Alendronate Sodium

TAGI Pharma, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Alendronate Sodium Oral Solution safely and effectively. See full prescribing information for Alendronate Sodium Oral Solution. Alendronate Sodium Oral Solution Initial U.S. Approval: 1995INDICATIONS AND USAGEAlendronate Sodium Oral Solution is a bisphosphonate indicated for: Treatment of osteoporosis in postmenopausal women (1.1) Treatment to increase bone mass in men with osteoporosis (1.3) Important limitations of use: The optimal duration of use has not been determined. The need for continued therapy should be re-evaluated on a periodic basis. (1.6)DOSAGE AND ADMINISTRATION Must be taken at least 30 minutes before the first food, drink, or medication of the day; do not lie down for at least 30 minutes after taking alendronate sodium oral solution and until after food. (2.6) Oral solution: Should be followed by at least 2 oz of water. (2.6) Treatment of osteoporosis in postmenopausal women and in men: 70 mg (oral solution) once weekly. (2.1, 2.3) DOSAGE FORMS AND STRENGTHSOral Solution: 70 mg (3)CONTRAINDICATIONS Abnormalities of the esophagus which delay emptying such as stricture or achalasia (4, 5.1) Inability to stand/sit upright for at least 30 minutes (2, 4, 5.1) Do not administer Alendronate Sodium 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 Severe irritation of upper gastrointestinal (GI) mucosa can occur. Follow dosing instructions. Use caution in patients with active upper GI disease. 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. Evaluate new thigh or groin pain to rule out an incomplete femoral fracture. (5.5) Side EffectsMost common adverse reactions (≥3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Roxane Laboratories, Inc. at 1-800-962-8364 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) Aspirin and nonsteroidal anti-inflammatory drug use may worsen GI irritation; use caution. (7.2, 7.3) USE IN SPECIFIC POPULATIONS Alendronate sodium is not indicated for use in pediatric patients. (8.4) Alendronate sodium is not recommended in patients with renal impairment (creatinine clearance

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 ALENDRONATE SODIUM INDICATIONS AND USAGE
  • 1.1 Treatment of Osteoporosis in Postmenopausal Women
  • 1.3 Treatment to Increase Bone Mass in Men with Osteoporosis
  • 1.6 Important Limitations of Use
• 2 ALENDRONATE SODIUM DOSAGE AND ADMINISTRATION
  • 2.1 Treatment of Osteoporosis in Postmenopausal Women
  • 2.3 Treatment to Increase Bone Mass in Men with Osteoporosis
  • 2.6 Dosing Instructions
  • 2.7 Recommendations for Calcium and Vitamin D Supplementation
  • 2.8 Dosing in Severe Renal Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 ALENDRONATE SODIUM 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
• 6 ALENDRONATE SODIUM 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 ALENDRONATE SODIUM 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
  • 14.3 Treatment to Increase Bone Mass in Men with Osteoporosis
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation
  • 17.2 Dosing Instructions

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Treatment of Osteoporosis in Postmenopausal Women

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

1.6 Important Limitations of Use

The safety and effectiveness of alendronate for the treatment of osteoporosis are based on clinical data of four years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.

2 DOSAGE AND 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 Dosing Instructions

Alendronate must be taken 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.

Alendronate should only be taken upon arising for the day. To facilitate gastric emptying alendronate oral solution should be followed by at least 2 oz (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 Counseling Information (17.2) ].

2.7 Recommendations for Calcium and Vitamin D Supplementation

Patients should receive 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 Dosing in Severe Renal Impairment

Alendronate is not recommended for patients with creatinine clearance <35 mL/min due to lack of experience in this population [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS

• Alendronate Sodium Oral Solution, 70 mg, is a clear, colorless to pale pink solution with a raspberry flavor

4 CONTRAINDICATIONS

• 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 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 urticaria and angioedema have been reported [see Adverse Reactions (6.2) ].

5 WARNINGS AND PRECAUTIONS

5.1 Upper Gastrointestinal Side Effects

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 oz) 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), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).

