Trelagliptin Tablets 100 mg

Trelagliptin Tablets 25 mg / 50 mg / 100 mg

Trelaglip 25

Each film coated tablet contains :

Trelagliptin Succinate

equivalent to Trelagliptin 25 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow)and Titanium Dioxide IP

Trelaglip 50

Each film coated tablet contains :

Trelagliptin Succinate equivalent to Trelagliptin 50 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow) and Titanium Dioxide IP

Trelaglip 100

Each film coated tablet contains :

Trelagliptin Succinate

equivalent to Trelagliptin 100 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow) and Titanium Dioxide IP

Tablet, 25 mg / 50 mg / 100 mg

4.1 Therapeutic indications

For the treatment of type 2 diabetes mellitus.

4.2 Posology and method of administration

The usual adult dosage is 100 mg of Trelaglip administered orally once a week.

Patients with moderate or severe renal dysfunction

The blood concentration of this drug increases due to delayed excretion; therefore, the dose should be reduced according to the degree of renal function, referring to the table below.

Dosage for patients with moderate or severe renal impairment

¹ Conversion value equivalent to CCR (age 60 years, weight 65 kg).

² For patients with end-stage renal disease, the time relationship between administration of this drug and haemodialysis does not matter.

Elderly

Carefully administer the drug while paying attention to the occurrence of side effects and carefully observing the course. In general, renal function is often impaired.

Method of administration

• Trelaglip is to be taken once a week and should be taken on the same day of the week.
• If you forget to take this drug, take only the prescribed dose at the time you notice it and then take it on a predetermined day of the week.

4.3 Contraindications

• Patients with severe ketosis, diabetic coma or precoma, Type 1 diabetes.
• Patients with severe infections, those undergoing surgery or those with severe trauma.
• Patients with a history of hypersensitivity to the ingredients of this drug.

4.4 Special warnings and precautions for use

• This drug may cause hypoglycemia. When using this drug, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them and caution should be exercised.
• Acute pancreatitis may occur, so instruct patients to consult a doctor immediately if they experience initial symptoms such as persistent severe abdominal pain or vomiting.
• This drug is orally administered once a week and its action continues even after discontinuation of administration. Therefore, pay close attention to the blood glucose level and the occurrence of side effects. In addition, when using other diabetic drugs after discontinuation of this drug, the start time and dose of the drug should be examined based on the blood glucose control status.
• During administration of this drug, blood glucose levels should be checked regularly and the patient's condition should be closely monitored. If the patient shows no satisfactory response after 2 to 3 months of administration of this drug, consideration should be given to changing to a more appropriate treatment.
• Trelaglip and GLP-1 receptor agonists have a blood glucose lowering effect via the GLP-1 receptor. There are no clinical trial results when the two drugs are used together and their efficacy and safety have not been confirmed.

4.5 Drug Interactions

• When Trelagliptin was used in combination with Glimepiride or Metformin, no clear effect was observed on the pharmacokinetics of Trelagliptin and these concomitant drugs.
• When Trelagliptin was used in combination with Caffeine, Tolbutamide, Dextromethorphan or Midazolam, no clear effect was observed on the pharmacokinetics of these concomitant drugs.

4.6 Use in special populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.)

Patients with complications / medical history

Patients or conditions at risk of hypoglycemia :

• Pituitary or adrenal insufficiency.
• Malnutrition, starvation, irregular food intake, insufficient food intake or debilitation.
• Intense muscle exercise.
• People who consume excessive amounts of alcohol. Patients with a history of abdominal surgery or intestinal obstruction may cause intestinal obstruction.

Patients with moderate or severe renal dysfunction

Reduce the dose and carefully observe the patient's condition. The blood concentration of this drug increases due to delayed excretion depending on the degree of renal function.

Pregnant women

Pregnant women or women who may be pregnant should only be administered if the therapeutic benefits are judged to outweigh the risks. Placental crossing of drug has been reported in animal studies (rats).

