Ligliptin Tablets Instructions

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Ligliptin Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
[Medication Name].
Generic Name: Ligliptin Tablets
English Name: Linagliptin Tablets
Hanyu Pinyin: Ligelieting Pian
[Ingredients].
The main ingredient of this product is Ligliptin.
Chemical name: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl-1)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione.
Chemical structure formula.
Molecular formula: C25H28N8O2
Molecular weight: 472.54
[Properties
This product should be white or off-white round tablets with “S75” logo on one side and no logo on the other side, and should appear white or off-white after removing the coating.
[Indications
This product is indicated for the treatment of type 2 diabetes mellitus.
Monotherapy
This product is used as an adjunct to diet control and exercise to improve glycemic control in patients with type 2 diabetes.
In combination with metformin hydrochloride
When metformin hydrochloride alone is not effective in controlling blood glucose, this product can be used in combination with metformin hydrochloride to improve glycemic control in patients with type 2 diabetes based on diet and exercise.
In combination with metformin hydrochloride and sulfonylureas
When the combination of metformin hydrochloride and sulfonylureas is not effective in controlling blood glucose, this product can be used in combination with metformin hydrochloride and sulfonylureas to improve glycemic control in patients with type 2 diabetes on the basis of diet and exercise.
[Specifications
5mg[Dosage].
Adults
The recommended dose is 5 mg once daily. This product can be taken at any time of the day, with or without a meal.
Special Populations.
Patients with renal insufficiency
Patients with renal insufficiency do not require dose adjustment.
Patients with hepatic insufficiency
Patients with hepatic insufficiency do not require dose adjustment.
Dose omission
If a dose is missed, patients are advised not to take a double dose at the next dose.
[Adverse reactions] According to foreign literature
Experience from clinical trials
Because conditions in clinical trials vary widely, the rate of adverse reactions observed in clinical trials of one drug is not directly comparable to the incidence in clinical trials of another drug and may not reflect the incidence observed in clinical practice.
Studies based on fourteen placebo-controlled studies, one active drug-controlled study, and one study in patients with severe renal insufficiency evaluated the safety of ligliptin 5 mg once daily in patients with type 2 diabetes mellitus.
Ligagliptin 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks duration and five supplemental placebo-controlled trials of less than 18 weeks duration. The combination of ligliptin with other glucose-lowering agents was studied in six placebo-controlled trials: two with metformin (treatment duration of 12 and 24 weeks); one with a sulfonylurea (treatment duration of 18 weeks); one with metformin and a sulfonylurea (treatment duration of 24 weeks); one with pioglitazone (treatment duration of 24 weeks); and one with insulin in combination (primary endpoint at 24 weeks).
In the combined data set of 14 placebo-controlled clinical trials, adverse events occurred in ≥2% of patients receiving liglitazepam (n = 3625) and were more common than in patients receiving placebo (n = 2176) as shown in Table 1. The overall incidence of adverse events with liglitazepam was similar to that with placebo.
Table 1 Incidence of adverse events reported by patients treated with ligliptin ≥2% and higher than placebo in placebo-controlled ligliptin monotherapy or combination studies
Adverse reactionsNumber of patients (%)Ligliptin 5mg
n=3625placebo
n=2176Nasopharyngitis254 (7.0)132 (6.1)Diarrhea119 (3.3)65 (3.0)Coughing76 (2.1)30 (1.4)When ligliptin is combined with specific hypoglycemic agents The incidence of other adverse reactions when ligliptin 5 mg is combined with placebo are: urinary tract infection (3.1% vs. 0%) and hypertriglyceridemia (2.4% vs. 0%) when ligliptin is combined with sulfonylurea; hyperlipidemia (2.7% vs. 0.8%) and weight gain (2.3% vs. 0.8%) when ligliptin is combined with pioglitazone; constipation (2.1% vs. 0.8%) when ligliptin is combined with basal insulin therapy of constipation (2.1% versus 1%).