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 <35 mL/min [see Dosage and Administration (2.8) ].

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 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 IU 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 ≥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 ≥1% of Patients

	United States/Multinational Studies		Fracture Intervention Trial
	Alendronate10 mg/day for three years % (n=196)	Placebo % (n=397)	Alendronate5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years % (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	2.5	0.4	0.3
muscle cramp	0	1	0.2	0.1
Nervous System/Psychiatric
headache	2.6	1.5	0.2	0.2
dizziness	0	1	0	0.1
Special Senses
taste perversion	0.5	1	0.1	0

Rarely, 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 <8 mg/dL (2 mM) and serum phosphate 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 ≥1% of patients in either treatment group are presented in Table 2.

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 ≥2% of patients treated with either alendronate or placebo are presented in Table 4.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of alendronate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: hypersensitivity reactions including urticaria and rarely angioedema. Transient symptoms of myalgia, malaise, asthenia and rarely, fever have been reported with alendronate, typically in association with initiation of treatment. Rarely, symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Rarely, peripheral edema.

Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, rarely esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications, have also been reported [see Dosage and Administration (2); Warnings and Precautions (5.1) ].

Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported rarely [see Warnings and Precautions (5.4) ].

Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and rarely incapacitating [see Warnings and Precautions (5.3) ]; joint swelling; low-energy femoral shaft and subtrochanteric fractures [see Warnings and Precautions (5.5) ].

Nervous System: dizziness and vertigo.

Skin: rash (occasionally with photosensitivity), pruritus, alopecia, rarely severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Special Senses: rarely uveitis, scleritis or episcleritis.

7 DRUG INTERACTIONS

7.1 Calcium Supplements/Antacids

Co-administration of alendronate and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of alendronate. Therefore, patients must wait at least one-half hour after taking alendronate before taking any other oral medications.

7.2 Aspirin

In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate greater than 10 mg and aspirin-containing products.

7.3 Nonsteroidal Anti-Inflammatory Drugs

Alendronate may be administered to patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: There are no studies in pregnant women. Alendronate should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.

Reproduction studies in rats showed decreased postimplantation survival and decreased body weight gain in normal pups at doses less than half of the recommended clinical dose. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at approximately 3 times the clinical dose in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. No similar fetal effects were seen when pregnant rabbits were treated with doses approximately 10 times the clinical dose.

Both total and ionized calcium decreased in pregnant rats at approximately 4 times the clinical dose resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as one tenth the clinical dose when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) also occurred in the female rats treated at approximately 4 times the clinical dose for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; intravenous calcium supplementation prevented maternal, but not fetal deaths.

Exposure multiples based on surface area, mg/m², were calculated using a 40 mg human daily dose. Animal dose ranged between 1 and 15 mg/kg/day in rats and up to 40 mg/kg/day in rabbits.

8.3 Nursing Mothers

It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alendronate is administered to nursing women.

8.4 Pediatric Use

Alendronate is not indicated for use in pediatric patients.

The safety and efficacy of alendronate were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4 to 18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate daily (weight <40 kg) or 10 mg alendronate daily (weight ≥40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate-treated patients and 0.1 in the placebo-treated patients. Treatment with alendronate did not reduce the risk of fracture. Sixteen percent of the alendronate patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects. There were no statistically significant differences between the alendronate and placebo groups in reduction of bone pain. The oral bioavailability in children was similar to that observed in adults.

The overall safety profile of alendronate in OI patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate. However, there was an increased occurrence of vomiting in OI patients treated with alendronate compared to placebo. During the 24-month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate and 3 of 30 (10%) patients treated with placebo.

In a pharmacokinetic study, 6 of 24 pediatric OI patients who received a single oral dose of alendronate 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration. These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate [see Adverse Reactions (6.2) ].