Lactating women

Consider whether to continue or discontinue breast-feeding, taking into account the therapeutic benefits and the benefits of breast-feeding. Animal studies (rats) have shown that the drug is excreted in breast milk.

Pediatric population

No clinical trials have been conducted in children.

Elderly

Pay attention to the occurrence of side effects and administer with caution while closely monitoring the progress. Renal function is generally reduced in many cases.

4.7 Effects on ability to drive and use machines

Hypoglycemic symptoms may occur, so caution should be exercised when administering to patients engaged in activities such as working at heights or driving a car.

4.8 Undesirable effects

Serious side effects

Since the following side effects may appear, observe them thoroughly and if any abnormalities are found, take appropriate measures such as discontinuing administration.

Hypoglycemia (Less than 0.1 - 5%)

Hypoglycemia may occur. When used concomitantly with sulfonylurea agents or insulin preparations, severe hypoglycemic symptoms, including loss of consciousness, have been reported. If hypoglycemic symptoms are observed, appropriate measures should be taken, such as having the patient ingest foods containing carbohydrates. However, glucose should be administered when used concomitantly with an α-glucosidase inhibitor.

Pemphigoid (incidence unknown)

If blisters or erosions appear, consult with a dermatologist and take appropriate measures, such as discontinuing administration. Acute pancreatitis (incidence unknown) If any abnormalities such as persistent severe abdominal pain or vomiting are observed, discontinue administration and take appropriate measures.

Bowel obstruction (incidence unknown)

If any abnormalities such as severe constipation, abdominal distention, persistent abdominal pain, or vomiting are observed, discontinue administration and take appropriate measures.

Other side effects

The following adverse reactions may occur, so observe closely and if any abnormalities found, discontinue administration or take appropriate measures.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 email to : medico@zuventus.com Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

In clinical studies, QT prolongation has been reported when a single dose of 800 mg of Trelagliptin was administered.

Removal of this drug by hemodialysis is not considered useful.

5.1 Mechanism of action

Trelagliptin inhibits the activity of Dipeptidyl Peptidase-4 (DPP-4), which inactivates glucagon-like peptide-1 (GLP-1), which is secreted into the bloodstream from the intestinal tract in response to oral ingestion of a meal, thereby increasing the blood concentration of GLP-1 and promoting insulin secretion from the pancreas in a glucose concentration-dependent manner.

5.2 Pharmacodynamic properties

Inhibitory effects on DPP-4 Trelagliptin selectively inhibited DPP-4 activity in human plasma (IC50 value : 4.2 nmol/L) (in vitro). In order to compare the DPP-4 inhibitory activity of Trelagliptin and Alogliptin, the IC50 were compared under the same conditions (in vitro) and were found to be 1.3 and 5.3 nmol/L respectively. In a placebo-controlled, double-blind, parallel-group comparative study in which 100 mg of Trelagliptin was orally administered once weekly (before breakfast) for 12 weeks to type 2 diabetes patients with insufficient blood sugar control despite dietary and exercise therapy, the mean DPP-4 activity inhibition rate 7 days after the final administration was 77.4% in the 100 mg Trelagliptin. The plasma Trelagliptin concentration estimated to yield 50% inhibition of plasma DPP-4 activity (IC50) was 1.43 ng/mL (4.02 nmol/L).

Increased concentration of active GLP-1

In a placebo-controlled, double-blind, parallel-group comparative study in which 100 mg of Trelagliptin was orally administered (once a week before breakfast) for 12 weeks to type 2 diabetes patients with insufficient blood sugar control despite diet and exercise therapy, active GLP-1 concentrations in a meal loading test 12 weeks after administration were significantly increased compared to the placebo group.

Improvement of glucose tolerance

Trelagliptin was orally administered once to an overnight fasted obese type 2 diabetes model (Wistar fatty rats) and a non-obese type 2 diabetes model (N-STZ-1.5 rats) and a glucose tolerance test in which glucose was orally administered one hour after administration showed that Trelagliptin improved glucose tolerance.

