Date of approval.
Date of revision.
Instructions for Ligliptin Metformin Tablets (I)/(II)/(III)
Please read the instructions carefully and use under the guidance of a physician
Warning: Metformin-associated lactic acidosis
For complete black box warnings, please refer to the full instructions for this product [Caution].
Post-marketing cases of metformin-associated lactic acidosis have been reported resulting in death, hypothermia, hypotension, and intractable slow-type arrhythmias. Symptoms include malaise, myalgia, respiratory distress, drowsiness, and abdominal pain. Laboratory abnormalities include elevated blood lactate levels (>5 mmol/L), anion-gap acidosis (without evidence of ketonuria or ketonemia), and increased lactate/pyruvate ratio; accompanied by a plasma metformin concentration of typically >5 mcg /mL.
Risk factors included renal insufficiency, combined use of certain medications, age ≥65 years, radiographic examinations with contrast agents, surgical and other operations, hypoxic states, excessive alcohol consumption, and hepatic impairment. See the instructions for complete information on risk reduction and control measures for metformin-associated lactic acidosis in these high-risk groups.
If metformin-associated lactic acidosis is suspected, discontinue the product and begin general supportive measures at a hospital. Immediate hemodialysis is recommended.
Drug Name]
Generic name: Linagliptin Metformin Tablets (I)/(II)/(III)
English name: Linagliptin and Metformin Hydrochloride Tablets (Ⅰ)/(Ⅱ)/(Ⅲ)
Hanyu Pinyin: Ligelieting Erjiashuanggua Pian (Ⅰ)/(Ⅱ)/(Ⅲ)
【Ingredients】.
This product is a compound preparation, the active ingredients of which are ligagliptin and metformin hydrochloride.
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
Metformin hydrochloride chemical name: 1,1-dimethylbiguanide hydrochloride
Chemical structure formula.
Molecular formula: C4H11N5-HCl
Molecular weight: 165.63
Properties]: This product is white or off-white oval biconvex film-coated tablet with “L69” (2.5mg/1000mg specification) or “L68” (2.5mg/850mg specification) or “L66” (2.5mg/500mg specification) logo on one side and no logo on the other side.
Indications
This product can be used as an adjunct to diet control and exercise for adult patients with type 2 diabetes mellitus who are suitable for treatment with ligliptin and metformin to improve the level of blood glucose control in these patients.
Specification
(1) Linagliptin Metformin Tablets (I): Each tablet contains 2.5mg of Linagliptin and 500mg of Metformin Hydrochloride.
(2) Linagliptin Metformin Tablets (Ⅱ): each tablet contains 2.5mg of Linagliptin and 850mg of Metformin Hydrochloride.
(3) Ligliptin Metformin Tablets (III): each tablet contains 2.5mg of Ligliptin and 1000mg of Metformin Hydrochloride.
Dosage
Recommended Dosage
The dose of this product should be individualized according to effectiveness and tolerability, and should not exceed the maximum recommended dose of 2.5 mg of ligliptin/1000 mg of metformin hydrochloride twice daily. This product should be taken twice daily with meals. The dose should be increased gradually to reduce gastrointestinal side effects caused by metformin.
Recommended starting dose.
For patients already treated with metformin, the starting dose is 2.5 mg of ligliptin and the current dose of metformin taken twice daily with meals.
Patients already on two separate drugs, ligliptin and metformin, may switch to this product containing the same dose of both drugs.
The safety and efficacy of switching to this product has not been specifically studied in patients who have previously used other oral hypoglycemic agents. Because changes in glycemic control can occur, any changes to type 2 diabetes treatment should be made with caution and monitored appropriately.
Recommended dosing for patients with renal impairment
Renal function should be assessed prior to initiation of treatment with this product and periodically thereafter.
This product is contraindicated in patients with an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m2.
Discontinue this product if the patient’s eGFR subsequently falls below 45 mL/min/1.73 m2.
Discontinuation of therapy due to iodinated contrast imaging procedures
Intravascular injection of iodinated contrast media may lead to contrast nephropathy, which may cause metformin accumulation and an increased risk of lactic acidosis. Therefore, patients who are scheduled for this type of test must discontinue this product before or at the time of the test. Reassess eGFR 48 hours after the imaging procedure; if renal function is stable, restart treatment with this product.
[Adverse reactions] According to foreign literature
The following serious adverse reactions are described below.
Lactic acidosis
Pancreatitis
Heart failure
Combination with drugs known to cause hypoglycemia
Hypersensitivity reactions
Vitamin B12 levels
Pemphigus vulgaris
Rhabdomyolysis
Clinical Trial Experience
Because clinical trials are conducted under different and extensive conditions, the incidence of adverse reactions observed in clinical trials of drugs is not directly comparable to the incidence in clinical trials of other drugs and may not reflect the incidence observed in practice.
