Fosavance 70mg/2800IU

Herbal products may interfere with the absorption of alendronate. FOSAVANCE must be taken at least one-half hour before any herbal products.

If taken at the same time it is likely that calcium supplements, antacids, other multivalent cations and other oral medications will interfere with absorption of alendronate. Therefore, patients must wait at least one-half hour after taking FOSAVANCE before taking any other oral medication.

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; no other specific drug interaction studies were performed.

Concomitant use of hormone replacement therapy (HRT [estrogen±progestin]) and FOSAMAX was assessed in two clinical studies of one or two years’ duration in postmenopausal osteoporotic women. Combined use of FOSAMAX and HRT resulted in greater increases in bone mass, together with greater decreases in bone turnover, than seen with either treatment alone. In these studies, the safety and tolerability profile of the combination was consistent with those of the individual treatments (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Concomitant Use with Estrogen/Hormone Replacement Therapy). The studies were too small to detect antifracture efficacy, and no significant differences in fracture incidence among the treatment groups were found.

Specific interaction studies were not performed. FOSAMAX was used in osteoporosis studies in men, postmenopausal women, and glucocorticoid users, with a wide range of commonly prescribed drugs without evidence of clinical adverse interactions.

In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving daily therapy with dosages of FOSAMAX greater than 10 mg and ASA-containing products. This was not observed in a study with FOSAMAX 70 mg once weekly.

FOSAVANCE may be administered to patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In a three-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 FOSAMAX 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 FOSAVANCE.

Food and beverages other than plain water may markedly reduce the absorption and effectiveness of alendronate. FOSAVANCE must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (see Dosage and Administration, Administration).

Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.

Interactions with laboratory tests have not been established.

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

Animal studies have demonstrated that alendronate is highly concentrated in bone and is retained only minimally in soft tissue. No metabolites have been detected. Although alendronate is bound approximately 78% to plasma protein in humans, its plasma concentration is so low after oral dosing that only a small fraction of plasma-binding sites is occupied, resulting in a minimal potential for interference with the binding of other drugs. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to interfere with the excretion of other drugs by those systems in humans. In summary, alendronate is not expected to interact with other drugs based on effects on protein binding, renal excretion, or metabolism of other drugs.

The recommended dosage is one tablet of FOSAVANCE (70 mg/2800 IU) or FOSAVANCE (70 mg/5600 IU) once weekly. The appropriate dosage of FOSAVANCE must be determined by the physician based on the patient's vitamin D requirement.

All patients must receive supplemental calcium and/or vitamin D, if intake is inadequate (see Warnings and Precautions).

No dosage adjustment is necessary for the elderly or for patients with mild-to-moderate renal insufficiency (creatinine clearance 0.58 to 1 mL/s [35 to 60 mL/min]). FOSAVANCE is not recommended for patients with more severe renal insufficiency (creatinine clearance <0.58 mL/s [<35 mL/min]) due to lack of experience.

FOSAVANCE must be taken 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 known to reduce the absorption of alendronate (see Drug Interactions). Waiting less than 30 minutes will lessen the effect of FOSAVANCE by decreasing its absorption into the body.

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, FOSAVANCE should only be swallowed upon arising for the day with a full glass of water (200-250 mL) and patients should not lie down for at least 30 minutes and until after their first food of the day. FOSAVANCE 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).

All patients must receive supplemental calcium and/or vitamin D, if intake is inadequate. Physicians should consider the vitamin D intake from vitamins and dietary supplements. Patients at increased risk for vitamin D insufficiency (e.g. over the age of 70 years, home bound, or chronically ill) should receive FOSAVANCE (70 mg/5600 IU) and may also need additional vitamin D supplementation. For patients fifty years and over, the recommended dose is at least 800 IU per day. Those living in high latitudes (including most of Canada) may also need additional supplementation.

Although no specific studies have been conducted on the effects of switching patients on another therapy for osteoporosis to FOSAVANCE, there are no known or theoretical safety concerns related to FOSAVANCE in patients who previously received any other antiosteoporotic therapy.

Patients should be instructed that if they miss a dose of FOSAVANCE, they should take one tablet on the morning after they remember. They should not take two tablets on the same day but should return to taking one tablet once a week, as originally scheduled on their chosen day.

esophagitis, esophageal erosions, esophageal ulcers, rarely esophageal stricture or perforation, and oropharyngeal ulceration. Some of these have been serious and required hospitalization. Rarely, gastric or duodenal ulcers, some severe and with complications (see Warnings and Precautions and Dosage and Administration).

Localized osteonecrosis of the jaw (ONJ) has been reported rarely with oral bisphosphonate treatment. ONJ is generally associated with local infection (including osteomyelitis), tooth extraction with delayed healing (see Warnings and Precautions, General).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

rarely uveitis, scleritis or episcleritis.

