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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Alendronic Acid 10mg tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 10mg alendronic acid (as sodium alendronate trihydrate). Excipients: Each tablet contains 103.95 mg lactose monohydrate.

For a full list of excipients see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

White to off-white, capsule-shaped, stamped "AN 10" on one side and "Arrow logo" on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of post-menopausal osteoporosis. Alendronate Sodium 10 mg tablets reduces the risk of vertebral and hip fractures.

4.2 Posology and method of administration

For oral use only.

The recommended dosage is 10 mg once daily.

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.

To permit adequate absorption of alendronate:

Alendronic Acid 10 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 alendronate (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 10 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 only swallow Alendronic Acid 10 mg Tablets 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 Alendronic Acid 10 mg Tablets.

•    Alendronic Acid 10 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 alendronate. 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. Alendronate 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).

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 alendronate or to any of the excipients.

•    Hypocalcaemia.

See also section 4.4.

4.4 Special warnings and precautions for use

Alendronate 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 alendronate is given to patients with active upper gastrointestinal 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).

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, have been reported in patients receiving alendronate. Physicians should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue alendronate 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 alendronate properly and/or who continue to take alendronate 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 (postmarketing) 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 oral 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.

Bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. In postmarketing 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.

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 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.

Patients should be instructed that if they miss a dose of Alendronic Acid 10 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 day, as originally scheduled.

Alendronate 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 alendronate (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 hypocalcemia should be monitored during therapy with Alendronic Acid 10 mg Tablets.

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 hypocalcemia, 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.

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 alendronate. Therefore, patients must wait at least 30 minutes after taking alendronate 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 alendronate. 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 alendronate was used concomitantly with a wide range of commonly prescribed medicinal products without evidence of clinical adverse interactions.

4.6 Fertility, Pregnancy and lactation

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 section 5.3).

Use during lactation

It is not known whether alendronate is excreted into human breast milk. Alendronate 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 10 mg Tablets may affect some patients' ability to drive or operate machinery. Individual responses to Alendronic Acid 10 mg Tablets may vary. (See section 4.8).

4.8 Undesirable effects

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

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

	One-Year Study		Three-Year Studies
	alendronate	alendronate	alendronate	Placebo
	Once	10 mg/day	10 mg/day	(n=397)
	Weekly	(n=370)	(n=196)	%
	70 mg (n=519) %	%	%
Gastro-intestinal
abdominal pain	3.7	3.0	6.6	4.8
Dyspepsia	2.7	2.2	3.6	3.5
acid	1.9	2.4	2.0	4.3
regurgitation 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

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

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

Immune system disorders:

Rare: hypersensitivity reactions including urticaria and angioedema Metabolism and nutrition disorders:

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

Nervous system disorders:

Common: headache, dizziness^

Uncommon: dysgeusia^

Eye disorders:

Uncommon: eye inflammation (uveitis, scleritis, episcleritis)

Ear and labyrinth disorders:

Common: vertigo^

Gastrointestinal disorders:

Common: abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation Uncommon: nausea, vomiting, gastritis, oesophagitis*, oesophageal erosions*, melena^

Rare: oesophageal stricture*, oropharyngeal ulceration*, upper gastrointestinal PUBs (perforation, ulcers, bleeding)§

Skin and subcutaneous tissue disorders:

Common: alopecia^, pruritus^

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 severe*§

Common: joint swelling*

Rare: Osteonecrosis of the jaw*§ , atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction) #

General disorders and administration site conditions:

Common: asthenia*, peripheral oedema*

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

§See section 4.4

fFrequency in Clinical Trials was similar in the drug and placebo group.

*See sections 4.2 and 4.4

fThis 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 alendronate. 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates. ATC code: M05BA04

The active substance in Alendronic Acid 10 mg Tablets, sodium alendronate trihydrate, is a bisphosphonate that inhibits osteoclastic bone resorption without any direct effect on bone formation. Preclinical studies have demonstrated a preference for localisation of alendronate to sites where active resorption takes place. Osteoclastic activity is inhibited, but formation and binding of the osteoclasts is not affected. Bone formed during treatment with alendronate is of normal quality.

Treatment of post-menopausal osteoporosis

Osteoporosis is defined as bone mineral density (BMD) of the spine or hip 2.5 standard deviations below the mean value of a normal young population or as a previous fragility fracture, irrespective of bone mineral density.

The effects of alendronate on BMD and fracture incidence in post-menopausal women were studied in two initial efficacy studies of identical design (n=994), and in the Fracture Intervention Trial (FIT: n=6459).

In the initial efficacy studies, the increases in BMD with alendronate 10 mg daily relative to placebo after three years were 8.8 %, 5.9 % and 7.8 % at the spine, femoral neck and trochanter respectively. Total BMD also increased significantly. In the patients treated with alendronate, the proportion of patients who suffered one or more vertebral fractures was reduced by 48 % (alendronate 3.2 % versus placebo 6.2 %).

In the two-year extensions of these studies the BMD in the spine and trochanter continued to increase. In addition, BMD at the femoral neck and total body was 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, Alendronate tablets 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 Alendronate tablets 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 Alendronate tablets 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 Alendronate tablets 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 Alendronate tablets 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 Alendronate tablets 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 Alendronate tablets 10 mg once-daily and conjugated oestrogen (0.625 mg/day) either alone or in combination were assessed in 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 wither oestrogen or Alendronate tablets alone (both 6.0%).

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

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

Compared with an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64 % for doses ranging from 5 to 70 mg given after an overnight fast and two hours before a standardised breakfast. Bioavailability decreased to an estimated 0.46 % and 0.39 % when alendronate was given an hour or half an hour before a standardised breakfast.

In osteoporosis studies alendronate was effective when it was given at least 30 minutes before the first meal or drink of the day. Bioavailability was negligible irrespective of whether alendronate was given together with or up to two hours after a standardised breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approx.

60 %. In healthy persons, oral prednisolone (20 mg three times daily for five days) did not result in any clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 % to 44 %).

Distribution

Studies in rats show that alendronate is initially distributed to soft tissues after intravenous administration of 1 mg/kg, but is then rapidly redistributed to the skeleton 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 intravenous 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 intravenous dose of 10 mg, 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 intravenous administration. The terminal halflife 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 thought 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 intravenous 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 section 4.2).

5.3 Preclinical safety data

The usual studies of general toxicity, genotoxicity and carcinogenicity did not reveal any special risks for humans. Studies in female rats showed that treatment with alendronate during pregnancy was associated with dystocia during parturition, which was related to hypocalcaemia. Studies in which rats were given high doses showed an increased incidence of incomplete foetal bone formation. The relevance for humans is unknown.

PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Microcrystalline cellulose Lactose monohydrate Croscarmellose sodium Magnesium stearate

6.2    Incompatibilities

Not relevant

6.3    Shelf life

3 years

6.4    Special precautions    for    storage

Do not store above 25°C. Store in the original package.

6.5    Nature and contents of    container

The tablets are supplied in triplex blister (PVC/PE/PVDC/Al) packaging. 14, 28, 56, 98, 112 and 50x1 (unit dose).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special instructions.

7    MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegi 76-78 220 HafnarfjorQur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0528

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/12/2009

10    DATE OF REVISION OF THE TEXT

07/04/2014