Phase III clinical trial in India

A trial was conducted on Trelaglip to compare the efficacy and safety of once-weekly Trelaglip (Trelagliptin 100 mg) with twice-daily Vildagliptin 50 mg in patients with type 2 diabetes. Non-inferiority was assessed based on the difference in mean change from baseline in HbA1c at the end of the treatment period. The mean change in HbA1c (± SD) was 0.89 (± 1.46) % in the Trelagliptin group and 0.97 (± 1.42) % in the Vildagliptin group. The incidence of adverse effects was lower in the Trelagliptin group (6.67%) compared to the Vildagliptin group (9.17%), with no cases of hypoglycemia reported in either group. Trelaglip was found to be having better safety and similar efficacy to that of Vildagliptin. 

5.3 Pharmacokinetic properties

Single dose study

The pharmacokinetic parameters of Trelagliptin in plasma after a single dose of Trelaglip 100 were as follows. The average plasma concentration after 72 hours of administration was 17.233 ng/mL.

In an internationally conducted study, a single oral dose of 100 mg of Trelagliptin was administered orally 30 minutes before the start of breakfast in healthy adults, the changes in plasma concentrations and pharmacokinetic parameters were as follows and the average plasma concentration after 168 hours of administration was 2.1 ng/mL.

Mean value (standard deviation)

Repeated administration

In healthy adults (9 cases), a single oral dose of 100 mg of Trelagliptin was administered once daily 30 minutes before breakfast and three days later, it was administered once daily for 11 days 30 minutes before breakfast. The average values (standard deviation) of Cmax and AUC0-inf on the first day of administration were 544.3 (122.0) ng/mL and 5572.3 (793.2) ng·h/mL, respectively, while the average th values (standard deviation) of Cmax and AUC0-tau on the 14 day of administration were 602.6 (149.5) ng/mL and 5292.9 (613.8) ng·h/mL respectively.

The steady state was achieved after 12-week treatment with once-weekly Trelagliptin. The plasma concentration of unchanged Trelagliptin was 6.062 ng/mL at 7 days after the last dose. No drug accumulation was observed with repeated dosing of Trelagliptin.

Absorption

When 100 mg of Trelagliptin was orally administered to healthy adults (12 subjects) 30 minutes after the start of breakfast, the Cmax and AUC(0-inf) increased by 16.8% and decreased by 2.5% respectively, compared to when it was administered without breakfast.

Distribution

14 [ C] When Trelagliptin was added to human plasma at a concentration of 0.1 to 10 μg/mL, the protein binding rate was 22.1 to 27.6% (in vitro).

Metabolism

Trelagliptin is metabolized to the active metabolite MI, mainly via N -demethylation by CYP2D6. The amount of the active metabolite MI in human plasma was less than 1% of the amount of unchanged Trelagliptin. Trelagliptin exhibited weak inhibitory effects on CYP3A4/5 (direct inhibitory effect IC50 value : 100 μmol/L or more, metabolic inhibitory effect IC50 values : 12 μmol/L (midazolam 1'-hydroxylation activity) and 28 μmol/L (testosterone 6β-hydroxylation activity)), but did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 and did not induce CYP1A2, CYP2B6 or CYP3A4 (in vitro).

Excretion

When a single oral dose of 100 mg of Trelagliptin was administered to 12 healthy adults during breakfast fasting or 30 minutes after the start of breakfast, the cumulative urinary excretion rates of Trelagliptin up to 168 hours were 76.6% and 76.1% respectively. Trelagliptin is a substrate of P-glycoprotein and slightly inhibited the transport of Digoxin through P-glycoprotein (IC50 value : ≥ 500 μmol/L). In addition, Trelagliptin showed an inhibitory effect on the uptake of Metformin, which is a substrate of the organic cation transporter OCT2 (IC50 value : 55.9 μmol/L) (in vitro).

