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Boniva(ibandronate sodium FilmCoated Tablets)

2012-07-22 01:36:37  作者:新特药房  来源:本站原创  浏览次数:1972  文字大小:【】【】【
简介: 英文药名: Boniva(ibandronate sodium tablets) 中文药名: 伊班膦酸钠片 品牌药生产厂家: Glaxo Smith Kline 药品名称 英文药名: Boniva (ibandronate sodium tablets) 中文药名: 伊班膦酸钠片 药 ...

英文药名: Boniva(ibandronate sodium FilmCoated Tablets)

中文药名: 伊班膦酸钠片

生产厂家:罗氏等
药品名称
英文药名: Boniva(ibandronate sodium tablets)
中文药名: 伊班膦酸钠片
药品介绍
人体的骨骼是一个有生命的、复杂的组织器官。在人的一生中,老的骨组织不停地被清除,新的骨组织不停地建成并替代被清除的老的骨组织。它的生长发育及代谢是由成骨细胞和破骨细胞来调节和控制的。
当破骨细胞吸收的量大于成骨细胞分泌的量,导致体内骨量减少,即造成骨质疏松,极易发生骨折。
骨质疏松症是一个引起越来越多重视的世界范围的健康问题。其发病率已跃居常见病、多发病的第七位。目前全世界约2亿人患有骨质疏松,并且女性多于男性。根据世界卫生组织的标准,美国国家健康和营养调查(NHANES III,1988?1994年)结果表明, 50岁以上人群中,1/2的女性、1/5的男性在他们的一生中都会出现骨质疏松性骨折,一旦患者经历了第一次骨质疏松性骨折,继发性骨折的危险明显加大。世界卫生组织把每年的10月20日“国际骨质疏松日”。
罗氏公司(Roche )开发出了新一代的双膦酸盐,伊班膦酸盐(ibandronate),2003年被欧盟首先批准。它由罗氏公司和葛兰素史克公司以商品名邦罗力(Boniva)共同推出。伊班膦酸盐首先由弗莱施在和德国宝灵曼制药公司(Boehringer Mannheim)的合作中于1988年合成。宝灵曼公司于1997年被瑞士的罗氏公司兼并,于是伊班膦酸盐变成了罗氏的分子。当时肿瘤学和骨骼代谢是罗氏公司的两个研究重点。
后来的药理研究发现,在细胞水平,双膦酸盐对骨吸收部位特别是破骨细胞作用的部位有亲和性,能抑制破骨细胞的活性,并导致破骨细胞凋亡。ALN能抑制与降低骨的转换过程(例如,骨重建单位数量),而且使这些骨重建部位的骨吸收与骨量丢失减缓和降低,并延长了矿化时间,从而使相对骨密度值逐渐增加。
一月1次的口服伊班膦酸钠片
罗氏公司和葛兰素史克公司的口服伊班膦酸钠150mg片(商品名:Boniva),一月1次治疗绝经后妇女的骨质疏松。
本品是治疗任何慢性病中迄今首个上市一月1次1片的口服片。患者一年只要服用12片,而目前以双磷酸盐治疗每周服用共需52片。本品批准意义重大,它向患者提供了有效且服用方便的药品。
3年多的临床研究显示,原一日1次的伊班膦酸钠(2.5mg)用于治疗和预防骨质疏松可显著减少绝经后骨质疏松妇女脊椎新骨折的发生率和增加绝经后无骨质疏松妇女的骨矿物质密度(BMD)。
现一月1次口服伊班膦酸钠(150mg)片的批准是基于对1,602例绝经后骨质疏松妇女多国随机双盲研究的数据。结果显示,治疗一年后本品一月1次给药增加腰脊柱和其它骨骼部位的BMD至少可与小剂量一日1次连续给药一年相当。


