Fostepor Once Weekly 70mg Tablets

4.2 Posology and method of administration

Method of administration

For oral administration

To permit adequate absorption of alendronate:
Fostepor Once Weekly 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):

• Fostepor Once Weekly should only be swallowed upon arising for the day with a full glass of water (not less than 200 ml or 7 fl.oz.).

4.4 Special warnings and precautions for use

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

4.2 Posology and method of administration

Posology
The recommended dosage is one 70mg tablet once weekly. 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 Fostepor Once Weekly on an individual patient basis, particularly after 5 or more years of use.

Method of administration

For oral administration

To permit adequate absorption of alendronate:
Fostepor Once Weekly 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):
• Fostepor Once Weekly 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 Fostepor Once Weekly 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 Fostepor Once Weekly.
• Fostepor Once Weekly 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).

Special populations
Older patients:
In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate. Therefore no dosage adjustment is necessary for older people.

Patients with renal impairment:
No dosage adjustment is necessary for patients with creatinine clearance GFR greater than 35 ml/min. Alendronate is not recommended for patients with renal impairment where creatinine clearance GFR is less than 35 ml/min, due to lack of experience.

Paediatric population:
Alendronate sodium the active substance 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).


Method of administration

For oral administration

To permit adequate absorption of alendronate:
Fostepor Once Weekly 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):

• Fostepor Once Weekly 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 Fostepor Once Weekly 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 Fostepor Once Weekly.
• Fostepor Once Weekly 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).

Alendronate in a dosage of 70 mg once weekly has not been investigated in the treatment of glucocorticoid-induced osteoporosis.

4.4 Special warnings and precautions for use

Upper gastrointestinal adverse reactions
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 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).

Osteonecrosis of the jaw
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis), has been reported in patients with cancer who are 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.

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.

Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Musculosketal pain
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.

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

Missed dose
Patients should be instructed that if they miss a dose of Fostepor Once Weekly, 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 per week, as originally scheduled on their chosen day.

Renal impairment
Alendronate is not recommended for patients with renal impairment where creatinine clearance GFR is less than 35 ml/min, (see section 4.2).

Bone and mineral metabolism
Causes of osteoporosis other than oestrogen deficiency and ageing should be considered.

4.6 Fertility, pregnancy and lactation

Pregnancy
Alendronate should not be used during pregnancy. There are no or limited amount of adequate data from the use of alendronate in pregnant women.

Studies in animals have shown reproductive toxicity. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/feotal development, or postnatal development. Alendronate given during pregnancy in rats caused dystocia related to hypocalcaemia (see section 5.3).

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use (see section 5.2). There are no data on foetal risk in humans. However, there is a theoretical risk of foetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied

Breast-feeding
It is not known whether alendronate/metabolites are is excreted into human breast milk. A risk to the new-borns/infants cannot be excluded. Alendronate should not be used by breast-feeding women.

Fertility
Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use (see section 5.2). There are no data on foetal risk in humans. However, there is a theoretical risk of foetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.


4.7 Effects on ability to drive and use machines

Alendronate has no or negligible direct influence 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 Fostepor Once Weekly may affect some patients' ability to drive or operate machinery. Individual responses to Fostepor Once Weekly may vary (see section 4.8).


4.8 Undesirable effects

Summary of the safety profile
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.

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

Frequencies are defined as: [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)]

Identified in postmarketing experience

5.1 Pharmacodynamic properties

Clincal efficacy and safety
Treatment of post-menopausal osteoporosis:
Osteoporosis is defined as BMD (bone mass density) in the spine or the hip 2.5 SD below the average value of a normal, younger population or as a previous fragility fracture regardless of the BMD.

Pharmacodynamic effects
The therapeutic equivalence of alendronate 70 mg once weekly (n=519) and alendronate 10 mg daily (n=370) was demonstrated in a one-year multicenter study of post-menopausal women with osteoporosis. Average increases from baseline in columna lumbalis BMD following one year was 5.1% (95% CI: 4.8; 5.4%) in the 70 mg group and 5.4% (95% CI: 5.0; 5.8%) in the 10 mg group. Average increases in BMD in the treatment groups of 70mg once weekly and 10 mg once daily were 2.3% and 2.9%, respectively, in collum femoris and 2.9% and 3.1%, respectively, in the whole hip. The two treatment groups were also similar with regard to BMD increases at other skeletal sites.