Patients with impaired renal function

When a single dose of 50 mg of Trelagliptin was orally administered to patients with renal impairment and healthy adults, the AUC(0-tlqc) and Cmax were increased by 55.7% and 36.3% in patients with mild renal impairment (Ccr = 50 - 80 mL/min, 6 cases), 105.7% and 12.9% in patients with moderate renal impairment (Ccr = 30 - 50 mL/min, 6 cases), 201.4% and 9.1% in patients with severe renal impairment (Ccr < 30 mL/min, 6 cases), and 268.1% and 13.8% in patients with end-stage renal failure (6 cases) respectively, compared with healthy adults matched for age, sex, race and weight.

In addition, 9.2% of the administered dose of Trelagliptin was removed by 4 hours of hemodialysis.

Patients with impaired hepatic function

When a single dose of 50 mg of Trelagliptin was orally administered to patients with moderate hepatic impairment (Child-Pugh score 7-9, 8 cases) and healthy adults (8 cases), the AUC(0-inf) and Cmax were increased by 5.1% and decreased by 4.3% respectively, compared to healthy adults matched for age, sex, race, smoking history and weight.

6.1 Animal toxicology or pharmacology

Toxicity studies of Trelagliptin included single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity and other toxicity studies (phototoxicity study, skin toxicity studies).

Single dose toxicity

A single-dose toxicity study of Trelaglip was conducted in male and female Mus musculus mice and Wistar rats, with oral doses of 0 (vehicle), 10, 25, 50, 100 or 200 mg/kg body weight. No mortality, biochemical or hematological changes or signs of acute systemic toxicity were observed at the highest dose of 200 mg/kg. An international single-dose toxicity study was performed in male and female Sprague-Dawley (SD) rats with oral doses of 0 (vehicle), 600 or 2000 mg/kg body weight. Salivation was observed immediately after administration and no deaths occurred. The approximate lethal dose of Trelagliptin was determined to be > 2000 mg/kg. In a dose escalation study, escalating single oral doses of Trelagliptin 0 (control), 30, 300 and 2000 mg/kg were administered to male and female beagle dogs. Vomiting, erythema and swelling of the auricle and face, salivation and increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and alkaline phosphatase (ALP) were observed in animals receiving ≥ 300 mg/kg and a decrease in locomotor activity, lateral position and decreased body temperature were observed in animals receiving 2000 mg/kg but no deaths were observed. Thus, the approximate lethal dose was determined to be > 2000 mg/kg.

Repeated dose toxicity

Four-week repeated oral dose toxicity study in mice and rabbits

A four-week repeated-dose toxicity study of Trelaglip was conducted in male and female Swiss albinomice (0, 20.41, 102.9, 204.1 mg/kg) and New Zealand rabbits (0, 5.2, 25.7, 51.46 mg/kg), followed by a recovery phase in the vehicle and high-dose groups to evaluate toxicity reversibility after a two-week recovery period. No adverse effects were observed on growth, body weight or feed consumption in the test animals. While slight elevations in neutrophil and monocyte levels were observed, these remained within the normal laboratory range. Hematological and biochemical parameters showed no signifcant deviations from controls. Any external or internal pathological ndings were not observed after necropsy and gross examination.

Four-week repeated oral dose toxicity study in rats

Male and female SD rats orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 50, 250 or 1000 mg/kg/day for 4 weeks. In addition, a recovery study was conducted in the 0 and 1000 mg/kg/day groups to assess the reversibility of toxicity after a 2-week recovery period. Stained perianogenital fur; increase in neutrophil, lymphocyte and white blood cell counts; increase in inorganic phosphorus, total cholesterol and ALP; decrease in sodium, chloride, albumin and total protein : a trend towards increased urine protein; an increase in liver weight; a decrease in thymus weight; centrilobular hepatocellular hypertrophy and a decrease in lymphocytes in the thymic cortex were observed in the 1000 mg/kg/day group.

All findings were reversible after the 2-week recovery period.

