Description
Release form
Solution for sc administration is transparent, colorless.
0.5 ml: dulaglutide 0.75 mg
Excipients:
sodium citrate dihydrate 1.37 mg,
citric acid anhydrous 0.07 mg,
mannitol 23.2 mg,
polysorbate 80 (vegetable) 0.10 mg,
water d / qs up to 0.5 ml.
0.5 ml – syringes (1) – syringe pens (4) – packs of cardboard.
Pharmacological action of
Pharmacological action of
Mechanism of action of
Dulaglutide is a long-acting glucagon-like peptide l (GLP-1) receptor agonist. Its molecule consists of two identical chains linked by disulfide bonds, each of which contains an analogue of the modified human GLP-1, covalently linked to the heavy chain (Fc) fragment of the modified human immunoglobulin G4 (IgG4) using a small polypeptide chain.
The portion of dulaglutide, which is an analogue of GLP-1, is approximately 90% homologous to native human GLP-1. The half-life (t1 / 2) of native human GLP-1 due to cleavage by dipeptidyl peptidase-4 (DPP-4) and renal clearance is 1.5-2 minutes. Unlike native GLP-1, dulaglutide is resistant to DPP-4 cleavage and is large in size, which slows down absorption and reduces renal clearance. Such structural features provide a soluble form and a half-life of 4.7 days, which makes the drug suitable for subcutaneous administration once a week. In addition, the molecule of dulaglutide was created in order to reduce the immune response mediated by the Fc receptor and to reduce the immunogenic potential.
The hypoglycemic effect of dulaglutide is due to several mechanisms of action of GLP-1. With an increased glucose concentration, dulaglutide increases the content of intracellular cyclic adenosine monophosphate (cAMP) in the pancreatic beta cells, which leads to an increase in insulin secretion. Dulaglutide suppresses the excessive secretion of glucagon in patients with type 2 diabetes, which leads to a decrease in the release of glucose by the liver. In addition, dulaglutide slows the rate of gastric emptying.
Pharmacodynamics of
In patients with type 2 diabetes, starting from the first administration, dulaglutide improves glycemic control due to a steady decrease in fasting blood glucose concentration, before meals and after meals, which is maintained for a week before the next dose.
A pharmacodynamic study of dulaglutide showed that in patients with type 2 diabetes mellitus, the first phase of insulin secretion was restored to the value observed in healthy individuals who received placebo, and the second phase of insulin secretion improved in response to intravenous bolus administration. In the same study, it was also shown that with a single administration of dulaglutide at a dose of 1.5 mg, the maximum secretion of insulin by β-cells of the pancreas increased and the function of β-cells in patients with type 2 diabetes was improved compared with placebo.
The pharmacokinetic profile and the corresponding pharmacodynamic profile of dulaglutide allows the drug to be administered once a week.
Clinical efficacy and safety of
glycemic control
Safety and efficacy of dulaglutide were evaluated in 6 randomized controlled trials of phase III, in which 5171 patients with type 2 diabetes took part. Of these, 958 were over the age of 65, of which 93 were over the age of 75. The study data included 3136 patients who received dulaglutide, of which 1719 received dulaglutide at a dose of 1.5 mg once a week, and 1417 received dulaglutide at a dose of 0.75 mg once a week. In all studies, dulaglutide provided a clinically significant improvement in glycemic control, which was evaluated by glycated hemoglobin (HbAlc).
Monotherapy
The use of dulaglutide in monotherapy was studied in a clinical trial with an active control lasting 52 weeks compared with metformin. The effectiveness of dulaglutide when used in doses of 1.5 mg or 0.75 mg once a week was superior to the effectiveness of metformin at a dose of 1500-2000 mg / day in reducing HbAlc, and a significantly larger number of patients reached the HbAlc target. The frequency of documented cases of symptomatic hypoglycemia when using dulaglutide at doses of 1.5 mg or 0.75 mg once a week and when using metformin was 0.62 0.15 and 0.09 episodes / patient / year, respectively. There were no cases of severe hypoglycemia with dulaglutide.
