DALIJA

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DALLIA (DALIA)

Composition:

Active substance: vildagliptin;

1 tablet contains vildagliptin 50 mg;

Excipients: microcrystalline cellulose, anhydrous lactose, sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, uncoated tablet, white to slightly yellowish, with flat surface and bevelled edges, smooth on both sides.

Pharmacotherapeutic group. Antihyperglycemic agents, excluding insulin. Dipeptidyl peptidase-4 inhibitors. Vildagliptin.

ATC code A10BH02.

Pharmacological Properties

Pharmacodynamics

Vildagliptin belongs to the class of substances that enhance the function of pancreatic islet beta cells and is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4).

Administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity. Inhibition of DPP-4 by vildagliptin leads to increased endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) during both fasting and postprandial states.

As a result of elevated endogenous levels of these incretin hormones, vildagliptin improves beta-cell sensitivity to glucose, thereby enhancing glucose-dependent insulin secretion. Treatment of patients with type 2 diabetes with doses of 50 to 100 mg per day significantly improved markers of beta-cell function, including HOMA-β (homeostatic model assessment of β-cell function), proinsulin-to-insulin ratio, and measures of beta-cell sensitivity during repeated oral glucose tolerance tests. In non-diabetic individuals (with normal blood glucose levels), vildagliptin does not stimulate insulin secretion or reduce glucose levels.

Due to increased endogenous levels of GLP-1, vildagliptin also enhances alpha-cell sensitivity to glucose, leading to increased glucose-dependent glucagon secretion. The significant increase in the insulin-to-glucagon ratio during hyperglycemia, driven by elevated incretin hormone levels, results in reduced glucose production during both fasting and postprandial periods, thereby lowering glycemia.

The known effect of elevated GLP-1 levels—delayed gastric emptying—is not observed during treatment with vildagliptin.

Pharmacokinetics

Absorption. After oral administration in the fasting state, vildagliptin is rapidly absorbed, with Cmax reached at 1.7 hours. Co-administration with food slightly delays the time to reach Cmax in plasma—to 2.5 hours—but does not affect total exposure (AUC). Administration of vildagliptin with food results in a 19% reduction in maximum concentration (Cmax). However, this change is not considered clinically significant; therefore, vildagliptin can be administered independently of food intake. Absolute bioavailability is 85%.

Distribution. The plasma protein binding of vildagliptin is low (9.3%). Vildagliptin distributes evenly between plasma and erythrocytes. The mean steady-state volume of distribution after intravenous administration (Vss) is 71 liters, indicating extensive extravascular distribution.

Metabolism. Metabolism is the major route of elimination of vildagliptin in humans, accounting for 69% of the administered dose. The primary metabolite, LAY151, is pharmacologically inactive and results from hydrolysis of the cyanopyrrolidine moiety, representing 57% of the dose. This is accompanied by glucuronide (BQS867) and amide hydrolysis (4% of dose). Data from in vitro studies using human kidney microsomes suggest that the kidneys may be one of the primary organs responsible for the hydrolysis of vildagliptin to its major inactive metabolite LAY151. DPP-4 partially contributes to the hydrolysis of vildagliptin, as confirmed by in vivo studies in DPP-4-deficient rats.

Vildagliptin is not metabolized to any significant extent by cytochrome P450 enzymes. Therefore, concomitant administration of drugs such as inhibitors and/or inducers of CYP450 is not expected to affect the metabolic clearance of vildagliptin. In vitro studies have demonstrated that vildagliptin neither inhibits nor induces cytochrome P450 enzymes. Thus, vildagliptin is unlikely to affect the metabolic clearance of concomitantly administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5.

Elimination. After oral administration of [14C]-vildagliptin, approximately 85% of the dose is excreted in urine and 15% in feces. Renal excretion of unchanged vildagliptin accounts for 23% of the orally administered dose. After intravenous administration to healthy volunteers, total plasma clearance and renal clearance of vildagliptin are 41 L/h and 13 L/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The half-life after oral administration is approximately 3 hours.

Linearity/Non-linearity. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of vildagliptin increase almost proportionally with dose across the entire therapeutic dose range.

Special Patient Populations

Sex. No differences in the pharmacokinetics of the drug were observed between healthy male and female volunteers of various ages and body mass index (BMI). Inhibition of DPP-4 by vildagliptin is independent of patient sex.

Hepatic impairment. The effect of impaired liver function on the pharmacokinetics of vildagliptin was studied in patients with mild, moderate, and severe hepatic impairment based on Child-Pugh scores (ranging from 6 for mild to 12 for severe impairment), compared to patients with normal liver function. Exposure to vildagliptin after a single dose was reduced in patients with mild and moderate hepatic impairment (by 20% and 8%, respectively), whereas exposure increased by 22% in patients with severe hepatic impairment. The maximum change (increase or decrease) in vildagliptin exposure was approximately 30%, which is not considered clinically significant. No correlation was observed between the severity of hepatic impairment and changes in vildagliptin exposure.