8.5 Geriatric Use

Of the patients receiving alendronate in the Fracture Intervention Trial (FIT), 71% (n=2302) were ≥65 years of age and 17% (n=550) were ≥75 years of age. Of the patients receiving alendronate in the United States and Multinational osteoporosis treatment studies in women, and osteoporosis studies in men [see Clinical Studies (14.1), (14.3) ], 45% and 54% respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

Alendronate is not recommended for patients with creatinine clearance <35 mL/min. No dosage adjustment is necessary in patients with creatinine clearance values between 35 to 60 mL/min [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m²) and 966 mg/kg (2898 mg/m²), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m²).

No specific information is available on the treatment of overdosage with alendronate. Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.

Dialysis would not be beneficial.

11 DESCRIPTION

Alendronate sodium is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.

Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.

The empirical formula of alendronate sodium is C₄H₁₂NNaO₇P₂∙3H₂O and its formula weight is 325.12. The structural formula is:

Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform.

Each bottle of the oral solution contains 91.35 mg of alendronate monosodium salt trihydrate, which is the molar equivalent to 70 mg of free acid. Each bottle also contains the following inactive ingredients: citric acid (anhydrous), methyl paraben, propylparaben, raspberry blend, saccharin sodium, and sodium citrate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [³H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [³H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

12.2 Pharmacodynamics

Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.

Osteoporosis in Postmenopausal Women: Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral (spinal) fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in white women increases 50-fold and the risk of vertebral fracture 15 to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.

Daily oral doses of alendronate (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.

Long-term treatment of osteoporosis with alendronate 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type l collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received alendronate 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with alendronate. In osteoporosis treatment studies alendronate 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase by approximately 25 to 30% to reach a plateau after 6 to 12 months. In osteoporosis prevention studies alendronate 5 mg/day decreased osteocalcin and total serum alkaline phosphatase by approximately 40% and 15%, respectively. Similar reductions in the rate of bone turnover were observed in postmenopausal women during one-year studies with once weekly alendronate 70 mg for the treatment of osteoporosis and once weekly alendronate 35 mg for the prevention of osteoporosis. These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone.

As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with alendronate. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of alendronate 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward prestudy levels during years three through five. Similar reductions were observed with alendronate 5 mg/day. In one-year studies with once weekly alendronate 35 and 70 mg, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate but also a decrease in renal phosphate reabsorption.

Osteoporosis in Men: Treatment of men with osteoporosis with alendronate 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving once weekly alendronate 70 mg.

12.3 Pharmacokinetics

Absorption: Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.

Alendronate 70 mg oral solution and alendronate 70 mg tablet are equally bioavailable.

A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.

Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

Distribution: Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.

Metabolism: There is no evidence that alendronate is metabolized in animals or humans.

Excretion: Following a single intravenous dose of [¹⁴C] alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10 mg intravenous dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with alendronate (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.

Specific Populations: Gender: Bioavailability and the fraction of an intravenous dose excreted in urine were similar in men and women.

Geriatric: Bioavailability and disposition (urinary excretion) were similar in elderly and younger patients. No dosage adjustment is necessary in elderly patients.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Impairment: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.

No dosage adjustment is necessary for patients with creatinine clearance 35 to 60 mL/min. Alendronate is not recommended for patients with creatinine clearance <35 mL/min due to lack of experience with alendronate in renal failure.

Hepatic Impairment: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.

Drug Interactions: Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H₂-antagonists is unknown.

In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).

Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to approximately 0.1 to 1 times a maximum recommended daily dose of 40 mg (Paget's disease) based on surface area, mg/m². The relevance of this finding to humans is unknown.

Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to approximately 0.3 and 1 times a 40 mg human daily dose based on surface area, mg/m². The relevance of this finding to humans is unknown.

Alendronate was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results.

Alendronate had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (approximately 1 times a 40 mg human daily dose based on surface area, mg/m²).

13.2 Animal Toxicology and/or Pharmacology

The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.

