|
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
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.
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)
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
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. ---------------------------------------------------------------- 注：以下产品不同规格和不同价格，采购以咨询为准 ---------------------------------------------------------------- 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
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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