Renal impairment. An open-label, multiple-dose study was conducted to evaluate the pharmacokinetics of the lowest therapeutic dose of vildagliptin (50 mg once daily) in patients with varying degrees of chronic renal impairment, as defined by creatinine clearance (mild renal impairment — 50 to <80 mL/min, moderate renal impairment — 30 to <50 mL/min, and severe renal impairment — <30 mL/min), compared to a control group of study participants with normal renal function.

In patients with mild, moderate, and severe renal impairment, AUC of vildagliptin was increased compared to patients with normal renal function. AUC values for metabolites LAY151 and BQS867 increased on average by approximately 1.5-, 3-, and 7-fold in patients with mild, moderate, and severe renal impairment, respectively. Available data in patients with end-stage renal disease (ESRD) indicate that vildagliptin exposure is similar to that in patients with severe renal impairment. Concentrations of LAY151 were approximately 2–3 times higher than in patients with severe renal impairment.

Vildagliptin was eliminated to a limited extent by hemodialysis (3% over a 3–4 hour hemodialysis session initiated 4 hours after drug administration).

Elderly patients. In otherwise healthy patients aged 70 years and older, total exposure to vildagliptin (100 mg once daily) was increased by 32%, and maximum plasma concentration by 18%, compared to younger healthy volunteers (aged 18 to 40 years). However, these changes are not considered clinically significant. Inhibition of DPP-4 by vildagliptin is independent of patient age within the studied age groups.

Race. Available data suggest that race does not have a significant impact on the pharmacokinetics of vildagliptin.

Clinical characteristics

Indications. The medicinal product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus:

• as monotherapy in patients for whom the use of metformin is considered unacceptable due to contraindications or intolerance;
• in combination with other antidiabetic medicinal products, including insulin, when adequate glucose control is not achieved (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Pharmacological properties" for available data on various combinations).

Contraindications. Hypersensitivity to vildagliptin or to any of the excipients.

Interaction with other medicinal products and other forms of interaction

Vildagliptin has a low potential for interaction with other drugs. Since vildagliptin is not a substrate of cytochrome P450 (CYP) enzymes and is neither an inhibitor nor an inducer of CYP450 enzymes, clinically relevant interactions with other drugs that are substrates, inhibitors or inducers of these enzymes are unlikely.

Combination with pioglitazone, metformin, and gliburide. Studies conducted with these oral antidiabetic agents did not reveal clinically significant pharmacokinetic interactions.

Digoxin (Pgp substrate), warfarin (CYP2C9 substrate). Clinical studies conducted in healthy volunteers did not show clinically significant pharmacokinetic interactions. However, this has not been established in the target population.

Combination with amlodipine, ramipril, valsartan, or simvastatin. Drug interaction studies were conducted in healthy volunteers with amlodipine, ramipril, valsartan, and simvastatin. These studies did not reveal clinically significant pharmacokinetic interactions following concomitant administration with vildagliptin.

Combination with ACE inhibitors. There is an increased risk of angioedema in patients taking angiotensin-converting enzyme inhibitors [ACE inhibitors] concomitantly (see section "Adverse reactions").

Certain active substances, including thiazides, corticosteroids, thyroid hormones, and sympathomimetics, may reduce the hypoglycemic effect of oral antidiabetic medicinal products, including vildagliptin.

Special precautions for use

General. Dalia is not a substitute for insulin in insulin-dependent patients. The drug should not be used in patients with type 1 diabetes or diabetic ketoacidosis.

Renal impairment. Experience with the use of the drug in patients with moderate or severe renal impairment, as well as in patients with end-stage renal disease (ESRD) on hemodialysis, is limited. Therefore, the use of Dalia is not recommended in these patient groups.

Hepatic impairment. Dalia is not recommended for use in patients with hepatic dysfunction, including patients whose alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels were more than 3 times above the upper limit of normal prior to treatment.

Rare cases of hepatic dysfunction (including hepatitis) have been reported during treatment with vildagliptin. In such cases, the course in patients was predominantly asymptomatic, without clinical consequences, and liver function test (LFT) results returned to normal after discontinuation of treatment. Prior to initiating treatment with Dalia, LFTs should be performed to establish baseline values in the patient. LFT results should be monitored during treatment with the drug every three to four months during the first year of treatment, and periodically thereafter.

