FOSAMAX™

Alendronate sodium

5mg, 10mg & 40mg tablet

Presentation

5 mg: A round white tablet with an outline of a bone image on one side and MSD 925 on the other .The diameter is 7.94 mm

10 mg: An oval white tablet engraved with 936 on one side and plain on the other. The dimensions are approximately 5mm x11mm.

40 mg: A triangular white tablet with FOSAMAX engraved on one side and MSD212 on the other. The side length is 7.5mmx 8mm

Therapeutic Class

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

Indications

FOSAMAX is indicated:

In postmenopausal women for the treatment of osteoporosis to prevent fractures, including those of the hip and spine (vertebral compression fractures).

In postmenopausal women who are at risk of developing osteoporosis FOSAMAX is indicated for the prevention of osteoporosis to reduce the risk of future fracture

For the treatment and prevention of glucocorticoid-induced osteoporosis in men and women

For treatment of Paget's disease of bone in men and women

Dosage and Administration

FOSAMAX 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 likely to reduce the absorption of FOSAMAX (see Interactions).

To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation, FOSAMAX should only be swallowed upon arising for the day with a full glass of water and patients should not lie down for at least 30 minutes and until after their first food of the day. FOSAMAX should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of oesophageal adverse experiences (see Warnings and Precautions).

Patients should receive supplemental calcium and vitamin D, if dietary calcium 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 35 to 60 mL/min) . FOSAMAX is not recommended for patients with more severe renal insufficiency (creatinine clearance < 35 mL/min) due to lack of experience.

Treatment of Osteoporosis in Postmenopausal Women

The recommended dosage is 10 mg once a day.

Prevention of Osteoporosis in Postmenopausal Women

The recommended dosage is 5mg once a day

Treatment and Prevention of Glucocorticoid -Induced Osteoporosis in Men and Women

The recommended dosage is 5mg once a day, except for postmenopausal women not receiving oestrogen, for whom the recommended dosage is 10mg once a day.

Paget's Disease of Bone in men and women

The recommended treatment regimen is 40 mg once a day for six months.

Retreatment of Paget's Disease

In clinical studies during the 12 months following therapy, relapses occurred in only 9% (3 out of 32) of patients who responded to treatment with FOSAMAX. Specific retreatment data are not available, although responses to FOSAMAX were similar in patients who had received prior bisphosphonate therapy and those who had not. Retreatment with FOSAMAX may be considered following a six month post-treatment evaluation period in patients who have relapsed based on increases in serum alkaline phosphatase. Retreatment may also be considered in those who failed to normalise their serum alkaline phosphatase.

Contraindications

Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia

Inability to stand or sit upright for at least 30 minutes

Hypersensitivity to any component of this product

Hypocalcaemia (see Warnings and Precautions)

Warnings and Precautions

FOSAMAX, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.

Oesophageal adverse experiences, such as oesophagitis, oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture have been reported in patients receiving treatment with FOSAMAX. In some cases these have been severe and required hospitalisation. Physicians should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue FOSAMAX and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe oesophageal adverse experiences appears to be greater in patients who lie down after taking FOSAMAX and/or who fail to swallow it with a full glass of water, and/or who continue to take FOSAMAX after developing symptoms suggestive of oesophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see Dosage and Administration).

While no increased risk was observed in extensive clinical trials, there have been rare (post-marketing) reports of gastric and duodenal ulcers, some severe and with complications. However, a causal relationship has not been established.

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

To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation patients should be instructed to swallow FOSAMAX with a full glass of water 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 FOSAMAX at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of oesophageal problems. Patients should be instructed that if they develop symptoms of oesophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking FOSAMAX and consult their physician.

FOSAMAX is not recommended for patients with creatinine clearance <35mL/min (see Dosage and Administration).

Causes of osteoporosis other than oestrogen deficiency, ageing, and glucocorticoid use should be considered.

Hypocalcaemia must be corrected before initiating therapy with FOSAMAX (see Contraindications). Other disturbances of mineral metabolism (such as Vitamin D deficiency) should also be effectively treated. Due to the positive effects of FOSAMAX to increase 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.

Pregnancy

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

Nursing Mothers

FOSAMAX has not been studied in breastfeeding women and should not be given to them.

Paediatric Use

FOSAMAX has not been studied in children and should not be given to them.

