Alendronic Acid Once weekly 70 mg Tablets

Each tablet contains 70mg alendronic acid (as alendronate sodium)

Excipients: Each tablet contains 272.070 mg of Lactose Anhydrous

For a full list of excipients see section 6.1

Tablet

White to off- white, oval, biconvex, tablet, debossed with 'AHI' on one side and plain on other side.

Treatment of post-menopausal osteoporosis. Alendronic acid reduces the risk of vertebral and hip fractures.

The recommended dosage is one 70 mg tablet once weekly.

To permit adequate absorption of alendrnic acid:

Alendronic acid Tablet must be taken at least 30 minutes before the first food, beverage, or medicinal product of the day with plain water only. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronic acid (see section 4.5).

To facilitate delivery to the stomach and thus reduce the potential for local and oesophageal irritation/adverse experiences (see section 4.4):

• Alendronic acid Tablet should only be swallowed upon arising for the day with a full glass of water (not less than 200 ml or 7 fluid ounce).

• Patients should not 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 Alendronic acid.

• Alendronic acid Tablet 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 section 4.4).

Use in the elderly: In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronic acid. 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. Alendronic acid Tablet 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 (See also section 5.1).

Alendronic acid Once Weekly 70 mg has not been investigated in the treatment of glucocorticoid-induced osteoporosis.

Alendronic acid is contraindicated in:

• 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 alendronic acid or to any of the excipient.

• Hypocalcaemia (see section 4.4).

Alendronic acid 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 alendronic acid tablet is given to patients with active upper gastro-intestinal problems, such as dysphagia, oesophageal disease, gastritis, duodenitis, 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 section 4.3). 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 alendronic acid. Physicians should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue alendronic acid tablet 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 alendronic acid properly and/or who continue to take alendronic acid tablet 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 section 4.2). 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 periodontal disease.

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, radiotherapy, corticosteroids, poor oral hygiene, periodontal disease). 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.

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 section 4.8). 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.

Stress fractures (also known as insufficiency fractures) of the proximal femoral shaft have been reported in patients treated long-term with alendronic acid (time to onset in the majority of cases ranged from 18 months to 10 years). The fractures occurred after minimal or no trauma and some patients experienced thigh pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures were often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures was also reported. Discontinuation of bisphosphonate therapy in patients with stress fracture is advisable pending evaluation of the patient, based on an individual benefit risk assessment.

Patients should be instructed that if they miss a dose of Alendronic acid once weekly tablet, 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.

Alendronic acid tablet is not recommended for patients with renal impairment where GFR is less than 35 ml/min, (see section 4.2). Causes of osteoporosis other than oestrogen deficiency, ageing and glucocorticoid use should be considered.

Hypocalcaemia must be corrected before initiating therapy with alendronic acid (see section 4.3). 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 alendronic acid.

Due to the positive effects of alendronic acid 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 alendronic acid. Therefore, patients must wait at least 30 minutes after taking alendronic acid before taking any other oral medicinal product (see sections 4.2 and 5.2).

No other interactions with medicinal products of clinical significance are anticipated. A number of patients in the clinical trials received oestrogen (intravaginal, transdermal, or oral) while taking alendronic acid. No adverse experiences attributable to their concomitant use were identified.

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 alendronic acid was used concomitantly with a wide range of commonly prescribed medicinal products without evidence of clinical adverse interactions.

Use during pregnancy

There are no adequate data from the use of alendronic acid in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, or postnatal development. Alendronic acid given during pregnancy in rats caused dystocia related to hypocalcemia (see section 5.3). Given the indication, alendronic acid should not be used during pregnancy.

Use during lactation

It is not known whether alendronic acid is excreted into human breast milk. Given the indication, alendronic acid tablet should not be used by breast-feeding women.

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

In a one-year study in post-menopausal women with osteoporosis the overall safety profiles of Alendronic acid tablet 70 mg (n=519) and alendronic acid tablet 10 mg/day (n=370) were similar.

In two three-year studies of virtually identical design, in post-menopausal women (alendronic acid tablet 10 mg: n=196, placebo: n=397) the overall safety profiles of alendronic acid tablet 10 mg/day and placebo were similar.

Adverse experiences reported by the investigators as possibly, probably or definitely drug-related are presented below if they occurred in 1% in either treatment group in the one-year study, or in 1% of patients treated with alendronic acid tablet 10 mg/day and at a greater incidence than in patients given placebo in the three-year studies:

The following adverse experiences have also 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 not known (cannot be estimated from the available data)]

During post-marketing experience the following reactions have been reported (frequency unknown):

Nervous system disorders - rare: dizziness, dysgeusia

Ear and labyrinth disorders: vertigo

Skin and subcutaneous tissue disorders: alopecia

Musculoskeletal, connective tissue and bone disorders: joint swelling, stress fractures of the proximal femoral shaft (see section 4.4)

General disorders and administration site conditions: asthenia, peripheral oedema

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 alendronic acid tablet 10 mg/day 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.