Ligliptin/Metformin
The safety of the combined use of ligliptin (5 mg daily dose) and metformin (average daily dose of approximately 1800 mg) was evaluated in a clinical trial of 2816 patients with type 2 diabetes mellitus treated for ≥12 weeks.
Three placebo-controlled studies were conducted on ligliptin + metformin: two studies with a duration of 24 weeks and one study with a duration of 12 weeks. In the 3 placebo-controlled studies, adverse events occurred in ≥5% of patients (n=875) on ligliptin+metformin and were more common than in patients on placebo+metformin (n=539), and these included nasopharyngitis (5.7% vs 4.3%).
In a 24-week analytic design study, ≥5% of patients on ligliptin + metformin reported adverse events, a higher incidence than those on placebo, as shown in Table 1.
Table 1
In a 24-week cause-specific design study, ≥5% of patients treated with ligliptin + metformin reported adverse events, much greater than those treated with placebo
Placebo
n=72 ligliptin monotherapy
n=142 Metformin monotherapy
n=291 Combined treatment with ligliptin and metformin
n=286 n (%) n (%) n (%) n (%) nasopharyngitis 1 (1.4) 8 (5.6) 8 (2.7) 18 (6.3) diarrhea 2 (2.8) 5 (3.5) 11 (3.8) 18 (6.3) Other adverse reactions reported in clinical studies treated with ligliptin + metformin were hypersensitivity reactions (e.g. urticaria, angioedema or bronchial hyperreactivity ), cough, decreased appetite, nausea, vomiting, skin pruritus and pancreatitis.
Ligagliptin
Adverse reactions reported in ≥2% of patients treated with ligliptin 5 mg and more frequently than in the placebo group included nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).
Other adverse reactions reported in clinical studies with ligliptin monotherapy were hypersensitivity reactions (e.g., urticaria, angioedema, local skin peeling, or bronchial hyperreactivity) and myalgia. In the clinical trial program, the reported rate of pancreatitis was 15.2 cases per 10,000 patient-years of exposure when treated with ligliptin compared to 3.7 cases per 10,000 patient-years of exposure when treated with the control drug (placebo and active control sulfonylurea). Three additional cases of pancreatitis occurred after the last dose of ligliptin was administered.
Metformin
The most common adverse reactions due to initiation of metformin were diarrhea, nausea/vomiting, flatulence, malaise, dyspepsia, abdominal discomfort, and headache.
Hypoglycemia
Ligliptin/Metformin
In a 24-week analytic design study, hypoglycemia was reported in 4 of 286 subjects (1.4%) treated with ligliptin + metformin, 6 of 291 subjects (2.1%) treated with metformin, and 1 of 72 subjects (1.4%) treated with placebo. Adverse effects of hypoglycemia were based on all reports of hypoglycemia. In some patients, concomitant glucose measurement was not required or concomitant glucose measurement was normal. Therefore, it is not possible to conclusively determine that all of these reports reflect true hypoglycemia.
Use in patients with renal insufficiency
In a 52-week study that included 133 patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), ligliptin was further evaluated as an add-on therapeutic agent to an existing hypoglycemic agent.
In general, the incidence of adverse events, including severe hypoglycemia, was similar to that reported in other ligliptin trials. In particular, an increased incidence of hypoglycemia was observed during the first 12 weeks when background hypoglycemic therapy remained stable due to an increase in asymptomatic hypoglycemic events (63% for ligliptin vs 49% for placebo). At least one confirmed symptomatic hypoglycemia (with fingertip glucose ≤54 mg/dL) was reported in 10 (15%) and 11 (17%) patients in the ligliptin-treated and placebo-treated groups, respectively. During the same time interval, three (4.4%) and three (4.6%) patients in the ligliptin-treated and placebo-treated groups, respectively, reported a severe hypoglycemic event (defined as an event requiring the assistance of another person in order to actively administer carbohydrates, glucagon, or other resuscitative measures). Events considered life-threatening or requiring hospitalization were reported by 2 (2.9%) and 1 (1.5%) patients in the ligliptin-treated and placebo-treated groups, respectively.
Renal function, as measured by mean eGFR and creatinine clearance, was unchanged during the 52-week treatment period compared with placebo.
Laboratory Tests
Ligagliptin
Elevated uric acid levels: A more frequent and ≥1% more frequent change in laboratory values in the ligliptin group compared to the placebo group was elevated uric acid levels (1.3% in the placebo group compared to 2.7% in the ligliptin group).
