ALENDRONIC ACID

For oral use. The recommended dose is one 70 mg tablet per week. To obtain satisfactory absorption of alendronate Alendronic Acid must be taken on an empty stomach immediately on rising in the morning, with plain water only, at least 30 minutes before the first food, drink or other medication of the day.

5). 4). • Alendronic Acid should only be swallowed on arising for the day with a whole glass of water (not less than 200 ml or 7 fl. oz). • Alendronic Acid should be swallowed whole. The tablets should not be chewed, sucked or allowed to dissolve in the mouth on account of the risk of oropharyngeal ulceration.

• Patients should not lie down until after the first meal of the day, which must be at least 30 minutes after taking the tablet. • Patients should not lie down within 30 minutes of taking Alendronic Acid. • Alendronic Acid should not be taken at bedtime or before arising for the day.

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

4). Elderly In clinical trials there was no age-related difference with regard to efficacy or safety profiles of alendronate. Therefore no adjustment of the dose is necessary for elderly patients.

Renal function:

No dose adjustment is necessary in patients with a glomerular filtration rate (GFR) greater than 35 ml/min. Alendronate is not recommended for patients with impaired renal function if the GFR is less than 35 ml/min, as there is no experience of this.

Hepatic function No dose adjustment is necessary.

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. Alendronic acid has not been investigated in the treatment of glucocorticoid –induced osteoporosis.

Summary of the safety profile In a one-year study in post-menopausal women with osteoporosis the overall safety profiles for alendronate once-weekly tablets (n=519) and alendronate 10 mg daily (n=370) were similar. In two three-year studies of almost identical design, with post-menopausal women (alendronate 10 mg: n=196; placebo: n= 397) the overall safety profiles for alendronate 10 mg daily and placebo were similar.

5 The following undesirable effects have also been reported in clinical trials and/or post marketing: 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) , Nervous system disorders: Common: Headache Eye disorders: Rare: Uveitis, scleritis, episcleritis Gastrointestinal disorders: Common: Abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcers*, dysphagia*, abdominal distension, acid regurgitation.

Uncommon:

Nausea, vomiting, gastritis, oesophagitis* oesophageal erosions*, melaena. 4). 4.

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus, erythema. Rare: rash with photosensitivity.

Very rare:

Isolated cases of severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal and connective tissue 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 osteomyelistis). 4). 4). Very rare: osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction) General disorders and administration site conditions: Rare: Transient symptoms as in an acute phase reaction (myalgia, malaise and in rare cases fever) usually in connection with the start of treatment.

Immune system disorders:

Rare: hypersensitivity reactions including urticaria and angioedema. During post-marketing experience the following reactions have been reported (frequency unknown): Nervous system disorders: Dizziness Ear and labyrinth disorders: Vertigo Musculoskeletal and connective tissue disorders: Joint swelling General disorders and administration site conditions Asthenia, peripheral oedema During post-marketing experience the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction) Laboratory values: In clinical trials, asymptomatic, slight and transient decreases in serum calcium and serum phosphate were observed in approx.

18 and 10 % respectively of the patients taking alendronate 10 mg/day versus 12 and 3 % respectively of those taking placebo. 65 mmol/l was comparable in the two groups.

Upper gastrointestinal adverse reactions Alendronate can cause local irritation to the upper gastrointestinal mucosa. 3). In patients with known Barrett’s oesophagus, prescribers should consider the benefits and potential risks of alendronate on an individual patient basis.

Oesophageal side effects (in some cases severe and requiring hospitalisation) such as oesophagitis, oesophageal ulcers or oesophageal erosions, in rare cases followed by oesophageal stricture, have been reported in patients receiving treatment with alendronate.

The physician should therefore be alert to any signs or symptoms of possible oesophageal reaction. The patients should be instructed to discontinue alendronate and seek medical attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing, retrosternal pain or new/worsened heartburn.

The risk of severe oesophageal side effects is thought to be greater in patients who do not take alendronate correctly and/or continue to take alendronate after developing symptoms indicative of oesophageal irritation. 2). Patients should be informed that the risk of oesophageal problems may increase if they do not follow these instructions.

Despite no increased risk having been observed in extensive clinical trials, there have been post-marketing reports of rare cases of gastric and duodenal ulcers, some of them severe and with complications. 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 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, angiogenesis inhibitors, 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.

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

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 re-challenged with the same drug or another bisphosphonate.

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 […]

• Oesophageal abnormalities and other factors that delay oesophageal emptying, such as stricture or achalasia. • Inability to stand or sit upright for at least 30 minutes. • Hypersensitivity to the active substance or to any of the excipients.

• Hypocalcaemia.