Therapy in combination with metformin
The safety and efficacy of dulaglutide was evaluated in a placebo-controlled and actively-controlled clinical trial (sitagliptin 100 mg / day) lasting 104 weeks, in which all drugs were used in combination with metformin. The use of dulaglutide in doses of 1.5 mg or 0.75 mg once a week after 52 weeks led to a greater decrease in HbAlc compared with the use of sitagliptin, at the same time, a significantly larger number of patients when using dulaglutide reached the target HbAlc. The frequency of documented symptomatic hypoglycemia when using dulaglutide at doses of 1.5 mg or 0.75 mg once a week and when using sitagliptin was 0.19 0.18 and 0.17 episodes / patient / year, respectively. There were no cases of severe hypoglycemia with dulaglutide.
The safety and efficacy of dulaglutide was also evaluated in an actively controlled study compared with the use of liraglutide at a dose of 1.8 mg / day (the initial dose of 0.6 mg / day after 1 week, the dose was increased to 1.2 mg / day, and then at 2 weeks to 1.8 mg / day) for 26 weeks, both drugs were used in combination with metformin. The use of dulaglutide in a dose of 1. 5 mg once a week led to a comparable decrease in HbAlc and the number of patients who reached the target HbAlc. The frequency of documented symptomatic hypoglycemia with dulaglutide at a dose of 1.5 mg 1 time per week was 0.12 episodes / patient / year, and with liraglutide 0.29 episodes / patient / year. No cases of severe hypoglycemia were observed.
Therapy in combination with metformin and sulfonylurea derivatives
In a study with an active control of 78 weeks duration, dulaglutide was compared with insulin glargine, both drugs were used in combination with metformin and sulfonylurea derivatives. After 52 weeks, the use of dulaglutide at a dose of 1.5 mg once a week led to a significantly greater decrease in HbAlc compared with the use of insulin glargine, which persisted after 78 weeks, while a decrease in HbAlc with dulaglutide at a dose of 0.75 mg once a week was comparable to a decrease in HbAlc with insulin glargine. In the group of dulaglutide at a dose of 1.5 mg, a significantly larger number of patients reached the target HbAlc. The frequency of documented cases of symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once a week and with insulin glargine amounted to 1.67 1.67 and 3.02 episodes / patient / year respectively. When using dulaglutide at a dose of 1.5 mg once a week and when using insulin glargine, the same number of cases of severe hypoglycemia was observed (2 cases each).
Therapy in combination with metformin and pioglitazone
In placebo-controlled studies and studies with active control (the dose of exenatide was 5 mcg 2 times a day for the first 4 weeks and 10 mcg 2 times a day later), when using both drugs in combination with metformin and pioglitazone with the administration of dulaglutide in doses of 1.5 mg or 0.75 mg once a week, a significantly more significant decrease in HbAlc was demonstrated compared with placebo and exenatide, which was accompanied by a significantly larger number of patients who achieved goal Vågå index HbAlc frequency documented cases of symptomatic hypoglycemia dulaglutida when applied at doses of 1.5 mg or 0.75 mg once a week 1 and exenatide 2 times a day, was 0.19 0.14 and 0.75 episodes / patient / year, respectively. When dulaglutide was used, there were no cases of severe hypoglycemia, while exenatide was used, 2 cases of severe hypoglycemia were noted.
