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Alendronate Sodium and Cholecalciferol Tablet

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Alendronate sodium and cholecalciferol contains alendronate sodium, a bisphosphonate, and cholecalciferol (vitamin D3).

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.

Cholecalciferol (vitamin D3) is a secosterol that is the natural precursor of the calcium-regulating hormone calcitriol (1,25 dihydroxyvitamin D3). The chemical name of cholecalciferol is (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol. The empirical formula of cholecalciferol is C27H44O and its molecular weight is 384.6. The structural formula is:

Cholecalciferol is a white, crystalline, odorless powder. Cholecalciferol is practically insoluble in water, freely soluble in usual organic solvents, and slightly soluble in vegetable oils.

Alendronate sodium and cholecalciferol for oral administration contains 91.37 mg of alendronate monosodium salt trihydrate, the molar equivalent of 70 mg of free acid, and 70 or 140 mcg of cholecalciferol, equivalent to 2800 or 5600 International Units (IU) vitamin D, respectively. Each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, medium chain triglycerides, gelatin, croscarmellose sodium, sucrose, colloidal silicon dioxide, magnesium stearate, butylated hydroxytoluene, modified food starch, and sodium aluminum silicate.

2. INDICATIONS AND USAGE

Alendronate sodium and cholecalciferol is indicated for:

2.1 Treatment of Osteoporosis in Postmenopausal Women

For the treatment of osteoporosis, alendronate sodium and cholecalciferol increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures).

2.2 Treatment to Increase Bone Mass in Men with Osteoporosis

2.3 Important Limitations of Use

Alendronate sodium and cholecalciferol alone should not be used to treat vitamin D deficiency.

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

3. DOSAGE AND ADMINISTRATION

3.1 Treatment of Osteoporosis in Postmenopausal Women

The recommended dosage is one 70 mg alendronate/2800 IU vitamin D3 or one 70 mg alendronate/5600 IU vitamin D3 tablet once weekly. For most osteoporotic women, the appropriate dose is alendronate sodium and cholecalciferol (70 mg alendronate/5600 IU vitamin D3) once weekly.

3.2 Treatment to Increase Bone Mass in Men with Osteoporosis

The recommended dosage is one 70 mg alendronate/2800 IU vitamin D3 or one 70 mg alendronate/5600 IU vitamin D3 tablet once weekly. For most osteoporotic men, the appropriate dose is alendronate sodium and cholecalciferol (70 mg alendronate/5600 IU vitamin D3) once weekly.

3.3 Important Administration Instructions

Instruct patients to do the following:

• Take alendronate and cholecalciferol at least one-half hour before the first food, beverage, or medication of the day with plain water only. Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate [see Drug Interactions]. Waiting less than 30 minutes, or taking alendronate and cholecalciferol 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 and cholecalciferol upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, an alendronate and cholecalciferol tablet should be swallowed with a full glass of water (6-8 ounces). 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 and cholecalciferol 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].

3.4 Recommendations for Calcium and Vitamin D Supplementation

Patients should receive supplemental calcium if dietary intake is inadequate. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional 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.

The recommended intake of vitamin D is 400 IU-800 IU daily. Alendronate sodium and cholecalciferol 70 mg/2800 IU and 70 mg/5600 IU are intended to provide seven days’ worth of 400 and 800 IU daily vitamin D in a single, once-weekly dose, respectively.

3.5 Administration Instructions for Missed Doses

If a once-weekly dose of alendronate and cholecalciferol tablet 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.

4. CONTRAINDICATIONS

Alendronate and cholecalciferol is contraindicated in patients with the following conditions:

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions]

• Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration; Warnings and Precautions]

• Hypocalcemia [see Warnings and Precautions]

• Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported [see Adverse Reactions]

5. MECHANISM OF ACTION

Alendronate Sodium

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.

