HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
` These highlights do not include all the information needed to use
` FOSAMAX safely and effectively. See full prescribing information
`
` for FOSAMAX.
`
`
`
`FOSAMAX® (alendronate sodium) tablets, for oral use
`
`
`
`FOSAMAX® (alendronate sodium) oral solution
`
`
`
`
`
`Initial U.S. Approval: 1995
`
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`Indications and Usage (1.6)
`04/2013
`
`
`Dosage and Administration (2)
`11/2013
`
`
`Warnings and Precautions (5.4)
`04/2013
`
`
`
`
`----------------------------INDICATIONS AND USAGE ---------------------------­
`
`
`FOSAMAX is a bisphosphonate indicated for:
`
`
`
`• Treatment and prevention of osteoporosis in postmenopausal
`
`women (1.1, 1.2)
`
`
`• Treatment to increase bone mass in men with osteoporosis (1.3)
`
`
`• Treatment of glucocorticoid-induced osteoporosis (1.4)
`
`
`• Treatment of Paget's disease of bone (1.5)
`
`
`Limitations of use:
`
`
`
`
`Optimal duration of use has not been determined. For patients at low-
`
`
`
`
`risk for fracture, consider drug discontinuation after 3 to 5 years of use.
`
`
`
`
`(1.6)
`
`----------------------- DOSAGE AND ADMINISTRATION-----------------------­
`
`
`
`
`• Treatment of osteoporosis in postmenopausal women and in men:
`
`
`
`
`
`10 mg daily or 70 mg (tablet or oral solution) once weekly. (2.1, 2.3)
`
`
`
`• Prevention of osteoporosis in postmenopausal women: 5 mg daily
`
`
`or 35 mg once weekly. (2.2)
`
`
`• Glucocorticoid-induced osteoporosis: 5 mg daily; or 10 mg daily in
`
`
`
`postmenopausal women not receiving estrogen. (2.4)
`
`
`• Paget's disease: 40 mg daily for six months. (2.5)
`
`
`
`• Instruct patients to: (2.6)
`
`
`o
`Swallow tablets whole with 6-8 ounces plain water at least 30
`
`
`
`minutes before the first food, drink, or medication of the day.
`
`
`o
`Swallow oral solution followed by at least 2 ounces of water.
`
`
`
`
`o Not lie down for at least 30 minutes after taking FOSAMAX
`
`
`
`and until after food.
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
`
`
`Tablets: 70 mg (3)
`
`-------------------------------CONTRAINDICATIONS ------------------------------­
`
`
`
`
`• Abnormalities of the esophagus which delay emptying such as
`
`
`stricture or achalasia (4, 5.1)
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Treatment of Osteoporosis in Postmenopausal Women
`
`
`1.2 Prevention of Osteoporosis in Postmenopausal Women
`
`
`
`1.3 Treatment to Increase Bone Mass in Men with Osteoporosis
`
`
`1.4 Treatment of Glucocorticoid-Induced Osteoporosis
`
`
`
`
`1.5 Treatment of Paget's Disease of Bone
`
`
`1.6
`Important Limitations of Use
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Treatment of Osteoporosis in Postmenopausal Women
`
`
`2.2 Prevention of Osteoporosis in Postmenopausal Women
`
`
`2.3 Treatment to Increase Bone Mass in Men with Osteoporosis
`
`
`2.4 Treatment of Glucocorticoid-Induced Osteoporosis
`
`
`
`2.5 Treatment of Paget's Disease of Bone
`
`
`2.6
`Important Administration Instructions