Therapy in combination with insulin, with or without metformin metformin
In a clinical trial, patients who received insulin 1 or 2 times a day before the study started discontinued the previous regimen and were randomized to dulaglutide groups once a week or insulin glargine 1 once a day, both treatment regimens were carried out in combination with lispro prandial insulin, administered 3 times a day in combination with metformin or without metformin. After 26 weeks, the effectiveness of dulaglutide when used in doses of 1.5 mg or 0.75 mg once a week was superior to the effectiveness of insulin glargine in reducing HbAlc, the same effect persisted until week 52 of the study. The average change in HbAlc for dulaglutide administration groups at a dose of 1.5 mg or 0.75 mg once a week and insulin glargine administration groups once a day was -1.64% [p
Pharmacokinetics
Absorption
After sc administration to patients with type 2 diabetes mellitus the maximum plasma concentration (Cmax) of dulaglutide is observed after 48 hours. After repeated subcutaneous administration of dulaglutide at a dose of 1.5 mg to patients with type 2 diabetes mellitus, the average Cmax and the area under the concentration-time curve (AUC) were approximately 114 ng / ml and 14,000 ngh / ml, respectively about. An equilibrium plasma concentration was observed after 2-4 weeks of administration of dulaglutide at a dose of 1.5 mg once a week. Concentrations after sc administration of a single dose of dulaglutide (1.5 mg) in the abdomen, thigh, or shoulder were comparable. The average absolute bioavailability of dulaglutide after a single sc administration at a dose of 1.5 mg or 0.75 mg was 47% and 65%, respectively.
Distribution of
After sc administration of dulaglutide at doses of 0.75 mg or 1.5 mg in patients with type 2 diabetes mellitus in equilibrium, the average Vd was approximately 19.2 L and 17.4 L, respectively.
Metabolism
Dulaglutide is thought to break down into its constituent amino acids through the main pathways of protein catabolism.
Excretion
The average clearance of dulaglutide in humans in equilibrium after administration at doses of 0.75 mg or 1.5 mg was 0.073 l / h and 0.107 l / h, respectively, with T1 / 2 4.5 and 4.7 days, respectively.
Special patient groups
Elderly patients (over 65)
Patient age did not have a clinically significant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide.
Sex and race
Gender and race did not have a clinically significant effect on the pharmacokinetics of dulaglutide.
Body mass or body mass index
Pharmacokinetic analysis showed a statistically significant inverse relationship between body weight or body mass index (BMI) and dulaglutil therapy, however, there was no clinically significant effect of body weight or BMI on glycemic control.
Patients with impaired renal function
The pharmacokinetics of dulaglutide was evaluated during a clinical and pharmacological study,
Patients with impaired liver function
The pharmacokinetics of dulaglutide was evaluated during a clinical and pharmacological study, in which patients with impaired liver function showed a statistically significant decrease in mean Cmax and AUC by 30% and 33%, respectively, compared with healthy patients. When liver function worsened, the time to reach Cmax (tmax) of dulaglutide increased. The pharmacokinetic parameters of dulaglutide did not depend on the degree of impaired liver function. Such changes were not considered clinically significant.
Children
Studies of the pharmacokinetics of dulaglutide in children have not been conducted.
Indications
The drug Trulicity ¢ is indicated in adult patients with type 2 diabetes mellitus in order to improve glycemic control in the form of: –
monotherapy If the diet and exercise do not provide the necessary glycemic control in patients who are not indicated for use of metformin because intolerance or contraindications.
– combination therapy
In combination with other hypoglycemic drugs, including insulin, if these drugs along with diet and exercise do not provide the necessary glycemic control.
Pregnancy and lactation
Pregnancy
There are no data on the use of dulaglutide in pregnant women or their volume is limited. Animal studies have shown reproductive toxicity, so the use of dulaglutide is contraindicated during pregnancy.
Breastfeeding
There is no information on the penetration of dulaglutide into breast milk. The risk to newborns / infants cannot be ruled out. The use of dulaglutide during breastfeeding is contraindicated.
Special instructions
Dulaglutide is not recommended for use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Gastrointestinal disorders
Use of GLP-1 receptor agonists may be associated with adverse reactions in the gastrointestinal tract. This should be considered when using dulaglutide in patients with impaired renal function, since dyspeptic symptoms (nausea, vomiting and / or diarrhea) can cause dehydration, which can lead to impaired renal function. The use of dulaglutide in patients with severe gastrointestinal diseases, including severe paresis of the stomach, has not been studied, therefore, the drug is not recommended for this group of patients.
