4.1. Therapeutic indications

FOSAVANCE is indicated for the treatment of postmenopausal osteoporosis in women at risk of vitamin D insufficiency. It reduces the risk of vertebral and hip fractures.

4.2. Posology and method of administration

Posology

The recommended dose is one tablet once weekly.

Patients should be instructed that if they miss a dose of FOSAVANCE they should take one tablet on the morning after they remember. They should not take two tablets on the same day but should return to taking one tablet once a week, as originally scheduled on their chosen day.

Due to the nature of the disease process in osteoporosis, FOSAVANCE is intended for long-term use.

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

Patients should receive supplemental calcium if intake from diet is inadequate (see section 4.4). Additional supplementation with vitamin D should be considered on an individual basis taking into account any vitamin D intake from vitamins and dietary supplements.

FOSAVANCE 70 mg/2,800 IU tablets

The equivalence of intake of 2,800 IU of vitamin D3 weekly in FOSAVANCE to daily dosing of vitamin D 400 IU has not been studied.

FOSAVANCE 70 mg/5,600 IU tablets

The equivalence of intake of 5,600 IU of vitamin D3 weekly in FOSAVANCE to daily dosing of vitamin D 800 IU has not been studied.

Elderly

In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate. Therefore no dose adjustment is necessary for the elderly.

Renal impairment

FOSAVANCE is not recommended for patients with renal impairment where creatinine clearance is less than 35 ml/min, due to lack of experience. No dose adjustment is necessary for patients with a creatinine clearance greater than 35 ml/min.

Paediatric population

The safety and efficacy of FOSAVANCE in children less than 18 years of age have not been established. This medicinal product should not be used in children less than 18 years of age because no data are available for the alendronic acid/colecalciferol combination. Currently available data for alendronic acid in the paediatric population is described in section 5.1.

Method of administration

Oral use.

To permit adequate absorption of alendronate:

FOSAVANCE must be taken with water only (not mineral water) at least 30 minutes before the first food, beverage, or medicinal product (including antacids, calcium supplements and vitamins) of the day. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate (see sections 4.5 and 4.8).

The following instructions should be followed exactly in order to minimise the risk of oesophageal irritation and related adverse reactions (see section 4.4):

• FOSAVANCE should only be swallowed after getting up for the day with a full glass of water (not less than 200 ml).

• Patients should only swallow FOSAVANCE 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 for at least 30 minutes after taking FOSAVANCE and until after the first food of the day.

• FOSAVANCE should not be taken at bedtime or before arising for the day.

4.3. Contraindications

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- 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.

- Hypocalcaemia.

4.4. Special warnings and precautions for use

Alendronate

Upper gastrointestinal adverse reactions

Alendronate can cause local irritation of the upper gastrointestinal mucosa. Because there is a potential for worsening of the underlying disease, caution should be used when alendronate is given to patients with active upper gastrointestinal problems, such as dysphagia, oesophageal disease, gastritis, duodenitis, ulcers, or with a recent history (within the previous year) of major gastrointestinal disease such as peptic ulcer, or active gastrointestinal bleeding, or surgery of the upper gastrointestinal tract other than pyloroplasty (see section 4.3). In patients with known Barrett's oesophagus, prescribers should consider the benefits and potential risks of alendronate on an individual patient basis.

Oesophageal reactions (sometimes severe and requiring hospitalisation), such as oesophagitis, oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture, have been reported in patients receiving alendronate. Physicians should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue alendronate and seek medical attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing or retrosternal pain or new or worsening heartburn (see section 4.8).

The risk of severe oesophageal adverse reactions 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 are 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 with alendronate, there have been rare (post-marketing) reports of gastric and duodenal ulcers, some of which were severe and with complications (see section 4.8).

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.

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 such as pain or discharge, or chronic ear infections.

Musculoskeletal 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 treatment. A subset had recurrence of symptoms when rechallenged with the same medicinal product 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 incomplete femur fracture.

Atypical fractures of other bones

Atypical fractures of other bones, such as the ulna and tibia have also been reported in patients receiving long-term treatment. As with atypical femoral fractures, these fractures occur after minimal, or no trauma and some patients experience prodromal pain prior to presenting with a completed fracture. In cases of ulna fracture, this may be associated with repetitive stress loading associated with the long-term use of walking aids.

Renal impairment

FOSAVANCE is not recommended for patients with renal impairment where creatinine clearance 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.

Hypocalcaemia must be corrected before initiating therapy with FOSAVANCE (see section 4.3). Other disorders affecting mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be effectively treated before starting this medicinal product. The content of vitamin D in FOSAVANCE is not suitable for correction of vitamin D deficiency. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with FOSAVANCE.