For patients who have shown elevated transaminase levels, repeat monitoring of liver function should be performed to confirm results, as well as continued monitoring with frequent liver function testing until abnormal levels return to normal. If ALT or AST levels increase to 3 times or more above the upper limit of normal, discontinuation of treatment with the drug is recommended. Patients who develop jaundice or other signs of hepatic dysfunction should discontinue use of the medicinal product Dalia. After discontinuation of treatment and normalization of LFT results, treatment with vildagliptin should not be restarted.

Heart failure. A clinical study of vildagliptin use in patients with NYHA (New York Heart Association) functional class I–III heart failure showed that treatment with vildagliptin was not associated with changes in left ventricular function or worsening of existing congestive heart failure. Clinical experience in patients with NYHA functional class III heart failure remains limited, and results are not conclusive.

There is no experience with the use of vildagliptin in patients with NYHA functional class IV heart failure in clinical trials; therefore, the drug is not recommended for use in these patients.

Skin disorders. Skin lesions, including blistering and ulceration of the extremities, were reported in preclinical toxicological studies in monkeys. Although no increased incidence of skin lesions was observed during clinical trials, experience regarding skin-related adverse events in patients with diabetes is limited.

Furthermore, cases of bullous and exfoliative skin lesions have been reported during the post-marketing period of drug use.

Therefore, as part of standard care for patients with diabetes, monitoring for skin disorders such as blistering or ulceration is recommended.

Pancreatitis. The use of vildagliptin is associated with a risk of developing acute pancreatitis. Patients should be informed about the characteristic symptoms of acute pancreatitis.

If pancreatitis is suspected, vildagliptin should not be continued. Upon confirmed diagnosis of acute pancreatitis, reinitiation of vildagliptin treatment is not recommended.

Hypoglycemia. Sulfonylureas are known to cause hypoglycemia. Patients receiving vildagliptin in combination with a sulfonylurea may be prone to hypoglycemia. Therefore, lower doses of sulfonylureas may be considered to reduce the risk of hypoglycemia.

Others. The medicinal product Dalia contains lactose. The drug is contraindicated in patients with rare hereditary conditions such as lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Sodium content. The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. Adequate studies on the use of vildagliptin in pregnant women have not been conducted. Animal studies have revealed reproductive toxicity when high doses of the drug were administered. The potential risk to humans is unknown. Due to the lack of data, the drug should not be used during pregnancy.

Breastfeeding period. It is unknown whether vildagliptin passes into human breast milk. Animal studies have shown excretion of vildagliptin into animal milk. Dalia should not be administered to women who are breastfeeding.

Fertility. Studies on the effect of vildagliptin on human fertility have not been conducted.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted. Patients who experience dizziness should not drive vehicles or operate machinery.

Dosage and Administration

When used as monotherapy or in combination with metformin, in combination with thiazolidinedione, in combination with metformin and sulfonylurea, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg, divided into two doses: 50 mg in the morning and 50 mg in the evening.

When used in combination with sulfonylurea, the recommended dose of vildagliptin is 50 mg once daily in the morning. In this patient population, vildagliptin at a dose of 100 mg daily was not more effective than vildagliptin at a dose of 50 mg once daily.

When used in combination with sulfonylurea, to reduce the risk of hypoglycemia, low doses of sulfonylurea may be considered.

Doses exceeding 100 mg are not recommended.

If a dose of Dalia is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

The safety and efficacy of vildagliptin in triple oral combination therapy with metformin and thiazolidinedione have not been established.

Dosing in patients with hepatic or renal impairment. Dalia is not recommended for patients with hepatic impairment, including patients who have baseline ALT or AST levels more than 3 times the upper limit of normal before treatment.

For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min), no dose adjustment of Dalia is required. For patients with moderate to severe renal impairment or end-stage renal disease (ESRD), the recommended dose is 50 mg once daily.

Dosing in elderly patients. No dose adjustment is required for patients aged 65 years and older.

Dosing in pediatric patients. Vildagliptin is not recommended for use in children (under 18 years of age) due to lack of data on safety and efficacy.

Administration. For oral use. Dalia can be administered independently of food intake.

Pediatric patients. The use of this medicinal product is not recommended in children (under 18 years of age) due to lack of data on safety and efficacy.

Overdose

Data on vildagliptin overdose are limited.

Symptoms. Information on potential overdose symptoms was obtained from a dose escalation tolerability study in healthy volunteers who received vildagliptin for 10 days. At a dose of 400 mg, three cases of muscle pain were observed, along with several cases of mild, transient paresthesia, fever, development of edema, and temporary elevation of lipase levels. At a dose of 600 mg, one volunteer developed swelling of the legs and arms, a marked increase in creatine phosphokinase (CPK) levels, accompanied by elevated AST, C-reactive protein, and myoglobin levels. Three volunteers in this group developed bilateral leg edema, which was accompanied by paresthesia in two cases. All symptoms and laboratory abnormalities resolved after discontinuation of the investigational drug.