In a controlled study comparing ligliptin with glimepiride, in which all patients received concomitant metformin, after 104 weeks of treatment, adverse events reported at an incidence of ≥5% in patients treated with ligliptin (n = 776) and higher than in those receiving sulfonylurea (n = 775) were back pain (9.1% versus 8.4%), arthralgia (8.1% versus 6.1%), upper respiratory tract infection (8.0% versus 7.6%), headache (6.4% versus 5.2%), cough (6.1% versus 4.9%), and extremity pain (5.3% versus 3.9%).
Other adverse reactions reported in clinical studies treated with ligliptin were hypersensitivity reactions (eg, urticaria, angioedema, local skin peeling, or bronchial hypersensitivity reactions) and myalgia. In the clinical trial program, 15.2 cases of pancreatitis were reported per 10,000 patient-years of exposure in patients treated with ligliptin compared to 3.7 cases per 10,000 patient-years of exposure in patients receiving control therapy (placebo and the active control agent sulfonylurea). Three additional cases of pancreatitis were reported after the last dose of ligliptin.
Low blood sugar
In the placebo-controlled study, hypoglycemia was reported in 199 (6.6%) of 2994 patients treated with ligagliptin 5 mg compared with 56 (3.6%) of 1546 placebo-treated patients. The incidence of hypoglycemia was similar to that of placebo when ligliptin was administered as monotherapy, or in combination with metformin or pioglitazone. When ligliptin was administered in combination with metformin and sulfonylurea, hypoglycemia was reported in 181 of 792 patients (22.9%) compared with 39 of 263 patients (14.8%) who received placebo in combination with metformin and sulfonylurea. The summarized hypoglycemic adverse reactions are based on all reported hypoglycemia without the need to also obtain blood glucose measurements or, alternatively, it is possible that some patients had normal blood glucose values. Therefore it cannot be determined that all of these reported events reflect true hypoglycemic events.
In the study of ligliptin in combination with stable doses of insulin for up to 52 weeks (n=1261), there was no significant difference between the ligliptin group (31.4%) and the placebo group (32.9%) in terms of investigator-reported hypoglycemic events (defined as all events with symptomatic or asymptomatic self-measured glucose ≤70 mg/dL). During the same period, severe hypoglycemic events (defined as requiring assistance from others and using carbohydrates, glucagon, or other resuscitation measures) were reported in 11 (1.7%) of patients treated with ligliptin and in 7 (1.1%) of patients receiving placebo. Life-threatening or hospital-needing events were reported in 3 (0.5%) of patients treated with ligliptin and 1 (0.2%) of patients receiving placebo.
Use in Patients With Renal Insufficiency
In 133 patients with severe renal insufficiency [assessed glomerular filtration rate (eGFR) values<30 mL/min] compared the addition of ligliptin or placebo treatment to the original antidiabetic therapy for 52 weeks. During the initial 12-week period of the study, the original antidiabetic background treatment was required to remain stable, including insulin, sulfonylureas, glinides, and pioglitazone. Dose adjustment of the antidiabetic background therapy was allowed for the remainder of the study period.
In general, the incidence of adverse events, including severe hypoglycemia, was similar to the incidence reported in other liglitazepam trials. The higher incidence of observed hypoglycemia (63% with ligliptin compared with 49% with placebo) resulted from an increased incidence of asymptomatic hypoglycemic events during the initial 12 weeks when background hypoglycemic therapy remained stable. 10 patients treated with ligliptin (15%) and 11 patients receiving placebo (17%) reported at least one confirmed episode of symptomatic hypoglycemia (with finger prick glucose test value ≤54 mg/dL). During the same period, severe hypoglycemic events (defined as requiring assistance from others and using carbohydrates, glucagon, or other resuscitation measures) were reported by 3 (4.4%) of patients receiving ligliptin and 3 (4.6%) of patients receiving placebo. Life-threatening or hospital-needing events were reported in 2 (2.9%) of patients treated with ligliptin and 1 (1.5%) of patients receiving placebo.
Renal function as measured by mean eGFR and creatinine clearance did not change during the 52-week treatment period compared with the placebo group.