The overall safety and tolerability profile in the glucocorticoid-induced osteoporosis population that continued therapy for the second year of the studies was consistent with that observed in the first year.

In a ten-week endoscopy study in men and women (n=277; mean age: 55) no difference was seen in upper gastrointestinal tract lesions between FOSAMAX 70 mg once weekly and placebo.

In an additional one-year study in men and women (n=335; mean age: 50) the overall safety and tolerability profiles of FOSAMAX 70 mg once weekly were similar to that of placebo and no difference was seen between men and women.

hypersensitivity reactions including urticaria and rarely angioedema. As with other bisphosphonates, transient symptoms as in an acute-phase response (myalgia, malaise, asthenia and rarely, fever) have been reported with alendronate, typically in association with initiation of treatment. Rarely, symptomatic hypocalcemia has occurred, both in association with predisposing conditions and in patients without known predisposing conditions. Rarely, peripheral edema.

dizziness, vertigo.

bone, joint, and/or muscle pain, rarely severe and/or incapacitating (see Warnings and Precautions); joint swelling; low-energy femoral shaft fracture (see Warnings and Precautions).

In clinical studies, FOSAMAX was generally well tolerated. In studies of up to five years in duration, side effects, which usually were mild, generally did not require discontinuation of therapy.

FOSAMAX has been evaluated for safety in clinical studies in approximately 7200 postmenopausal women.

In two studies (of one and two years' duration) of postmenopausal osteoporotic women (total: n=853), the safety and tolerability profile of combined treatment with FOSAMAX 10 mg once daily and estrogen±progestin (n=354) was consistent with those of the individual treatments.

The following adverse reactions have been reported in post-marketing use with alendronate:

In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of FOSAMAX 10 mg/day [n=146] and a one-year study of FOSAMAX 70 mg once weekly [n=109]), the safety profile of FOSAMAX was generally similar to that seen in postmenopausal women. The rates of discontinuation of therapy due to any clinical adverse experience were 2.7% for FOSAMAX 10 mg/day vs. 10.5% for placebo, and 6.4% for FOSAMAX 70 mg once weekly vs. 8.6% for placebo.

In clinical studies (Paget's disease and osteoporosis), adverse experiences reported in 175 patients taking FOSAMAX 40 mg/day for 3-12 months were similar to those in postmenopausal women treated with FOSAMAX 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse experiences in patients taking FOSAMAX 40 mg/day (17.7% FOSAMAX vs. 10.2% placebo). Isolated cases of esophagitis and gastritis resulted in discontinuation of treatment.

Additionally, musculoskeletal pain (bone, muscle or joint), which has been described in patients with Paget's disease treated with other bisphosphonates, was reported by the investigators as possibly, probably, or definitely drug-related in approximately 6% of patients treated with FOSAMAX 40 mg/day versus approximately 1% of patients treated with placebo, but rarely resulted in discontinuation of therapy. Discontinuation of therapy due to any clinical adverse experience occurred in 6.4% of patients with Paget's disease treated with FOSAMAX 40 mg/day and 2.4% of patients treated with placebo.

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

In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18 and 10%, respectively, of patients taking FOSAMAX versus approximately 12 and 3% of those taking placebo. However, the incidences of decreases in serum calcium to <8.0 mg/dL (2.0 mM) and serum phosphate to ≤2.0 mg P{*P: Elemental phosphorus. }/dL (0.65 mM) were similar in both treatment groups.

In a small, open-label study, at higher doses (80 mg/day) some patients had elevated transaminases. However, this was not observed at 40 mg/day. No clinically significant toxicity was associated with these laboratory abnormalities.

Rare cases of leukemia have been reported following therapy with other bisphosphonates. Any causal relationship to either the treatment or to the patients' underlying disease has not been established.

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

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.

Vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at a dose less than 10 000 IU/day. In a clinical study of healthy adults, a 4000 IU daily dose of vitamin D³ for up to five months was not associated with hypercalciuria or hypercalcemia.

Each white to off-white, modified capsule-shaped tablet, with code 710 on one side and an outline of a bone image on the other, contains: alendronate monosodium salt trihydrate 91.37 mg, the molar equivalent of 70 mg of free acid and cholecalciferol 70 µg (equivalent to 2800 IU Vitamin D₃). Nonmedicinal ingredients: butylated hydroxytoluene, colloidal silicon dioxide, croscarmellose sodium, gelatin, lactose anhydrous, magnesium stearate, medium chain triglycerides, microcrystalline cellulose, modified food starch (corn), sodium aluminum silicate and sucrose. Gluten-free. Blister packages of 4.

Each white to off-white, modified rectangle-shaped tablet, with code 270 on one side and an outline of a bone image on the other, contains: alendronate monosodium salt trihydrate 91.37 mg, the molar equivalent of 70 mg of free acid and cholecalciferol 140 µg (equivalent to 5600 IU Vitamin D₃). Nonmedicinal ingredients: butylated hydroxytoluene, colloidal silicon dioxide, croscarmellose sodium, gelatin, lactose anhydrous, magnesium stearate, medium chain triglycerides, microcrystalline cellulose, modified food starch (corn), sodium aluminum silicate and sucrose. Gluten-free. Blister packages of 4.