Cholecalciferol

Vitamin D3 is produced in the skin by photochemical conversion of 7-dehydrocholesterol to previtamin D3 by ultraviolet light. This is followed by non-enzymatic isomerization to vitamin D3. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient. Vitamin D3 in skin and dietary vitamin D3 (absorbed into chylomicrons) is converted to 25-hydroxyvitamin D3 in the liver. Conversion to the active calcium-mobilizing hormone 1,25 dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption. Vitamin D is required for normal bone formation. Vitamin D insufficiency develops when both sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance, increased parathyroid hormone levels, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness, bone pain and osteomalacia.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

Alendronate Sodium

Reproduction studies in rats showed decreased postimplantation survival at 2 mg/kg/day and decreased body weight gain in normal pups at 1 mg/kg/day. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at 10 mg/kg/day in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. The above doses ranged from one time (1 mg/kg) to 10 times (10 mg/kg) a maximum recommended daily dose of 10 mg/day based on surface area, mg/m2. No similar fetal effects were seen when pregnant rabbits were treated at doses up to 35 mg/kg/day (40 times a 10 mg human daily dose based on surface area, mg/m2).

Both total and ionized calcium decreased in pregnant rats at 15 mg/kg/day (13 times a 10-mg human daily dose based on surface area, mg/m2) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as 0.5 mg/kg/day (0.5 times a 10 mg human daily dose based on surface area, mg/m2) when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) occurred in the female rats treated with 15 mg/kg/day 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.

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.

Cholecalciferol

No data are available for cholecalciferol (vitamin D3). Administration of high doses (greater than or equal to 10,000 international units/every other day) of ergocalciferol (vitamin D2) to pregnant rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of vitamin D2 (40,000 international units/day) to pregnant rats resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally.

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

6.2 Nursing Mothers

Cholecalciferol and some of its active metabolites pass into breast milk. 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 sodium and cholecalciferol is administered to nursing women.

6.3 Pediatric Use

Alendronate sodium and cholecalciferol is not indicated for use in children.

The efficacy and safety of alendronate were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4-18 years, with severe osteogenesis imperfecta. One-hundred-and-nine patients were randomized to 5 mg alendronate daily (weight less than 40 kg) or 10 mg alendronate daily (weight greater than or equal to 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.

6.4 Geriatric Use

Of the patients receiving alendronate in the Fracture Intervention Trial (FIT), 71% (n=2302) were greater than or equal to 65 years of age and 17% (n=550) were greater than or equal to 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, 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. Dietary requirements of vitamin D3 are increased in the elderly.

7. WARNINGS AND PRECAUTIONS

7.1 Upper Gastrointestinal Adverse Reactions

Alendronate sodium and cholecalciferol, like other bisphosphonate-containing products, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when alendronate sodium and cholecalciferol 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 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 sodium and cholecalciferol 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 alendronate sodium and cholecalciferol and/or who fail to swallow it with a full glass (6-8 oz) of water, and/or who continue to take alendronate sodium and cholecalciferol 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]. In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium and cholecalciferol 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].

7.2 Mineral Metabolism

Alendronate Sodium

Hypocalcemia must be corrected before initiating therapy with alendronate sodium and cholecalciferol [see Contraindications]. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate sodium and cholecalciferol.

Presumably due to the effects of alendronate on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur.

Cholecalciferol

Alendronate sodium and cholecalciferol alone should not be used to treat vitamin D deficiency (commonly defined as 25-hydroxyvitamin D level below 9 ng/mL). Patients at increased risk for vitamin D insufficiency may require higher doses of vitamin D supplementation [see Dosage and Administration]. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.

Vitamin D3 supplementation may worsen hypercalcemia and/or hypercalciuria when administered to patients with diseases associated with unregulated overproduction of 1,25 dihydroxyvitamin D (e.g., leukemia, lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.

7.3 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]. 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.

7.4 Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium and cholecalciferol. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.

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

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.

7.5 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.

7.6 Renal insufficiency

Alendronate sodium and cholecalciferol is not recommended for patients with renal insufficiency (creatinine clearance <35 mL/min). [See Dosage and Administration]

8. ADVERSE REACTIONS

8.1 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.

Alendronate Sodium

Alendronate has been evaluated for safety in approximately 8000 postmenopausal women in clinical studies.

