OSTAGI®-D3

Composition: Each tablet contains:
Alendronic acid . . . . . . . . . . . . . . . . . . . . . . . . 70 mg
(as sodium alendronate trihydrate . . . . . . . . .91.35 mg)
Cholecalciferol . . . . . . . . . . . . . . . . . . . . .. .2,800 IU
(as Cholecalciferol oily solution 1 M.IU/ g . . . . . 2.8 mg)
Presentation:
1 blister of 4 tablets in a carton box.
Indications:
Ostagi-D3 is indicated for the treatment of osteoporosis in postmenopausal women, the treatment of osteoporosis in men. Ostagi-D3 increases bone mass and prevents fractures, including those of the hip, wrist and spine (vertebral compression fractures) and vitamin D supplementation to the body.
Prevention and treatment of corticosteroid-induced osteoporosis.
Paget’s disease treatment: Paget’s disease where the level of serum alkaline phosphatase is at least twice upper limit of normal, in those who are symptomatic, or who are at risk for future complications of disease.

Additional information

Dosage and administration

Dosage:
The recommended dose is only one tablet once weekly.
Patients should take Ostagi-D3 on the same day of each week.
Patients should be instructed that if they miss a dose of Ostagi-D3, 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.
Elderly: No dose adjustment is necessary in the elderly patients.
Renal impairment:
No dose adjustment is necessary in patients with moderate and mild renal impairment (creatinine clearance from 35 ml/minute to 60 ml/minute).
Ostagi-D3 is not recommended for patients with severve renal impairment (creatinine clearance < 35 ml/minute) due to lack of clinical experience.
Administration:
To permit adequate absorption of alendronate, Ostagi-D3 must be taken in the morning at least 30 minutes before the first food, beverage, or medicinal product of the day with plain water only. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronic acid.
Ostagi-D3 should be swallowed whole with a full glass of water (not less than 200 ml). Patients should not suck or chew the tablet. Patients should sit upright or stand upright for at least 30 minutes after taking Ostagi-D3 to facilitate delivery to the stomach and thus reduce the potential for esophageal irritation (oesophagitis, oesophageal ulcers and oesophageal erosions, perforation). Ostagi-D3 should not be taken at bedtime.

Contraindications

Alendronic acid:
Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.
Inability to stand or sit upright for at least 30 minutes, people with a choking risk on taking medicines.
Patients with upper gastrointestinal problems (dysphagia, oesophageal disease, gastritis, duodenitis, gastroduodenal ulcers).
Hypersensitivity to bisphosphonates or to any of the excipients of the drug.
Hypocalcemia.
Severe renal impairment.
Cholecalciferol:
A known history of hypersensitivity to vitamin D.
Hypercalcemia.
Nephrolithiasis accompanied with hypercalciuria
Primary hyperparathyroidism.

Warnings and precautions for use

Alendronate:
Upper gastrointestinal adverse reactions
Alendronate may cause local irritation of the upper gastrointestinal mucosa. Caution should be used when alendronate is given to patients with active upper gastrointestinal problems, such as dysphagia, oesophageal disease, gastritis, duodenitis, gastroduodenal 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.
Oesophageal reactions (sometimes severe and required hospitalisation), such as oesophagitis, oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture or perforation, have been reported in patients receiving alendronate. Some cases are severe and required hospitalisation. Physicians should therefore be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Ostagi-D3 and seek medical attention if they develop symptoms of dysphagia, pain on swallowing or retrosternal pain or new or worsening heartburn.
The risk of severe oesophageal adverse reactions appears to be greater in patients who lie down after taking Ostagi-D3 or fail to take this medicine with the recommended amount of water, 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.
Although 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.
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 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 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.
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 have hindered normal daily activities. 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.
Renal impairment:
Ostagi-D3 is not recommended for patients with renal impairment where creatinine clearance is less than 35 ml/min.
Bone and mineral metabolism:
Due to the positive effects of alendronate in on 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).
Hypocalcaemia must be corrected before initiating therapy with alendronate. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated before starting this medicinal product.
Patients should be advised to supplement calcium if the daily intake is insufficient.
Caution should be considered in patients with renal insufficiency or kidney stones, heart disease, atherosclerosis, hyperphosphatemia.
Cholecalciferol:
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. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption should not take this medicine.

Recommendation for pregnancy and breastfeeding

Ostagi-D3 is indicated for postmenopausal women, contraindicated for pregnant women or breast-feeding women.

Effects on ability to drive and use machines

There are no studies on the effects of the drug on the driver and the operator of machines, but caution should be exercised as the rare side effects of unreal hearing, visual disturbances may occur.