FOSAVANCE, like other bisphosphonate-containing products, may cause local irritation of the upper gastrointestinal mucosa.

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, 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 FOSAVANCE immediately 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 FOSAVANCE and/or who fail to swallow it with a full glass (200-250 mL) of water, and/or who continue to take FOSAVANCE 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).

Because of possible irritant effects of alendronate on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when FOSAVANCE is given to patients with active upper gastrointestinal problems, such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers.

While no increased risk was observed in extensive clinical trials, there have been rare (post-marketing) reports of gastric and duodenal ulcers with alendronate, some severe and with complications.

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). However, such reports have been infrequent. This category of drugs includes FOSAMAX (alendronate sodium). Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping the medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

In placebo-controlled clinical studies of FOSAMAX, the percentages of patients with these symptoms were similar in the FOSAMAX and placebo groups.

Low-energy fractures of the subtrochanteric and proximal femoral shaft have been reported in some alendronate-treated patients. Some were stress fractures (also known as insufficiency fractures) occurring in the absence of trauma. Some patients experienced prodromal pain in the affected area, often associated with imaging features of stress fracture, weeks to months before a complete fracture occurred. Patients with suspected stress fractures should be evaluated, including evaluation for causes of stress fractures (e.g., vitamin D deficiency, malabsorption, glucocorticoid use, lower extremity arthritis or fracture, extreme or increased exercise, diabetes mellitus, chronic alcohol abuse), and receive appropriate orthopedic care. Interruption of alendronate therapy in patients with stress fractures should be considered based on individual benefit/risk assessment.

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. The majority of reports occurred following tooth extractions with delayed healing and involved cancer patients treated with intravenous bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. However, some cases have also occurred in patients receiving oral bisphosphonate treatment for postmenopausal osteoporosis and other diagnoses. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection, including osteomyelitis.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer, chemotherapy, head and neck radiotherapy, corticosteroids, periodontal disease, poor oral hygiene).

Patients who develop osteonecrosis of the jaw should receive appropriate antibiotic therapy and/or oral surgery and discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. Dental surgery may exacerbate the condition. For patients requiring dental procedures (e.g. tooth extraction, dental implants), there are no definitive data available to establish whether discontinuation of bisphosphonate treatment reduces the risk of ONJ.

Clinical judgment of the treating physician and/or oral surgeon should guide the management plan, including bisphosphonate treatment, of each patient based on individual benefit/risk assessment.

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, patients should be instructed to swallow each tablet of FOSAVANCE with a full glass of water (200-250 mL) and not to lie down for at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take FOSAVANCE 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 FOSAVANCE immediately and consult their physician.

Causes of osteoporosis other than estrogen deficiency, aging and glucocorticoid use should be considered.

Not applicable.

FOSAVANCE has not been studied in patients <18 years of age and should not be given to them.

In clinical studies, there was no age-related difference in the efficacy or safety profiles of FOSAMAX.

Daily requirements of vitamin D₃ may be increased in the elderly.

FOSAVANCE has not been studied in pregnant women and should not be given to them.

FOSAVANCE has not been studied in nursing mothers and should not be given to them.

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 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. Increased bone turnover is an independent risk factor of fractures. 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 FOSAMAX 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type I collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. 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 FOSAMAX. In osteoporosis treatment studies, FOSAMAX 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. Similar reductions in the rate of bone turnover were observed in postmenopausal women during a one-year study with FOSAMAX 70 mg once weekly for the treatment 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 FOSAMAX. 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 FOSAMAX 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment, however, serum phosphate returned toward pre-study levels during years three through five. In a one-year study with FOSAMAX 70 mg once weekly, 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 FOSAMAX but also a decrease in renal phosphate reabsorption.

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

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 IV 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 0.58 to 1 mL/s [35 to 60 mL/min]). FOSAVANCE is not recommended for patients with more severe renal insufficiency (creatinine clearance <0.58 mL/s [<35 mL/min]) due to lack of experience.

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

Alendronate pharmacokinetics have not been investigated in patients <18 years of age.

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

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

Cholecalciferol (vitamin D₃) is a secosterol that is the natural precursor of the calcium-regulating hormone calcitriol (1,25-dihydroxyvitamin D₃).

Pharmacokinetic differences due to race have not been studied.

Even though osteoporosis is less prevalent in men than in postmenopausal women, a significant proportion of osteoporotic fractures occur in men. The prevalence of vertebral deformities appears to be similar in men and women. Treatment of men with osteoporosis with FOSAMAX 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 FOSAMAX 70 mg once weekly.