FOSAMAX® 10 mg Tablets

Each tablet contains 13.05 mg of alendronate sodium, which is the molar equivalent to 10 mg of alendronic acid.

Excipients:

Each tablet contains 103.95 mg lactose anhydrous.

For a full list of excipients see section 6.1

Tablets

Oval white tablets marked with '936' on one side, and plain on the other.

'Fosamax' is indicated for the treatment of osteoporosis in post-menopausal women to prevent fractures.

'Fosamax' is indicated for the treatment of osteoporosis in men to prevent fractures.

'Fosamax' is indicated for the treatment of glucocorticoid-induced osteoporosis and prevention of bone loss in post-menopausal women considered at risk of developing the disease.

Risk factors often associated with the development of osteoporosis include thin body build, family history of osteoporosis, early menopause, moderately low bone mass and long-term glucocorticoid therapy, especially with high doses (15 mg/day).

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of ‘Fosamax’ on an individual patient basis, particularly after 5 or more years of use.

Treatment of osteoporosis in post-menopausal women: The recommended dosage is 10 mg once a day.

Treatment of osteoporosis in men: The recommended dosage is 10 mg once a day.

Treatment and prevention of glucocorticoid-induced osteoporosis: For post-menopausal women not receiving hormone replacement therapy (HRT) with an oestrogen, the recommended dosage is 10 mg once a day.

To permit adequate absorption of 'Fosamax':

'Fosamax' must be taken at least 30 minutes 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 4.5 'Interaction with other medicinal products and other forms of interaction').

To facilitate delivery to the stomach and thus reduce the potential for local and oesophageal irritation/adverse experiences (see 4.4 'Special warnings and precautions for use'):

• 'Fosamax' should only be swallowed upon arising for the day with a full glass of water (not less than 200 mls or 7 fl.oz.).

• Patients should only swallow 'Fosamax' whole. Patients should not crush or chew the tablet or allow the tablet to dissolve in their mouths because of a potential for oropharyngeal ulceration.

• Patients should not lie down until after their first food of the day which should be at least 30 minutes after taking the tablet.

• Patients should not lie down for at least 30 minutes after taking 'Fosamax'.

• 'Fosamax' should not be taken at bedtime or before arising for the day.

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see 4.4 'Special warnings and precautions for use').

Use in the elderly: In clinical studies there was no age-related difference in the efficacy or safety profiles of 'Fosamax'. Therefore no dosage adjustment is necessary for the elderly.

Use in renal impairment: No dosage adjustment is necessary for patients with GFR greater than 35 ml/min. 'Fosamax' is not recommended for patients with renal impairment where GFR is less than 35 ml/min, due to lack of experience.

Paediatric patients: Alendronate sodium is not recommended for use in children under the age of 18 years due to insufficient data on safety and efficacy in conditions associated with paediatric osteoporosis (also see section 5.1).

• Abnormalities of the oesophagus and other factors 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 4.4 'Special warnings and precautions for use').

'Fosamax' can cause local irritation of the upper gastro-intestinal mucosa. Because there is a potential for worsening of the underlying disease, caution should be used when 'Fosamax' is given to patients with active upper gastro-intestinal problems, such as dysphagia, oesophageal disease, gastritis, duodenitis or ulcers or with a recent history (within the previous year) of major gastro-intestinal disease such as peptic ulcer, or active gastro-intestinal bleeding, or surgery of the upper gastro-intestinal tract other than pyloroplasty (see 4.3 'Contraindications'). In patients with known Barrett's oesophagus prescribers should consider the benefits and potential risks of alendronate on an individual patient basis.

Oesophageal reactions (sometimes severe and requiring hospitalisation), such as oesophagitis, oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture or perforation, have been reported in patients receiving 'Fosamax'. 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 symptoms of oesophageal irritation such as dysphagia, pain on swallowing or retrosternal pain, new or worsening heartburn.

The risk of severe oesophageal adverse experiences appears to be greater in patients who fail to take 'Fosamax' properly and/or who continue to take 'Fosamax' after developing symptoms suggestive of oesophageal irritation. It is very important that the full dosing instructions are provided to, and understood by the patient (see 4.2 'Posology and method of administration'). Patients should be informed that failure to follow these instructions may increase their risk of oesophageal problems.

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.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

The following risk factors should be considered when evaluating an individual's risk of developing osteonecrosis of the jaw:

• potency of the bisphosphonate (highest for zoledronic acid), route of administration (see above) and cumulative dose

• cancer, chemotherapy, radiotherapy, corticosteroids, smoking

• a history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures and poorly fitting dentures.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with poor dental status.

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

During bisphosphonate treatment, all patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and report any oral symptoms such as dental mobility, pain or swelling.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique, fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilaterial; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bishphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. During bishphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. In post-marketing experience, these symptoms have rarely been severe and/or incapacitating (see '4.8 Undesirable effects'). The time to onset of symptoms varied from one day to several months after starting treatment. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

'Fosamax' is not recommended for patients with renal impairment where GFR is less than 35 ml/min, (see 4.2 'Posology and method of administration').

