FOSAMAX 10 mg Merck Sharp & Dhome

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1 FOSAMAX 10 mg Merck Sharp & Dhome 1. NAME OF THE MEDICINAL PRODUCT FOSAMAX* 10 mg 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet of FOSAMAX contains 6.53 or mg of alendronate monosodium salt trihydrate, which is the molar equivalent to 10 mg of free acid. For excipients, see section PHARMACEUTICAL FORM Tablets. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications - Treatment of postmenopausal osteoporosis in order to reduce the risk of vertebral compression fractures and/or hip fractures. - Treatment of glucocorticoid-induced osteoporosis in men and women. 4.2 Posology and method of administration FOSAMAX must be taken at least one half hour before the first food, beverage, or medication of the day with a full glass of plain water only, since other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate (see section 4.5). To facilitate delivery to the stomach and to reduce the potential for local and esophageal irritation/ adverse experiences (see section 4.4): * FOSAMAX should only be swallowed upon arising for the day with a full glass of water. * Patients should not chew the tablet or allow the tablet to dissolve in their mouths because of a potential for oropharyngeal ulceration. * Patients should not lie down until after their first food of the day which should be at least 30 minutes after taking the tablet. * FOSAMAX should not be taken at bedtime or before arising for the day. Use in the elderly: no dosage adjustment is necessary for the elderly. Use in renal impairment: no dosage adjustment is necessary for patients with mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 ml/min). FOSAMAX is not recommended for patients with more severe renal insufficiency (creatinine clearance <35 ml/min) due to lack of experience. Based on known pharmacokinetics of alendronate, no dosage adjustment is necessary for patients with liver function abnormalities. Treatment of osteoporis in postmenopausal woman The recommended dosage is 10 mg once a day. Treatment of glucocorticoid-induced osteoporosis in men and women The recommended dosage is one 5 mg tablet once a day, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is one 10 mg tablet once a day. Use in children This drug has not been studied in children and should not be given to them. 4.3 Contra-indications - Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia - Inability to stand or sit upright for at least 30 minutes - Hypersensitivity to any component of this product - Hypocalcemia (see section 4.4) 4.4 Special warnings and precautions for use FOSAMAX may cause local irritation of the upper gastrointestinal mucosa. Esophageal adverse experiences, such as esophagitis, esophageal ulcers, and esophageal erosions, rarely followed by esophageal stricture or perforation have been reported in patients receiving treatment with FOSAMAX. In some cases these have been severe and required hospitalization.

2 FOSAMAX 10 mg - p.2/7 Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue this drug and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who fail to take FOSAMAX properly and/or who continue to take FOSAMAX after developing symptoms suggestive of esophageal 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 esophageal problems. While no increased risk was observed in extensive clinical trials, there have been rare (post-marketing) reports of gastric and duodenal ulcers, some severe and with complications. However a causal relationship has not been established. Because of possible irritant effects of FOSAMAX on the upper gastrointestinal mucosa and a potential for worsening of the underlying disease, caution should be used when this drug is given to patients with active upper gastrointestinal problems, such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers. Renal insufficiency FOSAMAX is not recommended for patients with renal insufficiency (creatinine clearance <35 ml/min) (see section 4.2). Causes of osteoporosis other than estrogen deficiency, aging and glucocorticoid use should be considered. Impaired calcium and mineral metabolism Hypocalcemia 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. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with FOSAMAX Due to the positive effects of FOSAMAX in increasing bone mineral, decreases in serum calcium and phosphate may occur. These are usually small and asymptomatic. However there have been rare reports of symptomatic hypocalcemia, which have occasionally been severe and often occurred in patients with predisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption). All patients with osteoporosis, especially patients receiving glucocorticoids, should have adequate dietary calcium ( mg/day) and vitamin D in accordance with recommendations of the Food Councel 4.5 Interaction with other medicaments and other forms of interaction If taken at the same time it is likely that calcium supplements and antacids will interfere with absorption of alendronate. Other oral medications may also interfere with absorption. Therefore, patients must wait at least one half hour after taking FOSAMAX before taking any other oral medication. Concomitant use of HRT (estrogen ± progestin) and FOSAMAX was assessed in two clinical studies of one or two years duration in postmenopausal osteoporotic women. Combined use of FOSAMAX 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 No other drug interactions of clinical significance are anticipated based on effects on protein binding, renal excretion, or metabolism of other drugs (see section 5.2), and none have been observed with FOSAMAX in osteoporosis studies in men, postmenopausal women, and glucocorticoid users. 4.6 Pregnancy and lactation Use during pregnancy There are no adequate data from the use of alen-