Use In The Elderly

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

Effects On The Ability To Drive And Use Machines

There are no data to suggest that FOSAMAX affects the ability to drive or use machines

Animal Toxicology

Carcinogenicity

No evidence of carcinogenic effect was observed in a 105-week study in rats receiving oral doses up to 3.75 mg/kg/day and in a 92-week study in mice receiving oral doses up to 10 mg/kg/day

Mutagenesis

Alendronate was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation. Similarly, no evidence of mutagenicity was observed in an in vitro mammalian cell mutagenesis assay, an in vitro alkaline elution assay in rat hepatocytes, and an in vivo chromosomal aberration assay in mice at IV doses up to 25 mg/kg/day (75 mg/m2). In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate was weakly positive at concentrations >5 mM in the presence of cytotoxicity. This is of no relevance to safety in humans since similar concentrations are not achievable in vivo at therapeutic doses. Furthermore, clear negative results in four of five genotoxicity studies, including the most relevant studies for human carcinogenic potential (the in vivo chromosomal aberration assay and the microbial mutagenesis assay), and negative carcinogenicity studies in rats and mice lead to the conclusion that there is no evidence of genotoxic or carcinogenic risks from alendronate in humans.

Reproduction

Alendronate had no effect on fertility or reproductive performance (male or female) in rats at oral doses up to 5 mg/kg/day. The only medicine-related effect seen in these studies was difficulty in parturition in rats, which is directly related to pharmacologically mediated hypocalcaemia. This effect can be prevented in rats by calcium supplementation. Furthermore, a clear no-effect level of 1.25 mg/kg/day was established.

Development

In developmental toxicity studies, there were no adverse effects at doses up to 25 mg/kg/day in rats and 35 mg/kg/day in rabbits.

Adverse Effects

Clinical Studies

In clinical studies FOSAMAX was generally well tolerated. In studies of up to 5 years duration adverse effects which usually were mild generally did not require discontinuation of therapy.

Treatment of Osteoporosis in Postmenopausal Women

In two large, three-year, placebo-controlled, double-blind, multicentre studies (United States and Multinational) of virtually identical design, the overall safety profiles of FOSAMAX 10 mg/day and placebo were similar. The following upper gastrointestinal adverse experiences were reported by the investigators as possibly, probably, or definitely medicine related in > 1% of patients treated with FOSAMAX 10 mg/day and at a greater incidence than in patients treated with placebo: abdominal pain (FOSAMAX, 6.6% vs placebo, 4.8%), dyspepsia (3.6%, 3.5%), oesophageal ulcer (1.5%, 0.0%), dysphagia (1.0%, 0.0%), and abdominal distention (1.0%, 0.8%).

Rarely, rash and erythema have occurred.

Additionally, the following adverse experiences were reported by the investigators as possibly, probably or definitely medicine related in > 1% of patients treated with FOSAMAX 10 mg/day and at a greater incidence than in patients treated with placebo: musculoskeletal (bone, muscle or joint) pain (FOSAMAX, 4.1% vs placebo 2.5%), constipation (3.1%, 1.8%), diarrhoea (3.1%, 1.8%), flatulence (2.6%, 0.5%), and headache (2.6%, 1.5%).

In the two-year extension (treatment years 4 and 5) of the above studies ,the overall safety profile of FOSAMAX 10 mg/day was similar to that observed during the three-year placebo-controlled period. Additionally, the proportion of patients who discontinued FOSAMAX 10 mg/day due to any clinical adverse experience was similar to that during the first three years of the study.

Prevention of Osteoporosis in Postmenopausal Women

The safety of FOSAMAX in postmenopausal women 40-60 years of age has been evaluated in three double- blind, placebo-controlled studies involving over 1,400 patients randomised to receive FOSAMAX for either two or three years. In these studies ,the safety and tolerability profile of FOSAMAX 5 mg/day (n=642) was similar to that of placebo (n=648). The only adverse experience reported by the investigators as possibly, probably or definitely medicine related in 1% of patients treated with FOSAMAX 5 mg/day and at a greater incidence than placebo was dyspepsia (FOSAMAX,1.9% vs. placebo, 1.7%)

Concomitant use with oestrogen/hormone replacement therapy

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

Treatment and Prevention of Glucocorticoid- Induced Osteoporosis

In two, one-year, placebo controlled, double -blind, multicentre studies in patients receiving glucocorticoid treatment, the overall safety and tolerability profiles of FOSAMAX 5 and 10mg /day were generally similar to that of placebo. The following gastrointestinal adverse experiences were reported by the investigators as possibly, probably, or definitely medicine related in 1% of patients treated with either FOSAMAX 5 or 10 mg/day and at a greater incidence than placebo: abdominal pain (FOSAMAX 10mg, 3.2%; FOSAMAX 5mg, 1.9%; placebo, 0.0%), acid regurgitation (2.5%,1.9%,1.3%), constipation (1.3%,0.6%,0.0%), melena (1.3%,0.0%,0.0%) and nausea (0.6%,1.2%,0.6%).

