Alendronate Sodium: Package Insert and Label Information

ALENDRONATE SODIUM — alendronate sodium solution
ANI Pharmaceuticals, Inc.

1 INDICATIONS & USAGE

1.1 Treatment of Osteoporosis in Postmenopausal Women

Alendronate sodium is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, alendronate increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures) [see Clinical Studies (14.1)].

1.3 Treatment to Increase Bone Mass in Men with Osteoporosis

Alendronate sodium is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.3)].

1.6 Important Limitations of Use

The optimal duration of use has not been determined. The safety and effectiveness of alendronate 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 & ADMINISTRATION

2.1 Treatment of Osteoporosis in Postmenopausal Women

The recommended dosage is:

• one bottle of 70 mg oral solution once weekly

2.3 Treatment to Increase Bone Mass in Men with Osteoporosis

The recommended dosage is:

• one bottle of 70 mg oral solution once weekly

2.6 Important Administration Instructions

Instruct patients to do the following:

• Take alendronate 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 alendronate with food, beverages (other than plain water) or other medications will lessen the effect of alendronate by decreasing its absorption into the body.
• Take alendronate upon arising for the day. To facilitate gastric emptying alendronate 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. Alendronate 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 CounselingInformation (17.2)].

2.7 Recommendations for Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium if dietary intake is inadequate [see Warnings andPrecautions (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 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 & STRENGTHS

• Alendronate Sodium Oral Solution, 70 mg, is a clear, colorless to pale pink solution with a raspberry flavor, free from visible particulate matter.

4 CONTRAINDICATIONS

Alendronatesodiumiscontraindicatedinpatientswiththefollowing conditions:

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions(5.1)]
• Inabilitytostandorsituprightforatleast 30 minutes [see Dosage and Administration(2.6);Warnings and Precautions(5.1)]
• Do not administer alendronate sodium 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 urticarial and angioedema have been reported [see AdverseReactions(6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Upper Gastrointestinal Adverse Reactions

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

Presumably due to the effects of alendronate 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. 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, the percentages of patients with these symptoms were similar in the alendronate 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. 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 is not recommended for patients with creatinine clearance less than 35 mL/min.

5.7 Glucocorticoid-Induced Osteoporosis

The risk versus benefit of alendronate sodium 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 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. 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 group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the alendronate 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 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 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
	Alendronate* % (n=196)	Placebo % (n=397)	Alendronate† % (n=3236)	Placebo % (n=3223)
Gastrointestinal abdominalpain	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
acidregurgitation	2.0	4.3	1.1	0.9
esophagealulcer	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
abdominaldistention	1.0	0.8	0.0	0.0
gastritis	0.5	1.3	0.6	0.7
Musculoskeletal musculoskeletal(bone,muscle orjoint)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 tasteperversion	0.5	1.0	0.1	0.0

* 10 mg/dayforthreeyears

† 5 mg/dayfor 2 yearsand 10 mg/dayforeither 1 or 2 additionalyears

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 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 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 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 Sodium 70 mg % (n=519)	Alendronate Sodium 10 mg/day % (n=370)
Gastrointestinal abdominal paindyspepsiaacid regurgitationnauseaabdominal distentionconstipationflatulencegastritisgastric ulcer	3.72.71.91.91.00.80.40.20.0	3.02.22.42.41.41.61.61.11.1
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 sodium 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 sodium for either two or three years. In these studies the overall safety profiles of alendronate sodium 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 sodium 5 mg/day and 5.7% of 648 patients treated with placebo.

Weekly Dosing: The safety of alendronate sodium 35 mg once weekly compared to alendronate sodium 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 sodium 35 mg and alendronate sodium 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 sodium 35 mg, alendronate sodium 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
	Alendronate Sodium 5 mg/day % (n=642)	Placebo % (n=648)	Alendronate Sodium 5 mg/day % (n=361)	Once Weekly Alendronate Sodium 35 mg % (n=362)
Gastrointestinal dyspepsiaabdominal painacid regurgitationnauseadiarrheaconstipationabdominaldistention	1.91.71.41.41.10.90.2	1.43.42.51.41.70.50.3	2.24.24.22.51.11.71.4	1.72.24.71.40.60.31.1
Musculoskeletal musculoskeletal(bone, muscle orjoint) 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 alendronate sodium 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 sodium 10 mg/day and a one-year study of once weekly alendronate sodium 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for alendronate sodium 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate sodium 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 Sodium 10 mg/day % (n=146)	Placebo % (n=95)	Once Weekly Alendronate 70 mg % (n=109)	Placebo % (n=58)
Gastrointestinal acid regurgitationflatulencegastroesophagealreflux diseasedyspepsiadiarrheaabdominal painnausea	4.14.10.73.41.42.12.1	3.21.13.20.01.11.10.0	0.00.02.82.82.80.90.0	0.00.00.01.70.03.40.0

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 sodium 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 sodium 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 Sodium 10 mg/day % (n=157)	Alendronate Sodium 5 mg/day % (n=161)	Placebo % (n=159)
Gastrointestinal abdominal pain acid regurgitationconstipationmelenanauseadiarrhea	3.22.51.31.30.60.0	1.91.90.60.01.20.0	0.01.30.00.00.61.3
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 (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 sodium 40 mg/day for 3 to 12 months were similar to those in postmenopausal women treated with alendronate sodium 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse reactions in patients taking alendronate sodium 40 mg/day (17.7% alendronate sodium 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 sodium 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 sodium 40 mg/day and 2.4% of patients treated with placebo.