Bonviva 150mg Film-Coated Tablets
1. Name of the medicinal product
Bonviva 150 mg film-coated tablets
2. Qualitative and quantitative composition
Each film-coated tablet contains 150 mg ibandronic acid (as sodium monohydrate).
Excipients with known effect:
Contains 154.6 mg anhydrous lactose (equivalent to 162.75 mg lactose monohydrate).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet
White to off white film-coated tablets, of oblong shape marked “BNVA” on one side, and “150” on the other side.
4. Clinical particulars
4.1 Therapeutic indications
Treatment of osteoporosis in postmenopausal women at increased risk of fracture (see section 5.1).
A reduction in the risk of vertebral fractures has been demonstrated, efficacy on femoral neck fractures has not been established.
4.2 Posology and method of administration
Posology
The recommended dose is one 150 mg film-coated tablet once a month. The tablet should preferably be taken on the same date each month.
Bonviva should be taken after an overnight fast (at least 6 hours) and 1 hour before the first food or drink (other than water) of the day (see section 4.5) or any other oral medicinal products or supplementation (including calcium).
In case a dose is missed, patients should be instructed to take one Bonviva 150 mg tablet the morning after the tablet is remembered, unless the time to the next scheduled dose is within 7 days.
Patients should then return to taking their dose once a month on their originally scheduled date.
If the next scheduled dose is within 7 days, patients should wait until their next dose and then continue taking one tablet once a month as originally scheduled.
Patients should not take two tablets within the same week.
Patients should receive supplemental calcium and / or vitamin D if dietary intake is inadequate (see section 4.4 and section 4.5).
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Bonviva on an individual patient basis, particularly after 5 or more years of use.
Special populations
Patients with renal impairment
Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min due to limited clinical experience (see section 4.4 and section 5.2).
No dose adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal or greater than 30 ml/min.
Patients with hepatic impairment
No dose adjustment is required (see section 5.2).
Elderly population (>65 years)
No dose adjustment is required (see section 5.2).
Paediatric population
There is no relevant use of Bonviva in children below 18 years, and Bonviva was not studied in this population. (see section 5.1 and section 5.2).
Method of administration
For oral use.
- Tablets should be swallowed whole with a glass of water (180 to 240 ml) while the patient is sitting or standing in an upright position. Water with a high concentration of calcium should not be used. If there is a concern regarding potentially high levels of calcium in the tap water (hard water), it is advised to use bottled water with a low mineral content.
- Patients should not lie down for 1 hour after taking Bonviva.
- Water is the only drink that should be taken with Bonviva.
- Patients should not chew or suck the tablet, because of a potential for oropharyngeal ulceration
4.3 Contraindications
- Hypersensitivity to ibandronic acid or to any of the excipients listed in section 6.1
- Hypocalcaemia
- Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia
- Inability to stand or sit upright for at least 60 minutes
4.4 Special warnings and precautions for use
Hypocalcaemia
Existing hypocalcaemia must be corrected before starting Bonviva therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients.
Gastrointestinal irritation
Orally administered bisphosphonates 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 Bonviva is given to patients with active upper gastrointestinal problems (e.g. known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).
Adverse reactions such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalisation, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention to and be able to comply with the dosing instructions (see section 4.2).
Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Bonviva and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.
Since Nonsteroidal Anti-Inflammatory medicinal products and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant administration.
Osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bonviva for osteoporosis (see section 4.8).
The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth.
A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Bonviva in patients with concomitant risk factors.
The following risk factors should be considered when evaluating a patient's risk of developing ONJ:
- Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy
- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking
- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck
- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions
All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Bonviva. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Bonviva administration.
The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of Bonviva treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Renal impairment
Due to limited clinical experience, Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min (see section 5.2).
Galactose intolerance
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Medicinal product-Food Interaction
Oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular, products containing calcium, including milk, and other multivalent cations (such as aluminium, magnesium, iron), are likely to interfere with absorption of Bonviva, which is consistent with findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking Bonviva and continue fasting for 1 hour following intake of Bonviva (see section 4.2).
Interactions with other medicinal products
Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.
Calcium supplements, antacids and some oral medicinal products containing multivalent cations
Calcium supplements, antacids and some oral medicinal products containing multivalent cations (such as aluminium, magnesium, iron) are likely to interfere with the absorption of Bonviva. Therefore, patients should not take other oral medicinal products for at least 6 hours before taking Bonviva and for 1 hour following intake of Bonviva.
Acetylsalicylic acid and NSAIDs
Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) and bisphosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration (see section 4.4).
H2 blockers or proton pump inhibitors
Of over 1500 patients enrolled in study BM 16549 comparing monthly with daily dosing regimens of ibandronic acid, 14 % and 18 % of patients used histamine (H2) blockers or proton pump inhibitors after one and two years, respectively. Among these patients, the incidence of upper gastrointestinal events in the patients treated with Bonviva 150 mg once monthly was similar to that in patients treated with ibandronic acid 2.5 mg daily.
In healthy male volunteers and postmenopausal women, intravenous administration of ranitidine caused an increase in ibandronic acid bioavailability of about 20 %, probably as a result of reduced gastric acidity. However, since this increase is within the normal variability of the bioavailability of ibandronic acid, no dose adjustment is considered necessary when Bonviva is administered with H2-antagonists or other active substances which increase gastric pH.
4.6 Fertility, pregnancy and lactation
Pregnancy
Bonviva is only for use in postmenopausal women and must not be taken by women of childbearing potential.
There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Bonviva should not be used during pregnancy.
Breast-feeding
It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration.
Bonviva should not be used during breast-feeding.
Fertility
There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).
4.7 Effects on ability to drive and use machines
On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Bonviva has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis of the jaw, gastrointestinal irritation, ocular inflammation, (see paragraph “Description of selected adverse reactions” and section 4.4).
The most frequently reported adverse reactions are arthralgia and influenza-like symptoms. These symptoms are typically in association with the first dose, generally of short duration, mild or moderate in intensity, and usually resolve during continuing treatment without requiring remedial measures (see paragraph “Influenza like illness”).
Tabulated list of adverse reactions
In table 1 a complete list of known adverse reactions is presented. The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three year fracture study (MF4411).
In a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety of Bonviva 150 mg once monthly and ibandronic acid 2.5 mg daily was similar. The overall proportion of patients who experienced an adverse reaction, was 22.7 % and 25.0 % for Bonviva 150 mg once monthly after one and two years, respectively. Most cases did not lead to cessation of therapy.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000),very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse reactions occurring in postmenopausal women receiving Bonviva 150 mg once monthly or ibandronic acid 2.5 mg daily in the phase III studies BM16549 and MF4411 and in post-marketing experience.