14 CLINICAL STUDIES

14.1 Treatment of Osteoporosis in Postmenopausal Women

Daily Dosing: The efficacy of alendronate 10 mg daily was assessed in four clinical trials. Study 1, a three-year, multicenter double-blind, placebo-controlled, US clinical study enrolled 478 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 2, a three-year, multicenter double blind placebo controlled Multinational clinical study enrolled 516 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 3, the Three-Year Study of the Fracture Intervention Trial (FIT) a study which enrolled 2027 postmenopausal patients with at least one baseline vertebral fracture; and Study 4, the Four-Year Study of FIT: a study which enrolled 4432 postmenopausal patients with low bone mass but without a baseline vertebral fracture.

Effect on Fracture Incidence: To assess the effects of alendronate on the incidence of vertebral fractures (detected by digitized radiography; approximately one third of these were clinically symptomatic), the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of alendronate (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a statistically significant reduction in the proportion of patients treated with alendronate experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk reduction). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the pooled analysis, patients who received alendronate had a loss in stature that was statistically significantly less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm).

The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone mass but without a baseline vertebral fracture. In both studies of FIT, 96% of randomized patients completed the studies (i.e., had a closeout visit at the scheduled end of the study); approximately 80% of patients were still taking study medication upon completion.

Fracture Intervention Trial: Three-Year Study (patients with at least one baseline radiographic vertebral fracture): This randomized, double-blind, placebo-controlled, 2027-patient study (Alendronate, n=1022; placebo, n=1005) demonstrated that treatment with alendronate resulted in statistically significant reductions in fracture incidence at three years as shown in Table 6.

Table 6: Effect of Alendronate on Fracture Incidence in the Three-Year Study of FIT (patients with vertebral fracture at baseline)

	Percent of Patients
	Alendronate (n=1022)	Placebo (n=1005)	Absolute Reduction in Fracture Incidence	Relative Reduction in Fracture Risk %
Patients with:
Vertebral fractures (diagnosed by X-ray)Number evaluable for vertebral fractures: alendronate, n=984; placebo, n=966
≥1 new vertebral fracture	7.9	15	7.1	47p<0.001
≥2 new vertebral fractures	0.5	4.9	4.4	90p<0.001
Clinical (symptomatic) fractures
Any clinical (symptomatic) fracture	13.8	18.1	4.3	26p=0.007
≥1 clinical (symptomatic) vertebral fracture	2.3	5	2.7	54p<0.01
Hip fracture	1.1	2.2	1.1	51p<0.05
Wrist (forearm) fracture	2.2	4.1	1.9	48p<0.05

Furthermore, in this population of patients with baseline vertebral fracture, treatment with alendronate significantly reduced the incidence of hospitalizations (25% vs. 30.7%).

In the Three-Year Study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on alendronate, p=0.047. Figure 1 displays the cumulative incidence of hip fractures in this study.

Figure 1:

Cumulative Incidence of Hip Fractures in the Three-Year Study of FIT (patients with radiographic vertebral fracture at baseline)

Fracture Intervention Trial: Four-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture): This randomized, double-blind, placebo-controlled, 4432-patient study (alendronate, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to alendronate. The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and nonosteoporotic women. The results are shown in Table 7 for the patients with osteoporosis.

Table 7: Effect of Alendronate on Fracture Incidence in OsteoporoticBaseline femoral neck BMD at least 2 SD below the mean for young adult women Patients in the Four-Year Study of FIT (patients without vertebral fracture at baseline)

	Percent of Patients
	Alendronate (n=1545)	Placebo (n=1521)	Absolute Reduction in Fracture Incidence	Relative Reduction in Fracture Risk %
Patients with:
Vertebral fractures (diagnosed by X-ray)Number evaluable for vertebral fractures: alendronate, n=1426; placebo, n=1428
≥1 new vertebral fracture	2.5	4.8	2.3	48p<0.001
≥2 new vertebral fractures	0.1	0.6	0.5	78p=0.035
Clinical (symptomatic) fractures
Any clinical (symptomatic) fracture	12.9	16.2	3.3	22p=0.01
≥1 clinical (symptomatic) vertebral fracture	1	1.6	0.6	41 (NS)Not significant. This study was not powered to detect differences at these sites.
Hip fracture	1	1.4	0.4	29 (NS)Not significant. This study was not powered to detect differences at these sites.
Wrist (forearm) fracture	3.9	3.8	-0.1	NSNot significant. This study was not powered to detect differences at these sites.

