Trulicity solution for p / leather. the introduction of 1.5 mg / 0.5 ml syringe pen 0.5 ml 4 pcs. (Dulahlutyd)

Latin name

TRULICITY

Release form

Solution for SC administration transparent, colorless.

Indications

The drug Trulicity ™ is indicated in adult patients with type 2 diabetes mellitus in order to improve glycemic monitoring in the form of:

- monotherapy

If diet and exercise do not provide the desired glycemic control in patients, which do not show the use of metformin because of intolerance or the presence of 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.

Contraindications

- hypersensitivity to the active or any of the excipients that are part of the drug

- type 1 diabetes diseases of the gastrointestinal tract, including severe paresis of the stomach

- acute pancreatitis

- children under 18 years of age.

Caution: in patients taking oral medications, which require rapid absorption in the gastrointestinal tract in patients aged 75 years and older.

Use during 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, therefore, 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 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 taken into account when using dulaglutide in patients with impaired renal function, since dyspeptic symptoms (nausea, vomiting and / or diarrhea) can cause dehydration, which can lead to a deterioration of 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.

Composition

Active ingredient:

dulaglutide 1.5 mg

Excipients:

citric acid anhydrous 0.07 mg

mannitol 23.2 mg

polysorbate 80 (plant) 0.10 mg

sodium citrate 7 citrate 7 citrate water for injection qs up to 0.5 ml.

Side effects

Overview of the

safety profile 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 listed in the table 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 -

Table: Frequency of adverse reactions with dulaglutide

Organs and organ systems Very often Often Infrequently Rarely

Metabolic and nutritional disorders Hypoglycemia *

(when used in combination with prandial insulin metformin1 or metformin and glimepipe readom) Hypoglycemia * (when used as monotherapy or in combination with metformin plus pioglitazone)

Gastrointestinal disorders Nausea, diarrhea, vomiting1, abdominal pain Decreased appetite, dyspepsia, constipation, flatulence, bloating, gastroesophageal reflux disease, belching Acute pancreatitis

General disorders and disorders at the injection site Weakness Reactions at the injection site

Laboratory and instrumental data Sinus tachycardia, atrioventricular block (AVB) of the first degree

* documented blood pressure only for symptomatic 1 dose of 1.5 mg. The frequency of adverse reactions for dulaglutide at a dose of 0.75 mg corresponds to a lower category.

Description of individual adverse reactions

Hypoglycemia

When applying dulaglutide in doses of 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.

When using 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%). Usually they 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 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, there was a slight average increase in heart rate by 2-4 beats per minute (bpm) and sinus tachycardia by 1.3% and 1.4%, respectively, which was accompanied by an increase of> 15 bpm / min

I stage atrioventricular block / increase in the PR interval

When applying 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

In 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 IgG4 sites in the dulaglutide molecule along with the high homology to native GLP-1 and native IgG4 minimize the risk of developing an immune response during treatment with dulaglutide. Patients who developed antibodies to dulaglutide usually had a low titer of antibodies, however, despite the small number of patients who formed antibodies to dulaglutide, evaluation of the results of clinical trials of phase III 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 administration 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 interaction

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 concentration of S- and R-warfarin, as well as Cmax of R-warfarin did not change, and Cmax of 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 significance, the effect on the maximum value of the international normalized ratio (MNOmax) was not 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 about 38% and 27%, respectively, and the median Tmax increased by about 24 hours. dulaglutide has a high degree of protection against inactivation of DPP-4.

Overdose

Symptoms of overdose of dulaglutide in clinical studies included gastrointestinal disorders and hypoglycemia.

Treatment. In case of overdose, symptomatic therapy should be initiated according to clinical signs and symptoms.

Storage conditions

Do not freeze in a dark place at 2 to 8 ° C.

Do not use the product if it has been frozen.

The drug purchased at the pharmacy is allowed to be stored at a temperature not higher than 30 ° C for 14 days.

Keep out of the reach and sight of children.

Shelf life

2 years. Do not use after the expiration date indicated on the package.

Conditions of release from

pharmacies Prescription

dosage form

injection

Possible product names

Trulicity rr for p / leather. the introduction of 1.5 mg / 0.5 ml syringe pen 0, 5 ml 4 pcs



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