recommended for patients with creatinine clearance less than 35 mL/min.
,
8.6 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 (12.3)]
.
)

FOSAMAX PLUS D is contraindicated in patients with the following conditions:

Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia
[see
5.1 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 (2.3)]
. 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 (6.2)]
.
]
Inability to stand or sit upright for at least 30 minutes
[see
2.3 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
[see Patient Counseling Information (17.2)]
. Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate
[see Drug Interactions (7.1)]
. 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
[see Warnings and Precautions (5.1)and Patient Counseling Information (17.2)]
.
,
5.1 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 (2.3)]
. 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 (6.2)]
.
]
Hypocalcemia
[see
5.2 Mineral Metabolism
Alendronate Sodium
Hypocalcemia must be corrected before initiating therapy with FOSAMAX PLUS D
[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 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 (2.4)]
. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.
Vitamin D₃supplementation 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.
]
Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported
[see
6.2 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of FOSAMAX and FOSAMAX PLUS D. 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
[see Dosage and Administration (2.3)and Warnings and Precautions (5.1)]
.
Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported
[see Warnings and Precautions (5.4)]
.
Musculoskeletal:
bone, joint, and/or muscle pain, occasionally severe, and incapacitating
[see Warnings and Precautions (5.3)]
; joint swelling; low-energy femoral shaft and subtrochanteric fractures
[see Warnings and Precautions (5.5)]
.
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).
].

Upper Gastrointestinal Adverse Reactions
can occur. Instruct patients to follow dosing instructions. Discontinue if new or worsening symptoms occur. (
5.1 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 (2.3)]
. 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 (6.2)]
.
)
Hypocalcemia
can worsen and must be corrected prior to use. (
5.2 Mineral Metabolism
Alendronate Sodium
Hypocalcemia must be corrected before initiating therapy with FOSAMAX PLUS D
[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 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 (2.4)]
. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.
Vitamin D₃supplementation 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.
)
Severe Bone, Joint, Muscle Pain
may occur. Discontinue use if severe symptoms develop. (
5.3 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 (6.2)]
. 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
has been reported. (
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 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 Femur Fractures
have been reported. Patients with new thigh or groin pain should be evaluated to rule out an incomplete femoral fracture. (
5.5 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.
)

Most common adverse reactions (greater than or equal to 3%) for alendronate are: abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea. (

6.1 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 [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 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
	FOSAMAX10 mg/day for three years % (n=196)	Placebo % (n=397)	FOSAMAX5 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 0.7
Musculoskeletal musculoskeletal (bone, muscle or joint) pain muscle cramp	4.1 0.0	2.5 1.0	0.4 0.2	0.3 0.1
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	0.0

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.

[See 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 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 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 0.0

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 D₃was similar to that of FOSAMAX PLUS D (70 mg/2800 international units).

)

To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Report Adverse Event

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