Treatment. In case of overdose, supportive therapy is recommended. Vildagliptin is not eliminated by hemodialysis; however, the majority of hydrolysis metabolites (LAY 151) can be removed by hemodialysis.

Adverse Reactions

Summary of safety profile. Safety data were obtained from a total of 5,451 patients who received vildagliptin at a daily dose of 100 mg (50 mg twice daily) in randomized, double-blind, placebo-controlled studies of at least 12 weeks' duration. Of these patients, 4,622 received vildagliptin as monotherapy and 829 received placebo. The majority of adverse reactions in these studies were mild in nature and transient, and did not require discontinuation of treatment. No association was observed between the occurrence of adverse reactions and patient age or race, duration of drug exposure, or daily dose. Hypoglycemia was observed in patients receiving vildagliptin concomitantly with sulfonylurea derivatives and insulin. Risk of acute pancreatitis has been reported with vildagliptin use (see section "Special precautions").

Adverse reactions observed during double-blind studies in patients receiving vildagliptin as monotherapy or in combination therapy are listed below by system organ class and absolute frequency. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (> 1/10,000, ≤ 1/1,000), very rare (≤ 1/10,000), frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions reported in patients receiving vildagliptin as monotherapy or as add-on therapy in controlled clinical trials and in the post-marketing period

Infections and infestations: very common — nasopharyngitis; common — upper respiratory tract infection.

Metabolism and nutrition disorders: uncommon — hypoglycemia.

Nervous system disorders: common — dizziness, headache, tremor.

Eye disorders: common — blurred vision.

Gastrointestinal disorders: common — constipation, nausea, gastroesophageal reflux disease, diarrhea, abdominal pain including upper abdominal pain, vomiting; uncommon — flatulence; rare — pancreatitis.

Hepatobiliary disorders: frequency not known* — hepatitis.

Skin and subcutaneous tissue disorders: common — hyperhidrosis, pruritus, rash, dermatitis; uncommon — urticaria; frequency not known* — exfoliative or bullous skin disorders, including bullous pemphigoid, skin vasculitis.

Musculoskeletal and connective tissue disorders: common — arthralgia, myalgia.

Reproductive system and breast disorders: uncommon — erectile dysfunction.

General disorders and administration site conditions: common — asthenia, peripheral edema; uncommon — fatigue, chills.

Investigations: uncommon — liver function test abnormalities, weight increase.

* Based on post-marketing experience.

Description of selected adverse reactions

Hepatic failure. Isolated cases of hepatic dysfunction (including hepatitis) have been reported. These cases were generally asymptomatic, without clinical consequences, and liver function test results returned to normal after discontinuation of treatment. In controlled monotherapy and add-on therapy studies of up to 24 weeks' duration, the incidence of ALT or AST elevations at least three times the upper limit of normal (based on at least two consecutive measurements or at the last visit during treatment) was 0.2%, 0.3%, and 0.2% with vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily, and all comparator agents, respectively. Transaminase elevations were predominantly asymptomatic, did not progress, and were not associated with cholestasis or jaundice.

Angioedema. Isolated cases of angioedema were observed with vildagliptin at a similar frequency as in the control group. A higher frequency of such events was observed in the group receiving vildagliptin in combination with an ACE inhibitor. Most events were mild in severity and resolved while continuing vildagliptin treatment.

Hypoglycemia was uncommon with vildagliptin monotherapy (0.4%) compared to active comparator or placebo (0.2%) in controlled monotherapy studies. No severe or serious hypoglycemic events were reported. When used as add-on to metformin, hypoglycemia occurred in 1% of patients receiving vildagliptin and in 0.4% of those receiving placebo. After adding pioglitazone, hypoglycemia occurred in 0.6% of patients receiving vildagliptin and in 1.9% of those receiving placebo. When sulfonylurea was added, hypoglycemia occurred in 1.2% of patients receiving vildagliptin and in 0.6% of those receiving placebo. After adding both sulfonylurea and metformin, hypoglycemia occurred in 5.1% of patients receiving vildagliptin and in 1.9% of those receiving placebo. Among patients receiving vildagliptin in combination with insulin, the frequency of hypoglycemia was 14% in the vildagliptin group and 16% in the placebo group.

Reporting of adverse reactions. Reporting of adverse reactions after marketing authorization is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 10 tablets per blister, 3 or 6 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. Medochemie Limited.

Manufacturer's address and place of business

Konstantinoupoleos 1-10, Limassol, 3011, Cyprus.