Hypocalcaemia, hypophosphataemia and upper gastro-intestinal adverse events, such as upset stomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdosage.

No specific information is available on the treatment of overdosage with alendronic acid. Milk or antacids should be given to bind alendronic acid tablet. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

ATC Code: M05B A04

Pharmacotherapeutic group:.

Drugs affecting bone structure and mineralisation, bisphosphonates. The active ingredient of 'Alendronic acid Tablets', alendronate sodium, is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect on bone formation. Preclinical studies have shown preferential localisation of alendronic acid to sites of active resorption. Activity of osteoclasts is inhibited, but recruitment or attachment of osteoclasts is not affected. The bone formed during treatment with alendronic acid is of normal quality.

Treatment of post-menopausal osteoporosis

Osteoporosis is defined as BMD of the spine or hip 2.5 SD below the mean value of a normal young population or as a previous fragility fracture, irrespective of BMD.

The therapeutic equivalence of 'Alendronic acid Tablets' 70 mg (n=519) and alendronic acid 10 mg daily (n=370) was demonstrated in a one-year multicentre study of post-menopausal women with osteoporosis. The mean increases from baseline in lumbar spine BMD at one year were 5.1% (95% CI: 4.8, 5.4%) in the 70 mg once-weekly group and 5.4% (95% CI: 5.0, 5.8%) in the 10 mg daily group. The mean BMD increases were 2.3% and 2.9% at the femoral neck and 2.9% and 3.1% at the total hip in the 70 mg once weekly and 10 mg daily groups, respectively. The two treatment groups were also similar with regard to BMD increases at other skeletal sites.

The effects of alendronic acid tablet 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 alendronic acid 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 (alendronic acid 3.2% vs placebo 6.2%) in the proportion of patients treated with alendronic acid 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 using alendronic acid daily (5 mg daily for two years and 10 mg daily for either one or two additional years):

• FIT 1: A three-year study of 2,027 patients who had at least one baseline vertebral (compression) fracture. In this study alendronic acid daily reduced the incidence of 1 new vertebral fracture by 47% (alendronic acid 7.9% vs. placebo 15.0%). In addition, a statistically significant reduction was found in the incidence of hip fractures (1.1% vs. 2.2%, a reduction of 51%).

• FIT 2: A four-year study of 4,432 patients with low bone mass but without a baseline vertebral fracture. In this study, a significant difference was observed in the analysis of the subgroup of osteoporotic women (37% of the global population who correspond with the above definition of osteoporosis) in the incidence of hip fractures (alendronic acid 1.0% vs. placebo 2.2%, a reduction of 56%) and in the incidence of 1 vertebral fracture (2.9% vs. 5.8%, a reduction of 50%).

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 reference dose, the oral mean bioavailability of alendronic acid tablet in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardised breakfast. Bioavailability was decreased similarly to an estimated 0.46% and 0.39% when alendronic acid tablet was administered one hour or half an hour before a standardised breakfast. In osteoporosis studies, alendronic acid tablet was effective when administered at least 30 minutes before the first food or beverage of the day.

Bioavailability was negligible whether alendronic acid was administered with, or up to two hours after, a standardised breakfast. Concomitant administration of alendronic acid tablet 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 alendronic acid tablet (a mean increase ranging from 20% to 44%).

Distribution

Studies in rats show that alendronic acid tablet 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 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 alendronic acid is metabolised in animals or humans.

Elimination

Following a single intravenous dose of [¹⁴C] alendronic acid tablet, 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 intravenous dose, the renal clearance of alendronic acid tablet was 71 ml/min, and systemic clearance did not exceed 200 ml/min. Plasma concentrations fell by more than 95% within six hours following intravenous administration. The terminal half-life in humans is estimated to exceed ten years, reflecting release of alendronic acid from the skeleton. Alendronic acid tablet 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 medicinal products 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 intravenous doses up to 35 mg/kg in animals. Although no clinical information is available, it is likely that, as in animals, elimination of alendronic acid via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronic acid in bone might be expected in patients with impaired renal function (see section 4.2).

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in female rats have shown that treatment with alendronic acid tablet during pregnancy was associated with dystocia in dams during parturition which was related to hypocalcaemia. In studies, rats given high doses showed an increased incidence of incomplete fetal ossification. The relevance to humans is unknown.

Lactose anhydrous

Cellulose microcrystalline (E460)

Croscarmellose sodium

Magnesium stearate

Not applicable

3 years

This medicinal product does not require any special storage conditions

OPA-AL-PVC/Al blister

Pack size: 4 tablets or 12* tablets

* Not for UK market

Any unused product or waste material should be disposed of in accordance with local requirements.

Accord Healthcare Limited

Sage House

319, Pinner Road

North Harrow

Middlesex HA1 4 HF

United Kingdom

PL 20075/0071

26/09/2008

27/02/2012