System Organ Class

Common

Uncommon

Rare

Very rare

Immune system disorders

 

Asthma exacerbation

Hypersensitivity reaction

Anaphylactic reaction/shock*†

Nervous system disorders

Headache

Dizziness

   

Eye disorders

   

Ocular inflammation*†

 

Gastrointestinal disorders*

Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea

Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence

Duodenitis

 

Skin and subcutaneous tissues disorders

Rash

 

Angioedema, Face oedema, Urticaria

Stevens-Johnson Syndrome†, Erythema Multiforme†, Dermatitis Bullous†

Musculoskeletal and connective tissue disorders

Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness

Back pain

Atypical subtrochanteric and diaphyseal femoral fractures†

Osteonecrosis of jaw*†

Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)†

General disorders and administration site conditions

Influenza like illness*

Fatigue

   
See further information below
Identified in post-marketing experience.
Description of selected adverse reactions
Gastrointestinal adverse reactions
Patients with a previous history of gastrointestinal disease including patients with peptic ulcer without recent bleeding or hospitalisation, and patients with dyspepsia or reflux controlled by medication were included in the once monthly treatment study. For these patients, there was no difference in the incidence of upper gastrointestinal adverse events with the 150 mg once monthly regimen compared to the 2.5 mg daily regimen.
Influenza-like illness
Influenza-like illness includes events reported as acute phase reaction or symptoms including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.
Osteonecrosis of jaw
Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJ have been reported in the post marketing setting for ibandronic acid.
Ocular inflammation
Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.
Anaphylactic reaction/shock
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail:medsafety@hpra.ie
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
No specific information is available on the treatment of overdose with Bonviva.
However, based on a knowledge of this class of compounds, oral overdose may result in upper gastrointestinal adverse reactions (such as upset stomach, dyspepsia, oesophagitis, gastritis, or ulcer) or hypocalcaemia. Milk or antacids should be given to bind Bonviva, and any adverse reactions treated symptomatically. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicinal products for treatment of bone diseases, bisphosphonates, ATC code: M05-BA06
Mechanism of action
Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group of bisphosphonates, which act selectively on bone tissue and specifically inhibit osteoclast activity without directly affecting bone formation. It does not interfere with osteoclast recruitment. Ibandronic acid leads to progressive net gains in bone mass and a decreased incidence of fractures through the reduction of elevated bone turnover towards premenopausal levels in postmenopausal women.
Pharmacodynamic effects
The pharmacodynamic action of ibandronic acid is inhibition of bone resorption. In vivo, ibandronic acid prevents experimentally induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. In young (fast growing) rats, the endogenous bone resorption is also inhibited, leading to increased normal bone mass compared with untreated animals.
Animal models confirm that ibandronic acid is a highly potent inhibitor of osteoclastic activity. In growing rats, there was no evidence of impaired mineralization even at doses greater than 5,000 times the dose required for osteoporosis treatment.
Both daily and intermittent (with prolonged dose-free intervals) long-term administration in rats, dogs and monkeys was associated with formation of new bone of normal quality and maintained or increased mechanical strength even at doses in the toxic range. In humans, the efficacy of both daily and intermittent administration with a dose-free interval of 9-10 weeks of ibandronic acid was confirmed in a clinical trial (MF 4411), in which ibandronic acid demonstrated anti-fracture efficacy.
In animal models ibandronic acid produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including suppression of urinary biochemical markers of bone collagen degradation (such as deoxypyridinoline, and cross-linked N-telopeptides of type I collagen (NTX)).
In a Phase 1 bioequivalence study conducted in 72 postmenopausal women receiving 150 mg orally every 28 days for a total of four doses, inhibition in serum CTX following the first dose was seen as early as 24 hours post-dose (median inhibition 28 %), with median maximal inhibition (69 %) seen 6 days later. Following the third and fourth dose, the median maximum inhibition 6 days post dose was 74 % with reduction to a median inhibition of 56 % seen 28 days following the fourth dose. With no further dosing, there is a loss of suppression of biochemical markers of bone resorption.
Clinical efficacy
Independent risk factors, for example, low BMD, age, the existence of previous fractures, a family history of fractures, high bone turnover and low body mass index should be considered in order to identify women at increased risk of osteoporotic fractures.
Bonviva 150 mg once monthly
Bone mineral density (BMD)
Bonviva 150 mg once monthly was shown to be at least as effective as ibandronic acid 2.5 mg daily at increasing BMD in a two year, double-blind, multicentre study (BM 16549) of postmenopausal women with osteoporosis (lumbar spine BMD T score below -2.5 SD at baseline). This was demonstrated in both the primary analysis at one year and in the confirmatory analysis at two years endpoint (Table 2).
Table 2: Mean relative change from baseline of lumbar spine, total hip, femoral neck and trochanter BMD after one year (primary analysis) and two years of treatment (Per-Protocol Population) in study BM 16549.

One year data in study BM 16549

Two year data in study

BM 16549

Mean relative changes from baseline % [95% CI]

ibandronic acid 2.5 mg daily

(N=318)

Bonviva 150 mg once monthly

(N=320)

ibandronic acid 2.5 mg daily

(N=294)

Bonviva 150 mg once monthly

(N=291)

Lumbar spine L2-L4 BMD

3.9 [3.4, 4.3]

4.9 [4.4, 5.3]

5.0 [4.4, 5.5]

6.6 [6.0, 7.1]

Total hip BMD

2.0 [1.7, 2.3]

3.1 [2.8, 3.4]

2.5 [2.1, 2.9]

4.2 [3.8, 4.5]

Femoral neck BMD

1.7 [1.3, 2.1]

2.2 [1.9, 2.6]

1.9 [1.4, 2.4]