Postmenopausal Women

Alendronate daily

In two identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational; n=994), discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with alendronate 10 mg/day and 6.0% of 397 patients treated with placebo. In the Fracture Intervention Trial (n=6459), discontinuation of therapy due to any clinical adverse experience occurred in 9.1% of 3236 patients treated with alendronate 5 mg/day for 2 years and 10 mg/day for either one or two additional years and 10.1% of 3223 patients treated with placebo. Discontinuations due to upper gastrointestinal adverse experiences were: alendronate, 3.2%; placebo, 2.7%. In these study populations, 49-54% had a history of gastrointestinal disorders at baseline and 5489% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies. Adverse experiences 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 Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in ≥1% of Patients

* 10 mg/day for three years

* * 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years

Rarely, rash and erythema have occurred.

The adverse experience profile was similar for the 401 patients treated with either 5- or 20-mg doses of alendronate in the United States and Multinational studies. The adverse experience profile for the 296 patients who received continued treatment with either 5- or 10-mg doses of alendronate in the two-year extension of these studies (treatment years 4 and 5) was similar to that observed during the three-year placebo-controlled period. During the extension period, of the 151 patients treated with alendronate 10 mg/day, the proportion of patients who discontinued therapy due to any clinical adverse experience was similar to that during the first three years of the study.

Alendronate Once-Weekly

In a one-year, double-blind, multicenter study, the overall safety and tolerability profiles of once weekly alendronate 70 mg and alendronate 10 mg daily were similar. The adverse experiences 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 Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients

Concomitant Use With Estrogen or Estrogen/Progestin Products

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.

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 experience 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 experiences 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 3.

Table 3: Osteoporosis Studies in Men Adverse Experiences Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 2% of Patients

Laboratory Test Findings

In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate sodium versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to less than 8.0 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.

Alendronate Sodium and Cholecalciferol

In a fifteen-week double-blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile of alendronate sodium and cholecalciferol (70 mg/2800 international units) was similar to that of alendronate sodium once weekly 70 mg. In the 24-week double-blind extension study in women (n=619) and men (n=33), the safety profile of alendronate sodium and cholecalciferol (70 mg/2800 international units) administered with an additional 2800 international units vitamin D3 was similar to that of alendronate sodium and cholecalciferol (70 mg/2800 international units).

8.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of alendronate sodium and alendronate sodium and cholecalciferol. 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 angioedema. Transient symptoms of myalgia, malaise, asthenia and rarely, fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema.

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

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

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

Nervous System: dizziness and vertigo.

Pulmonary: acute asthma exacerbations.

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

Special Senses: uveitis, scleritis or episcleritis.

9. OVERDOSAGE

Alendronate Sodium

Significant lethality after single oral doses with alendronate 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.

Cholecalciferol

Significant lethality occurred in mice treated with a single high oral dose of calcitriol (4 mg/kg), the hormonal metabolite of cholecalciferol.

There is limited information regarding doses of cholecalciferol associated with acute toxicity, although intermittent (yearly or twice yearly) single doses of ergocalciferol (vitamin D2) as high as 600,000 international units have been given without reports of toxicity. Signs and symptoms of vitamin D toxicity include hypercalcemia, hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia, weakness, and lethargy. Serum and urine calcium levels should be monitored in patients with suspected vitamin D toxicity. Standard therapy includes restriction of dietary calcium, hydration, and systemic glucocorticoids in patients with severe hypercalcemia.

Dialysis to remove vitamin D would not be beneficial.

10. DRUG INTERACTIONS

10.1 Calcium Supplements/Antacids

It is likely that calcium supplements, antacids, and some oral medications will interfere with absorption of alendronate. Therefore, patients must wait at least one-half hour after taking alendronate sodium and cholecalciferol before taking any other oral medications.

10.2 Aspirin

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

10.3 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Alendronate sodium and cholecalciferol may be administered to patients taking 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 sodium 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 sodium and cholecalciferol.

10.4 Drugs that May Impair the Absorption of Cholecalciferol

Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D. Additional vitamin D supplementation should be considered.

