FOSAMAX (Page 2 of 8)

5.2 Mineral Metabolism

Hypocalcemia must be corrected before initiating therapy with FOSAMAX [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.

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

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

5.3 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 FOSAMAX (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.

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. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.

For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.

Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.

5.5 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.

5.6 Renal Impairment

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

5.7 Glucocorticoid-Induced Osteoporosis

The risk versus benefit of FOSAMAX for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established [see Indications and Usage (1.4)]. Before initiating treatment, the gonadal hormonal status of both men and women should be ascertained and appropriate replacement considered.

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

6 ADVERSE REACTIONS

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.

Treatment of Osteoporosis in Postmenopausal Women

Daily Dosing

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
FOSAMAX *%(n=196) Placebo%(n=397) FOSAMAX %(n=3236) Placebo%(n=3223)
*
10 mg/day for three years
5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years
Gastrointestinal
abdominal pain 6.6 4.8 1.5 1.5
nausea 3.6 4.0 1.1 1.5
dyspepsia 3.6 3.5 1.1 1.2
constipation 3.1 1.8 0.0 0.2
diarrhea 3.1 1.8 0.6 0.3
flatulence 2.6 0.5 0.2 0.3
acid regurgitation 2.0 4.3 1.1 0.9
esophageal ulcer 1.5 0.0 0.1 0.1
vomiting 1.0 1.5 0.2 0.3
dysphagia 1.0 0.0 0.1 0.1
abdominal distention 1.0 0.8 0.0 0.0
gastritis 0.5 1.3 0.6 0.7
Musculoskeletal
musculoskeletal (bone, muscle or joint) pain 4.1 2.5 0.4 0.3
muscle cramp 0.0 1.0 0.2 0.1
Nervous System/Psychiatric
headache 2.6 1.5 0.2 0.2
dizziness 0.0 1.0 0.0 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.

Weekly Dosing

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 FOSAMAX70 mg%(n=519) FOSAMAX10 mg/day%(n=370)
Gastrointestinal
abdominal pain 3.7 3.0
dyspepsia 2.7 2.2
acid regurgitation 1.9 2.4
nausea 1.9 2.4
abdominal distention 1.0 1.4
constipation 0.8 1.6
flatulence 0.4 1.6
gastritis 0.2 1.1
gastric ulcer 0.0 1.1
Musculoskeletal
musculoskeletal (bone, muscle, joint) pain 2.9 3.2
muscle cramp 0.2 1.1

Prevention of Osteoporosis in Postmenopausal Women

Daily Dosing

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

Weekly Dosing

The safety of FOSAMAX 35 mg once weekly compared to FOSAMAX 5 mg daily was evaluated in a one-year, double-blind, multicenter study of 723 patients. The overall safety and tolerability profiles of once weekly FOSAMAX 35 mg and FOSAMAX 5 mg daily were similar.

The adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either once weekly FOSAMAX 35 mg, FOSAMAX 5 mg/day or placebo are presented in Table 3.

Table 3: Osteoporosis Prevention Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients
Two/Three-Year Studies One-Year Study
FOSAMAX5 mg/day%(n=642) Placebo%(n=648) FOSAMAX5 mg/day%(n=361) Once Weekly FOSAMAX35 mg%(n=362)
Gastrointestinal
dyspepsia 1.9 1.4 2.2 1.7
abdominal pain 1.7 3.4 4.2 2.2
acid regurgitation 1.4 2.5 4.2 4.7
nausea 1.4 1.4 2.5 1.4
diarrhea 1.1 1.7 1.1 0.6
constipation 0.9 0.5 1.7 0.3
abdominal distention 0.2 0.3 1.4 1.1
Musculoskeletal
musculoskeletal (bone, muscle or joint) pain 0.8 0.9 1.9 2.2

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 4.

Table 4: 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
FOSAMAX10 mg/day%(n=146) Placebo%(n=95) Once Weekly FOSAMAX 70 mg%(n=109) Placebo%(n=58)
Gastrointestinal
acid regurgitation 4.1 3.2 0.0 0.0
flatulence 4.1 1.1 0.0 0.0
gastroesophageal reflux disease 0.7 3.2 2.8 0.0
dyspepsia 3.4 0.0 2.8 1.7
diarrhea 1.4 1.1 2.8 0.0
abdominal pain 2.1 1.1 0.9 3.4
nausea 2.1 0.0 0.0 0.0

Glucocorticoid-Induced Osteoporosis

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

Table 5: One-Year Studies in Glucocorticoid-Treated Patients Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients
FOSAMAX10 mg/day%(n=157) FOSAMAX5 mg/day%(n=161) Placebo%(n=159)
Gastrointestinal
abdominal pain 3.2 1.9 0.0
acid regurgitation 2.5 1.9 1.3
constipation 1.3 0.6 0.0
melena 1.3 0.0 0.0
nausea 0.6 1.2 0.6
diarrhea 0.0 0.0 1.3
Nervous System/Psychiatric
headache 0.6 0.0 1.3

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

Paget’s Disease of Bone

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

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

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