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英文药名：Victoza(liraglutide [rDNA origin] injection) 中文药名：利拉鲁肽注射液 生产厂家：诺和诺德公司
Description of selected adverse reactions In a clinical trial with liraglutide as monotherapy, rates of hypoglycaemia reported with liraglutide were lower than rates reported for patients treated with active comparator (glimepiride). The most frequently reported adverse reactions were gastrointestinal disorders, infections and infestations. Hypoglycaemia Most episodes of confirmed hypoglycaemia in clinical trials were minor. No episodes of major hypoglycaemia were observed in the trial with liraglutide used as monotherapy. Major hypoglycaemia may occur uncommonly and has primarily been observed when liraglutide is combined with a sulphonylurea (0.02 events/subject year). Very few episodes (0.001 events/subject year) were observed with administration of liraglutide in combination with oral antidiabetics other than sulphonylureas. The risk of hypoglycaemia is low with combined use of basal insulin and liraglutide (1.0 events per subject year, see section 5.1). Gastrointestinal adverse reactions When combining liraglutide with metformin, 20.7% of patients reported at least one episode of nausea, and 12.6% of patients reported at least one episode of diarrhoea. When combining liraglutide with a sulphonylurea, 9.1% of patients reported at least one episode of nausea and 7.9% of patients reported at least one episode of diarrhoea. Most episodes were mild to moderate and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea. Patients >70 years may experience more gastrointestinal effects when treated with liraglutide. Patients with mild renal impairment (creatinine clearance 60-90 ml/min) may experience more gastrointestinal effects when treated with liraglutide. Withdrawal The incidence of withdrawal due to adverse reactions was 7.8% for liraglutide-treated patients and 3.4% for comparator-treated patients in the long-term controlled trials (26 weeks or longer). The most frequent adverse reactions leading to withdrawal for liraglutide-treated patients were nausea (2.8% of patients) and vomiting (1.5%). Injection site reactions Injection site reactions have been reported in approximately 2% of patients receiving Victoza in long-term (26 weeks or longer) controlled trials. These reactions have usually been mild. Pancreatitis Few cases (<0.2%) of acute pancreatitis have been reported during long-term clinical trials with Victoza. Pancreatitis was also reported post-marketing. Allergic reactions Allergic reactions including urticaria, rash and pruritus have been reported from marketed use of Victoza. Few cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnoea and oedema have been reported with marketed use of Victoza. Few cases (0.05%) of angioedema have been reported during all long-term clinical trials with Victoza. 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 via: Ireland Pharmacovigilance Section Irish Medicines Board Kevin O'Malley House Earlsfort Centre Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 67625177836 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose From clinical trials and marketed use, overdoses have been reported of up to 40 times (72 mg) the recommended maintenance dose. Events reported included severe nausea and severe vomiting. None of the reports included severe hypoglycaemia. All patients recovered without complications. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excl. insulins. ATC code: A10BX07 Mechanism of action Liraglutide is a GLP-1 analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. Following subcutaneous administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidyl peptidase -4 (DPP-4) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life. Liraglutide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in cyclic adenosine monophosphate (cAMP). Liraglutide stimulates insulin secretion in a glucose-dependent manner. Simultaneously, liraglutide lowers inappropriately high glucagon secretion, also in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying. Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake. Pharmacodynamic effects Liraglutide has 24-hour duration of action and improves glycaemic control by lowering fasting and postprandial blood glucose in patients with type 2 diabetes mellitus. Clinical efficacy and safety Five double-blind, randomised, controlled clinical trials were conducted to evaluate the effects of liraglutide on glycaemic control. Treatment with liraglutide produced clinically and statistically significant improvements in glycosylated haemoglobin A1c (HbA1c), fasting plasma glucose and postprandial glucose compared with placebo. These trials included 3,978 exposed patients with type 2 diabetes (2,501 patients treated with Victoza), 53.7% men and 46.3% women, 797 patients (508 treated with liraglutide) were ≥65 years of age and 113 patients (66 treated with liraglutide) were ≥75 years of age. • Glycaemic control Combination with oral antidiabetics Liraglutide in combination therapy, for 26 weeks, with metformin, glimepiride or metformin and rosiglitazone resulted in statistically significant (p<0.0001) and sustained reductions in HbA1c compared with patients receiving placebo (Tables 2 to 5). Combination with metformin Table 2 Victoza in combination with metformin (26 weeks)
Combination with sulphonylurea Table 3 Victoza in combination with glimepiride (26 weeks)
1 Rosiglitazone 4 mg/day; 2 glimepiride 4 mg/day; 3 metformin 2000 mg/day Combination with thiazolidinedione and metformin Table 4 Victoza in combination with metformin + rosiglitazone (26 weeks)
Combination with sulphonylurea and metformin Table 5 Victoza in combination with glimepiride + metformin (26 weeks)
1 The dosing of insulin glargine was open-labelled and was applied according to the following titration guideline. Titration of the insulin glargine dose was managed by the patient after instruction by the investigator. 2 Metformin 2,000 mg/day; 3 rosiglitazone 4 mg twice daily; 4 glimepiride 4 mg/day.
