Alendronic acid, colecalciferol.
Each tablet contains: Alendronic acid (as alendronate sodium trihydrate) BP 70 mg, Colecalciferol (Vitamin D3) EP 5,600 IU.
Pharmacology: Pharmacokinetics: Alendronate: Absorption: Relative to an intravenous reference dose, the oral mean bioavailability of alendronate in women was 0.64 % for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Bioavailability was decreased similarly to an estimated 0.46 % and 0.39 % when alendronate was administered one hour or half an hour before a standardized breakfast. In osteoporosis studies, alendronate was effective when administered at least 30 minutes before the first food or beverage of the day.
Bioavailability was negligible whether alendronate was administered with, or up to two hours after, a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60 %.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in oral bioavailability of alendronate (a mean increase ranging from 20 % to 44 %).
Distribution: Studies in rats show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine.
The mean steady-state volume of distribution, exclusive of bone, is at least 28 liters in human. Concentration of alendronate in plasma following therapeutic oral doses are too low for analytical detection (<5 ng/ml).
Protein binding in human plasma is approximately 78 %.
Biotransformation: There is no evidence that alendronate is metabolized in animals or humans.
Elimination: Following a single intravenous dose of [14C] alendronate, approximately 50 % of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the faeces.
Following a single 10 mg intravenous dose, the renal clearance of alendronate was 71 ml/min, and systemic clearance did not exceed 200 ml/min. Plasma concentrations fell by more than 95 % within six hours following intravenous administration. The terminal half-life in humans is estimated to exceed ten years, reflecting release of alendronate from the skeleton. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to interfere with the excretion of other medicinal products by those systems in humans.
Colecalciferol: Absorption: In healthy adult subjects (males and females), following administration of Alendronic acid + Colecalciferol 70 mg/5600 IU after an overnight fast and two hours before a meal, the mean area under the serum-concentration-time curve (AUCO-80 hrs) for vitamin D3 (unadjusted for endogenous vitamin D3 levels) was 490.2 ng.hr/ml. The mean maximal serum concentration (Cmax) of vitamin D3 was 12.2 ng/ml and the median time to maximal serum concentration (Tmax) was 10.6 hours.
Distribution: Following absorption vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose and muscle tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.
Biotransformation: Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.
Elimination: When radioactive vitamin D3 was administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4 % and the mean faecal excretion of radio activity after 4 days was 4.9 %. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent.
The mean half-life of vitamin D3 in the serum following an oral dose of Alendronic acid + Colecalciferol (70 mg/2800 IU) is approximately 24 hours.
Renal Impairment: Preclinical studies show that alendronate that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone update was found after chronic dosing with cumulative intravenous doses up to 35 mg/kg in animals.
Although no clinical information is available, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be excreted in patients with impaired renal function.
Alendronic acid + Colecalciferol is indicated for the treatment of post-menopausal osteoporosis in women who are not receiving vitamin D supplementation and are at risk of vitamin D insufficiency.
Alendronic acid + Colecalciferol reduces the risk of vertebral and hip fractures.
Dosage: The recommended dose is one Alendronic acid + Colecalciferol tablet once weekly.
Patients should be instructed that if they miss a dose of Alendronic acid + Colecalciferol 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, Alendronic acid + Colecalciferol 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 Alendronic acid + Colecalciferol on an individual patient basis, particularly after 5 or more years of use.
Patients should receive supplemental calcium if intake from diet is inadequate. The equivalence of intake of 5600 IU of vitamin D3 weekly in Alendronic acid + Colecalciferol to daily dosing of vitamin D 800 IU has not been studied.
Elderly population: 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: Alendronic acid + Colecalciferol is not recommended for patients with renal impairment where glomerular filtration rate (GFR) is less than 35 mL/min, due to lack of experience. No dose adjustment is necessary for patients with a GFR greater than 35 mL/min.
Paediatric population: The safety and efficacy of Alendronic acid + Colecalciferol in children less than 18 years of age has not been established. Alendronic acid + Colecalciferol should not be used in children less than 18 years of age because no data are available.
Method of Administration: Oral Use: To permit adequate absorption of alendronate: Alendronic acid + Colecalciferol 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.
The following instructions should followed exactly in order to minimize the risk of oesophageal and related adverse reactions: Alendronic acid + Colecalciferol should only be swallowed after getting up for the day with a full glass of water (not less than 200 ml or 7 fl. oz.)
Patients should only swallow Alendronic acid + Colecalciferol whole. Patients should not crush or chew the tablet or allow the tablet to dissolve in their mouth because of potential for oropharyngeal ulceration.
Patients should not lie down until after their first food of the day.
Patients should not lie down for at least 30 minutes after taking Alendronic acid + Colecalciferol.
Alendronic acid + Colecalciferol should not be taken at bedtime or before arising for the day.
Alendronate: Hypocalcaemia, hypophosphatemia and upper gastrointestinal adverse reactions, such as upset stomach, heart burns, oesophagitis, gastritis or ulcer, may result from oral overdose.
No specific information is available on the treatment of overdosage with alendronate. In case of overdose with Alendronic acid + Colecalciferol, milk or antacids should be given to bind alendronate. Owing to the risk of esophageal irritation, vomiting should not be induced and the patient should remain full 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 4,000IU dose of vitamin D3 for up to five months was not associated with hypercalciuria or hypercalcaemia.
Hypersensitivity to the active substances or to any of the excipients.
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.
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. In patients with known Barrett's oesophagus, prescribers should consider the benefits and potential risks of alendronate or an individual patients 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 sign or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue alendronate and seek medicinal attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing or retrostemal pain or new or worsening heartburn.
The risk of severe oesophageal adverse reactions appears to be greater in patients who fails 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 patients. 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.
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 bisphosphonate.
The following risk factors should be considered when evaluating an individuals' risk of developing osteonecrosis of the jaw: Potency of the bisphosphonates (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 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 bisphosphonates 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 bisphosphonates 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.
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. 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: A typical 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 insufficiency: Alendronic acid + Colecalciferol is not recommended for patients with renal impairment where GFR is less than 35 mL/min.
Bone and mineral metabolism: Causes of osteoporosis other than estrogen deficiency and ageing should be considered.
Hypocalcaemia must be corrected before initiating therapy with Alendronic acid + Colecalciferol. Other disorders affecting mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be effectively treated before starting Alendronic Acid + Colecalciferol. The content of vitamin D in Alendronic acid + Colecalciferol is not suitable for correction of vitamin D deficiency. In patients with these condition, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with Alendronic acid + Colecalciferol.
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 occured in patients with predisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption).
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.
Effects on Ability to Drive and Use Machines: Alendronic acid + Colecalciferol has no or negligible direct influence on the ability to drive and use machines. Certain adverse reactions (for example blurred vision, dizziness and severe bone muscle or joint pain) that have been reported with Alendronic acid + Colecalciferol may affect some patients' ability to drive or operate machines.
Alendronic acid + Colecalciferol 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 adequate data from the use of Alendronic acid + Colecalciferol in pregnant women. Animal studies with alendronate do not indicate direct harmful effects with respect to pregnancy, embryofoetal development, or postnatal development. 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.
Breast-feeding: It is not known whether alendronate is excreted into human breast milk. Colecalciferol and some of its active metabolites pass into breast milk.
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. 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.
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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. 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.
Store at temperatures not exceeding 30°C.
M05BB03 - alendronic acid and colecalciferol ; Belongs to the class bisphosphonates, combinations. Used in the treatment of bone diseases.
Tab (white to
grayish white oval engraved "DWP" on one side and
"D3A" on the
other side) 4's.