Document: document 0 change

• document 0
• document 1
• document 2

---

NAME OF THE MEDICINAL PRODUCT

Alendronic Acid 10 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg alendronic acid (as sodium monohydrate).

For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Tablet

White to off-white, round biconvex tablet, debossed with "T" on one side and "10" on the other side.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

-    Treatment of osteoporosis in post-menopausal women. Alendronate reduces the risk of vertebral and hip fractures.

-    Treatment of osteoporosis in men.

Alendronate reduces the risk of vertebral fractures.

4.2 Posology and method of administration

For oral use

The recommended dosage is 10 mg once a day.

To permit adequate absorption of alendronate

Alendronate 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):

- Alendronate should only be swallowed upon rising for the day in the morning with a full glass of plain water (not less than 200 ml or 7 fl.oz.).

-    Patients should only swallow alendronate 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 [should stay upright (sitting or standing up)] 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 alendronate.

-    Alendronate should not be taken at bedtime or before rising for the day.

Patients should receive supplemental calcium and vitamin-D if dietary intake is inadequate (see section 4.4).

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.

Use in the elderly

In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate. There is therefore no need to reduce dosage 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, other biphosphonates, 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 exercised when alendronate 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 Barett’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 alendronate. Physicians should therefore be alert to any signs or symptoms indicating 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, or new or worsening heartburn.

The risk of severe oesophageal adverse events 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. A causal relationship cannot be ruled out.

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 hypocalcaemia should be monitored during therapy with alendronate.

Due to the positive effects of alendronate in increasing bone mineral, decreases in serum calcium and phosphate may occur. 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 (eg hypoparathyroidism, vitamin D deficiency and calcium malabsorption).

Ensuring adequate calcium and vitamin D intake is particularly important in patients receiving glucocorticoids.

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.

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 osteroporosis 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.

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

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 section 4.2).

No other interactions 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 hypocalcaemia (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 alendronate may affect some patients' ability to drive or operate machinery. Individual responses to alendronate may vary (see section 4.8).

4.8 Undesirable effects

Alendronate has been studied in nine major clinical studies (n=5,886). In the longest running trials in postmenopausal women, up to five years’ experience has been accumulated. Two years’ safety data is available in men with osteoporosis.

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 once weekly 70 mg (n=519) %	Alendronate 10 mg/day (n=370) %	Alendronate 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	1.0	1.4	1.0	0.8
distention
- 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	2.9	3.2	4.1	2.5
(bone, 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 events have been reported in clinical studies and/or after the marketing of alendronate:

very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), Not known (cannot be estimated from the available data)._

Immune system disorders

Uncommon	Hypersensitivity reactions including urticaria and angioedema
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*, melaena*
Rare	Oesophageal stricture*, oropharyngeal ulceration*, upper gastrointestinal PUBs (perforation, ulcers, bleeding)5 although the causal relationship has not been established
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 and connective tissue disorders
Very common	Musculoskeletal (bone, muscle or joint) pain which is sometimes severe*5
Common	Joint swelling*
Rare	Osteonecrosis of the jaw*5, atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)
Metabolism and nutrition disorders
Rare	Symptomatic hypocalcaemia, occasionally severe, often in association with predisposing conditions5
General disorders and administration site conditions
Common	Asthenia*, peripheral oedema*
Uncommon	Transient symptoms as in an acutephase respons (myalgia, malaise and rarely fever), typically in association with initiation of treatment. *
5see section 4.4
* frequency 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

4.9 Overdose

Hypocalcaemia, hypophosphataemia and upper gastrointestinal 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 consumed in order 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: Bisphosphonate, for the treatment of bone diseases. ATC Code: M05B A04

The active ingredient 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 (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 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.

5.2 Pharmacokinetic properties

Oral bioavailability of alendronate in women is 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 approx. the same as in women. Bioavailability is reduced by approx. 40%, when alendronate was administered % hour to 1 hour before a standardised breakfast. In osteoporosis studies, alendronate was effective when administered at least 30 minutes before the first food or beverage of the day.

Bioavailability was negligible if alendronate was taken with or up to two hours after a standard breakfast. Coffee and orange juice reduced bioavailability by approx. 60% (see section 4.2).

In healthy test subjects, oral prednisone (20 mg 3 times daily for 5 days) did not significantly affect the oral bioavailability of alendronate (average increase 20-44%).

Distribution:

Protein binding is approx. 78%. Preclinical investigation shows that alendronate is distributed to the soft tissues and then is rapidly redistributed to the bones, where is binds or is eliminated in the urine. The steady-state distribution volume in the soft areas of the body are at least 28 litres (2235 litres). Plasma concentrations of the active substance after administration of an oral therapeutic dose are below the level of detection (<5 ng/ml).

Biotransformation:

Alendronate has no known metabolites.

Elimination:

Approx. 50% of ¹⁴C-tagged alendronate is excreted in the urine within 72 hours. Very little or no radioactivity was recovered in the faeces. The remainder is deposited in bone tissue, where it is inactive. Renal clearance was 71 ml/minute, systemic clearance did not exceed 200 ml/minute, after a single I.V. dose of 10 mg. Within 6 hours the plasma concentration fell by more than 95% after I.V. administration. This is followed by a slow release of alendronate from the skeleton. The estimated half-life is thus > 10 years.

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 active substances by those systems in humans.

Characteristics in patients:

Preclinical investigations show that the active substances, which is not deposited in the bones, is rapidly excreted in the urine. After chronic dosage with cumulative doses I.V., up to 35 mg/kg in animals, no saturation of bone uptake was observed. In animals, elimination of alendronate via the kidneys was reduced in impaired renal function. There is no corresponding information in man, but greater accumulation of alendronate in bone should be anticipated in people 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 alendronate during pregnancy was associated with dystocia in dams during parturition which was related to hypocalcaemia. Fetuses from rats given high doses showed an increased incidence of incomplete ossification. The relevance to humans is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Low-substituted hyprolose Hyprolose

Colloidal hydrated silica Sodium stearyl fumarate

6.2. Incompatibilities

Not applicable.

Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5. Nature and contents of container

PVC/PVdC/Aluminium blister pack containing 14, 28, 30, 50, 56, 84, 90, 98, 112, 140 tablets, 28 tablets in calendar pack, 50 x 1 (individual blisters)

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7.    MARKETING AUTHORISATION HOLDER.

TEVA UK Limited,

Brampton Road Hampden Park Eastboume East Sussex BN229AG

8.    MARKETING AUTHORISATION NUMBER

PL 00289/0703

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

31/10/2007

10 DATE OF REVISION OF THE TEXT

30/11/2012