Laboratory Tests
Findings from laboratory tests in patients treated with ligliptin 5 mg were similar to those in patients treated with placebo.
Elevated uric acid levels: were more common in the ligliptin group and occurred in excess of ≥1% change in laboratory values in the placebo group with elevated uric acid (1.3% in the placebo group versus 2.7% in the ligliptin group).
Elevated lipase levels: In a placebo-controlled clinical trial of ligliptin in patients with type 2 diabetes in the presence of microalbuminuria or massive albuminuria, lipase concentrations increased by an average of 30% from baseline to 24 weeks in the ligliptin group, compared with an average decrease of 2% in the placebo group. The proportion of patients with lipase levels above 3 times the upper limit of normal was 8.2% and 1.7% in the ligliptin and placebo groups, respectively.
Vital Signs
No clinically significant changes in vital signs were observed in patients treated with ligliptin.
Postmarketing Experience
Other adverse reactions have been identified during the post-approval use of ligliptin tablets. Because these adverse reactions were spontaneously reported from a population of uncertain size, it is usually not possible to reliably estimate their frequency or to establish their causal relationship with drug exposure.
Acute pancreatitis, including fatal pancreatitis
hypersensitivity reactions, including tachyphylaxis, angioedema, and exfoliative dermatitis
Pustular aspergillosis
Rash
Mouth ulcers, stomatitis
[Contraindicated
It is contraindicated in patients with a history of hypersensitivity to ligliptin, such as tachyphylaxis, angioedema, exfoliative dermatitis, urticaria, or bronchial hypersensitivity reactions.
[Precautions].
General Information
This product should not be used for the treatment of patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Pancreatitis
Advise patients that postmarketing reports of acute pancreatitis, including fatal pancreatitis, have been received after the introduction of ligliptin tablets. Advise patients to watch carefully for potential signs and symptoms of pancreatitis, such as the occurrence of persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting, which is the hallmark symptom of acute pancreatitis. If pancreatitis is suspected, stop taking ligliptin tablets immediately and contact your doctor for appropriate measures. When ligliptin tablets are taken by a patient with a history of pancreatitis, it is uncertain whether there is an increased risk of pancreatitis.
Heart failure
An association between dipeptidyl peptidase-4 (DPP-4) inhibitor therapy and heart failure has been observed in cardiovascular outcomes trials for two other DPP-4 inhibitor classes, which evaluated patients with type 2 diabetes and atherosclerotic cardiovascular disease.
The risks and benefits of ligliptin tablets were considered before starting treatment in patients at risk for heart failure (e.g., those with a prior history of heart failure and renal impairment), and these patients were observed during treatment to see if Develop signs and symptoms of heart failure. Inform patients of the characteristic symptoms of heart failure and report such symptoms as soon as they occur. If heart failure progresses, evaluate and treat according to the current standard of care and consider discontinuing the ligliptin tablets.
Co-administration with medications known to cause hypoglycemia
Proinsulin secretagogues and insulin are known to cause hypoglycemia. In one clinical trial, the incidence of hypoglycemia caused by the combination of ligliptin with a proinsulin secreting agent (eg, a sulfonylurea) was higher than that of placebo. The combination of ligliptin and insulin caused a higher incidence of hypoglycemia in patients with severe renal insufficiency. Therefore, lower doses of proinsulin secretagogues or insulin are required in combination with ligagliptin, thereby reducing the risk of hypoglycemia.
hypersensitivity reactions
Serious hypersensitivity reactions have been reported in patients using ligliptin since its introduction. These reactions included tachyphylaxis, angioedema, and exfoliative dermatitis. Hypersensitivity reactions usually occurred within the first 3 months after initiation of ligliptin therapy, with some reports occurring after the first dose. If a severe hypersensitivity reaction is suspected, discontinue ligagliptin therapy, evaluate other potential etiologies for the event, and select other alternative treatment options for diabetes.
Patients treated with other dipeptidyl peptidase-4 (DPP-4) inhibitors have also reported angioedema events. Patients with a history of angioedema associated with treatment with other DPP-4 inhibitors should use ligliptin with caution because it is not known whether this group of patients is susceptible to angioedema when receiving ligliptin administration.