3.1 [2.7, 3.6]

Trochanter BMD

3.2 [2.8, 3.7]

4.6 [4.2, 5.1]

4.0 [3.5, 4.5]

6.2 [5.7, 6.7]

Furthermore, Bonviva 150 mg once monthly was proven superior to ibandronic acid 2.5 mg daily for increases in lumbar spine BMD in a prospectively planned analysis at one year, p=0.002, and at two years, p<0.001.
At one year (primary analysis), 91.3 % (p=0.005) of patients receiving Bonviva 150 mg once monthly had a lumbar spine BMD increase above or equal to baseline (BMD responders), compared with 84.0 % of patients receiving ibandronic acid 2.5 mg daily. At two years, 93.5 % (p=0.004) and 86.4 % of patients receiving Bonviva 150 mg once monthly or ibandronic acid 2.5 mg daily, respectively, were responders.
For total hip BMD, 90.0 % (p<0.001) of patients receiving Bonviva 150 mg once monthly and 76.7 % of patients receiving ibandronic acid 2.5 mg daily had total hip BMD increases above or equal to baseline at one year. At two years 93.4 % (p<0.001) of patients receiving Bonviva 150 mg once monthly and 78.4 %, of patients receiving ibandronic acid 2.5 mg daily had total hip BMD increases above or equal to baseline.
When a more stringent criterion is considered, which combines both lumbar spine and total hip BMD, 83.9 % (p<0.001) and 65.7 % of patients receiving Bonviva 150 mg once monthly or ibandronic acid 2.5 mg daily, respectively, were responders at one year. At two years, 87.1 % (p<0.001) and 70.5 %,of patients met this criterion in the 150 mg monthly and 2.5 mg daily arms respectively.
Biochemical markers of bone turn-over
Clinically meaningful reductions in serum CTX levels were observed at all time points measured, i.e. months 3, 6, 12 and 24. After one year (primary analysis) the median relative change from baseline was -76 % for Bonviva 150 mg once monthly and -67 % for ibandronic acid 2.5 mg daily. At two years the median relative change was -68 % and -62 %, in the 150 mg monthly and 2.5 mg daily arms respectively.
At one year, 83.5 % (p= 0.006) of patients receiving Bonviva 150 mg once monthly and 73.9 % of patients receiving ibandronic acid 2.5 mg daily were identified as responders (defined as a decrease ≥50 % from baseline). At two years 78.7 % (p=0.002) and 65.6 % of patients were identified as responders in the 150 mg monthly and 2.5 mg daily arms respectively.
Based on the results of study BM 16549, Bonviva 150 mg once monthly is expected to be at least as effective in preventing fractures as ibandronic acid 2.5 mg daily.
Ibandronic acid 2.5 mg daily
In the initial three-year, randomised, double-blind, placebo-controlled, fracture study (MF 4411), a statistically significant and medically relevant decrease in the incidence of new radiographic morphometric and clinical vertebral fractures was demonstrated (table 3). In this study, ibandronic acid was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently as an exploratory regimen. Ibandronic acid was taken 60 minutes before the first food or drink of the day (post-dose fasting period). The study enrolled women aged 55 to 80 years, who were at least 5 years postmenopausal, who had a BMD at lumbar spine of 2 to 5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. All patients received 500 mg calcium and 400 IU vitamin D daily. Efficacy was evaluated in 2,928 patients. ibandronic acid 2.5 mg administered daily, showed a statistically significant and medically relevant reduction in the incidence of new vertebral fractures. This regimen reduced the occurrence of new radiographic vertebral fractures by 62 % (p=0.0001) over the three year duration of the study. A relative risk reduction of 61 % was observed after 2 years (p=0.0006). No statistically significant difference was attained after 1 year of treatment (p=0.056). The anti-fracture effect was consistent over the duration of the study. There was no indication of a waning of the effect over time.
The incidence of clinical vertebral fractures was also significantly reduced by 49 % (p=0.011). The strong effect on vertebral fractures was furthermore reflected by a statistically significant reduction of height loss compared to placebo (p<0.0001).
Table 3: Results from 3 years fracture study MF 4411 (%, 95 % CI)