a According to the individualised recommendation by the investigator at the previous visit, for example depending on whether the patient has experienced hypoglycaemia. Combination with insulin In a 104-week clinical trial, 57% of patients with type 2 diabetes treated with insulin degludec in combination with metformin achieved a target HbA1c <7% and the remaining patients continued in a 26-week open label trial and were randomised to add liraglutide or a single dose of insulin aspart (with the largest meal). In the insulin degludec + liraglutide arm, the insulin dose was reduced by 20% in order to minimize the risk of hypoglycaemia. Addition of liraglutide resulted in a statistically significantly greater reduction of HbA1c (-0.73% for liraglutide vs -0.40% for comparator) and body weight (-3.03 vs 0.72 kg). The rate of hypoglycaemic episodes (per patient year of exposure) was statistically significantly lower when adding liraglutide compared to adding a single dose of insulin aspart (1.0 vs 8.15; ratio: 0.13; 95% CI: 0.08 to 0.21). In a 52-week clinical trial, the addition of insulin detemir to liraglutide 1.8 mg and metformin in patients not achieving glycaemic targets on liraglutide and metformin alone resulted in a HbA1c decrease from baseline of 0.54%, compared to 0.20% in the liraglutide 1.8 mg and metformin control group. Weight loss was sustained. There was a small increase in the rate of minor hypoglycaemic episodes (0.23 versus 0.03 events per subject years). • Proportion of patients achieving reductions in HbA1c Liraglutide in combination with metformin, glimepiride, or metformin and rosiglitazone resulted in a statistically significant (p≤0.0001) greater proportion of patients achieving an HbA1c≤6.5% at 26 weeks compared with patients receiving these agents alone. • Fasting plasma glucose Treatment with liraglutide alone or in combination with one or two oral antidiabetic drugs resulted in a reduction in fasting plasma glucose of 13-43.5 mg/dl (0.72-2.42 mmol/l). This reduction was observed within the first two weeks of treatment. • Postprandial glucose Liraglutide reduces postprandial glucose across all three daily meals by 31-49 mg/dl (1.68-2.71 mmol/l). • Beta-cell function Clinical trials with liraglutide indicate improved beta-cell function based on measures such as the homeostasis model assessment for beta-cell function (HOMA-B) and the proinsulin to insulin ratio. Improved first and second phase insulin secretion after 52 weeks treatment with liraglutide was demonstrated in a subset of patients with type 2 diabetes (N=29). • Body weight Liraglutide in combination with metformin, metformin and glimepiride or metformin and rosiglitazone was associated with sustained weight reduction over the duration of trials in a range from 1.0 kg to 2.8 kg. Larger weight reduction was observed with increasing body mass index (BMI) at baseline. • Cardiovascular evaluation Blood pressure Over the duration of the trials, liraglutide decreased the systolic blood pressure on average of 2.3 to 6.7 mmHg from baseline and compared to active comparator the decrease was 1.9 to 4.5 mmHg. Post-hoc analysis of serious major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke) from all intermediate and long-term phase 2 and 3 trials (ranging from 26 and up to 100 weeks duration) including 5,607 patients (3,651 exposed to liraglutide), showed no increase in cardiovascular risk (incidence ratio of 0.75 (95% CI 0.35; 1.63) for the composite endpoint for liraglutide versus all comparators (metformin, glimepiride, rosiglitazone, insulin glargine, placebo)). High-risk cardiovascular patients were excluded from the trials and the incidence rates of serious major cardiovascular events in the trials were low (6.02 per 1,000 patient years in liraglutide-treated patients and 10.45 in all-comparator-treated patients), precluding firm conclusions. Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop anti-liraglutide antibodies following treatment with liraglutide. On average, 8.6% of patients developed antibodies. Antibody formation has not been associated with reduced efficacy of liraglutide. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Victoza in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use). Other clinical data In an open label trial comparing the efficacy and safety of liraglutide (1.2 mg and 1.8 mg) and sitagliptin (a DPP-4 inhibitor, 100 mg) in patients inadequately controlled on metformin therapy (mean HbA1c 8.5%), liraglutide at both doses was statistically superior to sitagliptin treatment in reducing HbA1c after 26 weeks (-1.24%, -1.50% vs -0.90%, p<0.0001). Patients treated with liraglutide had a significant decrease in body weight compared to that of patients treated with sitagliptin (-2.9 kg and -3.4 kg vs -1.0 kg, p<0.0001). Greater proportions of patients treated with liraglutide experienced transient nausea vs patients treated with sitagliptin (20.8% and 27.1% for liraglutide vs. 4.6% for sitagliptin). The reductions in HbA1c and superiority vs sitagliptin observed after 26 weeks of liraglutide treatment (1.2 mg and 1.8 mg) were sustained after 52 weeks of treatment (-1.29% and -1.51% vs -0.88%, p<0.0001). Switching patients from sitagliptin to liraglutide after 52 weeks of treatment resulted in additional and statistically significant reduction in HbA1c (-0.24% and -0.45%, 95% CI: -0.41 to -0.07 and -0.67 to -0.23 ) at week 78, but a formal control group was not available. In an open label trial comparing the efficacy and safety of liraglutide 1.8 mg once daily and exenatide 10 mcg twice daily in patients inadequately controlled on metformin and/or sulphonylurea therapy (mean HbA1c 8.3%), liraglutide was statistically superior to exenatide treatment in reducing HbA1c after 26 weeks (-1.12% vs -0.79%; estimated treatment difference: -0.33; 95% CI: -0.47 to -0.18). Significantly more patients achieved HbA1c below 7% with liraglutide compared with exenatide (54.2% vs 43.4%, p=0.0015). Both treatments resulted in mean body weight loss of approximately 3 kg. Switching patients from exenatide to liraglutide after 26 weeks of treatment resulted in an additional and statistically significant reduction in HbA1c (-0.32%, 95% CI: -0.41 to -0.24) at week 40, but a formal control group was not available. During the 26 weeks, there were 12 serious events in 235 patients (5.1%) using liraglutide, whereas there were 6 serious adverse events in 232 patients (2.6%) using exenatide. There was no consistent pattern with respect to system organ class of events. 5.2 Pharmacokinetic properties Absorption The absorption of liraglutide following subcutaneous administration is slow, reaching maximum concentration 8-12 hours post dosing. Estimated maximum liraglutide concentration was 9.4 nmol/l for a subcutaneous single dose of liraglutide 0.6 mg. At 1.8 mg liraglutide, the average steady state concentration of liraglutide (AUC/24) reached approximately 34 nmol/l. Liraglutide exposure increased proportionally with dose. The intra-subject coefficient of variation for liraglutide AUC was 11% following single dose administration. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%. Distribution The apparent volume of distribution after subcutaneous administration is 11-17 l. The mean volume of distribution after intravenous administration of liraglutide is 0.07 l/kg. Liraglutide is extensively bound to plasma proteins (>98%). Biotransformation During 24 hours following administration of a single radiolabelled [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Two minor plasma metabolites were detected (≤9% and ≤5% of total plasma radioactivity exposure). Liraglutide is metabolised in a similar manner to large proteins without a specific organ having been identified as major route of elimination. Elimination Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or faeces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or faeces (6% and 5%, respectively). The urine and faeces radioactivity was mainly excreted during the first 6-8 days, and corresponded to three minor metabolites, respectively. The mean clearance following subcutaneous administration of a single dose liraglutide is approximately 1.2 l/h with an elimination half-life of approximately 13 hours. Special populations Elderly patients: Age had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results from a pharmacokinetic study in healthy subjects and population pharmacokinetic data analysis of patients (18 to 80 