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Animal studies are insufficient with respect to reproductive toxicity. The use of this vaccine may be considered during pregnancy, if necessary. It is unknown whether this vaccine is excreted in human milk. No studies of the effects of Havrix Junior Monodose on the ability to drive and use machines have been performed.
However, some of the effects mentioned under section 4. The safety profile presented below is based on data from more than subjects that participated in clinical trials, plus reactions observed through post-marketing surveillance. Swelling at the site of injection was the next most frequently reported reactions. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Metabolism and nutrition disorders. General disorders and administration site conditions. Injection site reaction, such as swelling or induration uncommon with Havrix Junior Monodose formulation. Reporting suspected adverse reactions after authorisation of the medicinal product is important. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: Cases of overdose have been reported during post-marketing surveillance.
Adverse events reported following overdosage were similar to those reported with normal vaccine administration. Havrix confers immunisation against HAV by stimulating specific immune responses evidenced by the induction of antibodies against HAV.
In order to ensure long term protection, a booster dose should be given between 6 and 12 months after the primary dose. In clinical trials, virtually all vaccinees were seropositive one month after the booster dose. Long term persistence of hepatitis A antibody titres has been evaluated following 2 doses of Havrix given 6 to 12 months apart to healthy immunocompetent subjects aged 17 to 40 years.
Current data do not support the need for further booster vaccination among immunocompetent subjects after a 2 dose vaccination course. The efficacy of Havrix was evaluated in different community outbreaks. These studies indicated that administration of a single dose of Havrix contributed to termination of the outbreaks. A reduction in the incidence of hepatitis A was observed in countries where a two-dose Havrix immunization programme was implemented for children in their second year of life:.
The observed reduction in hepatitis A incidence in the general population vaccinated and non-vaccinated in both countries are consistent with herd immunity. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. These data are intended to guide healthcare professionals in case of temporary temperature excursion only.
The incidence of hypoglycaemia was not significantly different between the treatment groups sitagliptin, 1. Body weight decreased from baseline in both groups sitagliptin, In a study comparing the efficacy and safety of the addition of sitagliptin mg once daily or glipizide a sulphonylurea in patients with inadequate glycaemic control on metformin monotherapy, sitagliptin was similar to glipizide in reducing HbA 1c.
However, more patients in the sitagliptin group discontinued due to lack of efficacy than in the glipizide group. Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide In this study, the proinsulin to insulin ratio, a marker of efficiency of insulin synthesis and release, improved with sitagliptin and deteriorated with glipizide treatment.
The incidence of hypoglycaemia in the sitagliptin group 4. A week placebo-controlled study involving patients was designed to evaluate the insulin-sparing efficacy and safety of sitagliptin mg once daily added to insulin glargine with or without metformin at least 1, mg during intensification of insulin therapy.
Baseline HbA 1c was 8. Patients were instructed to titrate their insulin glargine dose based on fingerstick fasting glucose values. The reduction in HbA 1c in patients treated with sitagliptin and insulin with or without metformin was The incidence of hypoglycaemia was The difference was mainly due to a higher percentage of patients in the placebo group experiencing 3 or more episodes of hypoglycaemia 9.
There was no difference in the incidence of severe hypoglycaemia. A study comparing sitagliptin at 25 or 50 mg once daily to glipizide at 2. After 54 weeks, the mean reduction from baseline in HbA 1c was In this study, the efficacy and safety profile of sitagliptin at 25 or 50 mg once daily was generally similar to that observed in other monotherapy studies in patients with normal renal function.
The incidence of hypoglycaemia in the sitagliptin group 6. There was also a significant difference between groups with respect to change from baseline body weight sitagliptin Another study comparing sitagliptin at 25 mg once daily to glipizide at 2.
In this study, the efficacy and safety profile of sitagliptin at 25 mg once daily was generally similar to that observed in other monotherapy studies in patients with normal renal function.
The incidence of hypoglycaemia was not significantly different between the treatment groups sitagliptin, 6. In addition, after 12 weeks, the mean reductions in HbA 1c sitagliptin Over the course of the study, the overall estimated mean SD difference in HbA 1c between the sitagliptin and placebo groups was 0.
The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; first occurrence of the individual components of the primary composite; all-cause mortality; and hospital admissions for congestive heart failure. After a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk of major adverse cardiovascular events or the risk of hospitalization for heart failure compared to usual care without sitagliptin in patients with type 2 diabetes Table 3.
Cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. For composite endpoints, the p-values correspond to a test of non-inferiority seeking to show that the hazard ratio is less than 1. For all other endpoints, the p-values correspond to a test of differences in hazard rates. The European Medicines Agency has deferred the obligation to submit the results of studies with Januvia in one or more subsets of the paediatric population in type 2 diabetes mellitus see section 4.
Following oral administration of a mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations median T max occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, Januvia may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for C max and C 24hr C max increased in a greater than dose-proportional manner and C 24hr increased in a less than dose-proportional manner. The mean volume of distribution at steady state following a single mg intravenous dose of sitagliptin to healthy subjects is approximately litres. Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. Sitagliptin accumulates only minimally with multiple doses. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 hOAT-3 , which may be involved in the renal elimination of sitagliptin.
The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin.
However, ciclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin. In a clinical study sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of p-glycoprotein.
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes. A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin 50 mg in patients with varying degrees of chronic renal impairment compared to normal healthy control subjects.
The study included patients with mild, moderate, and severe renal impairment, as well as patients with ESRD on haemodialysis. In addition, the effects of renal impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, or severe renal impairment including ESRD were assessed using population pharmacokinetic analyses.
Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by approximately 1. Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not necessary. Sitagliptin was modestly removed by haemodialysis No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data.
No dose adjustment is necessary based on gender, race, or body mass index BMI. These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect level for this finding was fold based on the week rat study. The relevance of these findings for humans is unknown.
In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level. Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice.
In rats, there was an increased incidence of hepatic adenomas and carcinomas at systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was likely secondary to chronic hepatic toxicity at this high dose.
Because of the high safety margin fold at this no-effect level , these neoplastic changes are not considered relevant for the situation in humans. No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating. Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal rib malformations absent, hypoplastic and wavy ribs in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels.
Name of the medicinal product 2. Qualitative and quantitative composition 3. Marketing authorisation holder 8. Marketing authorisation number s 9. Date of revision of the text.