Placebo

(N=974)

ibandronic acid 2.5 mg daily

(N=977)

Relative Risk Reduction

New morphometric vertebral fractures

 

62 % (40.9, 75.1)

Incidence of new morphometric vertebral fractures

9.56 % (7.5, 11.7)

4.68 % (3.2,6.2)

Relative risk reduction of clinical vertebral fracture

 

49 %

(14.03, 69.49)

Incidence of clinical vertebral fracture

5.33 %

(3.73, 6.92)

2.75 %

(1.61, 3.89)

BMD – mean change relative to baseline lumbar spine at year 3

1.26 % (0.8, 1.7)

6.54 % (6.1, 7.0)

BMD – mean change relative to baseline total hip at year 3

-0.69 %

(-1.0, -0.4)

3.36 %

(3.0, 3.7)

The treatment effect of ibandronic acid was further assessed in an analysis of the subpopulation of patients who at baseline had a lumbar spine BMD T-score below –2.5. The vertebral fracture risk reduction was very consistent with that seen in the overall population.
Table 4: Results from 3 years fracture study MF 4411 (%, 95 % CI) for patients with lumbar spine BMD T-score below –2.5 at baseline

Placebo

(N=587)

ibandronic acid 2.5 mg daily

(N=575)

Relative Risk Reduction

New morphometric vertebral fractures

 

59 % (34.5, 74.3)

Incidence of new morphometric vertebral fractures

12.54 % (9.53, 15.55)

5.36 % (3.31, 7.41)

Relative risk reduction of clinical vertebral fracture

 

50 % (9.49, 71.91)

Incidence of clinical vertebral fracture

6.97 % (4.67, 9.27)

3.57 % (1.89, 5.24)

BMD – mean change relative to baseline lumbar spine at year 3

1.13 % (0.6, 1.7)

7.01 % (6.5, 7.6)

BMD – mean change relative to baseline total hip at year 3

-0.70 % (-1.1, -0.2)

3.59 % (3.1, 4.1)