`
`2.7 Recommendations
`for Calcium
`
`Supplementation
`
`
`
`2.8 Administration Instructions for Missed Doses
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Upper Gastrointestinal Adverse Reactions
`
`
`5.2 Mineral Metabolism
`
`
`
`5.3 Musculoskeletal Pain
`
`
`5.4 Osteonecrosis of the Jaw
`
`
`5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures
`
`
`
`5.6 Renal Impairment
`
`
`5.7 Glucocorticoid-Induced Osteoporosis
`
`
`and Vitamin D
`
`Reference ID: 3426836
`
`• Inability to stand/sit upright for at least 30 minutes (2.6, 4, 5.1)
`
`
`
`• Do not administer FOSAMAX oral solution to patients at increased
`
`
`
`
`risk of aspiration. (4)
`
`
`
`
`• Hypocalcemia (4, 5.2)
`
`
`• Hypersensitivity to any component of this product (4, 6.2)
`
`
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
`• Upper Gastrointestinal Adverse Reactions can occur. Instruct
`
`
`
`patients to follow dosing instructions. Discontinue if new or
`
`
`
`worsening symptoms occur. (5.1)
`
`
`
`• Hypocalcemia can worsen and must be corrected prior to use. (5.2)
`
`
`
`• Severe Bone, Joint, Muscle Pain may occur. Discontinue use if
`
`
`
`
`
`
`severe symptoms develop. (5.3)
`
`
`• Osteonecrosis of the Jaw has been reported. (5.4)
`
`
`
`
`
`
`• Atypical Femur Fractures have been reported. Patients with new
`
`
`
`
`
`
`
`
`thigh or groin pain should be evaluated to rule out an incomplete
`
`femoral fracture. (5.5)
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`
`Most common adverse reactions (greater than or equal to 3%) are
`
`
`
`
`
`abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia,
`
`
`musculoskeletal pain, nausea. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­
`
`
`
`
`
`
`
`
`
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS ------------------------------­
`
`
`
`
`
`• Calcium supplements, antacids, or oral medications containing
`
`
`multivalent cations interfere with absorption of alendronate. (2.6,
`
`
`
`
`
`7.1)
`
`• Use caution when co-prescribing aspirin/nonsteroidal anti-
`
`
`inflammatory drugs that may worsen gastrointestinal irritation. (7.2,
`
`
`
`
`
`7.3)
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
`
`
`
`
`• FOSAMAX is not indicated for use in pediatric patients. (8.4)
`
`
`• FOSAMAX is not recommended in patients with renal impairment
`
`
`
`
`
`(creatinine clearance less than 35 mL/min). (5.6, 8.6)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`
`
`
`Guide.
`
`
`
`
`Revised: 12/2013
`
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Post-Marketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Calcium Supplements/Antacids
`
`
`7.2 Aspirin
`
`
`7.3 Nonsteroidal Anti-Inflammatory Drugs
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`
`
`14.1 Treatment of Osteoporosis in Postmenopausal Women
`
`
`14.2 Prevention of Osteoporosis in Postmenopausal Women
`
`
`14.3 Treatment to Increase Bone Mass in Men with Osteoporosis
`
`
`14.4 Treatment of Glucocorticoid-Induced Osteoporosis
`
`Grun. Exh. 1013
`PGR for U.S. Patent No. 9,539,268
`
`

