Orthocole 5 600 5600 IU Tablet

ORTHOCOLE is indicated in women for the treatment of postmenopausal osteoporosis to reduce the risk of fractures, including those of the hip and spine (vertebral compression fractures) and to help ensure vitamin D adequacy.

Posology
For most osteoporotic patients, the appropriate dose is 70 mg/5 600 IU (one ORTHOCOLE tablet) once weekly. For osteoporotic patients receiving a separate vitamin D supplement (400 IU) daily, the appropriate dose is 70 mg/2 800 IU once weekly. As ORTHOCOLE is not available with the lower (2 800 IU) vitamin D content, another alendronate/colecalciferol product that only contains 2 800 IU vitamin D should be used in this case.

Special populations
No dosage adjustment is necessary for the elderly or for patients with mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 mL/min) (see section 4.3).
Paediatric population
Safety and efficacy in children have not been established (see section 4.3).

Method of administration
ORTHOCOLE must be taken at least one-half hour before the first food, beverage, or medicine of the day with plain water only. Other beverages (including mineral water), food, and some medicines are likely to reduce the absorption of alendronate, an ingredient of ORTHOCOLE (see section 4.5).
To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation, ORTHOCOLE should only be swallowed upon arising for the day with a full glass of water and patients should not lie down for at least 30 minutes and until after their first food of the day. ORTHOCOLE should not be taken at bedtime or before arising for the day.
Failure to follow these instructions may increase the risk of oesophageal adverse experiences (see section 4.4).

Patients should receive supplemental calcium and/or vitamin D, if intake is inadequate (see section 4.4). The medical practitioner should consider the vitamin D intake from vitamins and dietary supplements. ORTHOCOLE is intended to provide a weeku2019s supply of vitamin D based on a daily dose of 800 IU in a single, once weekly dose.

• Hypersensitivity to alendronate, colecalciferol or any of the other excipients of ORTHOCOLE (see section 6.1).
• Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia.
• The inability to stand or sit upright for at least 30 minutes.
• Hypocalcaemia (see section 4.4).
• Severe renal insufficiency (creatinine clearance less than 35 mL/minute).
• Pregnancy and lactation (see section 4.6).
• Paediatric age group.

Alendronate sodium
Upper gastrointestinal adverse reactions
ORTHOCOLE may cause local irritation of the upper gastrointestinal mucosa. Oesophageal adverse experiences, such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some instances followed by oesophageal stricture, have been reported in patients receiving treatment with alendronate as contained in ORTHOCOLE. In some cases, these have been severe and required hospitalisation. Medical practitioners should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue ORTHOCOLE and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe oesophageal adverse experiences appears to be greater in patients who lie down after taking ORTHOCOLE and/or who fail to swallow it with a full glass of water, and/or who continue to take ORTHOCOLE after developing symptoms suggestive of oesophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see section 4.2).

Patients should be instructed that if they miss a dose of ORTHOCOLE, 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.

While no increased risk was reported in clinical trials with alendronate as contained in ORTHOCOLE, there have been reports of gastric and duodenal ulcers, some severe and with complications. Because of possible irritant effects of alendronate, as contained in ORTHOCOLE, on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when ORTHOCOLE is given to patients with active upper gastrointestinal problems, such as dysphagia, oesophageal diseases (including known Barret's oesophagus), gastritis, duodenitis, or ulcers, or with a recent history (within the previous year) of major gastrointestinal diseases such as peptic ulcer, or active gastrointestinal bleeding, or surgery of the upper gastrointestinal tract, other than pyloroplasty.

To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation patients should be instructed to swallow ORTHOCOLE with a full glass of water and not to lie down for at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take ORTHOCOLE at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of oesophageal problems. Patients should be instructed that if they develop symptoms of oesophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking ORTHOCOLE and consult their medical practitioner.

Since non-steroidal anti-inflammatory drug (NSAID) use is associated with gastrointestinal irritation, caution is advised with the concomitant use of ORTHOCOLE and NSAIDs.

Osteonecrosis of the jaw
Localised osteonecrosis of the jaw (ONJ), generally associated with tooth extraction and/or local infection (including osteomyelitis) with delayed healing, has been reported with oral bisphosphonates (see section 4.8). A dental examination with appropriate preventative dentistry should be considered prior to treatment with oral bisphosphonates in patients with poor dental status. Most reported cases of bisphosphonate-associated ONJ have been in cancer patients treated with intravenous bisphosphonates. Known risk factors for ONJ include the potency of the bisphosphonates, route of administration, cumulative dose, a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, invasive dental procedures, poorly fitting dentures and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anaemia, coagulopathy, infection and smoking). Patients who develop ONJ should receive appropriate care by a dental practitioner and discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. Dental surgery may exacerbate the condition.

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 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 medicine or another bisphosphonate.