Clinical efficacy and safety
The alendronate effect on BMD and fracture incidence in post-menopausal women was investigated in two, identically designed, initial-effect-studies (n=994) and in the study “Fracture Intervention Trial” (FIT: n=6,459).

Paediatric population
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.

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 alendronate 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.

Paediatric population
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

Renal impairment Patient characteristics:
Preclinical investigations show that a medicinal product that is not deposited in the bone, is rapidly excreted in the urine. Following chronic dosage of cumulative IV doses of up to 35 mg/kg in animals, no saturation of bone uptake has been demonstrated. As in animals it is probable that the elimination of alendronate via the kidneys will be reduced in renally insufficient patients. However, there are no clinical data available on this. Consequently, a larger accumulation of alendronate in bones may be expected in humans with a reduced renal function (see section 4.2).

6.5 Nature and contents of container

Green, opaque aluminium/PVC blister packs containing 4, 8 or 12 tablets.
Polypropylene tablet container with polyethylene cap and optional polyethylene ullage filler containing 4, 8, 12 or 100 (dispensing pack) tablets.

Excipient with known effect:

Each tablet contains 150.94 mg lactose (as lactose monohydrate).

Posology

The recommended dosage is one 70mg tablet once weekly. 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 Fostepor Once Weekly on an individual patient basis, particularly after 5 or more years of use.

Method of administration

For oral administration

Older patients: In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate. Therefore no dosage adjustment is necessary for older people.

Patients with 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 population: Alendronate sodium the active substance 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).

section 4.5:

No other drug 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.

section 4.6:
feotal development 

section 4.8:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance,  Earlsfort Terrace, IRL – Dublin 2; Tel:+353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: medsafety@hpra.ie.

Pharmacotherapeutic group: 

Bisphosphonates for the treatment of bone diseases..

ATC code: M05BA04

6.5     Nature and contents of container

Green, opaque aluminium/PVC blister packs containing 4, 8 or 12 tablets.

Polypropylene container with polyethylene cap . containing 4, 8 or 12 tablets.

Polypropylene container with polyethylene cap containing 100 tablets (dispensing pack).

Pack sizes: 4, 8 or 12 tablets*.

*Not all pack sizes may be marketed.

section 10: updated

10.     DATE OF REVISION OF THE TEXT

January     March 2014

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 70 mg alendronic acid, as sodium alendronate.
Excipient with known effect: Lactose monohydrate.
For a the full list of excipients see section 6.1.

4.2 Posology and method of administration

Posology

The recommended dosage is one 70mg tablet once weekly. 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 Alendronat Mylan on an individual patient basis, particularly after 5 or more years of use.

Elderly patientsUse 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.

Patients with 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 populationPaediatric 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).

Alendronate Fostepor Once Weekly has not been investigated in the treatment of glucocorticoid-induced osteoporosis.

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 Fostepor Once Weekly 70mg Tablets on an individual patient basis, particularly after 5 or more years of use.

4.3 Contraindications

• Hypersensitivity to the active substance alendronate or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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 Fostepor Once Weekly, 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 per week, as originally scheduled on their chosen day.

4.6  Fertility, pregnancy and lactationPregnancy and lactation

Use during pPregnancy
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. Animal studies revealed effects on foetal bone formation (incomplete ossification) at high doses (see section 5.3).

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


(Ref: DK/H/0882/IB/041)

4.2 Posology and method of administration

Following added:
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 Alendronat Mylan 70mg Tablets on an individual patient basis, particularly after 5 or more years of use.


4.4 Special warnings and precautions for use

Added:
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.

Amended:
A dental examination with appropriate preventive dentistry should be considered prior to treatment with oral bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene, periodontal disease, smoking).dental status.

Added:
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.

Added:
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique, fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often 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.

4.8  Undesirable effects

Side effected updated and put into table format.

5.1 Pharmacodynamic properties

Added:
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.