3 FOSAMAX 10 mg - p.3/7 dronate in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/fetal development, or postnatal development. Alendronate given during pregnancy in rats caused dystocia related to hypocalcemia (see section 5.3). Alendronate should not be used during pregnancy. Use during lactation It is not known whether alendronate is excreted into human breast milk. Alendronate should not be used by breast-feeding women. 4.7 Effects on ability to drive and use machines There is no evidence that FOSAMAX affects the ability to drive or use machines. 4.8 Undesirable effects FOSAMAX has been studied in nine major clinical studies. In studies of up to five years in duration, side effects, which usually were mild, generally did not require discontinuation of therapy. In two threeyear studies of virtually identical design, in postmenopausal women the overall safety profiles of alendronate 10 mg/day and placebo were similar. Two years of safety data are available in both men with osteoporosis and men and women on glucocorticoids. The following adverse experiences have been reported during clinical studies and/or post-marketing use: Common ( 1/100, <1/10) Gastro-intestinal: abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation. Musculoskeletal: musculoskeletal (bone, muscle or joint) pain. Neurological: headache. Uncommon ( 1/1,000, <1/100) Body as a whole: rash, pruritis, erythema. Gastro-intestinal: nausea, vomiting, gastritis, oesophagitis*, oesophageal erosions*, melaena. Rare ( 1/10,000, <1/1,000) Body as a whole: hypersensitivity reactions including urticaria and angioedema. Transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever), typically in association with initiation of treatment. Rash with photosensitivity. Symptomatic hypocalcemia, often in association with predisposing conditions (see section 4.4). Gastro-intestinal: oesophageal stricture*, oropharyngeal ulceration*, upper gastrointestinal PUBs (perforation, ulcers, bleeding), although a causal relationship cannot be ruled out. Special senses: uveitis, scleritis. Isolated cases of severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. * See section 4.4 and section 4.2 Laboratory Test Findings In clinical studies, asymptomatic, mild and transient decreases in serum calcium and phosphate were more commonly observed in patients treated with this drug than in those treated with placebo. However, the incidences of decreases in serum calcium to <2.0 mmol/l and serum phosphate to 0.65 mmol/l were similar in both treatment groups. 4.9 Overdose Hypocalcemia, hypophosphatemia and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage. No specific information is available on the treatment of overdosage with FOSAMAX. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Bisphosphonate, for the treatment of bone diseases ATC Code: M05B A04

4 FOSAMAX 10 mg - p.4/7 Alendronate is abisphosphonate, that, in animal studies, localizes preferentially to sites of bone resorption, specifically under osteoclasts, and inhibits osteoclastic bone resorption with no direct effect on bone formation. In nonclinical studies, alendronate on resorption surfaces is taken up by osteoclasts where it reversibly inhibits their resorption of bone. Since bone formation and bone resorption are coupled, bone formation is also reduced, but less so than resorption, leading to gains in bone mass. During exposure to alendronate, normal bone is formed that incorporates alendronate into its matrix where it is pharmacologically inactive. Alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. In rats the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. Alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia. Osteoporosis in postmenopausal women Osteoporosis is characterized by low bone mass and a consequent increased risk of fracture, usually of the spine, hip or wrist. It occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation, leading to loss of bone mass. In long term treatment of osteoporosis with alendronate 10 mg/day (for up to five years) reduces urinary excretion of markers of bone resorption, including deoxypyridinoline and crosslinked N-telopeptides of type I collagen, by approximately 50% and 70%, respectively to reach levels similar of those seen in healthy premenopausal woman. Similar decreases were seen in patients in osteoporosis prevention studies who received alendronate 5 mg/day. The decrease in the rate of bone resorption, indicated by these markers, was evident as early as one month and at three to six months reached a plateau that is maintained for the entire duration of treatment with FOSAMAX. In osteoporosis treatment studies, alendronate 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50% and total serum alkaline phosphatase, by approximately 25 to 30%, to reach a plateau after 6 to 12 months. In osteoporosis prevention studies alendronate 5 mg/ dag decreased osteocalcine and total serum alkaline phosphatase by approximately 40% and 15% respectively. Treatment Effect on bone mineral density In postmenopausal women with osteoporosis receiving alendronate 10 mg/day, the mean increases in bone mineral density (BMD) of the lumbar spine, femoral neck, and trochanter at three years of treatment are 8.8, 5.9, and 7.8%, respectively, relative to placebo. These increases are significant relative both to baseline and placebo at each measurement site. Total body BMD also increases significantly, suggesting that the increases in bone mass of the spine and hip do not occur at the expense of other skeletal sites. Increases in BMD are evident as early as three months and continued throughout the entire three years of treatment. In the two year extension of these studies, treatment with alendronate 10 mg/ day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine 0,94%: trochanter 0,88%). BMD at the femoral neck, forearm and total body were maintained. Thus alendronate reverses the progression of osteoporosis. Fosamax is equally effective in older (>65 year) and younger (<65 year) patients. Following discontinuation of therapy with alendronate, bone turnover gradually returned toward pretreatment levels, and BMD no longer increased although accelerated bone loss was not observed. These data indicate that daily continuous treatment with alendronate is required to produce progressive increases in bone mass, as seen for the duration of 3-year clinical trials. Effect on fracture incidence Analysis of the data pooled across doses at three