Elevated lipase levels: In a placebo-controlled clinical trial of ligliptin in patients with type 2 diabetes mellitus with microalbuminuria or macroalbuminuria, 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.
Metformin
Reduced vitamin B12 absorption: Treatment with metformin is associated with reduced absorption of vitamin B12, which can lead to clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) (see [Precautions])
Postmarketing Experience
The following adverse reactions were identified after the product was marketed, but because these reactions were spontaneously reported by an indeterminate size patient population, the frequency of these adverse reactions cannot usually be estimated with certainty, nor can a causal relationship between them and drug exposure be clearly established.
Ligliptin
Acute pancreatitis, including fatal pancreatitis
Hypersensitivity reactions including tachyphylaxis, angioedema, and exfoliative skin disease
Severe, disabling arthralgia
rashes
herpetiform aspergillosis
Mouth ulcers, stomatitis
Metformin
Cholestatic, hepatocellular and mixed liver injury
Contraindications
This product is contraindicated in patients with
Severe renal failure (eGFR less than 45 mL/min/1.73 m2).
Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
Acute conditions that may affect renal function, such as: dehydration, severe infection, shock.
Conditions that can cause tissue hypoxia (especially acute conditions or worsening of chronic conditions), such as decompensated heart failure, respiratory failure, recent onset myocardial infarction and shock.
Severe infections and trauma, major surgical procedures with clinical hypotension and hypoxia, etc.
Diabetic coma prodromal phase.
Liver insufficiency, acute alcoholism, alcohol abuse.
uncorrected vitamin B12, folic acid deficiency.
– Hypersensitivity reactions to ligliptin, metformin or any of the excipients in this product, such as rapid-onset allergic reactions, angioedema, exfoliative skin disease, urticaria or bronchial hyperreactivity when using ligliptin.
[Precautions].
Lactic acidosis
Metformin
There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases were insidious in onset and were associated with nonspecific symptoms such as malaise, myalgia, abdominal pain, respiratory distress, or increased drowsiness; however, hypothermia, hypotension, and intractable bradycardia have been observed in patients with severe acidosis. Metformin-associated lactic acidosis manifests as decreased pH (<7.35), increased blood lactate concentration (>5 mmol/L), anion-gap metabolic acidosis (without evidence of ketonuria or ketonemia), and increased lactate/pyruvate ratio; metformin plasma levels are usually >5 mcg/mL. metformin decreases hepatic lactate uptake and increases blood lactate levels, which can increase the risk of lactic acidosis, especially in high-risk patients.
If metformin-associated lactic acidosis is suspected, give immediate general supportive measures in a hospital setting and discontinue the product immediately. In patients taking this treatment with a diagnosis of lactic acidosis or a strong suspicion of lactic acidosis, immediate hemodialysis is recommended to correct the acidosis and to remove accumulated metformin (in good hemodynamic conditions, dialysis clearance of metformin can be as high as 170 mL/min). Hemodialysis often leads to reversal and recovery of symptoms.
Educate patients and their families about the symptoms of lactic acidosis and instruct them to discontinue the product if these symptoms occur and to report them to their healthcare professional.
For each of the known and possible risk factors for metformin-associated lactic acidosis, the following provides recommendations for the reduction and management of metformin-associated lactic acidosis.
Renal impairment: Post-marketing cases of metformin-associated lactic acidosis are seen primarily in patients with severe renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment, as metformin is primarily excreted via the kidneys. Clinical recommendations based on the patient’s renal function include.
● Obtain an estimate of glomerular filtration rate (eGFR) prior to initiating treatment with this product.
● This product is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2.
● Obtain an eGFR result at least once a year in all patients taking this product. In patients at increased risk of renal impairment (e.g., elderly), renal function should be assessed more frequently.
● This product should be temporarily discontinued in patients who develop acute conditions affecting renal function such as dehydration, severe infection, or shock.
Drug Interactions: Combination of this product with certain drugs may increase the risk of metformin-associated lactic acidosis: drugs that impair renal function [including antihypertensives, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs)], drugs that cause significant hemodynamic changes, drugs that affect acid-base balance, or drugs that increase metformin accumulation. Therefore, more frequent monitoring of patients should be considered.
Patients aged ≥65 years: The risk of metformin-associated lactic acidosis increases with patient age because older patients are more likely to develop hepatic, renal, or cardiac impairment than younger patients. Renal function should be assessed more frequently in older patients.