`

`
`
`
` 16
`
` 17
`
` 14.5 Treatment of Paget's Disease of Bone
`
`
`
` HOW SUPPLIED/STORAGE AND HANDLING
`
`
` PATIENT COUNSELING INFORMATION
` 17.1 Osteoporosis Recommendations, Including Calcium and
`
`
` Vitamin D Supplementation
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 17.2 Dosing Instructions
`
`*Sections or subsections omitted from the full prescribing information
`
`
` are not listed.
`
`
`
` INDICATIONS AND USAGE
` 1
`
`
`
`
` 1.1 Treatment of Osteoporosis in Postmenopausal Women
`
`
` FOSAMAX®
`In
`the
`indicated
`in postmenopausal women.
`is
`for
`treatment of osteoporosis
`
`
`
`
`
`
`
`postmenopausal women, FOSAMAX increases bone mass and reduces the incidence of fractures,
`
`
`
`
`
`
`
`
`including those of the hip and spine (vertebral compression fractures). [See Clinical Studies (14.1).]
`
`
`1.2 Prevention of Osteoporosis in Postmenopausal Women
`
`
`FOSAMAX is indicated for the prevention of postmenopausal osteoporosis [see Clinical Studies
`
`
`
`
`
`(14.2)].
`
`1.3 Treatment to Increase Bone Mass in Men with Osteoporosis
`
`
`FOSAMAX is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical
`
`
`Studies (14.3)].
`
`
`1.4 Treatment of Glucocorticoid-Induced Osteoporosis
`
`
`FOSAMAX is indicated for the treatment of glucocorticoid-induced osteoporosis in men and women
`
`
`
`receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have
`
`
`
`low bone mineral density [see Clinical Studies (14.4)].
`
`
`1.5 Treatment of Paget's Disease of Bone
`
`
`
`FOSAMAX is indicated for the treatment of Paget’s disease of bone in men and women. Treatment is
`
`
`
`
`indicated in patients with Paget's disease of bone who have alkaline phosphatase at least two times the
`
`
`
`
`
`
`
`upper limit of normal, or those who are symptomatic, or those at risk for future complications from their
`
`
`
`
`
`
`
`
`
`
`
`
`
`disease. [See Clinical Studies (14.5).]
`
`
`Important Limitations of Use
`1.6
`
`
`The optimal duration of use has not been determined. The safety and effectiveness of FOSAMAX 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.
`
`
`
`2
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`
`
`Although alendronate tablets 5 mg, 10 mg, 35 mg, and 40 mg are available in the marketplace,
`
`
`
`
`
`FOSAMAX is no longer marketed in the 5 mg, 10 mg, 35 mg, and 40 mg strengths.
`
`
`
`Although an oral solution of alendronate may be available in the marketplace, FOSAMAX oral solution
`
`is no longer marketed.
`
`2.1 Treatment of Osteoporosis in Postmenopausal Women
`
`
`The recommended dosage is:
`
`
`
`
`• one 70 mg tablet once weekly
`
`
`or
`
`
`
`• one bottle of 70 mg oral solution once weekly
`
`
`or
`
`
`
`
`• one 10 mg tablet once daily
`
`
`2.2 Prevention of Osteoporosis in Postmenopausal Women
`
`
`The recommended dosage is:
`
`
`
`
`• one 35 mg tablet once weekly
`
`
`or
`
`
`
`
`• one 5 mg tablet once daily
`
`
`
`
`2.3 Treatment to Increase Bone Mass in Men with Osteoporosis
`
`The recommended dosage is:
`
`
`
`• one 70 mg tablet once weekly
`
`
`or
`
`
`
`• one bottle of 70 mg oral solution once weekly
`
`
`or
`
`
`
`• one 10 mg tablet once daily
`
`
`
`
`Reference ID: 3426836
`
`
`2
`
`
`