Fracture Results Across Studies: In the Three-Year Study of FIT, alendronate reduced the percentage of women experiencing at least one new radiographic vertebral fracture from 15% to 7.9% (47% relative risk reduction, p<0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1% (44% relative risk reduction, p=0.001); and in the combined U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction, p=0.034).

Alendronate reduced the percentage of women experiencing multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk reduction, p<0.001) in the combined U.S./Multinational studies and from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in the Three-Year Study of FIT. In the Four-Year Study of FIT, alendronate reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).

Thus, alendronate reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture.

Effect on Bone Mineral Density: The bone mineral density efficacy of alendronate 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years' duration.

Figure 2 shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving alendronate 10 mg/day relative to placebo-treated patients at three years for each of these studies.

Figure 2:

Osteoporosis Treatment Studies in Postmenopausal Women Increase in BMD Alendronate 10 mg/day at Three Years

At three years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received alendronate 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as three months and continued throughout the three years of treatment. (See Figure 3 for lumbar spine results.) In the two-year extension of these studies, treatment of 147 patients with alendronate 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm and total body were maintained. Alendronate was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean).

Figure 3:

Osteoporosis Treatment Studies in Postmenopausal Women Time Course of Effect of Alendronate 10 mg/day Versus Placebo: Lumbar Spine BMD Percent Change From Baseline

In patients with postmenopausal osteoporosis treated with alendronate 10 mg/day for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups.

Bone Histology: Bone histology in 270 postmenopausal patients with osteoporosis treated with alendronate at doses ranging from 1 to 20 mg/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo. These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with alendronate is of normal quality.

Effect on Height: Alendronate, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. placebo in patients with and without baseline radiographic vertebral fractures. At the end of the FIT studies the between-treatment group differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.

Weekly Dosing: The therapeutic equivalence of once weekly alendronate 70 mg (n=519) and alendronate 10 mg daily (n=370) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70 mg once-weekly group (n=440) and 5.4% (5, 5.8%; 95% CI) in the 10 mg daily group (n=330). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.

Concomitant Use with Estrogen/Hormone Replacement Therapy (HRT): The effects on BMD of treatment with alendronate 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two-year, double-blind, placebo-controlled study of hysterectomized postmenopausal osteoporotic women (n=425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or alendronate alone (both 6%).

The effects on BMD when alendronate was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one-year, double-blind, placebo-controlled study in postmenopausal osteoporotic women (n=428). The addition of alendronate 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%).

In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD.

Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture. Compared to placebo there was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with alendronate and HRT, 94% on alendronate alone, and 78% on HRT alone. The long-term effects of combined alendronate and HRT on fracture occurrence and fracture healing have not been studied.

14.3 Treatment to Increase Bone Mass in Men with Osteoporosis

The efficacy of alendronate in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.

Daily Dosing: A two-year, double-blind, placebo-controlled, multicenter study of alendronate 10 mg once daily enrolled a total of 241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either a BMD T-score ≤-2 at the femoral neck and ≤-1 at the lumbar spine, or a baseline osteoporotic fracture and a BMD T-score ≤-1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving alendronate 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatment with alendronate also reduced height loss (alendronate, -0.6 mm vs. placebo, -2.4 mm).

Weekly Dosing: A one-year, double-blind, placebo-controlled, multicenter study of once weekly alendronate 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either a BMD T-score ≤-2 at the femoral neck and ≤-1 at the lumbar spine, or a BMD T-score ≤-2 at the lumbar spine and ≤-1 at the femoral neck, or a baseline osteoporotic fracture and a BMD T-score ≤-1 at the femoral neck. At one year, the mean increases relative to placebo in BMD in men receiving alendronate 70 mg once weekly were significant at the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter, 2%; and total body, 1.2%. These increases in BMD were similar to those seen at one year in the 10 mg once-daily study.