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

Hypocalcaemia must be corrected before initiating therapy with alendronate (see 4.3 'Contra-indications'). Other disorders affecting mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with 'Fosamax'.

Due to the positive effects of alendronate in increasing bone mineral, decreases in serum calcium and phosphate may occur especially in patients taking glucocorticoids in whom calcium absorption may be decreased. These are usually small and asymptomatic. However, there have been rare reports of symptomatic hypocalcaemia, which have occasionally been severe and often occurred in patients with predisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption). Ensuring adequate calcium and vitamin D intake is particularly important in patients receiving glucocorticoids.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

If taken at the same time, it is likely that food and beverages (including mineral water), calcium supplements, antacids, and some oral medicinal products will interfere with absorption of 'Fosamax'. Therefore, patients must wait at least 30 minutes after taking 'Fosamax' before taking any other oral medicinal product (see 4.2 'Posology and method of administration' and 5.2 'Pharmacokinetic properties').

No other drug 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 post-menopausal osteoporotic women (5.1 'Pharmacodynamic properties, concomitant use with oestrogen/hormone replacement therapy (HRT)'). 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.

Since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.

Although specific interaction studies were not performed, in clinical studies 'Fosamax' was used concomitantly with a wide range of commonly prescribed drugs without evidence of clinical adverse interactions (see 5.1 'Pharmacodynamic properties' 'Concomitant use with oestrogen/hormone replacement therapy (HRT)').

Use during pregnancy

Alendronate should not be used during pregnancy. There are no adequate data from the use of alendronate in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/fetal development, or postnatal development. Alendronate given during pregnancy in rats caused dystocia related to hypocalcemia (see 5.3 'Preclinical safety data').

Use during lactation

It is not known whether alendronate is excreted into human breast-milk. Alendronate should not be used by breast-feeding women.

No studies on the effects on the ability to drive and use machines has been performed. However, certain adverse reactions that have been reported with 'Fosamax' may affect some patients' ability to drive or operate machinery. Individual responses to 'Fosamax' may vary (see section 4.8).

'Fosamax' has been studied in nine major clinical studies (n=5,886). In the longest running trials in post-menopausal women up to five years experience has been collected. Two years safety data are available in both men with osteoporosis and men and women on glucocorticoids.

The following adverse experiences have been reported during clinical studies and/or post-marketing use:

[Common (1/100, < 1/10), Uncommon (1/1000, < 1/100), Rare (1/10,000, < 1/1000), Very rare (< 1/10,000 including isolated cases)]

Laboratory test findings

In clinical 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 mmol/l) and serum phosphate to 2.0 mg/dl (0.65 mmol/l) were similar in both treatment groups.

No specific information is available on the treatment of overdosage with 'Fosamax'. Hypocalcaemia, hypophosphataemia and upper gastro-intestinal 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. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

'Fosamax' is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect on bone formation. The bone formed during treatment with 'Fosamax' is of normal quality.

Treatment of post-menopausal osteoporosis

The effects of 'Fosamax' on bone mass and fracture incidence in post-menopausal women were examined in two initial efficacy studies of identical design (n=994) as well as in the Fracture Intervention Trial (FIT: n=6,459).

In the initial efficacy studies, the mean bone mineral density (BMD) increases with 'Fosamax' 10 mg/day relative to placebo at three years were 8.8%, 5.9% and 7.8% at the spine, femoral neck and trochanter, respectively. Total body BMD also increased significantly. There was a 48% reduction in the proportion of patients treated with 'Fosamax' experiencing one or more vertebral fractures relative to those treated with placebo. In the two-year extension of these studies BMD at the spine and trochanter continued to increase and BMD at the femoral neck and total body were maintained.

FIT consisted of two placebo-controlled studies: a three-year study of 2,027 patients who had at least one baseline vertebral (compression) fracture and a four-year study of 4,432 patients with low bone mass but without a baseline vertebral fracture, 37% of whom had osteoporosis as defined by a baseline femoral neck BMD at least 2.5 standard deviations below the mean for young, adult women. In all FIT patients with osteoporosis from both studies, 'Fosamax' reduced the incidence of: 1 vertebral fracture by 48%, multiple vertebral fractures by 87%, 1 painful vertebral fracture by 45%, any painful fracture by 31% and hip fracture by 54%.

Overall these results demonstrate the consistent effect of 'Fosamax' to reduce the incidence of fractures, including those of the spine and hip, which are the sites of osteoporotic fracture associated with the greatest morbidity.

