Alendronate: Package Insert and Label Information

ALENDRONATE- alendronate sodium tablet
Marlex Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

1.1 Treatment of Osteoporosis in Postmenopausal Women

Alendronate sodium tablets are indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, alendronate sodium tablets increase bone mass and reduce 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

Alendronate sodium tablets are indicated for the prevention of postmenopausal osteoporosis [ see Clinical Studies (14.2)].

1.3 Treatment to Increase Bone Mass in Men with Osteoporosis

Alendronate sodium tablets are indicated for treatment to increase bone mass in men with osteoporosis

[See Clinical Studies ( 14.3 )].

1.4 Treatment of Glucocorticoid-Induced Osteoporosis

Alendronate sodium tablets are 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

Alendronate sodium tablets are 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).]

1.6 Important Limitations of Use

The optimal duration of use has not been determined. The safety and effectiveness of alendronate sodium tablets 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

2.1 Treatment of Osteoporosis in Postmenopausal Women

The recommended dosage is:

  • one 70 mg tablet 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 10 mg tablet once daily

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 40mg once a day for six months.

Re-treatment of Paget’s Disease

Re-treatment with alendronate sodium tablets 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.

2.6 Important Administration Instructions

Instruct patients to do the following:

  • Take alendronate sodium tablets 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 sodium tablets [see Drug Interactions ( 7.1]. Waiting less than 30 minutes, or taking alendronate sodium tablets with food, beverages (other than plain water) or other medications will lessen the effect of alendronate sodium tablets by decreasing its absorption into the body.
  • Take alendronate sodium tablets upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, an alendronate sodium tablet should be swallowed with a full glass of water (6 to 8 ounces). Patients should not lie down for at least 30 minutes and until after their first food of the day. Alendronate sodium tablets 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 alendronate sodium tablets 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.

3 DOSAGE FORMS AND STRENGTHS

  • 35mg (alendronate) tablets are modified oval, white to off-white tablets; one side debossed “AP207”, the other side blank.

  • 70mg (alendronate) tablets are modified oval, white to off-white tablets; one side debossed “AP205”, the other side blank.

4 CONTRAINDICATIONS

Alendronate sodium tablets are 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)]
  • 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)].

5 WARNINGS AND PRECAUTIONS

5.1 Upper Gastrointestinal Adverse Reactions

Alendronate sodium, 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 alendronate sodium 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 alendronate sodium. 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 alendronate sodium 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 alendronate sodium and/or who fail to swallow oral

bisphosphonates including alendronate sodium with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates including alendronate sodium 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 alendronate sodium 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 alendronate sodium [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 alendronate sodium.

Presumably due to the effects of alendronate sodium 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 alendronate sodium. 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 alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium 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 alendronate sodium. 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

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

5.7 Glucocorticoid-Induced Osteoporosis

The risk versus benefit of alendronate 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 alendronate sodium 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 alendronate sodium in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44 to 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 alendronate sodium. 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 alendronate sodium group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the alendronate sodium 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 alendronate sodium 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 alendronate sodium 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 Patient

United States/ Multinational Studies Fracture Intervention Trial

Alendronate Sodium*

% (n=196)

Placebo

% (n=397)

Alendronate Sodium**

% (n=3236)

Placebo

% (n=3223)
Gastrointestinal

abdominal pain

6.6

4.8

1.5

1.5

nausea 3.6 4 1.1 1.5
dyspepsia 3.6 3.5 1.1 1.2
constipation 3.1 1.8 0 0.2
diarrhea 3.1 1.8 0.6 0.3
flatulence 2.6 0.5 0.2 0.3
acid regurgitation 2 4.3 1.1 0.9
esophageal ulcer 1.5 0 0.1 0.1
vomiting 1 1.5 0.2 0.3
dysphagia 1 0 0.1 0.1
abdominal distention 1 0.8 0 0
gastritis 0.5 1.3 0.6 0.7
Musculoskeletal

musculoskeletal (bone, muscle or joint) pain

4.1 0.4 0.3
muscle cramp 0 0.2 0.1
Nervous System/Psychiatric
headache 2.6 0.2 0.2
dizziness 0 0 0.1
Special Sense
taste perversion 0.5 0.1 0

*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 alendronate (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 alendronate sodium were discontinued and the patient recovered. In the Study 1 and Study 2 populations, 49 to 54% had a history of gastrointestinal disorders at baseline and 54 to 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 alendronate sodium versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to less than 8 mg/dL (2 mm) and serum phosphate to less than or equal to 2 mg/dL (0.65 mm) were similar in both treatment groups.

Weekly Dosing

The safety of alendronate 70 mg once weekly for the treatment of postmenopausal osteoporosis was

assessed in a one-year, double-blind, multicenter study comparing alendronate 70 mg once weekly and alendronate 10 mg daily. The overall safety and tolerability profiles of once weekly alendronate 70 mg and alendronate 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 Alendronate 70 mg

% (n=519)

Alendronate 10 mg/day

% (n=370)
Gastrointestinal
abdominal pain 3.7 3
dyspepsia 2.7 2.2
acid regurgitation 1.9 2.4
nausea 1.9 2.4
abdominal distention 1 1.4
constipation 0.8 1.6
flatulence 0.4 1.6
gastritis 0.2 1.1
gastric ulcer 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 alendronate 5 mg/day in postmenopausal women 40 to 60 years of age has been evaluated in three double-blind, placebo-controlled studies involving over 1,400 patients randomized to receive alendronate for either two or three years. In these studies the overall safety profiles of alendronate 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 alendronate 5 mg/day and 5.7% of 648 patients treated with placebo.

Weekly Dosing

The safety of alendronate 35 mg once weekly compared to alendronate 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 alendronate 35 mg and alendronate 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 alendronate 35 mg, alendronate 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

Alendronate

5 mg/day

% (n=642)

Placebo

% (n=648)

Alendronate

5 mg/day

% (n=361)

Alendronate 35 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 0.9 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 alendronate 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 alendronate 10 mg/day and a one-year study of once weekly alendronate 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate 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 alendronate sodium 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

Alendronate 10 mg/day

% (n=146)

Placebo

% (n=95)

Once Weekly Alendronate 70 mg

% (n=109)

Placebo

% (n=58)
Gastrointestinal
acid regurgitation 4.1 3.2 0 0
flatulence 4.1 1.1 0 0
gastroesophageal reflux disease 0.7 3.2 2.8 0
dyspepsia 3.4 0 2.8 1.7
diarrhea 1.4 1.1 2.8 0
abdominal pain 2.1 1.1 0.9 3.4
nausea 2.1 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 alendronate 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 alendronate 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

Alendronate 10 mg/day

% (n=157)

Alendronate 5 mg/day

% (n=161)

Placebo

% (n=159)
Gastrointestinal
abdominal pain 3.2 1.9 0
acid regurgitation 2.5 1.9 1.3
constipation 1.3 0.6 0
melena 1.3 1.3 0
nausea 0.6 1.2 0.6
diarrhea 0 0 1.3
Nervous System/Psychiatric
headache 0.6 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 (alendronate sodium: 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 alendronate 40 mg/day for 3 to 12 months were similar to those in postmenopausal women treated with alendronate 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse reactions in patients taking alendronate 40 mg/day (17.7% alendronate 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 alendronate 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 alendronate 40 mg/day and 2.4% of patients treated with placebo.

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