5 FOSAMAX 10 mg - p.5/7 years from the above studies of postmenopausal women with osteoporosis reveals a statistically significant and clinically meaningful 48% reduction in the proportion of patients treated with alendronate experiencing one or more vertebral fractures (3.2%) relative to those treated with placebo (6.2%). Furthermore, of patients who sustained any vertebral fracture, those treated with alendronate experienced less height loss (5.9 mm vs mm) due to a reduction in both the number and severity of fractures. Additionally, analysis of the data pooled across doses of 2.5 mg from five studies of two or three years duration revealed a 29% reduction in non-vertebral fracture incidence (alendronate 9.0% vs. placebo12.6%). The Fracture Intervention Trial (FIT) consisted of two placebo-controlled studies: a three-year study of 2,027 patients who had at least one baseline vertebral (compression) fracture and a four-year study of 4,432 patients with low bone mass but without a baseline vertebral fracture. Of these 4,432 patients, 37% had osteoporosis as defined as a BMD of the femoral neck of at least 2.5 standard deviations below the mean for young, adult women. The Three-Year Study demonstrated statistically significant reductions in the incidence of 1 new vertebral fracture (FOSAMAX 7.9% vs. placebo 15.0%; a 47% reduction). Additionally, a statistically significant reduction was observed in the incidence hip fractures (1.1 vs. 2.2%; a 51% reduction). In the Four-Year Study, analysis of the subgroup of osteoporotic women (femoral neck T-score <=-2.5 at baseline) demonstrated a statistically significant reduction in the incidence of hipfractures (FOSAMAX 1.0% vs. placebo 2.2%, a 56% reduction) and the incidence of 1 vertebral fracture (2.9% vs. 5.8%, a 50% reduction). Bone histology Bone histology in postmenopausal patients with osteoporosis indicates that bone formed during therapy with alendronate is of normal quality. Prevention Prevention of bone loss was demonstrated in both a two- and a three-year study of women years of age who were at least 6 months postmenopausal. As expected, in the placebo-treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, alendronate 5 mg/day effectively prevented bone loss, and induced significant increases in bone mass at each of these sites. The mean percent increases in BMD from baseline at the lumbar spine, femoral neck, trochanter and total body at the end of the two-year study were 3.46%, 1.27%, 2.98% and 0.67%, respectively, and those at the end of the three-year study were 2.89%, 1.10%, 2.71% and 0.32%, respectively. In addition, alendronate 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. alendronate 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover. Bone histology was normal in the 28 patients biopsied at the end of three years who received alendronate at doses of up to 10 mg/day. Treatment of severe osteoporosis in men Even though osteoporosis is less prevalent in men than in postmenopausal women, a significant proportion of osteoporotic fractures occur in men. The prevalence of vertebral deformities appears to be similar in men and women. Treatment of men with osteoporosis with FOSAMAX 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. The efficacy of FOSAMAX 10 mg once daily in men (ages 31 to 87; mean, 63) with osteoporosis was demonstrated in a two-year study. At two years, the mean increases relative to placebo in BMD in men receiving FOSAMAX 10 mg/day were: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6% (all p 0.001). FOSAMAX was effective regardless of age, race, gonadal function,