Contrast agent radiology studies: Intravenous administration of iodinated contrast agents in patients treated with metformin can lead to an acute decline in renal function as well as the development of lactic acidosis. Therefore, patients scheduled for this type of exam must stop taking metformin before or at the time of the exam. Reassess eGFR 48 hours after the imaging procedure; if renal function is stable, restart treatment with this product.
Surgery or other operations: Suspension of food and fluid intake during surgery or other operations may increase the risk of hypovolemia, hypotension, and renal impairment. The administration of this product should be suspended while the patient is restricting food and fluid intake. Metformin must be discontinued during surgery undergoing conventional, spinal or epidural anesthesia. Treatment should not be restarted until at least 48 hours after surgery or after resumption of feeding and renal function has been assessed as stable.
Hypoxic state: Several post-marketing cases of metformin-associated lactic acidosis have been reported in the setting of acute congestive heart failure (especially when associated with inadequate perfusion and oxygen deficiency). Circulatory collapse (shock), acute myocardial infarction, sepsis, and other hypoxic conditions are associated with lactic acidosis and may also lead to prerenal azotemia. When such events occur, the product should be discontinued.
Excessive alcohol consumption: Alcohol may enhance the effects of metformin on lactate metabolism, which may increase the risk of metformin-associated lactic acidosis. Patients are warned not to consume excessive amounts of alcohol while taking this product.
Hepatic impairment: Patients with hepatic impairment may develop metformin-associated lactic acidosis. This may be due to impaired lactate clearance and consequently elevated blood lactate levels. Therefore, use of this product should be avoided in patients with clinical or laboratory evidence of hepatic disease.
Pancreatitis
Acute pancreatitis, including fatal pancreatitis, has been reported in patients on ligliptin. In the CARMELINA trial, acute pancreatitis was reported in 9 (0.3%) patients treated with ligliptin and 5 (0.1%) patients treated with placebo. Acute pancreatitis with a fatal outcome occurred in two patients treated with ligliptin in the CARMELINA trial.
It is important to pay extra attention to the potential signs and symptoms of pancreatitis. If pancreatitis is suspected, stop taking this product immediately and manage it appropriately. It is not known if there is an increased risk of pancreatitis in patients with a past history of pancreatitis.
Heart Failure
Patients with heart failure are at higher risk of hypoxia and renal insufficiency. Patients with heart failure are at higher risk of hypoxia and renal insufficiency. Patients with stable chronic heart failure can take metformin with regular checks of cardiac and renal function.
A correlation between DPP-4 inhibitor therapy and heart failure has been observed in cardiovascular outcomes trials conducted for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes as well as atherosclerotic cardiovascular disease. The risks and benefits of this product should be considered before initiating therapy in patients at risk for heart failure (e.g., with a prior history of heart failure and a history of renal impairment), and such patients should be observed for signs and symptoms of heart failure during therapy. Inform patients of the characteristic signs and symptoms of heart failure and report such signs and symptoms as soon as they are observed. If heart failure develops, evaluate and manage according to current treatment criteria and consider discontinuation of this product.
Renal Impairment
Metformin is excreted primarily by the kidneys and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. This product is contraindicated in patients with severe renal impairment with an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m2 .
If this product is discontinued due to evidence of renal impairment, treatment with the same total daily dose of 5 mg of ligagliptin as a single tablet may be continued. No dose adjustment is required for the use of ligliptin in patients with renal impairment.
Hepatic Impairment
The use of metformin in patients with hepatic impairment may result in lactic acidosis. Use of this product is not recommended in patients with hepatic impairment.
Use of drugs known to cause hypoglycemia
Proinsulin secretagogues and insulin are known to cause hypoglycemia. In a clinical trial, the incidence of hypoglycemia caused by the combination of ligliptin and insulin-producing agents (e.g., sulfonylureas) was higher than that of placebo. A higher incidence of hypoglycemia was observed in patients with severe renal impairment when this product was used in combination with insulin. Metformin may increase the risk of hypoglycemia when co-administered with insulin and/or insulin agonists. Therefore, when used with this product, a lower dose of an insulin-producing agent or insulin is required, thereby reducing the risk of hypoglycemia.
Hypersensitivity reactions
Serious hypersensitivity reactions have been reported in patients treated with ligliptin. These reactions include tachyphylactic reactions, angioedema, and exfoliative skin disease. These reactions have occurred within the first 3 months after initiation of ligliptin therapy, with some reports occurring after the first dose of the drug. If a severe hypersensitivity reaction is suspected, the product should be discontinued, other potential causes of the event should be evaluated, and alternative treatment for diabetes should be administered.
Angioedema has been reported in patients treated with other DPP-4 inhibitors. Because it is uncertain whether this group of patients will also be predisposed to angioedema while receiving this product, this product should be used with caution in this group of patients.