Added:
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 alendronate 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.

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

In order to ensure adequate absorption of Fostepor® Once Weekly:
Alendronate must be taken on an empty stomach with ordinary tap water at least 30 minutes before intake of other food or drinks or other medicine. Other drinks (including mineral water), food and other medicine may reduce the absorption of alendronate (see Section 4.5).

To ease the transport to the stomach and thus to reduce the risk of local and oesophageal irritation/adverse experiences (see Section 4.4), the following measures must be taken:

· Fostepor® Once Weekly should only be swallowed upon arising for the day with a full glass of tap water (at least 200 ml).
· Fostepor® Once Weekly tablets must be swallowed whole. The tablets must not be chewed or dissolved in the mouth due to the risk of oropharyngeal ulceration.
· Patients must not lie down until the first meal of the day has been consumed, which should be no earlier than half an hour following the intake of the tablet.
· The patient must not lie down for at least 30 minutes after taking the tablet. 
· Fostepor® Once Weekly must not be taken at bedtime or before getting up.

The patients should receive a supplement of calcium and vitamin D unless sufficient amounts are taken via food (see Section 4.4.).

The recommended dosage is one 70mg tablet once weekly

To permit adequate absorption of alendronate:
Fostepor Once Weekly 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 4.5 ‘Interaction with other medicinal products and other forms of interaction’).

To facilitate delivery to the stomach and thus reduce the potential for local and oesophageal irritation/adverse experiences (see 4.4 ‘Special warnings and precautions for use’):
• Fostepor Once Weekly 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 Fostepor Once Weekly 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 Fostepor Once Weekly.
• Fostepor Once Weekly should not be taken at bedtime or before arising for the day.
Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see 4.4 ‘Special warnings and precautions for use’).

Adults
The recommended dose is one tablet (70 mg) once a week.

Children
Fostepor® Once Weekly has not been studied in children and should not be given to them.

Elderly
In clinical trials no age related difference was shown. Reduction of dose is therefore not required in the elderly.

Renal impairment
Reduction of dose is not required in renally insufficient patients with creatinine clearance >35 ml/min.
Due to lack of experience, Fostepor® Once Weekly is not recommended for patients with creatinine clearance <35 ml/minute.

Alendronate 70 mg has not been investigated for the treatment of glucocorticoid induced osteoporosis.

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.

Use in children (under 18 years): Alendronate has been studied in a small number of patients with osteogenesis imperfecta under 18 years of age. Results are insufficient to support its use in children.

Fostepor Once Weekly has not been investigated in the treatment of glucocorticoid-induced osteoporosis.



Section 4.3

Abnormalities of the oesophagus and other factors which delay oesophageal emptying such as
• stricture or achalasia.
• Lack of ability to stand or sit in upright position for at least 30 minutes
• Inability to stand or sit upright for at least 30 minutes.
• Hypersensitivity to alendronate or to any of the excipients.
• Hypocalcaemia.
• See also 4.4 ‘Special warnings and precautions for use’.


Section 4.4

Alendronate may cause local irritation of mucous membranes in the upper part of the gastrointestinal tract.

Due to the risk of worsening of the pre-existing disease, caution must be exercised when administering alendronate to patients with existing gastrointestinal troubles, such as dysphagia, oesophagus syndrome, gastritis, duodenitis, ulcers or severe gastrointestinal disease like peptic ulcer within the last 12 months, active gastrointestinal haemorrhage or to patients who have been subject to surgical operations in the upper gastrointestinal tract apart from pyloroplastic surgery (see Section 4.3).

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 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 4.3 ‘Contraindications’).

Side effects in the oesophagus, such as oesophagitis, oesophageal ulcer and oesophageal erosion, rarely followed by oesophagus stricture, were reported in patients treated with alendronate. In some patients these effects were severe and required hospitalisation. Consequently, the doctor must be attentive to any sign of oesophagus reaction or symptom indicating oesophageal side effects. The patients must be instructed to discontinue treatment with alendronate and consult their doctor if they develop symptoms of oesophageal irritation, such as dysphagia, pain when swallowing, retrosternal pain, new or intensified heartburn.