Prevention of post-menopausal osteoporosis

The effects of 'Fosamax' to prevent bone loss were examined in two studies of post-menopausal women aged 60 years. In the larger study of 1,609 women (6 months post-menopausal) those receiving 'Fosamax' 5 mg daily for two years had BMD increases of 3.5%, 1.3%, 3.0% and 0.7% at the spine, femoral neck, trochanter and total body, respectively. In the smaller study (n=447), similar results were observed in women (6 to 36 months post-menopausal) treated with 'Fosamax' 5 mg daily for three years. In contrast, in both studies, women receiving placebo lost bone mass at a rate of approximately 1% per year. The longer term effects of 'Fosamax' in an osteoporosis prevention population are not known but clinical trial extensions of up to 10 years of continuous treatment are currently in progress.

Concomitant use with oestrogen/hormone replacement therapy (HRT)

The effects on BMD of treatment with 'Fosamax' 10 mg once-daily and conjugated oestrogen (0.625 mg/day) either alone or in combination were assessed in a two-year study of hysterectomised, post-menopausal, osteoporotic women. At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either oestrogen or 'Fosamax' alone (both 6.0%).

The effects on BMD when 'Fosamax' was added to stable doses (for at least one year) of HRT (oestrogen ± progestin) were assessed in a one-year study in post-menopausal, osteoporotic women. The addition of 'Fosamax' 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 favourable 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.

Treatment of osteoporosis in men

The efficacy of 'Fosamax' 10 mg once daily in men (ages 31 to 87; mean, 63) with osteoporosis was demonstrated in a two-year study. At two years, the mean increases relative to placebo in BMD in men receiving 'Fosamax' 10 mg/day were: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. 'Fosamax' was effective regardless of age, race, gonadal function, baseline rate of bone turnover, or baseline BMD. Consistent with much larger studies in post-menopausal women, in these 127 men, 'Fosamax' 10 mg/day reduced the incidence of new vertebral fracture (assessed by quantitative radiography) relative to placebo (0.8% vs. 7.1%) and, correspondingly, also reduced height loss (-0.6 vs. -2.4 mm).

Glucocorticoid-induced osteoporosis

The efficacy of 'Fosamax' 5 and 10 mg once-daily in men and women receiving at least 7.5 mg/day of prednisone (or equivalent) was demonstrated in two studies. At two years of treatment, spine BMD increased by 3.7% and 5.0% (relative to placebo) with 'Fosamax' 5 and 10 mg/day respectively. Significant increases in BMD were also observed at the femoral neck, trochanter, and total body. In post-menopausal women not receiving oestrogen, greater increases in lumbar spine and trochanter BMD were seen in those receiving 10 mg 'Fosamax' than those receiving 5 mg. 'Fosamax' was effective regardless of dose or duration of glucocorticoid use. Data pooled from three dosage groups (5 or 10 mg for two years or 2.5 mg for one year followed by 10 mg for one year) showed a significant reduction in the incidence of patients with a new vertebral fracture at two years ('Fosamax' 0.7% vs. placebo 6.8%).

Paediatric patients:

Alendronate sodium has been studied in a small number of patients with osteogenesis imperfecta under the age of 18 years. Results are insufficient to support the use of alendronate sodium in paediatric patients with osteogenesis imperfecta.

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 to an estimated 0.46% and 0.39% when alendronate was administered one hour or half an hour before a standardised breakfast. In osteoporosis 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 (20 mg three times daily for five days) did not produce a clinically meaningful change in oral bioavailability of alendronate (a mean increase ranging from 20% to 44%).

Distribution

Studies in rats show that alendronate transiently distributes to soft tissues following 1 mg/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 litres in humans. Concentrations of drug in plasma following therapeutic oral doses are too low for analytical detection (<5 ng/ml). Protein binding in human plasma is approximately 78%.

Biotransformation

There is no evidence that alendronate is metabolised 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 six hours following IV administration. The terminal half-life in humans is estimated to exceed ten years, reflecting release of alendronate from the skeleton. 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.

Characteristics in patients

Preclinical studies show that the drug 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 4.2 'Posology and method of administration').

In test animal species the main target organs for toxicity were kidneys and gastro-intestinal tract. Renal toxicity was seen only at doses >2 mg/kg/day orally (ten times the recommended dose) and was evident only on histological examination as small widely scattered foci of nephritis, with no evidence of effect on renal function. The gastro-intestinal toxicity, seen in rodents only, occurred at doses >2.5 mg/kg/day and appears to be due to a direct effect on the mucosa. There is no additional relevant information.

Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3,256 mg/m²) and 966 mg/kg (2,898 mg/m²) (equivalent to human oral doses* of 27,600 and 48,300 mg), respectively. In males, these values were slightly higher, 626 and 1,280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4,000 mg/m²) (equivalent to a human oral dose^* of 10,000 mg).

* Based on a patient weight of 50 kg.

10 mg tablets: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, magnesium stearate and carnauba wax.

None known.

3 years.

Do not store above 30°C.

Blisters of opaque white PVC lidded with aluminium foil.

Pack size: 28 tablets.

None.

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

10 mg tablets: PL 0025/0326

10 mg tablets: 28 July 1995/ 3 June 2008

December 2011

P.O.M.

© Merck Sharp & Dohme Limited 2011. All rights reserved.

SPC.FSM.11.UK.3504