Vitamin B12 Levels
In a 29-week controlled clinical trial of metformin, it was found that approximately 7% of patients treated with metformin had reduced serum vitamin B12 levels from normal to below normal without clinical signs. These reductions may be due to interference with the absorption of vitamin B12 from the intrinsic factor complex of vitamin B12, and these reductions may be associated with anemia or neurological manifestations. This risk may be more related to the long-term treatment of patients with metformin, and post-marketing reports of hematologic and neurologic adverse effects have been reported. The reduction in vitamin B12 levels appears to be rapidly reversed when metformin is discontinued or vitamin B12 supplements are used. It is recommended that patients on this product be tested annually for hematologic parameters and that any apparent abnormalities be observed and managed appropriately. Some individual patients (those with inadequate intake or absorption of vitamin B12 or calcium) appear to be prone to lower than normal levels of vitamin B12. Routine serum vitamin B12 testing may be performed in these patients every 2-3 years.
Severe, disabling arthralgia
Severe, disabling arthralgia has been reported post-marketing in patients taking DPP-4 inhibitors. The time between initiation of drug therapy and symptom onset varies from one day to several years. After discontinuation of the drug, patients experienced relief of symptoms. A subset of patients experienced a recurrence of symptoms upon reintroduction of the same medication or a different DPP-4 inhibitor. Considering that DPP-4 inhibitors may cause severe joint pain, the medication should be discontinued when appropriate.
Pemphigoid aspergillosis
In the CARMELINA trial, herpetic aspergillosis was reported in 7 (0.2%) patients treated with ligliptin, of whom 3 were hospitalized for herpetic aspergillosis; no such reports were made in patients treated with placebo. 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 discontinuing DPP-4 inhibitors. Advise patients to report if blistering or vesicles develop during treatment with this product. If herpetiform aspergillosis is suspected, discontinue this product and consider referring to a dermatologist for diagnosis and appropriate treatment.
Women of childbearing potential and men
Discuss the possibility of unplanned pregnancy with premenopausal women, as metformin treatment may cause ovulation in some anovulatory women.
[For pregnant and lactating women].
Pregnancy
Metformin is not recommended for patients who are planning to become pregnant or are already pregnant, but insulin can be used to maintain blood glucose levels as close to normal as possible, thereby reducing the risk of fetal malformations.
Summary of risks
Data on the use of metformin and ligliptin in pregnant women are limited and are not sufficient for understanding the risk of metformin-related or ligliptin-related serious birth defects or miscarriage. Published studies of metformin use during pregnancy have not reported any clear correlation between metformin and the risk of serious birth defects or miscarriage [see Data]. There are risks associated with poorly controlled diabetes during pregnancy for both mother and fetus [see Clinical Considerations].
The estimated background incidence of serious birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c>7% and is reported at rates as high as 20% to 25% in women with HbA1c>10%. Estimates of background risk of miscarriage in the population specified for the indication are not yet available. In the general US population, the background risk estimates for serious birth defects and miscarriage in clinically confirmed pregnancies are 2%-4% and 15%-20%, respectively.
Clinical considerations
Disease-related maternal and/or embryo-fetal risk
Poorly controlled diabetes in pregnancy increases maternal risk of diabetic ketoacidosis, pre-eclampsia, spontaneous abortion, preterm delivery, and delivery complications. Poorly controlled diabetes can increase the risk of severe birth defects, stillbirths, and morbidity associated with macrosomia in the fetus.
Data
Published data from postmarketing studies have not reported a clear association between metformin and serious birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy. However, due to methodological limitations, including small sample sizes and inconsistent control groups, these studies cannot definitively establish that there is no associated risk with metformin.
Lactation
Metformin can be excreted through breast milk. Breastfeeding is not recommended during metformin treatment
Summary of Risks
No information is available regarding the presence or absence of this product or ligliptin in human breast milk, the effect on breastfed infants, or the effect on lactation. There are limited published studies reporting the presence of metformin in human breast milk [see Data]. However, there is insufficient information to determine the effect of metformin on breastfeeding infants and no available information on the effect of metformin on lactation. Therefore, the developmental and health benefits of breastfeeding for the infant should be considered in the context of the mother’s clinical need for the product, the potential adverse effects of the product on the nursing infant, and the potential adverse effects of the underlying maternal disease on the nursing infant.
Data
Published clinical breastfeeding studies have reported that metformin is present in human breast milk, allowing infants to ingest doses of approximately 0.11% to 1% of the corrected maternal body weight dose, with milk/plasma ratios ranging from 0.13 to 1. However, studies were not designed to definitively determine the risk of metformin use during breastfeeding because of the small sample size and the limited data on adverse events collected in infants.