In the overall patient population of the study MF4411, no reduction was observed for non-vertebral fractures, however daily ibandronic acid appeared to be effective in a high-risk subpopulation (femoral neck BMD T-score < -3.0), where a non-vertebral fracture risk reduction of 69% was observed.
Daily treatment with 2.5 mg resulted in progressive increases in BMD at vertebral and nonvertebral sites of the skeleton.
Three-year lumbar spine BMD increase compared to placebo was 5.3 % and 6.5 % compared to baseline. Increases at the hip compared to baseline were 2.8 % at the femoral neck, 3.4 % at the total hip, and 5.5 % at the trochanter.
Biochemical markers of bone turnover (such as urinary CTX and serum Osteocalcin) showed the expected pattern of suppression to premenopausal levels and reached maximum suppression within a period of 3-6 months.
A clinically meaningful reduction of 50 % of biochemical markers of bone resorption was observed as early as one month after start of treatment with ibandronic acid 2.5 mg.
Following treatment discontinuation, there is a reversion to the pathological pre-treatment rates of elevated bone resorption associated with postmenopausal osteoporosis.
The histological analysis of bone biopsies after two and three years of treatment of postmenopausal women showed bone of normal quality and no indication of a mineralization defect.
Paediatric population (see section 4.2 and section 5.2)
Bonviva was not studied in the paediatric population, therefore no efficacy or safety data are available for this patient population.
5.2 Pharmacokinetic properties
The primary pharmacological effects of ibandronic acid on bone are not directly related to actual plasma concentrations, as demonstrated by various studies in animals and humans.
Absorption
The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration and plasma concentrations increase in a dose-proportional manner up to 50 mg oral intake, with greater than dose-proportional increases seen above this dose. Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6 %. The extent of absorption is impaired when taken together with food or beverages (other than water). Bioavailability is reduced by about 90 % when ibandronic acid is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before the first food of the day. Both bioavailability and BMD gains are reduced when food or beverage is taken less than 60 minutes after ibandronic acid is ingested.
Distribution
After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40-50 % of the circulating dose. Protein binding in human plasma is approximately 85 % - 87 % (determined in vitro at therapeutic concentrations), and thus there is a low potential for interaction with other medicinal products due to displacement.
Biotransformation
There is no evidence that ibandronic acid is metabolised in animals or humans.
Elimination
The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption (estimated to be 40-50 % in postmenopausal women) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the faeces.
The range of observed apparent half-lives is broad, the apparent terminal half-life is generally in the range of 10-72 hours. As the values calculated are largely a function of the duration of study, the dose used, and assay sensitivity, the true terminal half-life is likely to be substantially longer, in common with other bisphosphonates. Early plasma levels fall quickly reaching 10 % of peak values within 3 and 8 hours after intravenous or oral administration respectively.
Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance (about 60 mL/min in healthy postmenopausal females) accounts for 50-60 % of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.
The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.
Pharmacokinetics in special clinical situations
Gender
Bioavailability and pharmacokinetics of ibandronic acid are similar in men and women.
Race
There is no evidence for any clinically relevant inter-ethnic differences between Asians and Caucasians in ibandronic acid disposition. There are few data available on patients of African origin.
Patients with renal impairment
Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance.
No dose adjustment is necessary for patients with mild or moderate renal impairment (CLcr equal or greater than 30 ml/min), as shown in study BM 16549 where the majority of patients had mild to moderate renal impairment.
Subjects with severe renal failure (CLcr less than 30 ml/min) receiving daily oral administration of 10 mg ibandronic acid for 21 days, had 2-3 fold higher plasma concentrations than subjects with normal renal function and total clearance of ibandronic acid was 44 ml/min. After intravenous administration of 0.5 mg, total, renal, and non-renal clearances decreased by 67 %, 77 % and 50 %, respectively, in subjects with severe renal failure but there was no reduction in tolerability associated with the increase in exposure. Due to the limited clinical experience, Bonviva is not recommended in patients with severe renal impairment (see section 4.2 and section 4.4). The pharmacokinetics of ibandronic acid was not assessed in patients with end-stage renal disease managed by other than hemodialysis. The pharmacokinetics of ibandronic acid in these patients is unknown, and ibandronic acid should not be used under these circumstances.
Patients with hepatic impairment (see section 4.2)
There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid which is not metabolised but is cleared by renal excretion and by uptake into bone. Therefore dose adjustment is not necessary in patients with hepatic impairment.
Elderly population (see section 4.2)
In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age this is the only factor to take into consideration (see renal impairment section).
Paediatric population (see section 4.2 and section 5.1)
There are no data on the use of Bonviva in these age groups.
5.3 Preclinical safety data
Toxic effects, e.g signs of renal damage, were observed in dogs only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Mutagenicity/Carcinogenicity:
No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of genetic activity for ibandronic acid.
Reproductive toxicity:
There was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acid in orally treated rats and rabbits and there were no adverse effects on the development in F1 offspring in rats at an extrapolated exposure of at least 35 times above human exposure. In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as a class. They include a decreased number of implantation sites, interference with natural delivery (dystocia), and an increase in visceral variations (renal pelvis ureter syndrome).
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Lactose monohydrate
Povidone
Cellulose, microcrystalline
Crospovidone
Stearic acid
Silica, colloidal anhydrous
Tablet coat
Hypromellose
Titanium dioxide (E 171)
Talc
Macrogol 6,000
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Bonviva 150 mg film-coated tablets are supplied in blisters (PVC/PVDC, sealed with aluminium foil) containing 1 or 3 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements. The release of pharmaceuticals in the environment should be minimized.
7. Marketing authorisation holder
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8. Marketing authorisation number(s)
EU/1/03/265/003
EU/1/03/265/004
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 23 February 2004
Date of latest renewal: 18 December 2013
10. Date of revision of the text
21 April 2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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注:以下产品不同规格和不同价格,采购以咨询为准
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产地国家:英国
原产地英文药品名:
IBANDRONATE SODIUM
中文参考药品译名:
伊班膦酸钠
原产地英文商品名:
BONIVA 150mg/tab 1tabs/box
中文参考商品译名:
BONIVA 150毫克/片 1片/盒
生产厂家英文名:
ROCHE
生产厂家中文参考译名:
罗氏
----------------------------------------------------------------
产地国家:土耳其
原产地英文药品名:
IBANDRONATE SODIUM
中文参考药品译名:
伊班膦酸钠
原产地英文商品名:
BONIVA 150mg/tab 3tabs/box
中文参考商品译名:
BONIVA 150毫克/片 3片/盒
生产厂家英文名:
ROCHE
生产厂家中文参考译名:
罗氏
----------------------------------------------------------------
产地国家:日本
原产地英文药品名:
IBANDRONATE SODIUM
中文参考药品译名:
伊班膦酸钠
原产地英文商品名:
BONIVA 100mg/tab 1tabs/box
中文参考商品译名:
BONIVA 100毫克/片 1片/盒
生产厂家英文名:
Toyama Chemical
生产厂家中文参考译名:
富山化学