`

`
`
`
`
`2.4 Treatment of Glucocorticoid-Induced Osteoporosis
`
`
`
`
`
`The recommended dosage is one 5 mg tablet once daily, except for postmenopausal women not
`
`
`receiving estrogen, for whom the recommended dosage is one 10 mg tablet once daily.
`
`
`2.5 Treatment of Paget's Disease of Bone
`
`
`The recommended treatment regimen is 40 mg once a day for six months.
`
`Re-treatment of Paget’s Disease
`Re-treatment with FOSAMAX may be considered, following a six-month post-treatment evaluation
`
`period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be
`
`
`measured periodically. Re-treatment may also be considered in those who failed to normalize their serum
`
`alkaline phosphatase.
`
`
`
`Important Administration Instructions
`2.6
`
`Instruct patients to do the following:
`
`
`
`
`
`
`
`
`
`
`
`• Take FOSAMAX 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 FOSAMAX [see Drug
`
`
`Interactions (7.1)]. W aiting less than 30 minutes, or taking FOSAMAX with food, beverages (other
`
`
`
`
`than plain water) or other medications will lessen the effect of FOSAMAX by decreasing its absorption
`into the body.
`
`
`
`
`
`
`• Take FOSAMAX upon arising for the day. To facilitate delivery to the stomach and thus reduce the
`
`
`
`
`
`
`
`
`
`
`potential for esophageal irritation, a FOSAMAX tablet should be swallowed with a full glass of water
`
`
`
`
`
`
`
`(6-8 ounces). To facilitate gastric emptying FOSAMAX oral solution should be followed by at least 2
`
`
`
`
`
`ounces (a quarter of a cup) of water. Patients should not lie down for at least 30 minutes and until
`after their first food of the day. FOSAMAX 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)].
`
`
`
`2.7 Recommendations for Calcium and Vitamin D Supplementation
`
`
`Instruct patients to take supplemental calcium if dietary intake is inadequate [see Warnings and
`
`Precautions (5.2)]. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years,
`
`
`nursing home-bound, or chronically ill) may need 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.
`
`Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.
`
`2.8 Administration Instructions for Missed Doses
`
`
`If a once-weekly dose of FOSAMAX is missed, instruct patients to take one dose on the morning after
`
`
`
`
`
`they remember. They should not take two doses on the same day but should return to taking one dose
`
`
`
`
`
`
`once a week, as originally scheduled on their chosen day.
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`• 70 mg tablets are white, oval, uncoated tablets with code 31 on one side and an outline of a bone
`
`
`
`
`image on the other.
`
`
`•
`
`
`4
`
`
`CONTRAINDICATIONS
`
`FOSAMAX is contraindicated in patients with the following conditions:
`
`
`• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see
`
`
`
`
`
`
`
`
`Warnings and Precautions (5.1)]
`Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2.6); Warnings
`
`
`
`and Precautions (5.1)]
`
`• Do not administer FOSAMAX oral solution to patients at increased risk of aspiration.
`
`
`
`
`• Hypocalcemia [see Warnings and Precautions (5.2)]
`
`
`• Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and
`
`
`angioedema have been reported [see Adverse Reactions (6.2)].
`
`
`
`
`Reference ID: 3426836
`
`3
`
`
`

`

`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Upper Gastrointestinal Adverse Reactions
`
`
`
`FOSAMAX, 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 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. 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 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 and/or who fail to swallow oral bisphosphonates
`
`
`
`
`
`
`
`including FOSAMAX with the recommended full glass (6-8 ounces) of water, and/or who continue to take
`
`
`
`
`oral bisphosphonates including FOSAMAX after developing symptoms suggestive of esophageal irritation.
`
`
`Therefore, it is very important that the full dosing instructions are provided to, and understood by, the
`
`
`patient [see Dosage and Administration (2.6)]. In patients who cannot comply with dosing instructions due
`
`to mental disability, therapy with FOSAMAX 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)].
`
`
`
`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), 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.
`
`
`
`Reference ID: 3426836
`
`
`4
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
` ADVERSE REACTIONS
` 6
`
`
`
` 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.
`
`
`
`
`
`Reference ID: 3426836
`
`
`5
`
`