Pediatric Dosage]
The safety and efficacy of this product in pediatric patients under 18 years of age have not been established.
Geriatric Use】According to foreign literature
Ligliptin is rarely excreted by the kidneys, whereas metformin is mainly excreted by the kidneys. Considering that renal function decreases with age, this product should be used with caution as age increases.
Ligliptin
There were 4040 patients with type 2 diabetes treated with ligliptin 5 mg in 15 ligliptin clinical trials; 1085 (27%) patients were 65 years and older, while 131 (3%) patients were 75 years and older. Of these patients, 2566 were enrolled in 12 double-blind placebo-controlled studies; 591 (23%) patients were 65 years and older, while 82 (3%) were 75 years and older. The study found no difference in the overall safety and efficacy of patients aged 65 and older compared to younger patients. Therefore, no dose adjustment is recommended for the elderly population. However, clinical studies of ligliptin have not determined differences in treatment response between older and younger patients and cannot exclude some older patients with higher sensitivity.
Metformin
While differences in response between older and younger patients have not been determined in other reported clinical experiences, a sufficient number of older patients have not been included in metformin-controlled clinical studies to determine whether their response differs from that of younger patients. In general, older patients are advised to choose their doses carefully, usually starting at the lower end of the dose range, due to decreased hepatic, renal, or cardiac function as well as more frequent comorbidities or other medications and a higher risk of lactic acidosis. Older patients should have more frequent renal function evaluations.
[Drug Interactions].
Drug interactions with metformin
Carbonic anhydrase inhibitors
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, or diclofenamide) frequently decrease serum bicarbonate concentrations and induce non-anion gap, hyperchloremic metabolic acidosis. The combination of these drugs with this product may increase the risk of lactic acidosis. More frequent monitoring of these patients should be considered.
Drugs that may reduce the clearance of metformin
Some drugs may affect the renal tubular transport system normally involved in the renal elimination of metformin (e.g., organic cation transporter-2 [OCT2]/polydrug and toxic compound efflux transport [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine), and combining these drugs with this product may increase systemic exposure to metformin and may increase the risk of lactic acidosis . Consider the benefits and risks of combining medications.
Alcohol
Alcohol is known to enhance the effects of metformin on lactate metabolism. Patients are warned not to consume excessive amounts of alcohol during the administration of this product.
Drug interactions with ligliptin
P-glycoprotein and CYP3A4 enzyme inducers
Rifampin may reduce ligliptin exposure, indicating that the efficacy of ligliptin can be reduced when combined with strong P-glycoprotein inducers or CYP 3A4 inducers. Since this product is a fixed-dose combination of ligliptin and metformin, alternative therapy (without ligliptin) is strongly recommended when combination with strong P-glycoprotein inducers or CYP 3A4 inducers is necessary.
Pro-insulin secretagogue or insulin
Combination of this product with a proinsulin secretagogue (e.g., sulfonylureas) or insulin may require a lower dose of the proinsulin secretagogue or insulin to reduce the risk of hypoglycemia.
Medications that interfere with glycemic control
The use of certain medications often produces hyperglycemia and puts blood glucose out of control. These medications include thiazides and other diuretics, glucocorticoids, phenothiazines, thyroid medications, estrogens, oral contraceptives, phenytoin, niacin, sympathomimetics, calcium channel blockers, and isoniazid. When these drugs are administered to a patient on this product, the patient should be monitored closely so that his or her blood glucose can be properly controlled. When these drugs are discontinued in patients given this product, the patient should be closely monitored for hypoglycemia.
[Drug overdose].
In the event of an overdose of this drug, contact the Poison Control Center. Apply commonly used supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, perform clinical monitoring and develop supportive treatment measures) based on the patient’s oral clinical status. Removal of ligliptin by hemodialysis or peritoneal dialysis is unlikely. However, in good hemodynamic conditions, clearance of metformin by dialysis can be as high as 170 mL/min, so hemodialysis may be effective in removing accumulated metformin in patients with suspected overdose.
Ligliptin
In controlled clinical trials in healthy subjects, a single dose of up to 600 mg of ligliptin (120 times the recommended daily dose) did not produce dose-related clinical adverse drug reactions. There is no experience with human use of doses above 600 mg.
Metformin
Metformin overdose has occurred, including ingestion of amounts greater than 50 g. Hypoglycemia has been reported in approximately 10% of cases, but no causal relationship with metformin has been established. Lactic acidosis was reported in approximately 32% of metformin overdose cases.