Acute pancreatitis
Use of GLP-1 receptor agonists is associated with a risk of developing acute pancreatitis. Clinical studies have reported cases of acute pancreatitis associated with dulaglutide therapy. Patients should be informed of the characteristic symptoms of acute pancreatitis, including persistent severe pain in the abdomen. If pancreatitis is suspected, dulaglutide therapy should be discontinued. When confirming the diagnosis of pancreatitis, dulaglutide should be discontinued without resuming therapy. In the absence of other signs and characteristic symptoms of acute pancreatitis, increased pancreatic enzyme activity alone is not a prognostic factor for acute pancreatitis.
Hypoglycemia
Patients receiving dulaglutide concurrently with sulfonylurea derivatives or insulin may be at increased risk for hypoglycemia. The risk of hypoglycemia can be reduced by reducing the dose of sulfonylurea derivatives or insulin.
Unstudied patient groups
Experience with dulaglutide in patients with chronic heart failure is limited.
Sodium content
The preparation contains less than 1 mmol of sodium (23 mg) per dose of 1.5 mg, those. practically does not contain sodium.
Fertility
There are no data on the effects of dulaglutide on fertility in humans. In rats, there was no direct effect on mating or fertility after dulaglutide administration.
Impact on the ability to drive vehicles and mechanisms
Dulaglutide has minimal or no effect on the ability to drive vehicles and mechanisms. When using dulaglutide in combination with sulfonylurea derivatives or insulin, caution is recommended to avoid the development of hypoglycemia when driving vehicles and mechanisms.
Side effects of
During clinical trials of phases II and III, 4006 patients received dulaglutide as monotherapy or in combination with other hypoglycemic drugs. The most common adverse reactions in clinical trials were reactions from the gastrointestinal tract, including nausea, vomiting, and diarrhea. In general, these reactions were mild or moderate and temporary in character. The following adverse reactions were identified during the evaluation of the results of clinical trials of phase II and III: they are indicated in accordance with the damage to organs and organ systems in decreasing order of frequency (very often:> 1/10: often:> 1/100 – 1/1000 – 1/10000 – Description of individual adverse reactions
Hypoglycemia
When using dulaglutide in doses 0.75 mg or 1.5 mg once a week as monotherapy or in combination with metformin or metformin and pioglitazone, the frequency of documented symptomatic hypoglycemia ranged from 5.9% to 10.9% or from 0.14 to 0.62 events / patient / year, no cases of severe hypoglycemia were noted. the use of dulaglutide in doses of 0.75 mg or 1.5 mg once a week in combination with sulfonylurea derivatives (plus metformin), the frequency of documented symptomatic hypoglycemia was 39.0% and 40.3%, or 1.67 and 1.67 events / patient / year, respectively. The incidence of severe hypoglycemia was 0% and 0.7%, or 0.00 and 0.01 events / patient / year, respectively. When using dulaglutide in doses of 0.75 mg or 1.5 mg once a week in combination with prandial insulin, the incidence of hypoglycemia was 85.3% and 80.0% or 35.66 and 31.06 events / patient / year, respectively. The incidence of severe hypoglycemia was 2.4% and 3.4%, or 0.05 and 0.06 events / patient / year, respectively.
Adverse reactions from the gastrointestinal tract
Cumulative reporting of gastrointestinal events for up to 104 weeks when dulaglutide was used in doses of 0.75 mg or 1.5 mg once a week, respectively, included nausea (12.9% and 21.2%), diarrhea (10.7% and 13.7%) and vomiting (6.9% and 11.5%). They usually had mild or moderate severity, their maximum frequency was observed during the first 2 weeks of therapy and rapidly decreased over the next 4 weeks, after which the frequency remained relatively constant. In clinical and pharmacological studies, which were carried out with the participation of patients with type 2 diabetes mellitus and lasted up to 6 weeks, most gastrointestinal events were noted during the first 2-3 days after taking the first dose, their frequency decreased with the following doses.
