Source: Marketing Authorisation Holder Revision Year: 2023 Publisher: Tzamal Bio-Pharma Ltd., 20 Hamagshimim St., Petach-Tikva. Manufacturer: SwissCo Services AG, Sisseln, Switzerland.
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 gastro-intestinal 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 erosions and oesophageal ulcers, 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 (see section 4.8).
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 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 conducted with alendronate tablets, there have been rare (post-marketing) reports of gastric and duodenal ulcers, some severe and with complications (see section 4.8).
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:
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.
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.
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.
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.
Causes of osteoporosis other than oestrogen deficiency and ageing or glucocorticoid use 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 before starting Binosto treatment. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with Binosto 70 mg.
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.
This medicinal product contains 603 mg sodium per dose equivalent to 30 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. Binosto is considered high in sodium. This should be particularly taken into account for those patients on a low sodium diet.
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 and 5.2).
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 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.
There are no or limited 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 hypocalcemia (see section 5.3). Binosto should not be used during pregnancy.
It is unknown whether alendronate /metabolites are excreted into human milk. A risk to the newborns /infants cannot be excluded. Binosto should not be used by breast-feeding women.
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 fetal risk in humans. However, there is a theoretical risk of fetal 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.
Binosto 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.
In a one-year study in post-menopausal women with osteoporosis the overall safety profiles of alendronate 70 mg once weekly (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 reactions 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 10mg/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 distension | 1.0 | 1.4 | 1.0 | 0.8 |
| 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 pain (bone, muscle or joint) | 2.9 | 3.2 | 4.1 | 2.5 |
| muscle cramp | 0.2 | 1.1 | 0.0 | 1.0 |
| Neurological | ||||
| headache | 0.4 | 0.3 | 2.6 | 1.5 |
In a one-year post-authorization safety study the investigators reported related to Binosto, an oral buffered alendronate solution, the following adverse events occurring in ≥0.5% of the patients:
| ONE-YEAR, single arm, observational study in post- menopausal women with osteoporosis | |
|---|---|
| alendronate, oral buffered solution Once weekly 70 mg (n=1028) % | |
| Gastro-intestinal | |
| abdominal pain | 2.0 |
| dyspepsia | 2.7 |
| gastroesophageal reflux disease | 2.4 |
| nausea | 2.2 |
| abdominal distension | 0.6 |
| gastritis | 0.9 |
| Musculoskeletal | |
| musculoskeletal pain (bone, muscle or joint) | 1.2 |
The following adverse reactions have been reported during clinical studies and/or post-marketing use of oral alendronate tablets:
| Adverse reactions | |||||
|---|---|---|---|---|---|
| Very Common (≥1/10) | Common (≥1/100, <1/10) | Uncommon (>1/1,000, <1/100) | Rare (>1/10,000, <1/1,000) | Very Rare (<1/10,000) | |
| Immune system disorders | hypersensitivity reactions including urticaria and angioedema | ||||
| Metabolism and nutrition disorders | symptomatic hypocalcaemia, often in association with predisposing conditions# | ||||
| Nervous system disorders | headache, dizziness§ | dysgeusia§ | |||
| Eye disorders | eye inflammation (uveitis, scleritis, or episcleritis) | ||||
| Ear and labyrinth disorders | vertigo§ | ||||
| Gastrointestinal disorders‡ | abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation | nausea, vomiting, gastritis, oesophagitis*, oesophageal erosions*, melena§ | oesophageal stricture*, oropharyngeal ulceration*, upper gastrointestinal PUBs (perforation, ulcers, bleeding)# | ||
| Skin and subcutaneous tissue disorders | alopecia§, pruritus§ | rash, erythema | rash with photosensitivity, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis+ | ||
| Musculoskeletal, connective tissue and bone disorders | musculoskeletal (bone, muscle or joint) pain, which is sometimes severe#§ | joint swelling§ | Osteonecrosis of the jaw#+, atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)# | Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction) | |
| General disorders and administration site condition | asthenia§, peripheral oedema§ | 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 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 estimated based on relevant clinical trials.
‡ These adverse reactions were identified with the tablet form, and may not all apply to (Binosto) 70 mg, which is taken as a buffered oral solution.
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/
Not applicable.
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