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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Alendronic Acid 70 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 70 mg alendronic acid (as sodium trihydrate).

Each tablet contains 192.03 mg of lactose (as cellecatose 80).’

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

White, round, biconvex conventional tablets, marked with ‘70’ on one side and plain on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of postmenopausal osteoporosis. Alendronic Acid 70 mg Tablets reduce the risk of vertebral and hip fractures.

4.2    Posology and method of administration

For oral use

The recommended dosage is one 70 mg tablet once weekly.

To permit adequate absorption of alendronic acid:

Alendronic Acid 70 mg Tablets 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 70 mg Tablets should only be swallowed upon arising for the day with a full glass of water (not less than 200 ml or 7 fl.oz.).

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 70 mg Tablets.

Alendronic Acid 70 mg Tablets 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 a glomerular filtration rate (GFR) greater than 35 ml/min. Alendronic acid is not recommended for patients with renal impairment where GFR is less than 35 ml/min, due to lack of experience.

Use in paediatric patients: Alendronate sodium is not recommend 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).

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 Alendronic acid on an individual patient basis, particularly after 5 or more years of use.

Alendronic Acid 70 mg Tablets has not been investigated in the treatment of glucocorticoid-induced osteoporosis.

4.3 Contraindications

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 excipients

Hypocalcaemia

See also section 4.4.

4.4 Special warnings and precautions for use

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 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 gastrointestinal tract other than pyloroplasty (see section 4.3).

Oesophageal reactions (sometimes severe and requiring hospitalisation), such as oesophagitis, oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture, 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 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 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. A causal relationship cannot be ruled out.

Patients should be instructed that if they miss a dose of Alendronic Acid 70 mg Tablets, 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 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 and ageing 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 70 mg Tablets.

Due to 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 reports of symptomatic hypocalcaemia, which occasionally have 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 therefore particularly important in patients receiving glucocorticoids.

With reference to the presence of lactose monohydrate in the formulation, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 with corticosteriods. 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:

•    e.g. potency of the bisphosphonate (highest for zoledronic acid), route of administration (see above), and cumulative dose in cancer patients.

•    cancer, chemotherapy, radiotherapy, corticosteroids, smoking

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

A dental examination with appropriate preventive dentistry should be considered prior to treatment with oral biphosphonates 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 bisphosphonates 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 biphosphonate 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.

Bone, joint, and/or muscle pain has been reported in patients taking biphosphonates. 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 biphosphonate.

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 fractures of stress fractures, weeks to month before presenting with a completed femoral fracture. Fractures are 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 has also been reported. Discontinuation of bisphosphonate 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 bisphosphonate 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.

In post-marketing experience, there have been rare reports of severe skin reactions including Stevens Johnson syndrome and toxic epidermal necrolysis.

In patients with known Barrett’s oesophagus, prescribers should consider the benefits and potential risks of alendronate on an individual basis.

4.5    Interaction with other medicinal products and other forms of interaction

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

4.6    Fertility, pregnancy and lactation

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.

Lactation

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

4.7 Effects on ability to drive and use machines

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 70mg may affect some patients' ability to drive or operate machinery. Individual responses to alendronic acid 70mg may vary (see section 4.8).

Undesirable effects

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

In two three-year studies of virtually identical design, in post-menopausal women (alendronic acid 10 mg: n=196, placebo: n=397) the overall safety profiles of alendronic acid 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 10 mg/day and at a greater incidence than in patients given placebo in the three-year studies:

	One-Year Study		Three-Year Studies
	Alendronic Acid 70 mg once weeekly (n = 519) %	Alendronic Acid 10 mg/day (n = 370) %	Alendronic Acid 10 mg/day (n = 196) %	Placebo (n = 397) %
Gastro-intestinal
abdominal pain	3.7	3.0	6.6	4.8
dyspepsia	2.7	2.2	3.6	3.5
acid regurgitation	1.9	2.4	2.0	4.3
nausea	1.9	2.4	3.6	4.0
abdominal distention	1.0	1.4	1.0	0.8
constipation	0.8	1.6	3.1	1.8
diarrhoea	0.6	0.5	3.1	1.8
dysphagia	0.4	0.5	1.0	0.0
flatulence	0.4	1.6	2.6	0.5
gastritis	0.2	1.1	0.5	1.3
gastric ulcer	0.0	1.1	0.0	0.0
oesophageal ulcer	0.0	0.0	1.5	0.0
Musculoskeletal
musculoskeletal (bone,	2.9	3.2	4.1	2.5
muscle or joint) pain
muscle cramp	0.2	1.1	0.0	1.0
Neurological
headache	0.4	0.3	2.6	1.5

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

Very common feJ/10), Common fid/100, <1/10), Uncommon ^1/1,000, <1/100), Rare (>1/10,000, <1/1,000), Very rare (<1/10,000 including isolated cases

Blood and the lymphatic system disorders:

Rare: symptomatic hypocalcaemia, often in association with predisposing conditions (see section 4.4).

Immune system disorders:

Rare: hypersensitivity reactions including urticaria and angioedema. Transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever), typically in association with initiation of treatment.