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.

Paget's Disease of Bone

In clinical studies (Paget's disease and osteoporosis), adverse experiences reported in 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. Isolated cases of oesophagitis and gastritis resulted in discontinuation of treatment.

Additionally, musculoskeletal (bone, muscle or joint) pain, which has been described in patients with Paget's disease treated with other bisphosphonates, was reported by the investigators as possibly, probably, or definitely medicine 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.

Post-Marketing Experience

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

Body as a Whole: hypersensitivity reactions including urticaria and rarely, angioedema.

Gastrointestinal: nausea, vomiting, oesophagitis, oesophageal erosions, oesophageal ulcers, rarely oesophageal stricture, and oropharyngeal ulceration; rarely gastric or duodenal ulcers, some severe and with complications, although a causal relationship has not been established. (see Warnings and Precautions, and Dosage and Administration)

Skin: rash ( occasionally with photosensitivity).

Special Senses: rarely uveitis

Laboratory Test Findings

In double-blind, multicentre, 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 mgP/dL (0.65 mM) were similar in both treatment groups.

Interactions

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

No other medicine interactions of clinical significance are anticipated.

Concomitant use of HRT (oestrogen ± 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 Effects, Clinical Studies, Concomitant use with oestrogen/hormone replacement therapy).

Specific interaction studies were not performed. FOSAMAX (10 and 5 mg/day) was used in studies of treatment and prevention of osteoporosis in postmenopausal women and glucocorticoid users, with a wide range of commonly prescribed medicines (including NSAIDs) without evidence of clinical adverse interactions.

In a three year controlled clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of ulcer-related adverse events was similar in patients taking FOSAMAX 5 or 10mg compared to those taking placebo.

However, the incidence of upper gastrointestinal adverse events was increased in the patients receiving therapy with dosages of FOSAMAX greater than 10 mg/day and aspirin-containing products in other clinical studies

Overdosage

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

Actions

Mechanism of Action

Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localisation 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 localisation 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 where it is no longer 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. number of sites at which bone is remodelled). In addition bone formation exceeds bone resorption at these remodelling sites, leading to progressive gains in bone mass.

Pharmacokinetics

Absorption

Relative to an intravenous (IV) reference dose, the oral bioavailability of alendronate in women was 0.7% for doses ranging from 5 to 40 mg when administered after an overnight fast and two hours before a standardised breakfast. Oral bioavailability in men (0.6%) was similar to that in women. Bioavailability was decreased similarly (by approximately 40%) whether alendronate was administered one or one-half hour before a standardised breakfast. In osteoporosis and Paget's disease studies, FOSAMAX was effective when administered at least 30 minutes before the first food or beverage of the day

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

In healthy subjects, oral prednisone (20mg three times daily for 5 days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging 20 to 44 %).

Distribution

Studies in rats show that alendronate transiently distributes to soft tissues following 1mg/kg IV 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 medicine in plasma following therapeutic oral doses are too low for analytical detection (less than 5 ng/mL). Protein binding in human plasma is approximately 78%.

Metabolism

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

Elimination

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 faeces. Following a single 10 mg IV dose, the renal clearance of alendronate was 71 mL/min, 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, reflecting the release of alendronate from the skeleton.

Characteristics in Patients

Preclinical studies show that the medicine that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after chronic dosing with cumulative IV doses up to 35 mg/kg in animals. 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 (see Dosage and Administration).

Pharmaceutical Precautions

Store below 30°C.

Medicine Classification

Prescription Medicine.

Package Quantities

FOSAMAX 5 mg tablets are available in packs of 30 tablets

FOSAMAX 10 mg tablets are available in packs of 30 tablets.

FOSAMAX 40 mg tablets are available in packs of 30 tablets.

Further Information

Chemistry

FOSAMAX tablets contain alendronate sodium, which is described chemically as: (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.

The empirical formula is C4H12NNaO7P2 • 3H2O. The formula weight is 325.12. The structural formula is:

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