6 FOSAMAX 10 mg - p.6/7 baseline rate of bone turnover, or baseline BMD. Consistent with much larger studies in postmenopausal women, in these men, FOSAMAX 10 mg/ day reduced the incidence of new vertebral fracture (assessed by quantitative radiography) relative to placebo (0.8% vs. 7.1%, respectively; p=0.017) and, correspondingly, also reduced height loss ( 0.6 vs. 2.4 mm; respectively; p=0.022). Glucocorticoid-Induced Osteoporosis Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs both in males and females of all ages. Patients at increased risk may be defined as those using >7.5 mg/day prednisone (or equivalent) for at least three months. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Alendronate decreases bone resorption without directly inhibiting bone formation. In clinical studies of one year s duration, alendronate 5 and 10 mg/day reduced cross-linked N-telopeptides of type 1 collagen (a marker of bone resorption) by approximately 60% and reduced bone-specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 25 to 30% and 12 to 15%, respectively. As a result of inhibition of bone resorption, alendronate 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1%) and serum phosphate (approximately 2 to 7%). The efficacy of alendronate 5 and 10 mg once daily in men and women receiving glucocorticoids (at lease 7.5 mg/day of prednisone or equivalent) was demonstrated in two one-year studies of virtually identical design. Patients received supplemental calcium and vitamin D. At one year, the mean increases relative to placebo in BMD in patients receiving alendronate 5 mg/day from the combined studies were: lumbar spine, 2.41%: femoral neck, 2.19%: and trochanter, 1.65%. These increases were significant at each site. Total body BMD was maintained with alendronate 5 mg/day indicating that the increase in bone mass of the spine and hip did not occur at the expense of other sites. The increases in BMD with alendronate 10 mg/day were similar to those with alendronate 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with alendronate 10 mg/day were greater than those with alendronate 5 mg/ day at the lumbar spine (4.11% vs, 1.56%) and trochanter (2.84% vs, 1.67%), but not at other sites. Alendronate was effective regardless of dose or duration of glucocorticoid use. In addition, alendronate was similarly effective regardless of age (<65 vs. >65 years), race (Caucasian vs. other races), gender, baseline BMD, baseline bone turnover, and use with a variety of common medications. Bone histology was normal in the 49 patients biopsied at the end of one year who received alendronate at doses of up to 10 mg/day. 5.2 Pharmacokinetic properties Absorption The oral bioavailability of alendronate is 0.7% for doses ranging from 5 to 40 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability in men (0.6%) was similar to that in women. Bioavailability is decreased similarly (by approximately 40%) whether alendronate was administered one or one-half hour before a standardized breakfast. The total bioavailability is reduced to approximately 0.4% under these conditions. In osteoporosis studies, alendronate was effective when administered at least 30 minutes before the first food or beverage of the day (see section 5.1). Bioavailability is negligible whether alendronate is administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduces bioavailability by approximately 60%. In healthy subjects, oral prednisone (20 mg three times daily for five days) did not substantially alter the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).

7 FOSAMAX 10 mg - p.7/7 Distribution Studies in rats show that alendronate transiently distributes to soft tissues following 1 mg/kg IV 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 below detection level(<5 ng/ml). Protein binding in plasma is approximately 78%. Biotransformation There is no evidence that alendronate is metabolized in animals or humans. Elimination Following a single IV dose of [ 14 C]alendronate, approximately 50% of the radioactivity is excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. The remainder of the dose absorbed is presumably taken up by the bone tissue. Following a single 10 mg IV dose, the renal clearance of alendronate was 71 ml/min. Plasma concentrations fell by more than 95% within 6 hours following IV administration. The elimination half-life is estimated to exceed 10 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 is not anticipated to interfere with the excretion of other drugs by those systems in humans. Characteristics in Patients with impaired renal function 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 expected in patients with impaired renal function (see section 4.2). 5.3 Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in rats have shown that treatment with alendronate during pregnancy was associated with dystocia in dams during parturition which was related to hypocalcaemia. In studies, rats given high doses showed an increased incidence of incomplete fetal ossification. The relevance to humans is unknown. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate. The 10 mg tablet also contains carnauba wax. 6.2 Incompatibilities Not applicable. 6.3 Shelf life Two years. The expiry date is printed on the package (in some cases exp followed by month and year). 6.4 Special precautions for storage Store below 30 C in the original packaging. 6.5 Nature and contents of container Boxes with 3 or 5 Aluminum/PVC or Alu/Alu blister strips containing 10 tablets each. 6.6 Instructions for use/handling None. 6.7 Marketing authorization holder Merck Sharp & Dohme B.V. Haarlem 7. MARKETING AUTHORIZATION NUMBER FOSAMAX 10 mg: RVG DATE OF FIRST AUTHORIZATION/RENEWAL OF AUTHORIZATION 01 APR DATE OF (PARTIAL) REVISION OF THE TEXT 09 JUL 2004 *denotes trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA Here above is the latest summary of products characteristics submitted to the Ministry of Health in UAE (March 2007)