`

`
`
`
`
`
`
`
`
` FOSAMAX†
`
` %
` (n=3236)
`
`1.5
`
`1.1
`
`1.1
`
`0.0
`
`0.6
`
`0.2
`
`1.1
`
`0.1
`
`0.2
`
`0.1
`
`0.0
`
`
` 0.6
`
`
`
`0.4
`
`
` 0.2
`
`
`
`0.2
`
` 0.0
`
` 0.1
`
`
`
`
` Placebo
`
` %
`
` (n=3223)
`
`1.5
`
`1.5
`
`1.2
`
`0.2
`
`0.3
`
`0.3
`
`0.9
`
`0.1
`
`0.3
`
`0.1
`
`0.0
`
`
` 0.7
`
`
`
`0.3
`
`
` 0.1
`
`
`
`0.2
`
` 0.1
`
` 0.0
`
`
`
`
`
`
` 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
` Fracture Intervention Trial
`
`
` Studies
`
` FOSAMAX*
`
` %
`
` (n=196)
`
`6.6
`
`3.6
`
`3.6
`
`3.1
`
`3.1
`
`2.6
`
`2.0
`
`1.5
`
`1.0
`
`1.0
`
`1.0
`
`
` 0.5
`
`
`
`4.1
`
`
` 0.0
`
`
`2.6
`
`
` 0.0
`
` 0.5
`
`
`
`
`
`
`
`
` Placebo
`
` %
`
` (n=397)
`
`4.8
`
`4.0
`
`3.5
`
`1.8
`
`1.8
`
`0.5
`
`4.3
`
`0.0
`
`1.5
`
`0.0
`
`0.8
`
`
` 1.3
`
`
`
`2.5
`
`
`
` 1.0
`
`
`1.5
`
`
` 1.0
`
` 1.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3426836
`
`
`6
`
` Gastrointestinal
`
`
` abdominal pain
`
` nausea
` dyspepsia
`
`
` constipation
`
` diarrhea
` flatulence
`
`
` acid regurgitation
`
` esophageal ulcer
`
` vomiting
` dysphagia
`
` abdominal distention
`
` gastritis
` Musculoskeletal
`
` musculoskeletal
`
`
`
` (bone, muscle or
`
` joint) pain
`
`
` muscle cramp
`
` Nervous
` System/Psychiatric
`headache
`
`
` dizziness
`
` Special Senses
`
` taste perversion
`
`
`
`
` * 10 mg/day for three years
`† 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years
`
`
`
`
`
`
`Rash and erythema have occurred.
`
`
`Gastrointestinal Adverse Reactions: One patient treated with 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.
`
`
`W eekly 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 FOSAMAX
`
`
` FOSAMAX
`70 mg
`
`
` 10 mg/day
`
`
` %
` %
`
`
` (n=519)
` (n=370)
`
`
` Gastrointestinal
`
`3.7
`3.0
`
`
`
` abdominal pain
`2.7
`2.2
`
`
`
` dyspepsia
`1.9
`2.4
`
`
`
` acid regurgitation
`2.4
`
`1.9
`
`
` nausea
`1.4
`
`1.0
`
`abdominal distention
`
`1.6
`
`0.8
`
`constipation
`
`1.6
`
`0.4
`
`flatulence
`
`1.1
`
`0.2
`
`gastritis
`
`
` 0.0
`
` 1.1
`
` gastric ulcer
`
`
`
` Musculoskeletal
`2.9
`3.2
`
`
`
` musculoskeletal (bone,
`
`
`
` muscle, joint) pain
` 0.2
` 1.1
`
`
` muscle cramp
`
` 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.
`
`W eekly 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
`
`
`
`
`
`
`
`
` Once Weekly
`
`
` FOSAMAX Placebo
` FOSAMAX
`
` FOSAMAX
`5 mg/day
`
`
` 5 mg/day
` 35 mg
`
`
`
`%
`%
`
`
` %
` %
`
`
`
`
` (n=642)
` (n=648)
` (n=361)
` (n=362)
`
`
`
`
`
`
` 1.9
` 1.4
`
` 2.2
`
` 1.7
`
` 3.4
`
` 1.7
`
` 4.2
`
` 2.2
`
` 1.4
`
` 2.5
`
` 4.2
`
` 4.7
`
` 1.4
`
` 1.4
`
` 2.5
`
` 1.4
`
` 1.1
`
` 1.7
`
` 1.1
`
` 0.6
`
` 0.9
`
` 0.5
`
` 1.7
`
` 0.3
`
` 0.2
`
` 0.3
`
` 1.4
`
` 1.1
`
`
`
`
` 0.8
` 0.9
` 1.9
` 2.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Gastrointestinal
`
` dyspepsia
` abdominal pain
`
` acid regurgitation
`
`
` nausea
` diarrhea
`
` constipation
`
` abdominal distention
`
` Musculoskeletal
`
` musculoskeletal (bone,
`
`
`
` muscle or joint)
`
`
` pain
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3426836
`
`
`
` 7
`
`

`

`
`
`
`
`
`
` Placebo
`
` %
`
`
` (n=95)
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
` Once Weekly
`
` FOSAMAX
` FOSAMAX 70 mg
`
`
`
` 10 mg/day
`
`%
`
`
`(n=109)
` %
`
` (n=146)
`
` Gastrointestinal
`
`4.1
`
` acid regurgitation
`4.1
`
`
` flatulence
`0.7
`
` gastroesop