OSTEOFOS Tablets (Alendronate)

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1 Published on: 10 Jul 2014 OSTEOFOS Tablets (Alendronate) Composition OSTEOFOS 70 Each uncoated tablet contains: Sodium Alendronate, BP, equivalent to Alendronic Acid mg OSTEOFOS 35 Each uncoated tablet contains: Sodium Alendronate, BP, equivalent to Alendronic Acid mg Dosage Form Tablet for oral use. Pharmacology Pharmacodynamics Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Alendronate treatment reduces bone turnover (i.e. the number of sites at which bone is remodelled). In addition, bone formation exceeds bone resorption at these remodelling sites, leading to progressive gains in bone mass. Pharmacokinetics Absorption Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and 2 hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast. A study examining the effect of timing of a meal on the bioavailability of alendronate showed that bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 hours or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies on

2 treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast. Bioavailability was negligible whether alendronate was administered with or up to 2 hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced the bioavailability by approximately 60%. Distribution 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 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/ml) for analytical detection. Protein binding in human plasma is approximately 78%. Metabolism There is no evidence that alendronate is metabolized in animals or humans. Excretion Following a single intravenous dose of 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 (64, 78; 90% confidence interval ), and systemic clearance did not exceed 200 ml/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with alendronate (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract. Special Populations Gender Bioavailability and the fraction of an intravenous dose excreted in urine were similar in men and women. Geriatric Use Bioavailability and disposition (urinary excretion) were similar in elderly and younger patients. No dosage adjustment is necessary in elderly patients. Race Pharmacokinetic differences due to race have not been studied. Renal Impairment Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, 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 expected in patients with impaired renal function. No dosage adjustment is necessary for patients with creatinine clearance of 35 to 60 ml/min. Alendronate sodium is not recommended for patients with creatinine clearance <35 ml/min due to lack of experience with alendronate in renal failure. Hepatic Impairment As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary. Indications

3 Treatment and Prevention of Osteoporosis in Postmenopausal Women In the treatment of osteoporosis, OSTEOFOS increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). Treatment to Increase Bone Mass in Men with Osteoporosis Treatment of Glucocorticoid-induced Osteoporosis In men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density. Treatment of Paget s Disease of the Bone in Men and Women Treatment is indicated in patients with Paget s disease of the bone having alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease. Important Limitations of Use The safety and effectiveness of alendronate for the treatment of osteoporosis are based on clinical data of 4 years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture reevaluated periodically. Dosage And Administration OSTEOFOS must be taken at least one and a half hour before the first food, beverage or medication of the day, with plain water only. Other beverages (including mineral water), food and some medications are likely to reduce the absorption of OSTEOFOS. Waiting less than 30 minutes, or taking OSTEOFOS with food, beverages (other than plain water) or other medications will lessen the effect of OSTEOFOS by decreasing its absorption into the body. OSTEOFOS should only be taken upon arising for the day. To facilitate delivery to the stomach and, thus, reduce the potential for oesophageal irritation, the tablet should be swallowed with a full glass of water (6 8 oz.). Patients should swallow the tablet whole and should not crush or chew the tablet or allow the tablet to dissolve in mouth because of a potential for oropharyngeal ulceration. Patients should not lie down for at least 30 minutes and until after their first food of the day. OSTEOFOS 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. Patients should receive supplemental calcium and vitamin D, if dietary intake is inadequate. Patients at increased risk for vitamin D insufficiency (e.g. over the age of 70 years, nursing home-bound, or chronically ill) may need vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. Treatment of Osteoporosis in Postmenopausal Women The recommended dosage is one 70 mg tablet once weekly; or, one 10 mg tablet once daily. Treatment to Increase Bone Mass in Men with Osteoporosis The recommended dosage is