The risk of severe side effects in oesophagus seems larger in patients not taking alendronate as prescribed and/or who continue taking alendronate after having developed symptoms indicating irritation of the oesophagus. It is extremely important that the patients receive and understand completely the information on the dosage (see Section 4.2). The patients must be informed that the risk of problems with oesophagus is increased if they do not follow these instructions.

No increased risk was observed in extensive clinical studies, but rare cases (post marketing) of ulcus ventriculi and ulcus duodeni were reported, some of them severe and with complications. Causality cannot be excluded.

If the patients forget to take one tablet, they must be instructed to take the dose in the morning after they have realised the oversight. They must not take two tablets on the same day, but should continue taking one tablet once a week on the day originally chosen.

Alendronate is not recommended for renally insufficient patients with a creatinine clearance <35 ml/min (see Section 4.2).

Causes of osteoporosis other than lack of oestrogen and age should be considered.

Hypocalcaemia should be treated before initiating the alendronate therapy (see Section 4.3). Other disturbances of the mineral metabolism (e.g. vitamin D deficiency and hypoparathyroidism) should also be treated efficiently. In patients with such disturbances serum calcium and symptoms of hypocalcaemia should be monitored during treatment with Fostepor® Once Weekly. Due to the positive effect on the bone mineral density by alendronate, small, asymptomatic reductions of serum calcium and serum phosphate may occur during therapy, especially in patients in glucocorticoid therapy as such patients might have a reduced absorption of calcium.

However, symptomatic hypocalcaemia has been reported rarely. Some cases have been severe and occurred in patients who has an underlying predispose condition (eg. hypoparathyroidism, vitamin D deficiency or calcium malabsorption)
Consequently, it is especially important to ensure a sufficient intake of calcium and vitamin D in patients receiving glucocorticoids.

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

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 intravenous 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.

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).

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 judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

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 4.2 ‘Posology and method of administration’). Patients should be informed that failure to follow these instructions may increase their risk of oesophageal problems.

While no increased risk was observed in extensive clinical trials, there have been rare (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.
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, smoking).
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.

Atypical stress fractures
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 ranged from 18 months to 10 years). The fractures occurred after minimal or no trauma and some patients experienced thigh pain 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.

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 ‘4.8 Undesirable effects’).

The time to onset of symptoms varied from one day to several months after starting treatment. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Patients should be instructed that if they miss a dose of Fostepor Once Weekly, 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 per week, as originally scheduled.

Alendronate is not recommended for patients with renal impairment where GFR is less than 35 ml/min, (see 4.2 ‘Posology and method of administration’).
Causes of osteoporosis other than oestrogen deficiency and ageing should be considered. Hypocalcaemia must be corrected before initiating therapy with alendronate (see 4.3 ‘Contraindications’).

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 Fostepor Once Weekly.

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 alabsorption).

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.

Section 4.5

In case of concomitant administration, food and drinks (including mineral water), calcium supplement, antacids and certain orally administered drugs may affect the absorption of alendronate. Therefore, patients must wait for at least half an hour after the intake of alendronate, before they take other oral drugs (see Section 4.2 and 5.2).

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 4.2 ‘Posology and method of administration’ and 5.2 ‘Pharmacokinetic properties’).

No other clinically significant interactions are expected. Several patients in the clinical trials received oestrogen (intravaginally, transdermally or orally) concomitantly with alendronate. No side effects caused by the co-administration were observed

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 no specific interaction studies have been conducted, alendronate was co-administered in clinical trials with various commonly used medicinal products with no signs of clinical interaction.

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.


Section 4.6

Pregnancy:
The are no adequate data from the use of alendronate in pregnant women.
Animal studies do not indicate a direct harmful effect with respect to pregnancy, embryonal/fetal development, or postnatal development. Alendronate given to pregnant rats caused hypocalcemia-related dystocia (see section 5.3). Based on the indication, alendronate should not be used during pregnancy

Use during pregnancy
Alendronate should not be used during pregnancy. There are no adequate data from the use of alendronate in pregnant women. Alendronate given during pregnancy in rats caused dystocia related to hypocalcemia. Animal studies revealed effects on foetal bone formation (incomplete ossification) at high doses (see 5.3 ‘Preclinical safety data’).