----------------------------------------------------------------
产地国家:日本
原产地英文药品名:
IBANDRONATE SODIUM
中文参考药品译名:
伊班膦酸钠
原产地英文商品名:
BONIVA 100mg/tab 3tabs/box
中文参考商品译名:
BONIVA 100毫克/片 3片/盒
生产厂家英文名:
Chugai
生产厂家中文参考译名:
中外制药


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FDA批准一月1次的口服伊班膦酸钠片上市
• Administered over 15 to 30 seconds with an IV bolus injection
• Intravenous administration eliminates the need for pre- and post-dose fasting and activity restrictions
• Each BONIVA Injection kit contains a pre-filled syringe, butterfly needle, and two alcohol swabs
• No reconstitution or refrigeration is necessary (store kit between 59°F and 86°F)
• Patients with uncorrected hypocalcemia should not receive BONIVA Injection
• Patients must receive supplemental calcium and vitamin D
• Patients who receive BONIVA Injection should have serum creatinine measured prior to each dose
• Patients with severe renal impairment (creatinine clearance <30 mL/min) should not receive BONIVA Injection
BONIVA Injection is indicated for the treatment of osteoporosis in postmenopausal women.
Important Safety Information for BONIVA Injection
BONIVA Injection is contraindicated in patients with uncorrected hypocalcemia or known hypersensitivity to BONIVA Injection or any of its excipients. BONIVA Injection, like other bisphosphonates administered intravenously, may cause a transient decrease in serum calcium values. Hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism must be effectively treated before starting therapy. Patients must receive supplemental calcium and vitamin D. BONIVA Injection must be administered intravenously only by a healthcare professional. Patients who receive BONIVA Injection should have serum creatinine measured prior to each dose. BONIVA Injection should not be administered to patients with severe renal impairment (serum creatinine >2.3mg/dL or creatinine clearance <30 mL/min). Rarely, patients have reported severe bone, joint, and/or muscle pain after taking bisphosphonate therapy for osteoporosis. Osteonecrosis of the jaw has been reported in patients treated with bisphosphonates; most cases have been in cancer patients undergoing dental procedures who received intravenous bisphosphonates.
In a one-year study comparing BONIVA Injection 3 mg quarterly and BONIVA Tablets 2.5mg daily, the overall safety and tolerability profiles of the two dosing regimens were similar. The most commonly reported adverse events (>5.0%), regardless of causality, were arthralgia (9.6% BONIVA Injection vs 8.6% BONIVA Tablets 2.5 mg), back pain (7.0% vs 7.5%), hypertension (5.3% vs 7.1%), abdominal pain (5.1% vs 5.6%), influenza (4.7% vs 8.0%) and nasopharyngitis (3.4% vs 6.0%). In some patients acute phase reaction-like events (10% BONIVA Injection vs 4% BONIVA Tablets) have been reported within 3 days of an IV dose and lasting for 7 days or less, most commonly after the first injection. In most cases, no specific treatment was required and symptoms subsided within 24-48 hours

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