4 one 70 mg tablet once weekly; or, one 10 mg tablet once daily. Prevention of Osteoporosis in Postmenopausal Women The recommended dosage is one 35 mg tablet once weekly; or, one 5 mg tablet once daily. Treatment of Glucocorticoid-induced Osteoporosis in Men and Women The recommended dosage is one 5 mg tablet once daily except for postmenopausal women not receiving oestrogen, for whom the recommended dosage is one 10 mg tablet once daily. Paget s disease of the Bone in Men and Women The recommended treatment regimen is 40 mg once a day for 6 months. Re-treatment of Paget's Disease Re-treatment with alendronate may be considered, following a 6-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be measured periodically. Re-treatment may also be considered in those who failed to normalize their serum alkaline phosphatase. Administration Instructions for Missed Doses If a once-weekly dose of alendronate tablets is missed, patient should take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day. Contraindications Abnormalities of the oesophagus causing delay in oesophageal emptying such as stricture or achalasia. Inability to stand or sit upright for at least 30 minutes. Hypersensitivity to any component of this product. Hypersensitivity reactions, including urticaria and angiooedema, have been reported. Hypocalcaemia. Warnings And Precautions General Upper Gastrointestinal Adverse Reactions Alendronate, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and 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 known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis, or ulcers) or with a recent history (within the previous year) of major gastrointestinal disease such as peptic ulcer, or active gastro-intestinal bleeding, or surgery of the upper gastro-intestinal tract other than pyloroplasty. Oesophageal adverse experiences, such as oesophagitis, oesophageal ulcers and oesophageal erosions, occasionally with bleeding and rarely followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with alendronate. In some cases, these have been severe and required hospitalization. Physicians should

5 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 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 alendronate and/or who fail to swallow it with the recommended amount of water, and/or who continue to take alendronate 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. In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate should be used under appropriate supervision. There have been postmarketing reports of gastric and duodenal ulcers, some severe and with complications, although no increased risk was observed in controlled clinical trials. Mineral Metabolism Hypocalcaemia must be corrected before initiating therapy with alendronate. Other disorders affecting mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with alendronate. Presumably due to the effects of alendronate on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget s disease, in whom the pre-treatment rate of bone turnover may be greatly elevated and in patients receiving glucocorticoids, in whom calcium absorption may be decreased. 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 especially important in patients with Paget s disease of the bone and in patients receiving glucocorticoids. Musculoskeletal Pain In postmarketing experience, severe and, occasionally, incapacitating bone, joint and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis. This category of drugs includes alendronate. Most of the patients were postmenopausal women. The time to onset of symptoms varied from 1 day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when re-challenged with the same drug or another bisphosphonate. In placebo-controlled clinical studies of alendronate, the percentages of patients with these symptoms were similar in the alendronate and placebo groups. Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, has been reported in patients taking bisphosphonates. Known risk factors for ONJ include invasive dental procedures (e.g. tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids, smoking, angiogenesis inhibitors), poor oral hygiene, comorbid disorders (e.g. periodontal and/or other pre-existing dental disease, poor oral hygiene, dental trauma, anaemia, coagulopathy, infection, ill-fitting dentures), potency of the bisphosphonate (highest for zoledronic acid), route of administration, and cumulative dose in cancer patients. The risk of ONJ may increase with duration of exposure to bisphosphonates. While on treatment, patients should avoid invasive dental procedures if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. The clinical judgement of the treating physician should guide the

6 management plan of each patient, based on individual benefit/risk assessment. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis. Patients who develop ONJ while on bisphosphonate therapy should receive care from an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. A dental examination with appropriate preventive dentistry should be considered prior to treatment with oral bisphosphonates in patients with poor dental status. Osteonecrosis of the external auditory canal Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with longterm 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. Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no impact to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Subjects presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis. 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. 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. Renal Impairment Alendronate is not recommended for patients with creatinine clearance <35 ml/min. Glucocorticoid-induced Osteoporosis The risk versus benefit of alendronate for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established. Before initiating treatment, the gonadal hormonal status of both men and women should be ascertained and appropriate replacement considered. A bone mineral density measurement should be made at the initiation of therapy and repeated after 6 12 months of combined alendronate and glucocorticoid treatment. Skin Reactions In post-marketing experience, there have been rare reports of severe skin reactions including Stevens Johnson syndrome and toxic epidermal necrolysis. Laboratory Test Findings In clinical studies, asymptomatic, mild and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to <8.0 mg/dl (2.0 mmol/l) and serum phosphate