10.5 Drugs that May Increase the Catabolism of Cholecalciferol

Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D. Additional vitamin D supplementation should be considered.

11. PHARMACOKINETICS

Absorption

Alendronate Sodium

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.

In a study, the alendronate in the alendronate sodium and cholecalciferol (70 mg/2800 international units) tablet and the alendronate sodium 70-mg tablet were found to be equally bioavailable. In a separate study, the alendronate in the alendronate sodium and cholecalciferol (70 mg/5600 international units) tablet was found to be equally bioavailable to the alendronate in the alendronate sodium 70-mg tablet.

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%.

Cholecalciferol

Following administration of alendronate sodium and cholecalciferol (70 mg/2800 international units) after an overnight fast and two hours before a standard meal, the baseline adjusted mean area under the serum-concentration-time curve (AUC0-120 hrs) for vitamin D3 was 120.7 ng-hr/mL. The baseline adjusted mean maximal serum concentration (Cmax) of vitamin D3 was 4.0 ng/mL, and the baseline adjusted mean time to maximal serum concentration (Tmax) was 10.6 hrs. The bioavailability of the 2800 international units vitamin D3 in alendronate sodium and cholecalciferol is similar to 2800 international units vitamin D3 administered alone.

In a separate study, the baseline adjusted mean AUC0-80 hrs and baseline adjusted mean Cmax for vitamin D3 were 355.6 ng-hr/mL and 10.8 ng/mL, respectively. The baseline adjusted mean Tmax was 9.2 hrs. The bioavailability of the 5600 international units vitamin D3 in the alendronate sodium and cholecalciferol is similar to 5600 international units vitamin D3 administered as two 2800 international units vitamin D3 tablets.

Distribution

Alendronate Sodium

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%.

Cholecalciferol

Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.

Metabolism

Alendronate Sodium

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

Cholecalciferol

Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.

Excretion

Alendronate Sodium

Following a single IV 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 IV 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 IV 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 sodium (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.

Cholecalciferol

When radioactive vitamin D3 was intravenously administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4% of the administered dose, and the mean fecal excretion of radioactivity after 48 hours was 4.9% of the administered dose. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent. The mean half-life of baseline adjusted vitamin D3 in the serum following an oral dose of alendronate sodium and cholecalciferol is approximately 14 hours.

Special Populations

Pediatric: The oral bioavailability of alendronate in children was similar to that observed in adults; however, alendronate sodium and cholecalciferol is not indicated for use in children [see Use in Specific Populations].

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

Geriatric:

Alendronate Sodium

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

Cholecalciferol

Dietary requirements of vitamin D3 are increased in the elderly.

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

Renal Impairment:

Alendronate Sodium

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 clinical information is available, 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 mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). Alendronate sodium and cholecalciferol is not recommended for patients with more severe renal insufficiency (creatinine clearance less than 35 mL/min) due to lack of experience with alendronate in renal failure.

Cholecalciferol

Patients with renal insufficiency will have decreased ability to form the active 1,25-dihydroxyvitamin D3 metabolite.

Hepatic Impairment:

Alendronate Sodium

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

Cholecalciferol

Vitamin D3 may not be adequately absorbed in patients who have malabsorption due to inadequate bile production.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: FOSAMAX PLUS D, by Merck.

b) Generic drugs: None.

2) How Supplied:

No. 3870 — Tablets FOSAMAX PLUS D 70 mg/2800 IU are white to off-white, modified capsuleshaped tablets with code 710 on one side and an outline of a bone image on the other. They are supplied as follows:

NDC 0006-0710-44 unit of use blister packages of 4

No. 6746 — Tablets FOSAMAX PLUS D 70 mg/5600 IU are white to off-white, modified rectangle-shaped tablets with code 270 on one side and an outline of a bone image on the other. They are supplied as follows:

NDC 0006-0270-44 unit of use blister packages of 4

NDC 0006-0270-21 unit dose packages of 20.

3) Storage: Store at 20-25°C (68-77°F), excursions between 15-30°C (59-86°F) are allowed. Protect from moisture and light. Store tablets in the original blister package until use.

Rx only

Rev 04/13