[Pharmacology and Toxicology
Pharmacological effects
Ligliptin Metformin Tablets is a compound preparation of ligliptin and metformin.
Ligliptin
Ligliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), which is capable of degrading glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Ligliptin elevates the concentration of activated enteroglucagon 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 reduces glucagon secretion from pancreatic α-cells and hepatic glucose excretion is reduced.
Metformin
Metformin reduces hepatic gluconeogenesis, inhibits intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Toxicological studies
Ligliptin
Genotoxicity: The results of the Ames test, human lymphocyte chromosome aberration test and in vivo micronucleus test for ligliptin were negative.
Reproductive toxicity: In the rat fertility test, no adverse effects on early embryonic development, mating, fertility, or conception were observed at doses of up to 240 mg/kg (approximately 943 times the clinical dose in terms of AUC exposure) of ligliptin. In pregnant rats and rabbits, ligliptin was administered during organogenesis at doses up to 240 and 150 mg/kg (approximately 943 and 1943 times the clinical dose of 5 mg, respectively, in terms of exposure), and no adverse effects on development were observed. No adverse effects on offspring function, behavior or reproduction were observed in rats given ligliptin (49 times the clinical dose of 5 mg in terms of exposure) from day 6 of gestation to day 21 of lactation.
Carcinogenicity: In a 2-year carcinogenicity test in male and female rats, ligliptin did not increase tumor incidence at doses of 6, 18 and 60 mg/kg (60 mg/kg is approximately 418 times the clinical dose of 5 mg/day in terms of AUC exposure). In a 2-year carcinogenicity test in mice, ligliptin did not increase tumor incidence in males and females at doses of 80 mg/kg and 25 mg/kg (approximately 35 and 270 times the clinical dose in terms of AUC exposure), respectively. The incidence of lymphoma was increased in female mice at high doses of ligliptin of 80 mg/kg (approximately 215 times the clinical dose in terms of AUC exposure).
Metformin
Genotoxicity: Metformin Ames test, mouse lymphoma cell gene mutation test, human lymphocyte chromosome aberration test and in vivo micronucleus test in mice were negative.
Reproductive toxicity: Fertility was not affected in male and female rats given metformin 600 mg/kg/day, which is approximately twice the maximum recommended human dose (MRHD) based on body surface area. Pregnant rabbits were given metformin hydrochloride up to 600 mg/kg/day during organogenesis, which is approximately 6 times the clinical dose of 2000 mg based on body surface area, and no adverse effects on development were observed.
Carcinogenicity: Metformin was given to rats at 900 mg/kg/day for 104 weeks and to mice at 1500 mg/kg/day for 91 weeks, approximately 4 times the maximum recommended daily human dose of 2000 mg on a body surface area basis; no carcinogenicity was observed in mice and male rats, and an increased incidence of benign mesenchymal uterine polyps was observed in female rats at the 900 mg/kg/day dose.
Compounding studies
No adverse developmental effects were observed in pregnant rats given ligliptin with metformin during the organogenesis period at an exposure equivalent to the maximum recommended clinical dose; an increased incidence of rib and scapular deformities in fetal littermates was seen when metformin was given in the compound at a higher dose associated with maternal toxicity (exposure greater than or equal to 9 times the clinical dose of 2000 mg).
Pharmacokinetics】According to foreign literature
The results of bioequivalence studies in healthy subjects showed that the use of 2.5 mg/500 mg, 2.5 mg/850 mg, and 2.5 mg/1000 mg combination tablets was bioequivalent to the use of the corresponding doses of ligliptin and metformin monotherapy tablets in combination. The fixed-dose combination tablet of ligliptin 2.5 mg/metformin hydrochloride 1000 mg taken with a meal did not result in a change in the overall exposure to ligliptin. There was no change in the AUC of metformin, but the mean peak blood concentration of metformin was reduced by 18% when taken with a meal. The study found a 2-hour delay in the time to peak of metformin in the presence of a meal. These changes are unlikely to be clinically significant.
Absorption
Ligliptin
The absolute bioavailability of ligliptin is approximately 30%. After oral administration, the blood concentration of ligliptin decreases at least in a biphasic manner at a longer terminal half-life (> 100 hours), which is associated with saturation of binding of ligliptin and DPP-4. However, prolonged elimination is not conducive to drug accumulation. The effective half-life of ligagliptin accumulation is determined by multiple oral doses of ligagliptin 5 mg, which is approximately 12 hours. After once-daily administration, ligagliptin 5 mg reached steady-state blood concentrations at the third dose, with a 1.3-fold increase in Cmax and AUC at steady state compared to the first dose. In the dose range of 1-10 mg, the plasma AUC of ligagliptin increased in a manner not proportional to the dose.
