Fosamax Ref.[2470] Active ingredients: Alendronic acid

Fosamax 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 Fosamax is given to patients with active upper gastro-intestinal problems, such as dysphagia, oesophageal disease, gastritis, duodenitis or 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 4.3 ‘Contraindications’). 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 or perforation, have been reported in patients receiving Fosamax. Physicians should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue 'Fosamax' 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 Fosamax properly and/or who continue to take Fosamax 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 (post-marketing) 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 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.

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 bilaterial; 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 bishphosphonate 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 bishphosphonate 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.

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 ‘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.

Fosamax 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, ageing and glucocorticoid use should be considered.

Hypocalcaemia must be corrected before initiating therapy with alendronate (see 4.3 ‘Contra-indications’). 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 Fosamax.

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 hypocalcaemia, 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.

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 Fosamax. Therefore, patients must wait at least 30 minutes after taking Fosamax before taking any other oral medicinal product (see 4.2 ‘Posology and method of administration’ and 5.2 ‘Pharmacokinetic properties’).

No other drug interactions of clinical significance are anticipated. Concomitant use of HRT (oestrogen ± progestin) and Fosamax was assessed in two clinical studies of one or two years duration in post-menopausal osteoporotic women (5.1 ‘Pharmacodynamic properties, concomitant use with oestrogen/hormone replacement therapy (HRT)’). Combined use of Fosamax and HRT resulted in greater increases in bone mass, together with greater decreases in bone turnover, than seen with either treatment alone. In these studies, the safety and tolerability profile of the combination was consistent with those of the individual treatments.

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 Fosamax was used concomitantly with a wide range of commonly prescribed drugs without evidence of clinical adverse interactions (see 5.1 ‘Pharmacodynamic properties’ ‘Concomitant use with oestrogen/hormone replacement therapy (HRT)’).

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 5.3 ‘Preclinical safety data’).

Use during lactation

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

No studies on the effects on the ability to drive and use machines has been performed. However, certain adverse reactions that have been reported with Fosamax may affect some patients' ability to drive or operate machinery. Individual responses to Fosamax may vary (see section 4.8).

Fosamax has been studied in nine major clinical studies (n=5,886). In the longest running trials in post-menopausal women up to five years experience has been collected. Two years safety data are available in both men with osteoporosis and men and women on glucocorticoids.

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

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 (see section 4.4); severe musculoskeletal (bone, muscle or joint) pain (see 4.4 ‘Special warnings and precautions for use’); atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

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

Skin and subcutaneous tissue disorders: alopecia

Musculoskeletal, connective tissue and bone disorders: joint swelling.

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 Fosamax 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.

None known.