In both studies, BMD responses were similar regardless of age (≥65 years vs. <65 years), gonadal function (baseline testosterone <9 ng/dL vs. ≥9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score ≤-2.5 vs. >-2.5).

16 HOW SUPPLIED/STORAGE AND HANDLING

Alendronate Sodium Oral Solution, 70 mg, is a clear, colorless to pale pink solution with a raspberry flavor and is supplied as follows:

NDC 51224-301-10 unit-of-use cartons of 4 single-dose bottles containing 75 mL each

Store at 25°C (77°F), excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling ( Medication Guide ).

Physicians should instruct their patients to read the Medication Guide before starting therapy with alendronate and to reread it each time the prescription is renewed.

17.1 Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation

Patients should be instructed to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.

17.2 Dosing Instructions

Patients should be instructed that the expected benefits of alendronate may only be obtained when it is taken with plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage, or medication of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate [see Clinical Pharmacology (12.3) ].

To facilitate gastric emptying, patients should drink at least 2 oz (a quarter of a cup) of water after taking alendronate oral solution.

Patients should be instructed not to lie down for at least 30 minutes and until after their first food of the day.

Patients should be specifically instructed not to take alendronate at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems.

Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate and consult their physician.

Patients should be instructed that if they miss a dose of once weekly alendronate, they should 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.

Manufactured by:
Roxane Laboratories, Inc.
Columbus, OH 43216

Manufactured for:
TAGI Pharma, Inc.
722 Progressive Lane, Room 205
South Beloit, IL 61080

10005270/01
Revised February 2013
©RLI, 2013

MEDICATION GUIDE
ONCE WEEKLY
ALENDRONATE SODIUM
ORAL SOLUTION

Rx only

Read the Medication Guide that comes with alendronate before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about alendronate.

What is the most important information I should know about alendronate?

Alendronate can cause serious side effects including:

• Esophagus problems
• Low calcium levels in your blood (hypocalcemia)
• Bone, joint, or muscle pain
• Severe jaw bone problems (osteonecrosis)
• Unusual thigh bone fractures

1. Esophagus problems.

Some people who take alendronate may develop problems in the esophagus (the tube that connects the mouth and the stomach). These problems include irritation, inflammation, or ulcers of the esophagus which may sometimes bleed.

• It is important that you take alendronate exactly as prescribed to help lower your chance of getting esophagus problems. (See the section "How should I take once weekly alendronate sodium oral solution?")
• Stop taking alendronate and call your doctor right away if you get chest pain, new or worsening heartburn, or have trouble or pain when you swallow.

2. Low calcium levels in your blood (hypocalcemia).

Alendronate may lower the calcium levels in your blood. If you have low blood calcium before you start taking alendronate, it may get worse during treatment. Your low blood calcium must be treated before you take alendronate. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:

• Spasms, twitches, or cramps in your muscles
• Numbness or tingling in your fingers, toes, or around your mouth

Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take alendronate. Take calcium and vitamin D as your doctor tells you to.

3. Bone, joint, or muscle pain.

Some people who take alendronate develop severe bone, joint, or muscle pain.

4. Severe jaw bone problems (osteonecrosis).

Severe jaw bone problems may happen when you take alendronate. Your doctor should examine your mouth before you start alendronate. Your doctor may tell you to see your dentist before you start alendronate. It is important for you to practice good mouth care during treatment with alendronate.

5. Unusual thigh bone fractures.

Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh.

Call your doctor right away if you have any of these side effects.

What is alendronate?

Alendronate is a prescription medicine used to:

• Treat osteoporosis in women after menopause. It helps reduce the chance of having a hip or spinal fracture (break).
• Increase bone mass in men with osteoporosis.

It is not known how long alendronate works for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if alendronate is still right for you.

Alendronate is not for use in children.

Who should not take alendronate?