Severe and disabling arthralgia
Postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors have been reported. The time between starting drug therapy and the onset of symptoms ranged from one day to several years. After discontinuation of the drug, patients experience symptom relief. Recurrence of symptoms occurred in a subgroup of patients when the same drug or a different DPP-4 inhibitor was restarted. Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue the drug when appropriate.
Pherpetiform aspergillosis
Post-marketing cases of herpetiform aspergillosis associated with DPP-4 inhibitor dosing and requiring hospitalization have been reported. In the reported cases, patients usually recovered after receiving local or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitors. Patients are advised to report if they develop blisters or vesicles during ligliptin therapy. If herpetiform aspergillosis is suspected, stop ligliptin and consider referral to a dermatologist for diagnosis and appropriate treatment.
Impact on the ability to drive and operate machinery
No studies have been performed on the effects on the ability to drive and operate machinery. However, patients should be warned of the risk of hypoglycemia, especially in combination with sulfonylureas.
[Use in pregnant and lactating women].
Pregnancy
There are no adequate, well-controlled studies in women who are pregnant. This product should not be used during pregnancy unless it is truly necessary.
Lactation
The available animal data suggest that ligliptin can be secreted into breast milk at a milk/plasma ratio of 4:1. It is not clear whether the drug is secreted into human breast milk. Because many drugs are secreted in human milk, great care must be taken when lactating women receive ligagliptin administration.
[Pediatric Use
Safety and efficacy data have not been established for this product in pediatric patients younger than 18 years of age.
[Geriatric Use]
No dose adjustment is required in elderly patients.
A total of 4040 patients with type 2 diabetes were treated with ligliptin 5 mg in 15 clinical trials of ligliptin: 1085 patients (27%) were 65 years of age or older, while 131 patients (3%) were 75 years of age or older, as reported in the foreign literature. Of these patients, 2566 were enrolled in 12 double-blind placebo-controlled studies: 591 (23%) were 65 years of age or older and 82 (3%) were 75 years of age or older. No differences in overall safety or efficacy were found between patients 65 years and older and younger patients. Therefore, no dose adjustments were recommended for the elderly population. Although no differences were found between older and younger patients in clinical studies of ligliptin, the possibility that some older individuals would be more sensitive cannot be ruled out.
[Drug Interactions]
Pharmacokinetic interactions:
In vitro assessment of drug interactions
Ligliptin is a weak to moderate inhibitor of the CYP isoenzyme CYP3A4, but does not inhibit other CYP isoenzymes and is not an inducer of CYP isoenzymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.
Ligliptin is a P-glycoprotein (P-gp) substrate that, at high concentrations, inhibits P-glycoprotein-mediated digoxin transport. Based on these results and in vivo drug interaction studies, it is considered unlikely that ligagliptin interacts with other P-gp substrates at therapeutic concentrations.
In vivo assessment of drug interactions
According to foreign literature, inducers of CYP3A4 or P-gp (eg, rifampin) reduce rizagliptin exposure to subtherapeutic levels, likely to ineffective concentrations. For patients requiring such agents, replacement of ligliptin is strongly recommended. In vivo studies have shown a low propensity for drug interactions with CYP3A4, CYP2C9, CYP2C8, substrates of P-glycoprotein, and organic cation transporters (OCT). Based on the results of the described pharmacokinetic studies, no dose adjustments are recommended for ligliptin.