Lactation:
It is unknown whether alendronate is excreted in human breast milk. Based on the indication, alendronate should not be used by breast-feeding women.

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


Section 4.7

No effects on the ability to drive and use machines have been observed.

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 Fostepor Once Weekly may affect some patients' ability to drive or operate machinery. Individual responses to Fostepor Once Weekly may vary. (See 4.8 Undesirable effects).


Section 4.8

The following side effects were reported in clinical trials and/or post marketing:

Common (³1/100, < 1/10):
Gastrointestinal disorders: Abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension *, acid regurgitation.

Musculoskeletal and connective tissue disorders: Pain in bones, muscles or joints.

Nervous system disorders: Headache.

Uncommon (³ 1/1000, <1/100):
General disorders and administration site conditions: Rash, erythema, pruritus

Gastrointestinal disorders: Nausea, vomiting, gastritis, oesophagitis*, oesophagal erosions*, melaena

Rare (³1/10,000, < 1/1000):
General disorders and administration site conditions: Hypersensitivity reactions including urticaria and angiooedema. Rash with photohypersensitivity. Transient symptons as in an acute phase response (myalgia, discomfort and rarely fever) typically at the beginning of therapy

Metabolic and nutrition disorders: Symptomatic hypocalcaemia, often in association with predisposing conditions (see section 4.4)

Gastrointestinal disorders: Oesophagus stricture*, oropharyngeal ulcers*, upper gastrointestinal PUBs (perforation, ulcers, haemorrhage). Causality cannot be excluded.

Eye disorders: Uveitis, scleritis, episcleritis

Isolated cases of serious skin reactions, including Stevens-Johnson’s syndrome and epidermal toxic necrolysis were reported.

* See Section 4.2 and 4.4.

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and/or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids, and poor oral hygiene are also deemed as risk factors (see section 4.4).

Laboratory findings:
In clinical trials an asymptomatic, mild, transient reduction in serum calcium and phosphate was reported in approximately 18% and 10%, respectively, of the patients taking alendronate 10 mg/day, versus approximately 12% and 3%, respectively, in patients taking placebo. However, the incidence of the S-calcium reduction to <8.0 mg/dl (2.0 mmol/l) and of the S-phosphate reduction to £2.0 mg/dl (0.65 mmol/l) was the same in both groups.

The following adverse experiences have also been reported during clinical studies and/or postmarketing use:
[Common (≥1/100, < 1/10), Uncommon (≥1/1000, < 1/100), Rare (≥1/10,000, < 1/1000), Very rare (< 1/10,000 including isolated cases)]

Immune system disorders:
Rare: hypersensitivity reactions including urticaria and angioedema

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

Nervous system disorders:
Common: headache

Eye disorders:
Rare: uveitis, scleritis, episcleritis
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)(see section 4.4)
*See sections 4.2 and 4.4
Skin and subcutaneous tissue disorders:
Uncommon: rash, pruritus, erythema, alopecia
Rare: rash with photosensitivity
Very rare and isolated cases: isolated cases of severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis

Musculoskeletal, connective tissue and bone disorders:
Common: musculoskeletal (bone, muscle or joint) pain
Rare: Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene and smoking are also deemed as risk factors; severe musculoskeletal (bone, muscle or joint) pain (see 4.4 ‘Special warnings and precautions for use’).

General disorders and administration site conditions:
Rare: transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever), typically in association with initiation of treatment.

During post-marketing experience the following reactions have been reported (frequency unknown):
Nervous system disorders: dizziness, dysgeusia
Ear and labyrinth disorders: vertigo
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 alendronate 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.


Section 4.9

Overdosage may cause hypocalcaemia, hypophosphataemia and upper gastrointestinal side effects like stomach troubles, heartburn, oesophagitis, gastritis or gastric ulcer. There is no specific information about treatment of overdosage of alendronate. Milk or antacids should be taken to bind the alendronate. Due to risk of oesophageal irritation, vomiting should not be induced and the patient should remain in upright position.

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.