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) (see section 4.8).

Colecalciferol

Vitamin D3 may increase the magnitude of hypercalcaemia and/or hypercalciuria when administered to patients with disease associated with unregulated overproduction of calcitriol (e.g. leukaemia, lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.

Patients with malabsorption may not adequately absorb vitamin D3.

Excipients

This medicinal product contains lactose and sucrose. Patients with rare hereditary problems of fructose intolerance, galactose intolerance, total lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Alendronate

If taken at the same time, it is likely that food and beverages (including mineral water), calcium supplements, antacids, and some oral medicinal products will interfere with absorption of alendronate. Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product (see sections 4.2 and 5.2).

Since Non Steroidal Anti-Inflammatory Drug (NSAID) use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.

Colecalciferol

Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g. cholestyramine, colestipol) may impair the absorption of vitamin D. Anticonvulsants, cimetidine and thiazides may increase the catabolism of vitamin D. Additional vitamin D supplements may be considered on an individual basis.

4.6. Fertility, pregnancy and lactation

FOSAVANCE is only intended for use in postmenopausal women and therefore it should not be used during pregnancy or in breast-feeding women.

Pregnancy

There are no or limited amount of data from the use of alendronate in pregnant women. Studies in animals have shown reproductive toxicity. Alendronate given during pregnancy in rats caused dystocia related to hypocalcaemia (see section 5.3). Studies in animals have shown hypercalcaemia and reproductive toxicity with high doses of vitamin D (see section 5.3). FOSAVANCE should not be used during pregnancy.

Breast-feeding

It is unknown whether alendronate/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Colecalciferol and some of its active metabolites pass into breast milk. FOSAVANCE should not be used during breast-feeding.

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

FOSAVANCE has no or negligible direct influence on the ability to drive and use machines. Patients may experience certain adverse reactions (for example, blurred vision, dizziness and severe bone muscle or joint pain (see section 4.8)) that may influence the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are upper gastrointestinal adverse reactions including abdominal pain, dyspepsia, oesophageal ulcer, dysphagia, abdominal distension and acid regurgitation (> 1 %).

Tabulated list of adverse reactions

The following adverse reactions have been reported during clinical studies and/or post-marketing use with alendronate.

No additional adverse reactions have been identified for the combination of alendronate and colecalciferol.

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), not known (cannot be estimated from the available data).

System organ class

Frequency

Adverse reactions

Immune system disorders

Rare

hypersensitivity reactions including urticaria and angioedema

Metabolism and nutrition disorders

Rare

symptomatic hypocalcaemia, often in association with predisposing condition,§

Nervous system disorders

Common

headache, dizziness†

Uncommon

dysgeusia†

Eye disorders

Uncommon

eye inflammation (uveitis, scleritis, or episcleritis)

Ear and labyrinth disorders

Common

vertigo†

Very rare

osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)

Gastrointestinal disorders

Common

abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation

Uncommon

nausea, vomiting, gastritis, oesophagitis*, oesophageal erosions*, melena†

Rare

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

Skin and subcutaneous tissue disorders

Common

alopecia†, pruritus†

Uncommon

rash, erythema

Rare

rash with photosensitivity, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis‡

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal (bone, muscle or joint) pain which is sometimes severe†§

Common

joint swelling†

Rare

osteonecrosis of the jaw‡§; atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

Not known

atypical fractures of other bones

General disorders and administration site conditions

Common

asthenia†, peripheral oedema†

Uncommon

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

§See section 4.4

†Frequency in Clinical Trials was similar in the medicinal product and placebo group.

*See sections 4.2 and 4.4

‡This adverse reaction was identified through post-marketing surveillance. The frequency of rare was estimated based on relevant clinical trials.

Description of selected adverse reactions

Atypical subtrochanteric and diaphyseal femoral fractures

Although the pathophysiology is uncertain, consistent evidence from epidemiological studies suggests an increased risk of atypical subtrochanteric and diaphyseal femoral fractures with long-term bisphosphonate therapy for postmenopausal osteoporosis, particularly beyond three to five years of use. The absolute risk of atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction) remains rare.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Alendronate

Symptoms

Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse reactions, such as upset stomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdose.

Management

No specific information is available on the treatment of overdose with alendronate. In case of overdose with FOSAVANCE, 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.

Colecalciferol

Vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at a dose less than 10,000 IU/day. In a clinical study of healthy adults a 4,000 IU daily dose of vitamin D3 for up to five months was not associated with hypercalciuria or hypercalcaemia.