Table 2 Effect of combined dosing on systemic exposure to ligliptin
Combined medicationsCombined dose*Ligliptin dose*Geometric mean ratio
(Ratio with/without combined drugs)
No effect=1.0AUC +Cmax Ligliptin does not require dose adjustment when used in combination with:Metformin850mg TID 10mg QD1.201.03Glibenclamide1.75mg#5mg QD1.021.01pioglitazone45mg QD10mg QD1.131.07Ritonavir200mg BID5mg#2.012.96Liglitazar Riliglitin may be less effective when combined with strong CYP3A4 or P-gp inducers (e.g., rifampin). Other alternative medications are strongly recommended (see Drug Interactions)Rifampicin600mg QD5mg QD0.600.56*Unless otherwise noted, multiple dosing (steady state)
#Single dosing
+For single dosing, AUC=AUC (0 to 24 hours); for multiple dosing AUC=AUC (TAU)
QD=once daily
BID=twice-daily
TID=Three times a day
Table 3 Effect of ligliptin on systemic exposure of drugs administered in combination
Combined medicationsCombined dose*Ligliptin dose*Geometric mean ratio
(Ratio with/without combined drugs)
No effect=1.0 AUC+CmaxThe following combined medications do not require dose adjustment:Dimetformin850mg TID10mg QDDimethoprim1.010.89Glibenclamide1.75mg#5mg QDGlibenclamide0.860.86pioglitazone45mg QD10mg QDPioglitazone
Metabolite M-III
Metabolite M-IV0.94
0.98
1.040.86
0.96
1.05Digoxin0.25mg QD5mg QDDigoxin1.020.94Simvastatin40mg QD10mg QDSimvastatin
Simvastatin acid1.34
1.331.10
1.21Warrant10mg#5mg QDR-Chinese decree
S-Wafa
INR
PT0.99
1.03
0.93**
1.03**1.00
1.01
1.04**
1.15**Ethynylestradiol and levonorgestrelEthynylestradiol 0.03mg and Levonorgestrel 0.150mg QD5mg QDEthynylestradiol
Levonorgestrel1.01
1.091.08
1.13*Multiple dosing (steady state) unless otherwise noted
#Single dosing
+For single dosing, AUC=AUC(INF); for multiple dosing AUC=AUC(TAU)
**AUC=AUC(0-168), for pharmacokinetic endpoint Cmax=EmaxINR=International Normalized Rate
PT=Prothrombin Time
QD = once daily
TID=Three times per day
[Drug overdose
If a ligliptin overdose occurs, seek immediate medical attention. Common supportive measures (eg, removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring, and supportive therapy) should also be taken depending on the patient’s clinical condition. It is unlikely that ligliptin can be cleared by hemodialysis or peritoneal dialysis.
According to the foreign literature, there were no dose-related clinical adverse drug reactions to single doses of ligagliptin up to 600 mg (equivalent to 120 times the recommended daily dose) in controlled trials conducted in healthy subjects. There is no experience in humans with doses above 600 mg.
[Pharmacologic Toxicology].
Pharmacology
Ligliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), which degrades glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Ligliptin elevates the concentration of active entero-insulinotropic hormone, stimulates insulin release in a glucose-dependent manner, and reduces circulating glucagon levels. Both entero-insulin hormones are involved in the physiological regulation of glucose homeostasis. Entero-insulin secretion is maintained at low basal levels throughout the day and increases immediately after a meal. Under conditions of normal or elevated glucose levels, GLP-1 and GIP increase pancreatic beta-cell insulin biosynthesis and secretion. In addition, GLP-1 decreases glucagon secretion from pancreatic α-cells and hepatic glucose excretion is reduced.
 Pharmacodynamics.
Ligliptin reversibly binds to DPP-4, thereby elevating intestinal insulinotropic hormone concentrations. Ligliptin promotes insulin secretion in a glucose-dependent manner, while reducing glucagon secretion, thereby better regulating glucose homeostasis in the body. In vitro, ligliptin selectively binds to DPP-4 at near therapeutic exposure levels and selectively inhibits DPP-4, but does not inhibit DPP-8 or DPP-9 activity.
 Cardiac electrophysiology.
In a randomized, placebo-controlled, positive-controlled, 4-treatment-group crossover study, 36 healthy subjects received ligliptin 5 mg, ligliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo administration. No elevation in QTc was observed at either the recommended dose of 5 mg or the 100 mg dose. At the 100 mg dose, the peak plasma concentration level of ligagliptin was approximately 38 times higher than the peak concentration after 5 mg dose administration.
 Toxicological studies
Genotoxicity
Ligliptin Ames test, human lymphocyte chromosome aberration test and in vivo micronucleus test results were all negative.