Interactions, incompatibilities of medicine

Alendronate:
Oestrogen: The safety and efficacy of concurrent use of hormone replacement therapy and alendronate for postmenopausal women has not been established, so it is recommended not to use these two drugs concomitantly.
Milk, calcium supplements, magnesium or aluminum-containing drugs (antacids) may reduce the absorption of alendronate. Therefore, patients should wait at least half an hour after taking alendronate to take any other medication.
Intravenous ranitidine increases the oral bioavailability of alendronate.
Nonsteroidal anti-inflammatory drugs (NSAIDs): Combination with alendronate may increase the risk of gastric ulcer; caution should be used during concomitant use with alendronate.
Iron: Iron-containing drugs reduce the absorption of alendronate.
Aminoglycoside antibiotics increase risk of hypocalcaemia if used concurrently with alendronate.
Cholecalciferol:
Cholecalciferol should not be used concomitantly with cardiac glycosides since the glycosidic toxicity increases due to hypercalcemia, leading to arrhythmias.
Cholecalciferol should not be used concomitantly with corticosteroids because corticosteroids interfere with the effects of vitamin D.
Co-administration of cholecalciferol with cholestyramine, colestipol hydrochloride may decrease the absorption of vitamin D through the gastrointestinal tract.
Co-administration of cholecalciferol with thiazide diuretics for patients with parathyroidism can lead to hypercalcaemia.
Co-administration of cholecalciferol with phenobarbital, phenytoin may reduce plasma vitamin D metabolite levels and increase the conversion of vitamin D into biologically non-active products.

Undesirable effects (ADRs)

The adverse reactions of the drug are mainly caused by alendronate. These reactions are usually mild, and it is not generally necessary to discontinue Ostagi-D3. The most commonly reported adverse reactions are upper gastrointestinal adverse reactions.
Common, ADR > 1/100:
Nervous system: Headache (2.6%), pain (4.1%).
Gastrointestinal: Flatulence (2.6%), acid regurgitation (2%), esophageal ulcer (1.5%), dysphagia, abdominal distension (1%), diarrhoea.
Uncommon, 1/1000 < ADR < 1/100:
Skin: Rash, erythema (rarely).
Gastrointestinal: Gastritis (0.5%).
Rare: ADR < 1/1000:
Allergy to alendronate, in particular, and bisphosphonate, in general.
Unreal hearing, eye disorders. Osteonecrosis of the jaw, temporomandibular joint dysfunction. Femoral fractures may occur due to prolonged use.

Overdose and management

Symptoms of overdose:
Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse reactions, such as gastrointestinal disorders in the stomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdose.
Management:
No specific information is available on the treatment of overdose with alendronate.
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. Dialysis is not effective.

Pharmacodynamic properties

Alendronate: Alendronate is a synthetic aminobisphosphonate, an analogue of pyrophosphate, which acts as a specific inhibitor of osteoclastic bone resorption. Unlike pyrophosphates, but like etidronate and pamidronate, alendronate is not hydrolyzed by phosphatase. Preclinical studies have shown that alendronate is localized preferentially to sites of bone resorption where it inhibits osteoclast activity. Alendronate binds to the bone and its terminal half-life in humans is estimated to exceed ten years, however alendronate still has pharmacological activity when binding to the skeleton. Clinical studies have shown that treatment with alendronate can significantly increase bone mass in the spine bone, femoral neck and trochanter.
Clinical studies in postmenopausal women aged 40 to 85 with osteoporosis (defined as having a low bone mass, BMD at least 2 standard deviation units below the premenopausal mean), showed that the events of vertebral fractures are significantly reduced after 3 years of treatment with alendronate. Bone mineral density (BMD) apparently increased after 3 months of treatment with alendronate and continued throughout the course of the therapy. However, if alendronate therapy is stopped after 1 or 2 years of treatment, increase of bone mass is not maintained. This proves that daily treatment is necessary to maintain the treatment effect.
Cholecalciferol (vitamin D3):
Cholecalciferol (vitamin D3)‘s function is to maintain serum calcium and phosphorus concentrations within the normal range by enhancing the efficiency of the small intestine to absorb these minerals from the diet. Activated forms of cholecalciferol mobilize calcium from the bones into the bloodstream and promote reabsorption of phosphate in the renal tubules and directly affect osteoblast to stimulate bone growth. Activated forms of cholecalciferol have the opposite effect on the formation of parathyroid hormone (PTH).

Pharmacokinetic properties

Alendronate:
Oral alendronate is poorly absorbed. The absorption of alendronate is reduced by food, products containing calcium, or multivalent cations. Oral bioavailability is about 0.4% if alendronate is taken 30 minutes before meals; and almost negligible if taken within 2 hours after meals. Protein binding in human plasma is approximately 78%. The drug is not metabolized; about half of the absorbed alendronate dose is excreted in the urine; the other half remains in the bone for a long time.
Cholecalciferol (vitamin D3):
Cholecalciferol (vitamin D3) is readily absorbed from the small intestine if fat absorption is normal.
After absorption, cholecalciferol enters the blood via chylomicrons of lymph and then associates mainly with a specific alpha-globulin (vitamin D-binding protein). The hydroxylated metabolites of cholecalciferol also circulates associated with the same alpha-globulin.
Cholecalciferol is hydroxylated in the liver to form a 25-hydroxycholecalciferol which is further hydroxylated in the kidney to form a 1, 25-dihydroxycholecalciferol active metabolite and 1, 24, 25-trihydroxy derivatives. The half life of the 25-hydroxycholecalciferol metabolites in the blood ranges from 10 days to 3 weeks and half life of the 1.25-dihydroxycholecalciferol metabolites ranges from 4 to 6 hours.
Vitamin D and its metabolites are mainly excreted through the bile and the faeces with only a small amount appearing in urine.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.