Atypical fractures of the femur
Atypical, low-energy fractures of the subtrochanteric and proximal femoral shaft have been reported in long-term (usually longer than three years) bisphosphonate-treated patients. Some were stress fractures (some of which were reported as insufficiency fractures) occurring in the absence of apparent trauma. Some patients experienced prodromal pain in the affected area, often associated with imaging features of stress fracture, weeks to months before a complete fracture occurred. Approximately one-third of these fractures were bilateral; therefore, the contralateral femur should be examined in patients who have sustained a femoral shaft stress fracture. Bisphosphonate therapy in patients with stress fractures should be discontinued and they should receive appropriate orthopaedic care. 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.

Bone and mineral metabolism
Causes of osteoporosis other than oestrogen deficiency and aging should be considered. Hypocalcaemia must be corrected before initiating therapy with ORTHOCOLE (see section 4.3). Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. The content of vitamin D in ORTHOCOLE is not suitable for the correction of vitamin D deficiency. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with ORTHOCOLE. 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 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 D 3 may increase the magnitude of hypercalcaemia and/or hypercalciuria when administered to patients with diseases 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 D 3.

Special populations
Elderly patients
No age-related difference is reported in the efficacy or safety profiles of ORTHOCOLE.

Excipients
ORTHOCOLE contains lactose and sucrose. Patients with rare hereditary problems of fructose intolerance, galactose intolerance, total lactase deficiency, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take ORTHOCOLE.

Paediatric population
The safety and efficacy of ORTHOCOLE in children less than 18 years have not been established (see section 4.3).

Alendronate sodium
If taken concomitantly it is likely that food and beverages (including mineral water), calcium supplements, antacids and other oral medicines will interfere with the absorption of alendronate. Therefore, patients should be advised to wait at least 30 minutes after taking ORTHOCOLE before taking any other oral medicine (see section 4.2).
Since non-steroidal anti-inflammatory drug (NSAID) use is associated with gastrointestinal irritation, caution is advised with the concomitant use of ORTHOCOLE and NSAIDs.
No other interactions of clinical significance are anticipated.

According to published information a small number of postmenopausal women in the osteoporosis trials received oestrogen (intravaginal, transdermal, or oral) while taking alendronate. No adverse experiences attributable to their concomitant use were identified. Specific interaction studies were not performed. In postmenopausal osteoporosis studies, alendronate, an ingredient of ORTHOCOLE, was used with a wide range of commonly prescribed medicines without evidence of clinical adverse interactions.

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.

ORTHOCOLE is only intended for use in postmenopausal women and therefore it should not be used during pregnancy or in breast-feeding women (see section 4.3).

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. Studies in animals have shown hypercalcaemia and reproductive toxicity with high doses of vitamin D. ORTHOCOLE 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. ORTHOCOLE 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.

Adverse reactions such as dizziness, blurred vision, severe bone muscle or joint pain (see section 4.8) may affect the ability to drive or use machines.

Summary of the safety profile
Frequently reported adverse reactions are upper gastrointestinal adverse reactions including abdominal pain, dyspepsia, oesophageal ulcer, dysphagia, abdominal distension and acid regurgitation (> 1 %).

Tabulated summary of adverse reactions
Immune system disorders
Frequency unknown: hypersensitivity reactions including urticaria and angioedema
Metabolism and nutrition disorders
Frequency unknown: symptomatic hypocalcaemia, often in association with predisposing conditions (see section 4.4)
Nervous system disorders
Frequent headache
Frequency unknown dizziness, vertigo, dysgeusia
Eye disorders
Frequency unknown eye inflammation (uveitis, scleritis, or episcleritis)
Ear and labyrinth disorders
Less frequent osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)
Gastrointestinal disorders
Frequent abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer, dysphagia (see sections 4.4 and 4.2), abdominal distension, acid regurgitation
Less frequent nausea, gastritis, melena, oropharyngeal ulceration (see sections 4.4 and 4.2), upper gastrointestinal PUBs (perforation, ulcers, bleeding) (see section 4.4)
Frequency unknown vomiting, oesophagitis, oesophageal erosions, oesophageal stricture, oesophageal perforations (see sections 4.4 and 4.2)
Skin and subcutaneous tissue disorders
Less frequent rash, erythema
Frequency unknown pruritus, rash with photosensitivity, alopecia, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Frequent musculoskeletal (bone, muscle or joint) pain
Less frequent atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)
Frequency unknown severe and/or incapacitating bone, joint, and/or muscle pain (see section 4.4), localised osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection, with delayed healing (see section 4.4), joint swelling, low-energy femoral shaft fracture
General disorders and administration site conditions
Frequency unknown transient symptoms as in an acute-phase response (myalgia, malaise, asthenia and fever) typically in association with the initiation of treatment, peripheral oedema
Investigations
Frequency unknown Asymptomatic, mild and transient decreases in serum calcium and phosphate
Paediatric population
No data are available.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on the SAHPRA website.

Alendronate sodium
Symptoms
Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse events, such as upset stomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdosage.
Management
Milk or antacids should be given to bind alendronate. Due to the risk of oesophageal irritation, vomiting should not be induced, and the patient should remain fully upright.

Colecalciferol
Vitamin D toxicity may occur with hypercalcaemia or hypercalciuria. This has not been documented during chronic therapy in generally healthy adults at a dose less than 10 000 IU/day.