7 to <2.0 mg/dl (0.65 mmol/l) were similar in both treatment groups. 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 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. Effects on Ability to Drive and Use Machines Alendronate has no or negligible direct influence on the ability to drive and use machines. However, certain adverse reactions that have been reported with alendronate may affect some patients' ability to drive or operate machinery. Individual responses to alendronate may vary. Drug Interactions Calcium Supplements/Antacids It is likely that calcium supplements, antacids and or oral medications containing multivalent cations will interfere with the absorption of alendronate. Therefore, patients must wait at least one-half hour after taking alendronate before taking any other oral medications. AspirinIn clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate greater than 10 mg and aspirin-containing products. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Alendronate may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2,027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate 5 mg or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate. Oestrogen/Hormone Replacement Therapy (HRT) Concomitant use of HRT (oestrogen ± progestin) and alendronate was assessed in two clinical studies of 1 or 2 years duration in postmenopausal osteoporotic women. Combined use of alendronate and HRT resulted in greater increases in bone mass, together with greater decreases in bone turnover, than seen with either treatment alone. In these studies, the safety and tolerability profile of the combination was consistent with those of the individual treatments. Renal Impairment Alendronate is not recommended for patients with more severe renal impairment (creatinine clearance <35 ml/min) due to the lack of experience with alendronate in renal failure. No dosage adjustment is necessary for patients with mild-t- -moderate renal impairment (creatinine clearance of 35 to 60 ml/min). Hepatic Impairment As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary. Pregnancy Pregnancy Category C There are no studies in pregnant women. Alendronate should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and the foetus. Bisphosphonates are incorporated into the bone matrix, from

8 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 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. Lactation It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alendronate is administered to nursing mothers. Paediatric Use Alendronate is not indicated for use in children. Geriatric Use No overall differences in efficacy or safety were observed between older and younger patients, but the greater sensitivity of some older individuals cannot be ruled out. Undesirable Effects In a 1-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 3-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 experiences reported as possibly, probably or definitely drug-related are presented below if they occurred in 1% in either treatment group in the 1-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 3-year studies: 1-Year Study 3-Year Studies ALN 70 mg (n=519) % ALN 10 mg (n=370) % ALN 10 mg (n=196) % Placebo (n=397) % Gastrointestinal disorders Abdominal pain Dyspepsia Acid regurgitation Nausea Abdominal distention Constipation Diarrhoea Dysphagia Flatulence Gastritis Gastric ulcer Oesophageal ulcer Vomiting

9 Musculoskeletal, connective tissue and bone disorders Musculoskeletal (bone, muscle or joint) pain Muscle cramp Nervous system disorders Headache Dizziness Special Senses Taste perversion The following adverse experiences have been reported during clinical studies and/or postmarketing use: Immune System Disorders Rare: Hypersensitivity reactions, including urticaria and angio-oedema. Transient symptoms as in an acute-phase response (myalgia, malaise and, rarely, fever), typically in association with initiation of treatment. Metabolism and Nutrition Disorders Rare: Symptomatic hypocalcaemia, often in association with predisposing conditions Nervous System Disorders Common: Headache, dizziness Uncommon: Dysgeusia Eye Disorders Uncommon: Eye inflammation (uveitis, scleritis, 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, melaena, gastroesophageal reflux disease Rare: Oesophageal stricture, oropharyngeal ulceration, upper gastrointestinal PUBs (perforation, ulcers, bleeding), although a causal relationship cannot be ruled out. 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 Special Senses Rare: Taste perversion Musculoskeletal, Connective Tissue and Bone Disorders Very common: Musculoskeletal (bone, muscle or joint) pain which is sometimes severe Common: Joint swelling Rare: ONJ; severe musculoskeletal (bone, muscle or joint) pain; atypical subtrochanteric and diaphyseal femoral

10 fractures (bisphosphonate class adverse reaction) 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. During postmarketing experience, the following reactions have been reported (frequency unknown): Nervous System Disorders Dizziness, dysgeusia Skin and Subcutaneous Tissue Disorders Alopecia Musculoskeletal, Connective Tissue and Bone Disorders Joint swelling General Disorders and Administration Site Conditions Asthenia, peripheral oedema Special Senses Cholesteatoma of the external auditory canal (focal osteonecrosis) In post-marketing analysis, asthma exacerbations have been reported due to hypersensitivity. Atypical and diaphyseal femoral fractures have also been noted in post-marketing analysis. If you experience any side effects, talk to your doctor or pharmacist or write to You can also report side effects directly via the national pharmacovigilance program of India by calling on By reporting side effects you can help provide more information on the safety of this product. Overdosage No specific information is available on the treatment of overdosage with alendronate. Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse events, such as upset stomach, heartburn, oesophagitis, gastritis or ulcer, may result from oral overdosage. 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. Dialysis would not be beneficial. Storage And Handling Instructions Store in a well-closed container at room temperature. Packaging Information OSTEOFOS 70 is available in a blister pack of 4 tablets. OSTEOFOS 35 is available in a blister pack of 4 tablets. Last updated: Apr 2018 Last reviewed: Apr 2018 OSTEOFOS Tablets Source URL: