英文药名: Actonel(Risedronate Sodium Tablets)

中文药名: 利塞膦酸钠片

品牌药生产厂家: Sanofi Aventis

药品名称和成分

通用名称： 利塞膦酸钠片
英文名称： Risedronate Sodium Tablets
本品主要成份为利塞膦酸钠
化学名称： 2-(3-吡啶基)-1-羟基乙烷-1，1-双膦酸单钠盐二倍半水合物。
本品为白色薄膜衣片，除去包衣后显白色。
适应症

本品用于治疗和预防绝经后妇女的骨质疏松症。
规格

5mg（以C7H10NNaO7P2计）
用法用量

口服用药，需至少餐前30分钟直立位服用，一杯（200ml左右）清水送服，服药后30分钟内不宜卧床。用量为一日一次，一次5mg（一片）。
如果您有任何疑问，请遵医嘱。
不良反应

1、消化系统 可引起上消化道紊乱，表现为吞咽困难、食道炎、食道或胃溃疡，还可以引起腹泻、腹痛、恶心、便秘等；
其他如流感样综合征、头痛、头晕、皮疹、关节痛等。
禁忌

以下患者禁用
1、已知对本品过敏者；
2、低钙血症患者；
3、30分钟内难以坚持站立或端坐位者。
孕妇及哺乳期妇女用药

孕妇用药的安全有效性尚未确立，除非疾病本身对母子的危害性更大并无其他更安全药物替代时，才在妊娠期使用本品。
本品对哺乳婴儿有严重的不良反应，哺乳期妇女应停药或停止哺乳。
儿童用药

儿童用药的安全有效性尚未确立。
老年患者用药

临床试验资料表明，老年人和年轻人在服用本品时无安全性和有效性上的差异，但不排除老年人个体对本品具有高敏性。
注意事项

1、服药后2小时内，避免食用高钙食品（例如牛奶或奶制品）以及服用补钙剂或含铝、镁等的抗酸药物。
2、不宜与阿司匹林或非甾体抗炎药同服。
3、重度肾功能损害者慎用本品。
4、饮食中钙、维生素D摄入不足者，应加服这些药品。
5、勿嚼碎或吸吮本品。
药物相互作用

没有有关本品特殊的药物间相互作用的报道。本品不被代谢，也不诱导或抑制肝细胞色素酶P450。
钙剂/抗酸剂 本品与钙剂、抗酸剂以及含二价阳离子的口服制剂同服，会影响本品的吸收。
激素替代治疗 如运用得当，本品可与激素联合使用。
阿司匹林/非甾体抗炎药 在5700名病人参加的本品III期临床试验中，31％病人服用阿司匹林，其中24％为规律服用，48％的病人服用了非甾体类抗炎药，其中21％为规律服用，结果显示服用阿司匹林/非甾体抗炎药的病人中，上消化道不良反应的发生率，本品组（24.5%）与安慰剂组（24.8%）相似。
H2－受体阻滞剂和质子泵抑制剂 在上述同一试验中， 21%病人服用了H2－受体阻滞剂和质子泵抑制剂，这些病人中，上消化道副反应的发生率，本品组与安慰剂组相似。
药物过量

过量使用可能会引起血钙、磷下降，还会出现低血钙症状。牛奶或含钙的抗酸剂可以减少本品的吸收，洗胃可以清除未吸收的药物，静脉注射钙制剂，可减轻低血钙症状。
药理毒理

药理作用：
利塞膦酸钠能够与骨中羟磷灰石结合，具有抑制骨吸收的作用。在细胞水平，本品抑制破骨细胞。破骨细胞通常存在于骨表面上，但不具有明显的吸收活性。对大鼠、狗、小猪进行组织形态测定，发现本品可减少骨转换（活化频率，即骨组织重构部位被活化的速率）和骨再塑部位的吸收。
动物试验提示，本品可抑制骨质疏松模型大鼠和小型猪的破骨细胞，抑制骨吸收。大鼠和小猪分别经口给予本品（按体表面积折算，剂量分别为人用剂量5mg/m2 的4和25倍，计算方法下同），骨量和骨生物力学强度呈剂量依赖性增加，骨密度的增加与骨生物力学强度呈现正相关，对骨结构和骨矿化无明显影响。狗经口给予本品（剂量分别为人用剂量的0.35～1.4倍），可促进骨更新单元水平上的骨平衡。狗经口给予本品1mg/kg/天（约为人用剂量的5倍），可延迟骨折愈合。这种作用与其他二膦酸盐化合物相似，但在0.1mg/ kg/天的剂量下不发生。大鼠本品治疗后对骨骼进行组织检查，结果在高剂量（5mg/kg/天，皮下注射）下也没有影响骨矿化，也未出现骨软化。
毒理研究
遗传毒性：本品在沙门氏伤寒菌及大肠杆菌体外回复突变试验（Ames试验）、哺乳动物细胞基因突变试验（CHO/HPRT）、大鼠肝细胞程序外DNA合成试验、大鼠骨髓细胞微核试验中未见基因毒性。CHO细胞染色体裂变试验中，浓度达到细胞毒水平时（>675mcg/ml，存活率6%～7%）出现阳性结果，但在细胞存活率达29％的剂量水平时，未发现染色体损伤。
生殖毒性：雌性大鼠经口给予本品16mg/kg/天（按体表面积折算，相当于人用剂量30mg/天的5.2倍，下同），排卵受到抑制；剂量为7mg/kg/天（相当于人用剂量的2.3倍），着床减少。雄性大鼠经口给予本品40mg/kg/天，可见睾丸和附睾萎缩、炎性细胞浸润；大鼠连续13周经口给予本品16mg/kg/天，也可见睾丸萎缩；犬连续13周经口给予本品8mg/kg/天（相当于人用剂量的8倍），可见中度至重度的精子生成障碍。这些变化随给药剂量的增加和给药时间延长而趋严重。
妊娠期大鼠经口给予本品，剂量≥16mg/kg/天（相当于人用剂量的5.2倍）时，胎鼠成活率降低；在80mg/kg/天的剂量下，胎仔体重下降；在7.1mg/kg/天剂量下，见胸骨或颅骨骨化数明显增高；在≥16mg/kg/天剂量下，胸骨未骨化或骨化不完全均明显增加；在≥3.2mg/kg/天剂量下，可见胚胎腭裂发生率下降，但该发现与临床的相关性尚不清楚。妊娠家兔经口给予本品，剂量达10mg/kg/天（相当于人用剂量的6.7倍）时，未发现对胚胎骨化产生影响，但14窝中有1窝流产，另外1窝早产分娩。
与其他二膦酸类化合物类似，大鼠在交配期与妊娠期给药，剂量低至3.2mg/kg/天（相当于人用剂量的1倍）可致亲代动物分娩期低血钙症和死亡。此外，本品能在大鼠乳汁中分泌。
致癌性：在104周的致癌研究中，大鼠经口给予本品达24mg/kg/天，未发现明显因药物引起的肿瘤。试验中，雄鼠高剂量组（24mg/kg/天）因毒性反应较大，于第93周时停止试验。在大鼠80周的致癌研究中，本品给药剂量达32mg/kg/天时未发现明显因药物引起的肿瘤。
药代动力学

据文献报道，本品的药代动力学特点如下：
吸收 :本品口服后由上消化道迅速吸收，血药浓度达峰时间（Tmax）约为服药后1小时，在一定剂量范围内（单剂量给药：2.5～30mg、多剂量给药：2.5～5mg），吸收呈剂量依赖性。连续用药57天内可达到稳态血浆浓度。利塞膦酸钠片的平均绝对口服生物利用度为0.63%（90%置信限：0.54％～ 0.75％），与食物同服时生物利用度降低。与空腹给药相比，早餐前半小时或晚餐后2小时给药，吸收减少55％；早餐前1小时给药，吸收减少30％。本品在早餐前至少30分钟给药是有效的。
分布:人体平均稳态分布容积为6.3L/kg。人血浆蛋白结合率约为24%。给大鼠和狗静脉注射单剂量14C标记的本品，吸收量的大约60%分布到骨组织，其余随尿液排出，软组织分布极少，大鼠经多次灌胃后，大约有0.001%～0.01%的本品分布到软组织。
代谢: 本品在体内无明显代谢。
清除 口服给药后，吸收量的约一半在24小时内随尿排出，未吸收的药物以原型随粪便排出。其平均肾清除率为105ml/分，与肌酐清除率之间呈线性关系，而无剂量依赖性。终末半衰期（t1/2）达480h，代表本品从骨组织的解离速率。
特殊人群的药代动力学
儿童: 本品尚未在18岁以下患者中进行药代动力学研究。
性别: 本品的口服生物利用度和药代动力学基本上没有性别差异。
老年: 老年患者（＞60岁）和年轻患者具有相似的生物利用度，因此老年患者不需调整剂量。
肾功能不全: 本品主要以原形经肾排泄。与肾功能正常的人相比，肌酐清除率约为30ml/分的患者，本品的肾清除率约减少70%。严重肾功能损害（肌酐清除率＜30ml/分）的患者慎用本品。肌酐清除率≥30ml/分的患者不需要调整剂量。
肝功能不全: 尚未在肝功能损害的患者中评价过本品的安全性和有效性。
贮藏

密封，凉暗（避光并不超过20℃）处保存。请置于儿童不易拿到处。

DESCRIPTION
ACTONEL (risedronate sodium tablets) is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each ACTONEL tablet for oral administration contains the equivalent of 5, 30, or 35 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. The empirical formula for risedronate sodium hemi-pentahydrate is C 7 H 10 NO 7 P 2 Na ·2.5 H 2 O. The chemical name of risedronate sodium is [1-hydroxy-2-(3-pyridinyl) ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following:
Molecular Weight:

Anhydrous:305.10

Hemi-pentahydrate:350.13

Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.

Inactive Ingredients:
Crospovidone, ferric oxide red (35-mg tablets only), ferric oxide yellow (5 and 35-mg tablets only), hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide.

CLINICAL PHARMACOLOGY
Mechanism of Action:
ACTONEL has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, ACTONEL inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g., lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that ACTONEL treatment reduces bone turnover (activation frequency, i.e., the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

Pharmacokinetics:
Absorption:
Absorption after an oral dose is relatively rapid (t max ~1 hour) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, 2.5 to 30 mg; multiple dose, 2.5 to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30-mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution. The extent of absorption of a 30-mg dose (three 10-mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. ACTONEL is effective when administered at least 30 minutes before breakfast.

Distribution:
The mean steady-state volume of distribution is 6.3 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [ 14 C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.

Metabolism:
There is no evidence of systemic metabolism of risedronate.

Elimination:
Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min (CV = 34%) and mean total clearance is 122 mL/min (CV = 19%), with the difference primarily reflecting nonrenal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. Once risedronate is absorbed, the serum concentration-time profile is multi-phasic, with an initial half-life of about 1.5 hours and a terminal exponential half-life of 480 hours. This terminal half-life is hypothesized to represent the dissociation of risedronate from the surface of bone.

Special Populations:
Pediatric:
Risedronate pharmacokinetics have not been studied in patients <18 years of age.

Gender:
Bioavailability and pharmacokinetics following oral administration are similar in men and women.

Geriatric:
Bioavailability and disposition are similar in elderly (>60 years of age) and younger subjects. No dosage adjustment is necessary.

Race:
Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency:
Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance >/=30 mL/min.

Hepatic Insufficiency:
No studies have been performed to assess risedronate's safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (<0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.

Pharmacodynamics:
Treatment and Prevention of Osteoporosis in Postmenopausal Women:
Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist.

The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. Osteoporosis occurs in both men and women but is more common among women following menopause. In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly-formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of bone fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50 year-old women will experience an osteoporosis-related fracture during their remaining lifetimes. After experiencing 1 osteoporosis-related fracture, the risk of future fracture increases 5-fold compared to the risk among a non-fractured population.

ACTONEL treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of ACTONEL to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone specific alkaline phosphatase (a marker of bone formation). At the 5-mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing daily versus weekly oral dosing regimens of ACTONEL for the treatment of osteoporosis in postmenopausal women, ACTONEL 5-mg daily and ACTONEL 35-mg once a week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the ACTONEL 5-mg daily and ACTONEL 35-mg once a week groups, respectively. ACTONEL is not an estrogen and does not have the benefits and risks of estrogen therapy.

As a result of the inhibition of bone resorption, asymptomatic and usually transient decreases from baseline in serum calcium (<1%) and serum phosphate (<3%) and compensatory increases in serum PTH levels (<30%) were observed within 6 months in patients in osteoporosis clinical trials. There were no significant differences in serum calcium, phosphate, or PTH levels between the ACTONEL and placebo groups at 3 years. In a 1-year study comparing daily versus weekly oral dosing regimens of ACTONEL in postmenopausal women, the mean changes from baseline at 12 months were similar between the ACTONEL 5-mg daily and ACTONEL 35-mg once a week groups, respectively, for serum calcium (0.4% and 0.7%), phosphate (-3.8% and -2.6%) and PTH (6.4% and 4.2%).

Glucocorticoid-Induced Osteoporosis:
Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs in both males and females of all ages. The relative risk of a hip fracture in patients on >7.5 mg/day prednisone is more than doubled (RR = 2.27); the relative risk of vertebral fracture is increased 5-fold (RR = 5.18). Bone loss occurs most rapidly during the first 6 months of therapy with persistent but slowing bone loss for as long as glucocorticoid therapy continues. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. ACTONEL decreases bone resorption without directly inhibiting bone formation.

In two 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, ACTONEL 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone resorption), and serum bone specific alkaline phosphatase (a marker of bone formation) by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy.

Paget's Disease:
Paget's disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disordered bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.

Clinical manifestations of Paget's disease range from no symptoms to severe bone pain, bone deformity, pathological fractures, and neurological disorders. Serum alkaline phosphatase, the most frequently used biochemical marker of disease activity, provides an objective measure of disease severity and response to therapy.

In pagetic patients treated with ACTONEL 30 mg/day for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine (markers of bone resorption). Radiographic structural changes of bone lesions, especially improvement of a majority of lesions with an osteolytic front in weight-bearing bones, were also observed after ACTONEL treatment. In addition, histomorphometric data provide further support that ACTONEL can lead to a more normal bone structure in these patients.

Radiographs taken at baseline and after 6 months from patients treated with ACTONEL 30 mg daily demonstrate that ACTONEL decreases the extent of osteolysis in both the appendicular and axial skeleton. Osteolytic lesions in the lower extremities improved or were unchanged in 15/16 (94%) of assessed patients; 9/16 (56%) patients showed clear improvement in osteolytic lesions. No evidence of new fractures was observed.

CLINICAL STUDIES
Treatment of Osteoporosis in Postmenopausal Women:
The fracture efficacy of ACTONEL 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (ACTONEL 5 mg, n = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (ACTONEL 5 mg, n = 821). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and therefore, had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in VERT MN, and 2.5 in VERT NA, with a broad range of baseline bone mineral density (BMD) levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low vitamin D levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 IU/day.

Positive effects of ACTONEL treatment on BMD were also demonstrated in each of 2 large, randomized, placebo-controlled trials (BMD MN and BMD NA) in which almost 1200 postmenopausal women (ACTONEL 5 mg, n = 394) were recruited on the basis of low lumbar spine bone mass (more than 2 SD below the premenopausal mean) rather than a history of vertebral fracture.

ACTONEL 35-mg once a week (n = 485) was shown to be therapeutically equivalent to ACTONEL 5-mg daily (n = 480) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 4.0% (3.7, 4.3; 95% confidence interval [CI]) in the 5-mg daily group (n = 391) and 3.9% (3.6, 4.3; 95% CI) in the 35-mg once a week group (n = 387) and the mean difference between 5 mg daily and 35 mg weekly was 0.1%(-0.42, 0.55; 95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites.

The safety and efficacy of once weekly ACTONEL 35 mg in women without osteoporosis are currently being studied, but data are not yet available.

Effect on Vertebral Fractures:
Fractures of previously undeformed vertebrae (new fractures) and worsening of pre-existing vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (i.e., clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient's first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. ACTONEL 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 1). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population.

Table 1
The Effect of ACTONEL on the Risk of Vertebral Fractures

	Proportion of Patients with Fracture (%) a
VERT NA	Placebo n = 678	ACTONEL 5 mg n = 696	Absolute Risk Reduction (%)	Relative Risk Reduction (%)
New and Worsening
0 - 1 Year	7.2	3.9	3.3	49
0 - 2 Years	12.8	8.0	4.8	42
0 - 3 Years	18.5	13.9	4.6	33
New
0 - 1 Year	6.4	2.4	4.0	65
0 - 2 Years	11.7	5.8	5.9	55
0 - 3 Years	16.3	11.3	5.0	41
	Placebo	ACTONEL 5 mg	Absolute Risk	Relative Risk
VERT MN	n = 346	n = 344	Reduction (%)	Reduction (%)
New and Worsening
0 - 1 Year	15.3	8.2	7.1	50
0 - 2 Years	28.3	13.9	14.4	56
0 - 3 Years	34.0	21.8	12.2	46
New
0 - 1 Year	13.3	5.6	7.7	61
0 - 2 Years	24.7	11.6	13.1	59
0 - 3 Years	29.0	18.1	10.9	49
a Calculated by Kaplan-Meier methodology.

Effect on Osteoporosis-Related Nonvertebral Fractures:
In VERT MN and VERT NA, a prospectively planned efficacy endpoint was defined consisting of all radiographically confirmed fractures of skeletal sites accepted as associated with osteoporosis. Fractures at these sites were collectively referred to as osteoporosis-related nonvertebral fractures. ACTONEL 5 mg daily significantly reduced the incidence of nonvertebral osteoporosis-related fractures over 3 years in VERT NA (8% vs. 5%; relative risk reduction 39%) and reduced the fracture incidence in VERT MN from 16% to 11%. There was a significant reduction from 11% to 7% when the studies were combined, with a corresponding 36% reduction in relative risk. Figure 1 shows the overall results as well as the results at the individual skeletal sites for the combined studies.

Effect on Height:
In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. Both ACTONEL and placebo-treated groups lost height during the studies. Patients who received ACTONEL had a statistically significantly smaller loss of height than those who received placebo. In VERT MN, the median annual height change was -1.3 mm/yr in the ACTONEL 5-mg daily group compared to -2.4 mm/yr in the placebo group. In VERT NA, the median annual height change was -0.7 mm/yr in the ACTONEL 5-mg daily group compared to -1.1 mm/yr in the placebo group.

Effect on Bone Mineral Density:
The results of 4 randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that ACTONEL 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 2 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo. Thus, overall ACTONEL reverses the loss of BMD, a central factor in the progression of osteoporosis. In both VERT studies (VERT MN and VERT NA), ACTONEL 5 mg daily produced increases in lumbar spine BMD that were progressive over the 3 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points.

Table 2
Mean Percent Increase in BMD from Baseline in Patients
Taking ACTONEL 5 mg or Placebo at Endpoint ^a

	VERT MN b		VERT NA b		BMD MN c		BMD NA c
	Placebo    n = 323	5 mg    n = 323	Placebo    n = 599	5 mg    n = 606	Placebo    n = 161	5 mg    n = 148	Placebo    n = 191	5 mg    n = 193
Lumbar Spine	1.0	6.6	0.8	5.0	0.0	4.0	0.2	4.8
Femoral Neck	-1.4	1.6	-1.0	1.4	-1.1	1.3	0.1	2.4
Femoral	-1.9	3.9	-0.5	3.0	-0.6	2.5	1.3	4.0
Trochanter
Midshaft Radius	-1.5 *	0.2 *	-1.2 *	0.1 *	ND		ND
The endpoint value is the value at the study's last time point for all patients who had BMD measured at that time; otherwise the last postbaseline BMD value prior to the study's last time point is used.
b The duration of the studies was 3 years.
c The duration of the studies was 1.5 to 2 years.
*BMD of the midshaft radius was measured in a subset of centers in VERT MN (placebo, n = 222; 5 mg, n = 214) and VERT NA (placebo, n = 310; 5 mg, n = 306)
ND = analysis not done

Histology/Histomorphometry:
Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received daily ACTONEL (2.5 mg or 5 mg) or placebo for 2 to 3 years. Histologic evaluation (n = 103) showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in ACTONEL-treated women. These findings demonstrate that bone formed during ACTONEL administration is of normal quality. The histomorphometric parameter mineralizing surface, an index of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 23 patients treated with ACTONEL 5 mg and 21 treated with placebo. Mineralizing surface decreased moderately in ACTONEL-treated patients (median percent change: ACTONEL 5 mg, -74%; placebo, -21%), consistent with the known effects of treatment on bone turnover.

Prevention of Osteoporosis in Postmenopausal Women:
ACTONEL 5 mg daily prevented bone loss in a majority of postmenopausal women (age range 42 to 63 years) within 3 years of menopause in a 2-year, double-blind, placebo-controlled study in 383 patients (ACTONEL 5 mg, n = 129). All patients in this study received supplemental calcium 1000 mg/day. Increases in BMD were observed as early as 3 months following initiation of ACTONEL treatment. ACTONEL 5 mg produced significant mean increases in BMD at the lumbar spine, femoral neck, and trochanter compared to placebo at the end of the study (Figure 2). ACTONEL 5 mg daily was also effective in patients with lower baseline lumbar spine BMD (more than 1 SD below the premenopausal mean) and in those with normal baseline lumbar spine BMD. Bone mineral density at the distal radius decreased in both ACTONEL and placebo-treated women following 1 year of treatment.

Combined Administration with Hormone Replacement Therapy:
The effects of combining ACTONEL 5 mg daily with conjugated estrogen 0.625 mg daily (n = 263) were compared to the effects of conjugated estrogen alone (n = 261) in a 1-year, randomized, double-blind study of women ages 37 to 82 years, who were on average 14 years postmenopausal. The BMD results for this study are presented in Table 3.

Table 3
Percent Change from Baseline in BMD
After 1 Year of Treatment

	Estrogen 0.625 mg n = 261	ACTONEL 5 mg + Estrogen 0.625 mg n = 263
Lumbar Spine	4.6 ± 0.20	5.2 ± 0.23
Femoral Neck	1.8 ± 0.25	2.7 ± 0.25
Femoral Trochanter	3.2 ± 0.28	3.7 ± 0.25
Midshaft Radius	0.4 ± 0.14	0.7 ± 0.17
Distal Radius	1.7 ± 0.24	1.6 ± 0.28
Values shown are mean (± SEM) percent change from baseline.

Histology/Histomorphometry:
Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received ACTONEL 5 mg plus estrogen or estrogen alone once daily for 1 year. Histologic evaluation (n = 47) demonstrated that the bone of patients treated with ACTONEL plus estrogen was of normal lamellar structure and normal mineralization. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 12 patients treated with ACTONEL plus estrogen and 12 treated with estrogen alone. Mineralizing surface decreased in both treatment groups (median percent change: ACTONEL plus estrogen, -79%; estrogen alone, -50%), consistent with the known effects of these agents on bone turnover.

Glucocorticoid-Induced Osteoporosis:
Bone Mineral Density:
Two 1-year, double-blind, placebo-controlled trials in patients who were taking >/=7.5 mg/day of prednisone or equivalent demonstrated that ACTONEL 5 mg once daily was effective in the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who were either initiating or continuing glucocorticoid therapy.

The prevention study enrolled 228 patients (ACTONEL 5 mg, n = 76) (18 to 85 years of age), each of whom had initiated glucocorticoid therapy (mean daily dose of prednisone 21 mg) within the previous 3 months (mean duration of use prior to study 1.8 months) for rheumatic, skin, and pulmonary diseases. The mean lumbar spine BMD was normal at baseline (average T score 0.684). All patients in this study received supplemental calcium 500 mg/day. By the third month of treatment, and continuing through the year-long treatment, the placebo group experienced losses in BMD at the lumbar spine, femoral neck, and trochanter, while BMD was maintained or increased in the ACTONEL 5-mg group. At each skeletal site there were statistically significant differences between the ACTONEL 5-mg group and the placebo group at all timepoints (Months 3, 6, 9, and 12). The treatment differences increased with continued treatment. Although BMD increased at the distal radius in the ACTONEL 5-mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and ACTONEL 5 mg after 1 year were 3.8% at the lumbar spine, 4.1% at the femoral neck, and 4.6% at the trochanter, as shown in Figure 3. The results at these skeletal sites were similar to the overall results when the subgroups of men and postmenopausal women, but not premenopausal women, were analyzed separately. ACTONEL was effective at the lumbar spine, femoral neck, and trochanter regardless of age (<65 vs. >/=65), gender, prior and concomitant glucocorticoid dose, or baseline BMD. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

The treatment study of similar design enrolled 290 patients (ACTONEL 5 mg, n = 100) (19 to 85 years of age) with continuing, long-term (>/=6 months) use of glucocorticoids (mean duration of use prior to study 60 months; mean daily dose of prednisone 15 mg) for rheumatic, skin, and pulmonary diseases. The baseline mean lumbar spine BMD was low (1.63 SD below the young healthy population mean), with 28% of the patients more than 2.5 SD below the mean. All patients in this study received supplemental calcium 1000 mg/day and vitamin D 400 IU/day.

After 1 year of treatment, the BMD of the placebo group was within ±1% of baseline levels at the lumbar spine, femoral neck, and trochanter. ACTONEL 5 mg increased BMD at the lumbar spine (2.9%), femoral neck (1.8%), and trochanter (2.4%). The differences between ACTONEL and placebo were 2.7% at the lumbar spine, 1.9% at the femoral neck, and 1.6% at the trochanter as shown in Figure 4. The differences were statistically significant for the lumbar spine and femoral neck, but not at the femoral trochanter. ACTONEL was similarly effective on lumbar spine BMD regardless of age (<65 vs. >/=65), gender, or pre-study glucocorticoid dose. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

Vertebral Fractures:
In the prevention study of patients initiating glucocorticoids, the incidence of vertebral fractures at 1 year was reduced from 17% in the placebo group to 6% in theACTONEL group. In the treatment study of patients continuing glucocorticoids, the incidence of vertebral fractures was reduced from 15% in the placebo group to 5% in the ACTONEL group (Figure 5). The statistically significant reduction in vertebral fracture incidence in the analysis of the combined studies corresponded to an absolute risk reduction of 11% and a relative risk reduction of 70%. All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures).

Histology/Histomorphometry:
Bone biopsies from 40 patients on glucocorticoid therapy were obtained at endpoint. Patients had received daily ACTONEL (2.5 mg or 5 mg) or placebo for 1 year. Histologic evaluation (n = 33) showed that bone formed during treatment with ACTONEL was of normal lamellar structure and normal mineralization, with no bone or marrow abnormalities observed. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 10 patients treated with ACTONEL 5 mg. Mineralizing surface decreased 24% (median percent change) in these patients. Only a small number of placebo-treated patients had both baseline and post-treatment biopsy samples, precluding a meaningful quantitative assessment.

Treatment of Paget's Disease:
The efficacy of ACTONEL was demonstrated in 2 clinical studies involving 120 men and 65 women. In a double-blind, active-controlled study of patients with moderate-to-severe Paget's disease (serum alkaline phosphatase levels of at least 2 times the upper limit of normal), patients were treated with ACTONEL 30 mg daily for 2 months or Didronel® (etidronate disodium) 400 mg/day for 6 months. At Day 180, 77% (43/56) of ACTONEL-treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10.5% (6/57) of patients treated with Didronel (p<0.001). At Day 540, 16 months after discontinuation of therapy, 53% (17/32) of ACTONEL-treated patients and 14% (4/29) of Didronel-treated patients with available data remained in biochemical remission.

During the first 180 days of the active-controlled study, 85% (51/60) of ACTONEL-treated patients demonstrated a >/=75% reduction from baseline in serum alkaline phosphatase excess (difference between measured level and midpoint of the normal range) with 2 months of treatment compared to 20% (12/60) in the Didronel-treated group with 6 months of treatment (p<0.001). Changes in serum alkaline phosphatase excess over time (shown in Figure 6) were significant following only 30 days of treatment, with a 36% reduction in serum alkaline phosphatase excess at that time compared to only a 6% reduction seen with Didronel treatment at the same time point (p<0.01).

Response to ACTONEL therapy was similar in patients with mild to very severe Paget's disease. Table 4 shows the mean percent reduction from baseline at Day 180 in excess serum alkaline phosphatase in patients with mild, moderate, or severe disease.

Table 4
Mean Percent Reduction from Baseline at Day 180 in
Total Serum Alkaline Phosphatase Excess by Disease Severity

	ACTONEL 30 mg			DIDRONEL 400 mg
Subgroup: Baseline Disease Severity (AP)	n	Baseline Serum AP (U/L) *	Mean % Reduction	n	Baseline Serum AP (U/L) *	Mean % Reduction
>2, <3 × ULN	32	271.6 ± 5.3	-88.1	22	277.9 ± 7.45	-44.6
>/=3, <7 × ULN	14	475.3 ± 28.8	-87.5	25	480.5 ± 26.44	-35.0
>/=7 × ULN	8	1336.5 ± 134.19	-81.8	6	1331.5 ± 167.58	-47.2
*Values shown are mean ± SEM; ULN = upper limit of normal.

Response to ACTONEL therapy was similar between patients who had previously received anti-pagetic therapy and those who had not. In the active-controlled study, 4 patients previously non-responsive to 1 or more courses of anti-pagetic therapy (calcitonin, Didronel) responded to treatment with ACTONEL 30 mg daily (defined by at least a 30% change from baseline). Each of these patients achieved at least 90% reduction from baseline in serum alkaline phosphatase excess, with 3 patients achieving normalization of serum alkaline phosphatase levels.

Histomorphometry of the bone was studied in 14 patients with bone biopsies: 9 patients had biopsies from pagetic bone lesions and 5 patients from non-pagetic bone. Bone biopsy results in non-pagetic bone did not reveal osteomalacia, impairment of bone remodeling, or induction of a significant decline in bone turnover in patients treated with ACTONEL.

ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY
Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at oral doses up to 4 and 25 times the human recommended oral dose of 5 mg based on surface area, (mg/m 2 ) for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.35 to 1.4 times the human 5-mg dose based on surface area (mg/m 2 ).

In dogs treated with an oral dose of 1 mg/kg/day (approximately 5 times the human 5-mg dose based on surface area, mg/m 2 ), risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose of 0.1 mg/kg/day (approximately 0.5 times the human 5-mg dose based on surface area, mg/m 2 ).

The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested (5 mg/kg/day, subcutaneously), which was approximately 3500 times the lowest antiresorptive dose (1.5 mcg/kg/day in this model) and approximately 8 times the human 5-mg dose based on surface area (mg/m 2 ). This indicates that ACTONEL administered at the therapeutic dose is unlikely to induce osteomalacia.

INDICATIONS AND USAGE
Postmenopausal Osteoporosis:
ACTONEL is indicated for the treatment and prevention of osteoporosis in postmenopausal women.

Treatment of Osteoporosis:
In postmenopausal women with osteoporosis, ACTONEL increases BMD and reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures (see CLINICAL STUDIES ). Osteoporosis may be confirmed by the presence or history of osteoporotic fracture, or by the finding of low bone mass (for example, at least 2 SD below the premenopausal mean).

Prevention of Osteoporosis:
ACTONEL may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of fracture.

Factors such as family history of osteoporosis, previous fracture, smoking, BMD (at least 1 SD below the premenopausal mean), high bone turnover, thin body frame, Caucasian or Asian race, and early menopause are associated with an increased risk of developing osteoporosis and fractures. The presence of these risk factors may be important when considering the use of ACTONEL for prevention of osteoporosis.

Glucocorticoid-Induced Osteoporosis:
ACTONEL is indicated for the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage equivalent to 7.5 mg or greater of prednisone) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

Paget's Disease:
ACTONEL is indicated for treatment of Paget's disease of bone (osteitis deformans). Treatment is indicated in patients with Paget's disease of bone (1) who have a level of serum alkaline phosphatase at least 2 times the upper limit of normal, or (2) who are symptomatic, or (3) who are at risk for future complications from their disease, to induce remission (normalization of serum alkaline phosphatase).

CONTRAINDICATIONS

Hypocalcemia (see PRECAUTIONS , General )
Known hypersensitivity to any component of this product
Inability to stand or sit upright for at least 30 minutes

WARNINGS
Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer (see PRECAUTIONS ).

PRECAUTIONS
General:
Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ACTONEL therapy. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget's disease in whom bone turnover is significantly elevated. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).

Bisphosphonates have been associated with gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcers. This association has been reported for bisphosphonates in postmarketing experience, but has not been found in most pre-approval clinical trials, including those conducted with ACTONEL. Patients should be advised that taking the medication according to the instructions is important to minimize the risk of these events. They should take ACTONEL with sufficient plain water (6 to 8 oz) to facilitate delivery to the stomach, and should not lie down for 30 minutes after taking the drug.

Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures such as tooth extraction, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally.

For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment, prior to the procedure, reduces the risk of osteonecrosis of the jaw. Clinical judgment should guide the management plan of each patient based on individual benefit/risk assessment.

Musculoskeletal Pain:
In postmarketing experience, there have been infrequent reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates (see ADVERSE REACTIONS ). The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Glucocorticoid-Induced Osteoporosis:
The risk versus benefit of ACTONEL for the prevention and treatment of glucocorticoid-induced osteoporosis at daily doses of glucocorticoids <7.5 mg of prednisone or equivalent has not been established. Before initiating treatment, the hormonal status of both men and women should be ascertained and appropriate replacement considered.

The efficacy of ACTONEL for this indication has been established in studies of 1-year duration. The efficacy of ACTONEL beyond 1 year has not been studied.

Information for Patients:
The patient should be informed to pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions. Specifically, ACTONEL should be taken at least 30 minutes before the first food or drink of the day other than water.

To facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation, patients should take ACTONEL while in an upright position (sitting or standing) with a full glass of plain water (6 to 8 oz). Patients should not lie down for 30 minutes after taking the medication (see PRECAUTIONS , General ). Patients should not chew or suck on the tablet because of a potential for oropharyngeal irritation.

Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or severe persistent or worsening heartburn) they should consult their physician before continuing ACTONEL.

Patients should be instructed that if they miss a dose of ACTONEL 35-mg once a week, they should take 1 tablet on the morning after they remember and return to taking 1 tablet once a week, as originally scheduled on their chosen day. Patients should not take 2 tablets on the same day.

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see PRECAUTIONS , General ). Calcium supplements or calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of ACTONEL and should be taken at a different time of the day, as with food.

Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as excessive cigarette smoking, and/or alcohol consumption, if these factors exist.

Physicians should instruct their patients to read the Patient Information before starting therapy with ACTONEL 5 mg or 35 mg and to re-read it each time the prescription is renewed.

Patients should be reminded to give all of their health care providers an accurate medication history. Instruct patients to tell all of their health care providers that they are taking ACTONEL. Patients should be instructed that any time they have a medical problem they think may be from ACTONEL, they should talk to their doctor.

Drug Interactions:
No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450).

Calcium Supplements/Antacids:
Co-administration of ACTONEL and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of ACTONEL.

Hormone Replacement Therapy:
One study of about 500 early postmenopausal women has been conducted to date in which treatment with ACTONEL (5 mg/day) plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, ACTONEL may be used concomitantly with hormone replacement therapy.

Aspirin/Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
Of over 5700 patients enrolled in the ACTONEL Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in ACTONEL-treated patients (24.5%) was similar to that in placebo-treated patients (24.8%).

H 2 Blockers and Proton Pump Inhibitors (PPIs):
Of over 5700 patients enrolled in the ACTONEL Phase 3 osteoporosis studies, 21% used H 2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the ACTONEL-treated patients was similar to that in placebo-treated patients.

Drug/Laboratory Test Interactions:
Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed.

Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis:
In a 104-week carcinogenicity study, rats were administered daily oral doses up to 24 mg/kg/day (approximately 7.7 times the maximum recommended human daily dose of 30 mg based on surface area, mg/m 2 ). There were no significant drug-induced tumor findings in male or female rats. The high dose male group of 24 mg/kg/day was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses up to 32 mg/kg/day (approximately 6.4 times the 30-mg/day human dose based on surface area, mg/m 2 ). There were no significant drug-induced tumor findings in male or female mice.

Mutagenesis:
Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (>675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage.

Impairment of Fertility:
In female rats, ovulation was inhibited at an oral dose of 16 mg/kg/day (approximately 5.2 times the 30-mg/day human dose based on surface area, mg/m 2 ). Decreased implantation was noted in female rats treated with doses >/=7 mg/kg/day (approximately 2.3 times the 30-mg/day human dose based on surface area, mg/m 2 ). In male rats, testicular and epididymal atrophy and inflammation were noted at 40 mg/kg/day (approximately 13 times the 30-mg/day human dose based on surface area, mg/m 2 ). Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses of 16 mg/kg/day (approximately 5.2 times the 30-mg/day human dose based on surface area, mg/m 2 ). There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose of 8 mg/kg/day (approximately 8 times the 30-mg/day human dose based on surface area, mg/m 2 ). These findings tended to increase in severity with increased dose and exposure time.

Pregnancy:
Pregnancy Category C: Survival of neonates was decreased in rats treated during gestation with oral doses >/=16 mg/kg/day (approximately 5.2 times the 30-mg/day human dose based on surface area, mg/m 2 ). Body weight was decreased in neonates from dams treated with 80 mg/kg (approximately 26 times the 30-mg/day human dose based on surface area, mg/m 2 ). In rats treated during gestation, the number of fetuses exhibiting incomplete ossification of sternebrae or skull was statistically significantly increased at 7.1 mg/kg/day (approximately 2.3 times the 30-mg/day human dose based on surface area, mg/m 2 ). Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses >/=16 mg/kg/day (approximately 5.2 times the 30-mg/day human dose based on surface area, mg/m 2 ). A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses >/=3.2 mg/kg/day (approximately 1 time the 30-mg/day human dose based on surface area, mg/m 2 ). The relevance of this finding to human use of ACTONEL is unclear. No significant fetal ossification effects were seen in rabbits treated with oral doses up to 10 mg/kg/day during gestation (approximately 6.7 times the 30-mg/day human dose based on surface area, mg/m 2 ). However, in rabbits treated with 10 mg/kg/day, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.

Similar to other bisphosphonates, treatment during mating and gestation with doses as low as 3.2 mg/kg/day (approximately 1 time the 30-mg/day human dose based on surface area, mg/m 2 ) has resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation 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 this risk has not been studied.

There are no adequate and well-controlled studies of ACTONEL in pregnant women. ACTONEL should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Women:
Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether risedronate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bisphosphonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:
Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:
Of the patients receiving ACTONEL in postmenopausal osteoporosis studies (see CLINICAL STUDIES ), 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget's disease trials. No overall differences in efficacy or safety were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

Use in Men:
Safety and effectiveness have been demonstrated in clinical studies in men receiving ACTONEL both for Paget's disease and for treatment and prevention of glucocorticoid-induced osteoporosis. However, the safety and effectiveness in men for osteoporosis due to other causes have not beenestablished.

ADVERSE REACTIONS
Osteoporosis:
ACTONEL has been studied in over 5700 patients enrolled in the Phase 3 glucocorticoid-induced osteoporosis clinical trials and in postmenopausal osteoporosis trials of up to 3-years duration. The overall adverse event profile of ACTONEL 5 mg in these studies was similar to that of placebo. Most adverse events were either mild or moderate and did not lead to discontinuation from the study. The incidence of serious adverse events in the placebo group was 24.9% and in the ACTONEL 5-mg group was 26.3%. The percentage of patients who withdrew from the study due to adverse events was 14.4% and 13.5% for the placebo and ACTONEL 5-mg groups, respectively. Table 5 lists adverse events from the Phase 3 osteoporosis trials reported in >/=2% of patients and in more ACTONEL-treated patients than placebo-treated patients. Adverse events are shown without attribution of causality.

Table 5
Adverse Events Occurring at a Frequency >/=2% and in
More ACTONEL-Treated Patients than Placebo-Treated
Patients Combined Phase 3 Osteoporosis Trials

Body System	Placebo % (N = 1914)	ACTONEL 5 mg % (N = 1916)
Body as a Whole
Infection	29.7	29.9
Back Pain	23.6	26.1
Pain	13.1	13.6
Abdominal Pain	9.4	11.6
Neck Pain	4.5	5.3
Asthenia	4.3	5.1
Chest Pain	4.9	5.0
Neoplasm	3.0	3.3
Hernia	2.5	2.9
Cardiovascular
Hypertension	9.0	10.0
Cardiovascular Disorder	1.7	2.5
Angina Pectoris	2.4	2.5
Digestive
Nausea	10.7	10.9
Diarrhea	9.6	10.6
Flatulence	4.2	4.6
Gastritis	2.3	2.5
Gastrointestinal Disorder	2.1	2.3
Rectal Disorder	1.9	2.2
Tooth Disorder	2.0	2.1
Hemic and Lymphatic
Ecchymosis	4.0	4.3
Anemia	1.9	2.4
Musculoskeletal
Arthralgia	21.1	23.7
Joint Disorder	5.4	6.8
Myalgia	6.3	6.6
Bone Pain	4.3	4.6
Bone Disorder	3.2	4.0
Leg Cramps	2.6	3.5
Bursitis	2.9	3.0
Tendon Disorder	2.5	3.0
Nervous
Depression	6.2	6.8
Dizziness	5.4	6.4
Insomnia	4.5	4.7
Anxiety	3.0	4.3
Neuralgia	3.5	3.8
Vertigo	3.2	3.3
Hypertonia	2.1	2.2
Paresthesia	1.8	2.1
Respiratory
Pharyngitis	5.0	5.8
Rhinitis	5.0	5.7
Dyspnea	3.2	3.8
Pneumonia	2.6	3.1
Skin and Appendages
Rash	7.2	7.7
Pruritus	2.2	3.0
Skin Carcinoma	1.8	2.0
Special Senses
Cataract	5.4	5.9
Conjunctivitis	2.8	3.1
Otitis Media	2.4	2.5
Urogenital
Urinary Tract Infection	9.7	10.9
Cystitis	3.5	4.1

Duodenitis and glossitis have been reported uncommonly (0.1% to 1%). There have been rare reports (<0.1%) of abnormal liver function tests.

Laboratory Test Findings:
Asymptomatic and small decreases were observed in serum calcium and phosphorus levels. Overall, mean decreases of 0.8% in serum calcium and of 2.7% in phosphorus were observed at 6 months in patients receiving ACTONEL. Throughout the Phase 3 studies, serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (ACTONEL and placebo). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 11 (0.6%) treated with ACTONEL and 3 (0.2%) treated with placebo.

Endoscopic Findings:
ACTONEL clinical studies enrolled over 5700 patients, many with pre-existing gastrointestinal disease and concomitant use of NSAIDs or aspirin. Investigators were encouraged to perform endoscopies in any patients with moderate-to-severe gastrointestinal complaints, while maintaining the blind. These endoscopies were ultimately performed on equal numbers of patients between the treated and placebo groups [75 (14.5%) placebo; 75 (11.9%) ACTONEL]. Across treatment groups, the percentage of patients with normal esophageal, gastric, and duodenal mucosa on endoscopy was similar (20% placebo, 21% ACTONEL). The number of patients who withdrew from the studies due to the event prompting endoscopy was similar across treatment groups. Positive findings on endoscopy were also generally comparable across treatment groups. There was a higher number of reports of mild duodenitis in the ACTONEL group, however there were more duodenal ulcers in the placebo group. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% ACTONEL).

Once-a-week Dosing:
In a 1-year, double-blind, multicenter study comparingACTONEL 5-mg daily and ACTONEL 35-mg once a week in postmenopausal women, the overall safety and tolerability profiles of the 2 oral dosing regimens were similar. Table 6 lists the adverse events in >/=2% of patients from this trial. Events are shown without attribution of causality.

Table 6
Adverse Events Occurring in >/= 2% of Patients of Either
Treatment Group in the Daily vs. Weekly Osteoporosis
Treatment Study in Postmenopausal Women

Body System	5 mg Daily ACTONEL % (N = 480)	35 mg Weekly ACTONEL % (N = 485)
Body as a Whole
Infection	19.0	20.6
Accidental Injury	10.6	10.7
Pain	7.7	9.9
Back Pain	9.2	8.7
Flu Syndrome	7.1	8.5
Abdominal Pain	7.3	7.6
Headache	7.3	7.2
Overdose	6.9	6.8
Asthenia	3.5	5.4
Chest Pain	2.3	2.7
Allergic Reaction	1.9	2.5
Neoplasm	0.8	2.1
Neck Pain	2.7	1.2
Cardiovascular System
Hypertension	5.8	4.9
Syncope	0.6	2.1
Vasodilatation	2.3	1.4
Digestive System
Constipation	12.5	12.2
Dyspepsia	6.9	7.6
Nausea	8.5	6.2
Diarrhea	6.3	4.9
Gastroenteritis	3.8	3.5
Flatulence	3.3	3.1
Colitis	0.8	2.5
Gastrointestinal Disorder	1.9	2.5
Vomiting	1.9	2.5
Dry Mouth	2.5	1.4
Metabolic and Nutritional Disorders
Peripheral Edema	4.2	1.6
Musculoskeletal System
Arthralgia	11.5	14.2
Traumatic Bone Fracture	5.0	6.4
Myalgia	4.6	6.2
Arthritis	4.8	4.1
Bursitis	1.3	2.5
Bone Pain	2.9	1.4
Nervous System
Dizziness	5.8	4.9
Anxiety	0.6	2.7
Depression	2.3	2.3
Vertigo	2.1	1.6
Respiratory System
Bronchitis	2.3	4.9
Sinusitis	4.6	4.5
Pharyngitis	4.6	2.9
Cough Increased	3.1	2.5
Pneumonia	0.8	2.5
Rhinitis	2.3	2.1
Skin and Appendages
Rash	3.1	4.1
Pruritus	1.9	2.3
Special Senses
Cataract	2.9	1.9
Urogenital System
Urinary Tract Infection	2.9	5.2

Paget's Disease:
ACTONEL has been studied in 392 patients with Paget's disease of bone. As in trials of ACTONEL for other indications, the adverse experiences reported in the Paget's disease trials have generally been mild or moderate, have not required discontinuation of treatment, and have not appeared to be related to patient age, gender, or race.

In a double-blind, active-controlled study, the adverse event profile was similar for ACTONEL and Didronel: 6.6% (4/61) of patients treated with ACTONEL 30 mg/day for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg/day for 6 months.

Table 7
Adverse Events Reported in >/=2% of ACTONEL-Treated
Patients * in Phase 3 Paget's Disease Trials

Body System	30 mg/day × 2 months ACTONEL % (n = 61)	400 mg/day × 6 months DIDRONEL % (n = 61)
Body as a Whole
Flu Syndrome	9.8	1.6
Chest Pain	6.6	3.3
Asthenia	4.9	0.0
Neoplasm	3.3	1.6
Gastrointestinal
Diarrhea	19.7	14.8
Abdominal Pain	11.5	8.2
Nausea	9.8	9.8
Constipation	6.6	8.2
Belching	3.3	1.6
Colitis	3.3	3.3
Metabolic and Nutritional Disorders
Peripheral Edema	8.2	6.6
Musculoskeletal
Arthralgia	32.8	29.5
Bone Pain	4.9	4.9
Leg Cramps	3.3	3.3
Myasthenia	3.3	0.0
Nervous
Headache	18.0	16.4
Dizziness	6.6	4.9
Respiratory
Bronchitis	3.3	4.9
Sinusitis	4.9	1.6
Skin and Appendages
Rash	11.5	8.2
Special Senses
Amblyopia	3.3	3.3
Tinnitus	3.3	3.3
Dry Eye	3.3	0.0
*Considered to be possibly or probably causally related in at least one patient.

Three patients who received ACTONEL 30 mg/day experienced acute iritis in 1 supportive study. All 3 patients recovered from their events; however, in 1 of these patients, the event recurred during ACTONEL treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids.

Post-marketing Experience:
Very rare hypersensitivity and skin reactions have been reported, including angioedema, generalized rash and bullous skin reactions, some severe.

Musculoskeletal: bone, joint, or muscle pain, rarely described as severe or incapacitating (see PRECAUTIONS , Musculoskeletal Pain ).

OVERDOSAGE
Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind ACTONEL and reduce absorption of the drug.

In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia.

Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg. These values represent 320 to 620 times the 30-mg human dose based on surface area (mg/m 2 ).

DOSAGE AND ADMINISTRATION
ACTONEL should be taken at least 30 minutes before the first food or drink of the day other than water.

To facilitate delivery to the stomach, ACTONEL should be swallowed while the patient is in an upright position and with a full glass of plain water (6 to 8 oz). Patients should not lie down for 30 minutes after taking the medication (see PRECAUTIONS , General ).

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see PRECAUTIONS , General ). Calcium supplements and calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of ACTONEL and should be taken at a different time of the day. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min). No dosage adjustment is necessary in patients with a creatinine clearance >/=30 mL/min or in the elderly.

Treatment of Postmenopausal Osteoporosis (see INDICATIONS AND USAGE ):
The recommended regimen is:

one 5-mg tablet orally, taken daily
or
one 35-mg tablet orally, taken once a week

Prevention of Postmenopausal Osteoporosis (see INDICATIONS AND USAGE ):

The recommended regimen is one 5-mg tablet orally, taken daily
Alternatively, one 35-mg tablet orally, taken once a week may be considered

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis (see INDICATIONS AND USAGE ):
The recommended regimen is:

one 5-mg tablet orally, taken daily

Paget's Disease (see INDICATIONS AND USAGE ):
The recommended treatment regimen is 30 mg orally once daily for 2 months. Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment.

HOW SUPPLIED
ACTONEL is available as follows:

5-mg film-coated, oval, yellow tablets with RSN on 1 face and 5 mg on the other.

NDC 0149-0471-01      bottle of 30

5-mg film-coated, oval, yellow tablets with RSN on 1 face and 5 mg on the other.

NDC 0149-0471-03      bottle of 2000

30-mg film-coated, oval, white tablets with RSN on 1 face and 30 mg on the other.

NDC 0149-0470-01      bottle of 30

35-mg film-coated, oval, orange tablets with RSN on 1 face and 35 mg on the other.

NDC 0149-0472-01      dose pack of 4

Store at controlled room temperature 20°-25°C (68°-77°F) [See USP].

 
包装规格：
·150mg *1片 (Sanofi Aventis 生产)
·150mg *3 片 (Sanofi Aventis 生产)
·30mg *28 片 （Warner Chilcott 生产）
·35mg *12 片 （Sanofi Aventis 生产）
·35mg *4 片 （PROCTER & GAMBLE生产）
·5mg *84 片 （Warner Chilcott 生产）
·75mg *6 片 (Sanofi Aventis生产）
·30mg *30 片
·35mg *12 片
·5mg *30 片