Do not take alendronate if you:

• Have certain problems with your esophagus, the tube that connects your mouth with your stomach
• Cannot stand or sit upright for at least 30 minutes
• Have low levels of calcium in your blood
• Are allergic to alendronate or any of its ingredients. A list of ingredients is at the end of this leaflet.

What should I tell my doctor before taking alendronate?

Before you start alendronate, be sure to talk to your doctor if you:

• Have problems with swallowing
• Have stomach or digestive problems
• Have low blood calcium
• Plan to have dental surgery or teeth removed
• Have kidney problems
• Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome)
• Are pregnant, or plan to become pregnant. It is not known if alendronate can harm your unborn baby.
• Are breast-feeding or plan to breast-feed. It is not known if alendronate passes into your milk and may harm your baby.

Especially tell your doctor if you take:

• antacids
• aspirin
• Nonsteroidal Anti-Inflammatory (NSAID) medicines

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Certain medicines may affect how alendronate works.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How should I take once weekly alendronate sodium oral solution?

• Take alendronate exactly as your doctor tells you.
• Alendronate works only if taken on an empty stomach.
• Take alendronate while you are sitting or standing.
• Do not take alendronate with mineral water, coffee, tea, soda, or juice.
• Choose the day of the week that best fits your schedule.
• Drink your prescribed dose of alendronate sodium oral solution every week on your chosen day after you get up for the day and before taking your first food, drink or other medicine. Drink at least 2 ounces of plain water after you drink alendronate sodium oral solution.

After swallowing alendronate oral solution, wait at least 30 minutes:

• Before you lie down. You may sit, stand or walk, and do normal activities like reading.
• Before you take your first food or drink except for plain water.
• Before you take other medicines, including antacids, calcium, and other supplements and vitamins.

Do not lie down for at least 30 minutes after you take alendronate and after you eat your first food of the day.

If you miss a dose of alendronate, do not take it later in the day. Take your missed dose on the next morning after you remember and then return to your normal schedule. Do not take 2 doses on the same day.

If you take too much alendronate, call your doctor. Do not try to vomit. Do not lie down.

What are the possible side effects of alendronate?

Alendronate may cause serious side effects.

• See "What is the most important information I should know about alendronate?"

The most common side effects of alendronate are:

• Stomach area (abdominal) pain
• Heartburn
• Constipation
• Diarrhea
• Upset stomach
• Pain in your bones, joints, or muscles
• Nausea

You may get allergic reactions, such as hives or, in rare cases, swelling of your face, lips, tongue, or throat.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of alendronate. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store alendronate?

• Store alendronate at room temperature, 59°F to 86°F (15°C to 30°C).
• Keep alendronate in a tightly closed container.

Keep alendronate and all medicines out of the reach of children.

General information about the safe and effective use of alendronate.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use alendronate for a condition for which it was not prescribed. Do not give alendronate to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about alendronate. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about alendronate that is written for health professionals. For more information, go to: www.roxane.com or call 1-800-962-8364 (toll-free).

What are the ingredients in alendronate sodium oral solution?

Active ingredient: alendronate sodium

Inactive ingredients: citric acid (anhydrous), methyl paraben, propylparaben, raspberry blend, saccharin sodium, and sodium citrate

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:
Roxane Laboratories, Inc.
Columbus, OH 43216

Manufactured for:
TAGI Pharma, Inc.
722 Progressive Lane, Room 205
South Beloit, IL 61080

10005270/01
Revised February 2013
© RLI, 2013

PRINCIPAL DISPLAY PANEL - 70 mg Bottle Label

NDC 51224-301-10
75 mL

ONCE WEEKLY
ALENDRONATE
SODIUM
Oral Solution

70 mg*/75 mL

Pharmacist: Dispense with
accompanying Medication Guide.

Mark the day of the week you
prefer to take Alendronate Sodium
Oral Solution 70 mg/75 mL, and
remember to take one bottle each
week, on that day. Rx only

tagiPHARMA

Dist. by: TAGI Pharma, Inc.,
South Beloit, IL 61080