years). Gender: Gender had no clinically meaningful effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic data analysis of male and female patients and a pharmacokinetic study in healthy subjects. Ethnic origin: Ethnic origin had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analysis which included patients of White, Black, Asian and Hispanic groups. Obesity: Population pharmacokinetic analysis suggests that body mass index (BMI) has no significant effect on the pharmacokinetics of liraglutide. Hepatic impairment: The pharmacokinetics of liraglutide was evaluated in patients with varying degree of hepatic impairment in a single-dose trial. Liraglutide exposure was decreased by 13-23% in patients with mild to moderate hepatic impairment compared to healthy subjects. Exposure was significantly lower (44%) in patients with severe hepatic impairment (Child Pugh score >9). Renal impairment: Liraglutide exposure was reduced in patients with renal impairment compared to individuals with normal renal function. Liraglutide exposure was lowered by 33%, 14%, 27% and 28%, respectively, in patients with mild (creatinine clearance, CrCl 50-80 ml/min), moderate (CrCl 30-50 ml/min), and severe (CrCl <30 ml/min) renal impairment and in end-stage renal disease requiring dialysis. 5.3 Preclinical safety data Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeat-dose toxicity or genotoxicity. Non-lethal thyroid C-cell tumours were seen in 2-year carcinogenicity studies in rats and mice. In rats, a no observed adverse effect level (NOAEL) was not observed. These tumours were not seen in monkeys treated for 20 months. These findings in rodents are caused by a non-genotoxic, specific GLP-1 receptor-mediated mechanism to which rodents are particularly sensitive. The relevance for humans is likely to be low but cannot be completely excluded. No other treatment-related tumours have been found. Animal studies did not indicate direct harmful effects with respect to fertility but slightly increased early embryonic deaths at the highest dose. Dosing with Victoza during mid-gestation caused a reduction in maternal weight and foetal growth with equivocal effects on ribs in rats and skeletal variation in the rabbit. Neonatal growth was reduced in rats while exposed to Victoza, and persisted in the post-weaning period in the high dose group. It is unknown whether the reduced pup growth is caused by reduced pup milk intake due to a direct GLP-1 effect or reduced maternal milk production due to decreased caloric intake. Following intra-arterial injection of liraglutide to rabbits, slight to moderate haemorrhage, erythema and swelling at the injection site were observed. 6. Pharmaceutical particulars 6.1 List of excipients Disodium phosphate dihydrate Propylene glycol Phenol Water for injections 6.2 Incompatibilities Substances added to Victoza may cause degradation of liraglutide. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 30 months. After first use: 1 month. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Store away from the freezer compartment. After first use: Store below 30°C or store in a refrigerator (2°C - 8°C). Do not freeze. Keep the cap on the pen in order to protect from light. 6.5 Nature and contents of container Cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper (bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polyolefin and polyacetal. Each pen contains 3 ml solution, delivering 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg. Pack sizes of 1, 2, 3, 5 or 10 pre-filled pens. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Victoza should not be used if it does not appear clear and colourless, or almost colourless. Victoza should not be used if it has been frozen. Victoza can be administered with needles up to a length of 8 mm and as thin as 32G. The pen is designed to be used with NovoFine or NovoTwist disposable needles. Needles are not included. The patient should be advised to discard the injection needle in accordance with local requirements after each injection and store the pen without an injection needle attached. This prevents contamination, infection and leakage. It also ensures that the dosing is accurate. 7. Marketing authorisation holder Novo Nordisk A/S |