Reproductive toxicity
In the rat fertility and early embryonic development toxicity assay, ligliptin doses of 10, 30, and 240 mg/kg (exposure approximately 943 times the clinical dose of 5 mg/day) did not show adverse effects on early embryonic development, mating, and fertility, and conception.
Carcinogenicity
No increase in tumor incidence was seen with ligliptin at doses of 6, 18, and 60 mg/kg (high-dose exposure approximately 418 times the clinical dose) in a 2-year carcinogenicity test in rats. In a 2-year carcinogenicity study in mice with ligliptin doses of 8, 25, and 80 mg/kg, no increase in tumor incidence was seen in males and females at doses as high as 80 mg/kg or 25 mg/kg (approximately 35 and 270 times the clinical dose, respectively), but an increase in lymphoma incidence was seen in female mice at 80 mg/kg (approximately 215 times the clinical dose). The increased incidence of lymphoma was seen in female mice at a dose of 80 mg/kg (approximately 215 times the clinical dose).
[Pharmacokinetics] According to foreign literature
The pharmacokinetic profile of ligliptin was studied in healthy subjects and in patients with type 2 diabetes. After a single oral dose of 5 mg in healthy subjects, peak plasma concentrations occurred approximately 1.5 hours after dosing (Tmax); the mean plasma area under the curve (AUC) was 139 nmol-h/L and the maximum plasma concentration (Cmax) was 8.9 nmol/L.
Plasma concentrations of ligagliptin are eliminated in at least a diphasic manner with a long terminal half-life (>100 hours), which is associated with saturable binding of ligagliptin to DPP-4. The longer half-life does not cause accumulation of the drug. After multiple oral doses of 5 mg of ligliptin it was determined that the effective half-life of ligliptin accumulation is approximately 12 hours . After 1 daily dose, 5 mg ligliptin reached steady-state blood concentrations after the 3rd dose, and the Cmax and AUC achieved at steady state increased 1.3-fold compared with the first dose. The coefficients of variation for both self and inter-subject variability for the AUC of ligliptin were small (12.6% and 28.5%, respectively). In the dose range of 1 to 10 mg, the plasma AUC of ligagliptin increased in a less-than-dose proportional manner. The pharmacokinetics of ligagliptin in healthy subjects are generally similar to those of patients with type 2 diabetes.
Absorption
The absolute bioavailability of ligliptin is approximately 30%. High-fat meals reduced Cmax by 15% and increased AUC by 4%; this effect was not clinically relevant. Ligagliptin can be taken under fed or fasted conditions.
Distribution
The steady-state mean apparent volume of distribution after a single intravenous dose of 5 mg of ligliptin in healthy subjects was approximately 1110 liters, indicating that ligliptin has a broad distribution in tissues. The plasma protein binding of ligagliptin was concentration-dependent, with plasma protein binding decreasing from approximately 99% at 1 nmol/L to 75%-89% at ≥30 nmol/L, indicating that the saturation of bound DPP-4 increased with increasing ligagliptin concentrations. At high concentrations of fully saturated DPP-4, 70% to 80% of ligliptin is still bound to plasma proteins, so that 30% to 20% of plasma ligliptin is in an unbound state. Plasma binding is unaffected in patients with renal or hepatic insufficiency.
Metabolism
After oral administration, the majority (approximately 90%) of ligliptin is excreted as a prototype, indicating that metabolism is the secondary route of elimination. A small proportion of absorbed ligliptin is metabolized to metabolites with no pharmacologic activity at a steady-state exposure level of 13.3% of ligliptin.
Excretion
After oral administration of [14C] ligliptin to healthy subjects, approximately 85% of the radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) over the 4-day dosing period. Renal clearance at steady state was approximately 70 mL/min.