Metabolism and nutrition disorders:

Rare: symptomatic hypocalcaemia, often in association with predisposing conditions§.

Nervous system disorders:

Common: headache, dizziness¹)

Uncommon: dysgeusia¹

Eye disorders:

Uncommon: eye inflammation (uveitis, scleritis, episcleritis).

Ear and labyrinth disorders:

Common: vertigo¹

Gastro-intestinal disorders:

Common: abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation.

Uncommon: nausea, vomiting, gastritis, oesophagitis*, oesophageal erosions*, melaena.

Rare: oesophageal stricture*, oropharyngeal ulceration*, upper gastrointestinal PUBs (perforation, ulcers, bleeding), although a causal relationship cannot be ruled out.

Skin and subcutaneous tissue disorders Common: alopecia¹ pruritus¹ Uncommon: rash, erythema

Rare: Rash with photosensitivity, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal, connective tissue and bone disorders:

Very common: musculoskeletal (bone, muscle or joint) pain which is sometimes

1§

severe .

Common:    joint swelling¹

Rare: Osteonecrosis of the jaw¹§, atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction) .

General disorders and administration site conditions:

Common: asthenia¹, peripheral oedema¹

Uncommon: transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever), typically in association with initiation of treatment¹.

§See section 4.4

1Frequency in Clinical Trials was similar in the drug and placebo group.

*See sections 4.2 and 4.4

%This adverse reaction was identified through post-marketing surveillance. The frequency of rare was estimated based on relevant clinical trials

Identified in postmarketing experience.

4.9 Overdose

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. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Bisphosphonate, for the treatment of bone diseases. ATC Code: M05B A04

The active ingredient of Alendronic Acid 70 mg Tablets, alendronic acid sodium trihydrate, 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 70 mg Tablets (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 on bone mass and fracture incidence in postmenopausal 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%).

Osteoporosis in men with increased risk of fracture

The efficacy of alendronate 10 mg once daily in men (31-87 years, mean age 63 years, n=241) with osteoporosis was evaluated in a two-year study. After two years of treatment with alendronate 10 mg/day, BMD increased on average by 5.3 % in the spine, by 2.6 % in the femoral neck, by 3.1 % in the trochanter, and by 1.6 % for the skeleton as a whole, relative to placebo (p<0.001 for all measurement points). The effect of alendronate on BMD was independent of age, race, gonadal function, baseline BMD or baseline bone turnover. The incidence of new vertebral fractures was evaluated as a safety variable. In a retrospective analysis (assessed by quantitative radiography) one new fracture (0.8 %) was documented among patients treated with alendronate, compared with 6 new fractures (7.1 %) for placebo (p=0.017). The reduction in height was less after treatment with alendronate, relative to placebo (-0.6 mm and -2.4 mm respectively, p=0.02). No effect on non- vertebral fractures was seen.

Glucocorticoid-induced osteoporosis

Long-term use of steroids is often associated with the development of osteoporosis accompanied by fractures. This occurs in both men and women of all ages. The efficacy of alendronate 10 mg and alendronate 5 mg once daily in men and women treated with steroids (at least 7.5 mg/day of prednisone or equivalent, median dose 10 mg/day) was demonstrated in two one-year studies of practically identical design. These studies involved a total of 560 patients aged 17-83 years. The patients received calcium and vitamin D supplements. Relative to placebo, BMD increased significantly in the spine (2.41 %), femoral neck (2.19 %) and trochanter (1.65 %) in patients who were treated with alendronate 5 mg once daily. The increases in BMD with alendronate 10 mg once daily were the same as for alendronate 5 mg once daily in all patients, with the exception of post- menopausal women who were not being treated with oestrogen. In these women the increases (relative to placebo) with alendronate 10 mg once daily were greater than for alendronate 5 mg once daily in the spine (4.11 % versus 1.56 %) and trochanter (2.84 % versus 1.67 %). The fracture-preventing effect of increasing bone density with alendronate 10 mg or alendronate 5 mg in corticosteroid- induced osteoporosis has not been established.

Alendronate 10 mg and 5 mg were effective irrespective of the dose or duration of steroid use. In addition, alendronate 10 mg and alendronate 5 mg were effective irrespective of age (<65 years as against>65 years), gender, baseline BMD, baseline bone turnover and concomitant use of a number of common medicines. In the patients who received alendronate in doses up to 10 mg daily and in whom biopsy was performed after one year no signs of a disturbance of the bone mineralisation process were seen.

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.

5.2 Pharmacokinetic properties

Absorption

Relative to an intravenous reference dose, the oral mean bioavailability of alendronic acid 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 was administered one hour or half an hour before a standardised breakfast. In osteoporosis studies, alendronic acid 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 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 (a mean increase ranging from 20% to 44%).

Distribution

Studies in rats show that alendronic acid 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, 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 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 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).

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in rats have shown that treatment with alendronic acid 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 foetal ossification. The relevance to humans is unknown.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Cellactose 80 Croscarmellose sodium Colloidal anhydrous silica Magnesium stearate

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

6.4    Special precautions    for storage

No special precautions for storage.