Acute pancreatitis
The incidence of acute pancreatitis in clinical trials of phase II and III was 0.07% when using dulaglutide compared with 0.14% when using placebo and 0.19% when using comparison drugs, with or without additional basic hypoglycemic therapy. Pancreatic enzymes The use of dulaglutide is associated with an average increase in the activity of pancreatic enzymes (lipase and / or pancreatic amylase) by 11-21% compared to baseline. In the absence of other signs and symptoms of acute pancreatitis, increased pancreatic enzyme activity is not a prognostic factor for the development of acute pancreatitis.
Increased heart rate
When using dulaglutide in doses of 0.75 mg or 1.5 mg once a week, a slight average increase in heart rate by 2-4 beats per minute (bpm) and sinus tachycardia frequency was observed by 1.3% and 1.4%, respectively , which was accompanied by an increase compared to the initial rate by> 15 bpm. Atrioventricular block I degree / increase in the PR interval When using dulaglutide in doses of 0.75 mg or 1.5 mg once a week, a slight average increase in the PR interval by 2-3 ms was observed, compared with the initial indicator, and the frequency of atrioventricular block I degree by 1.5% and 2.4% respectively.
Immunogenicity
During clinical trials, the use of dulaglutide was accompanied by the detection of antibodies to dulaglutide that appeared during therapy with a frequency of 1.6%, which indicates that structural changes in GLP-1 and modified sections of IgG4 in the molecule of dulaglutide along with high homology to native GLP-1 and native IgG4 minimize the risk of developing an immune response with dulaglutide therapy. Patients who developed antibodies to dulaglutide usually had a low titer of antibodies, however despite the small number of patients who developed antibodies to dulaglutide, evaluation of the results of phase III clinical studies did not reveal a clear effect of antibodies to dulaglutide on the change in HbAlc.
Hypersensitivity
In clinical trials of phase II and III, the phenomena of systemic hypersensitivity (severe urticaria, extensive rashes, swelling of the face, swelling of the lips) were observed in 0.5% of patients who received dulaglutide. None of the patients with systemic hypersensitivity developed antibodies to dulaglutide.
Reactions at the injection site
Reactions at the injection site were observed in 1.9% of patients receiving dulaglutide. Potentially immuno-mediated adverse events at the injection site (e.g., rash, erythema) were observed in 0.7% of patients and were usually mild.
Early termination of participation in clinical trials due to adverse events
During studies lasting 26 weeks, the frequency of early termination of participation due to adverse events was 2.6% (0.75 mg once a week) and 6.1% (1.5 mg once a week) when applied dulaglutide compared with 3.7% with placebo. Throughout the study (up to 104 weeks), the frequency of early termination due to adverse events when using dulaglutide was 5.1% (0.75 mg once a week) and 8.4% (1.5 mg once a week). The most common adverse reactions that led to the early termination of participation in dulaglutide use groups at doses of 0.75 mg or 1.5 mg once a week were nausea (1.0% and 1.9%), diarrhea (0.5% and 6%) and vomiting (0.4%) and 0.6%), mainly such reactions were observed during the first 4-6 weeks of therapy.
Drug interactions
Dulaglutide causes a delay in the rate of gastric emptying, therefore, it has the ability to affect the absorption of oral drugs when used simultaneously. Dulaglutide should be used with caution in patients taking oral medications that require rapid absorption in the gastrointestinal tract. A delay in the rate of gastric emptying may slightly increase the exposure of sustained-release drugs by increasing the time of drug release.
Paracetamol
After administration of the first dose of dulaglutide in doses of 1 or 3 mg, Cmax of paracetamol decreased by 36% and 50%, respectively, and the median Tmax was reached later (after 3 and 4 hours, respectively). After simultaneous use with dulaglutide at a dose of up to 3 mg in equilibrium, there was no statistically significant difference in the values of AUC (0-?) (Area under the concentration-time curve from 0 to 12 hours), Cmax or Tmax of paracetamol. When used with dulaglutide, dose adjustment of paracetamol is not required.
Atorvastatin
The simultaneous use of dulaglutide with atorvastatin caused a decrease in Cmax and AUC (0-12) of atorvastatin and its main metabolite, o-hydroxyatorvastatin, to 70% and 21%, respectively. The average T1 / 2 of atorvastatin and o-hydroxyatorvastatin after administration of dulaglutide increased by 17% and 41%, respectively. Such changes are not considered clinically significant. When combined with dulaglutide dose adjustment of atorvastatin is not required.