Pharmacokinetics in Special Populations
Renal insufficiency
An open-label pharmacokinetic study was conducted to evaluate the pharmacokinetics of a 5 mg dose of ligliptin in men and women with varying degrees of chronic renal insufficiency. This study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with type 2 diabetes mellitus with mild renal insufficiency (CrCl: 50 to <80 mL/min), 6 patients with moderate renal insufficiency (30 to <50 mL/min), 10 patients with severe renal insufficiency (<30 mL/ min) in patients with type 2 diabetes mellitus, and 11 patients with normal renal function. Creatinine clearance was measured by measuring 24-hour urinary creatinine clearance or estimated with serum creatinine according to the Cockcroft-Gault formula.
At steady state, the levels of ligliptin exposure in patients with mild renal insufficiency were comparable to those in healthy subjects.
In patients with moderate renal insufficiency, exposure to ligliptin at steady state was higher than in healthy subjects (71% increase in AUCτ,ss and 46% increase in Cmax). The increased exposure levels were not accompanied by a prolongation of the accumulation half-life, terminal half-life, or an increase in the accumulation coefficient. Renal excretion of ligliptin was less than 5% of the administered dose and was not affected by reduced renal function.
Steady-state exposure levels were increased by approximately 40% in type 2 diabetic patients with severe renal insufficiency (42% increase in AUCτ,ss and 35% increase in Cmax) compared with type 2 diabetic patients with normal renal function. For both type 2 diabetic groups, renal excretion was below 7% of the administered dose.
The results of the population pharmacokinetic analysis further support these findings.
Hepatic insufficiency
In patients with mild hepatic insufficiency (Child-Pugh classification A), the steady-state exposure level (AUCτ,ss) of ligagliptin was approximately 25% lower and the Cmax was approximately 36% lower than in healthy subjects. In patients with moderate hepatic insufficiency (Child-Pugh classification B), AUCτ,ss was approximately 14% lower and Cmax was approximately 8% lower in ligagliptin than in healthy subjects. In patients with severe hepatic insufficiency (Child-Pugh classification C), the AUC0-24 of ligagliptin was comparable to that of healthy subjects and the Cmax was approximately 23% lower. In patients with hepatic insufficiency, the reduction in pharmacokinetic parameters did not result in a reduction in DPP-4 inhibition.
Body mass index (BMI)/weight
No dose adjustment based on BMI/body weight is required. Based on a population pharmacokinetic analysis, there was no clinically meaningful effect of BMI/body weight on the pharmacokinetics of ligliptin.
Gender
No gender-specific dose adjustment is required. Based on a population pharmacokinetic analysis, there was no clinically meaningful effect of gender on the pharmacokinetics of ligliptin.
Elderly
According to a population pharmacokinetic analysis, there was no clinically meaningful effect of age on the pharmacokinetics of ligliptin.
Children
The pharmacokinetic profile of ligliptin in pediatric patients has not been studied.
Race
No dose adjustment based on race is required. Based on available pharmacokinetic data, there is no clinically meaningful effect of race on the pharmacokinetics of ligliptin, which includes white, Hispanic, black, and Asian patients.
[Storage].
Store airtight, not to exceed 25°C.
[Packaging]
Double aluminum packaging
7tablets/ box (1board x7pieces/board),14pieces//pieces = “font-family:isoline”>box (2plates x7pieces/board),21pieces/box (3board x 77 (pieces/board),28sheets/Box (4Plates x7piece/board),board family:Arial”>10pieces/boxes (1board x10pieces/board),board family:Arial”>30pieces/boxes (3boards x10pieces/board),board family:Arial”>60pieces/boxes (6boards x10pieces/board).
HDPE bottle
30pieces/box (1bottle x30pieces/bottle).
[Expiration date] 36 months.
[Executive Standard]
[Approval Number]
[Drug Marketing Licensee
Name of the holder: Guangdong Dongyang Pharmaceutical Co.
Address of the holder: North Industrial Zone, Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province
Postal code: 523808
Sales phone number: 0769-85370280 Fax number: 0769-85370206
Medical consultation phone number: 4006707855
Website: http://pharm.hec.cn/
[Manufacturer]
Company name: Guangdong Dongyang Pharmaceutical Co.
Production Address: North Industrial Zone, Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province
Postal Code: 523808
Website: http://pharm.hec.cn/