As described above, stained fur associated with worsening of clinical signs and increased white blood cell count suggestive of inflammation were observed in the 1000 mg/kg/day group and therefore the no observed adverse effect level (NOAEL) was determined to be 250 mg/kg/day.

Genotoxicity Bacterial reverse mutation assay, gene mutation assay with mouse lymphoma (L5178Y/TK+/-) and mouse bone marrow micronucleus assay were conducted in a study. The result showed Trelagliptin to have no genotoxicity. Carcinogenecity Carcinogenicity dose-range finding study Male and female ICR mice orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 100, 300, 1000 or 2000 mg/kg/day for 1 week. Death occurred in 1 of 10 females in the 100 mg/kg/day group, 1 of 10 females in the 300 mg/kg/day group, 2 of 10 males and 1 of 10 females in the 1000 mg/kg/day group and 1 of 10 males and 1 of 10 females in the 2000 mg/kg/day group. In addition, among animals evaluated for toxicokinetics, 1 of 21 females died in the 1000 mg/kg/day group and 1 of 21 males and 7 of 21 females died in the 2000 mg/kg/day group. The deaths observed in the 2000 mg/kg/day group were considered attributable to Trelagliptin because of the high incidence of death. Findings in the 2000 mg/kg/day group were a decrease in locomotor activity, convulsion, abdominal distension, unkept fur, ataxia, decreased food consumption, decrease in lymphocyte and white blood cell counts and increase in ALP, ALT, AST and urea nitrogen.

Separately, an additional group of male and female ICR mice orally received daily 1000 mg/kg/day of Trelagliptin for 1 week.

A decrease in locomotor activity, prone position, bradypnea and hypothermia were observed after the first dose, but not after the second or subsequent doses. In addition, deaths or effects on body weight associated with Trelagliptin were not noted.

Furthermore, male and female ICR mice orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 150, 300, 600 or 1200 mg/kg/day for 13 weeks. No deaths associated with Trelagliptin occurred, nor were any toxicological findings observed in clinical signs, body weight, food consumption, ophthalmology, haematology, clinical chemistry, organ weights, necropsy or histopathology.

Trelaglip (Trelagliptin Succinate) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus).

Chemical name : R 22-({6-[(3 )-3-Aminopiperidin-1-yl] H -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2 ) -yl} methyl) -4-fluorobenzonitrile monosuccinate

Molecular formula : C₁₈H₂₀FN₅O₂.C₄H₆O₄

Molecular weight : 475.47 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A wallet pack of 4 tablets.

8.4 Storage and handling instructions

Store below 30°C. Protect from moisture.

Keep out of reach of children

Instruct patients on the following points when administering the drug.

• This drug should be taken once a week and should be taken on the same day of the week.
• If you forget to take this drug, take only the prescribed dose when you notice it and then take it on the predetermined day of the week.
• Since there is a risk of hypoglycemia, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them and caution should be called to them before using this drug.
• Patients should be instructed to seek immediate medical attention if they experience initial symptoms such as persistent severe abdominal pain or vomiting, as acute pancreatitis may occur.
• Since this drug is to be administered orally once a week and the effect continues even after discontinuation, pay close attention to blood glucose levels and the occurrence of side effects. In addition, when using other diabetes drugs after discontinuing administration of this drug, consider the timing and dose of administration based on the status of blood glucose management.
• During the course of administration of the drug, blood glucose should be tested regularly, the progress should be monitored thoroughly and if the effect of the drug is insufficient after 2 to 3 months, a change to a more appropriate treatment should be considered.
• Caution should be exercised when administering to patients who are engaged in high-altitude work, driving a car etc., as it may cause hypoglycemic symptoms.

06 January 2025

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What is in this leaflet

1. What Trelaglip Tablet is and what it is used for
2. What you need to know before you take Trelaglip Tablet
3. How to take Trelaglip Tablet
4. Possible side effects
5. How to store Trelaglip Tablet
6. Contents of the pack and other information