Digoxin
After the simultaneous use of digoxin in equilibrium with two consecutive doses of dulaglutide, the total exposure (AUCt) and Tmax of digoxin did not change. Cmax decreased as much as 22%. It is believed that such a change has no clinical consequences. When used with dulaglutide, dose adjustment of digoxin is not required.
Antihypertensive drugs
The simultaneous use of multiple doses of dulaglutide with lisinopril in the equilibrium state did not cause clinically significant changes in AUC or max max of lisinopril. A statistically significant delay Tmax of lisinopril for approximately 1 h was observed on days 3 and 24 of the study. With the simultaneous use of a single dose of dulaglutide with metoprolol, AUC or Cmax of metoprolol increased by 19% and 32%, respectively. Despite the fact that Cmax of metoprolol was reached 1 hour later, this change was not statistically significant. These changes were not considered clinically significant, therefore, dose adjustment of lisinopril or metoprolol when used with dulaglutide is not required.
Warfarin
After simultaneous use with dulaglutide, the concentrations of S- and R-warfarin, as well as Cmax R-warfarin did not change, and Cmax S-warfarin decreased to 22%, the area under the concentration-time curve for the international normalized ratio (AUCMNO) increased by 2%, which probably has no clinical value, no effect on the maximum value of the international normalized ratio (INRmax) was observed. The response time according to the international normalized ratio (TMHOmax) was extended by 6 hours, which is consistent with a Tmax delay of approximately 4 and 6 hours for S- and R-warfarin, respectively. Such changes are not considered clinically significant. Dose adjustment of warfarin when used with dulaglutide is not required.
Oral contraceptives
Concomitant use of dulaglutide with oral contraceptives (norgestimate 0.18 mg / ethinyl estradiol 0.025 mg) did not affect the total exposure of norelgestromine and aginyl estradiol. For norelgestromine and ethinyl estradiol, a statistically significant decrease in Cmax by 26% and 13% and a delay in Tmax by 2 and 0.30 h, respectively, were observed. Such observations are not considered clinically significant. Dose adjustment of oral contraceptives when used with dulaglutide is not required.
Metformin
After multiple doses of dulaglutide and metformin were administered simultaneously with normal equilibrium release, AUCt increased to 15%. and Cmax decreased to 12%, Tmax did not change. Such changes correspond to the delay in gastric emptying caused by dulaglutide, and are within the variability of metformin pharmacokinetics and are therefore not considered clinically significant. Dosage adjustment of metformin usual release with simultaneous use with dulaglutide is not required.
Sitagliptin
With simultaneous use with a single dose of dulaglutide, the concentration of sitagliptin did not change. After simultaneous use with two consecutive doses of dulaglutide AUC0-t) and Cmax, sitagliptin decreased by approximately 7.4% and 23.1%, respectively. Tmax of sitagliptin increased by approximately 0.5 h after simultaneous use with dulaglutide compared with monotherapy with sitagliptin. Sitagliptin can cause inhibition of 80% DPP-4 within 24 hours. With the simultaneous use of dulaglutide and sitagliptin, the exposure and Cmax of dulaglutide increased by approximately 38% and 27%, respectively, and the median Tmax increased by approximately 24 h. Thus, dulaglutide has a high degree of protection against inactivation of DPP-4.
Overdose of
Symptoms of an overdose of dulaglutide in clinical trials included gastrointestinal disturbances and hypoglycemia.
treatment. In case of an overdose, it is necessary to begin symptomatic therapy in accordance with the clinical signs and symptoms.
Storage conditions
Do not freeze in a dark place at a temperature of 2 to 8 ° C.
Do not use if it has been frozen.
The drug purchased in a pharmacy can be stored at a temperature not exceeding 30 ° C for 14 days.
Keep out of the reach of children.
Expiration
2 years. Do not use after the expiry date stated on the packaging.
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