The pharmacokinetics of ligagliptin were similar in healthy subjects and in patients with type 2 diabetes.
Metformin
The absolute bioavailability of metformin hydrochloride 500 mg tablets in the fasting state is approximately 50-60%. Studies performed on single doses of oral metformin tablets 500 mg to 1500 mg and 850 mg to 2550 mg showed no proportionality with increasing dose, which was due to a decrease in absorption rather than a change in elimination.
Distribution
Ligliptin
A single intravenous dose of 5 mg of ligliptin in healthy subjects resulted in a mean apparent volume of distribution of approximately 1110 L at steady state, indicating that ligliptin is widely distributed to the tissues. Plasma protein binding of ligagliptin decreased in a concentration-dependent manner from approximately 99% at 1 nmol/L to 75% to 89% at ≥30 nmol/L, indicating saturation of binding to DPP-4 with increasing ligagliptin concentrations. At high concentrations, DPP-4 is fully saturated and 70%-80% of ligliptin remains bound to hemoglobin, while 20%-30% is not bound in plasma. Plasma binding is unchanged in patients with renal or hepatic impairment.
Metformin
The mean apparent volume of distribution (V/F) of metformin was 654 ± 358 L after single-dose oral administration of metformin hydrochloride immediate-release tablets 850 mg.
Binding of metformin to plasma proteins was negligible compared to the more than 90% binding of sulfonylureas to proteins. Metformin is most likely to be distributed over time into the red blood cells. At commonly used clinical doses and dosing schedules for metformin tablets, steady-state blood concentrations of metformin are achieved within 24-48 hours and are usually <1 mcg/mL. In controlled clinical trials of metformin, the maximum blood concentration of metformin did not exceed 5 mcg/mL even at the maximum dose.
Metabolism
Ligliptin
Following oral administration, the majority (approximately 90%) of ligliptin is excreted in its native form, indicating that a small proportion is metabolized by secondary routes. A small fraction of ligliptin is metabolized after absorption to a pharmacologically inactive metabolite, demonstrating a steady-state exposure of 13.3% relative to ligliptin.
Metformin
Intravenous single-dose administration studies in healthy subjects have shown that metformin is excreted in the urine in its native form and is not metabolized by the liver (no metabolites were identified in humans) nor is it excreted via the bile.
Excretion
Ligliptin
In healthy subjects following oral administration of [14C]ligliptin, approximately 85% of the radioactive component is eliminated via the hepatic-intestinal system (80%) or urine (5%) within 4 days of dosing. The renal clearance at steady state is approximately 70 mL/min.
Metformin
Renal clearance is approximately 3.5 times higher than creatinine clearance, indicating that renal tubular secretion is the major route of metformin elimination.
After oral administration, approximately 90% of the absorbed drug is eliminated by the kidneys within 24 hours, with a plasma elimination half-life of approximately 6.2 hours. The elimination half-life in the blood is approximately 17.6 hours, suggesting a possible distribution in the erythrocyte masses.
Special Populations
Renal impairment
Studies on the kinetic characteristics of the pharmacokinetics of ligagliptin and metformin have not been conducted in patients with renal impairment administered with this product.
Ligliptin
Under steady-state conditions, the exposure of ligliptin in patients with mild renal impairment was comparable to that of healthy subjects. Patients with moderate renal impairment had increased mean exposure to ligliptin under steady-state conditions compared to healthy subjects (71% increase in AUCτ,ss and 46% increase in Cmax). This increase was not associated with a prolonged accumulation half-life, terminal half-life, or increased accumulation factors. Renal excretion of ligliptin is less than 5% of the administered dose and is not affected by reduced renal function.
Patients with type 2 diabetes mellitus with severe renal impairment had approximately 40% higher steady-state exposure (42% increase in AUC and 35% increase in Cmax) than patients with type 2 diabetes mellitus with normal renal function. In both groups of type 2 diabetic patients, renal excretion of the drug was less than 7% of the administered dose.
Metformin
In patients with reduced renal function, the half-life of metformin in plasma and blood is prolonged and renal clearance is decreased.
Hepatic Impairment
Studies on the pharmacokinetic profile of ligliptin and metformin have not been conducted with administration of this product in patients with hepatic impairment.
Linagliptin
Patients with mild hepatic impairment (Child-Pugh class A) had approximately 25% lower steady-state exposure (AUCτ,ss) and 36% lower Cmax,ss for ligliptin compared to healthy subjects. Patients with moderate hepatic impairment (Child-Pugh class B) had approximately 14% lower AUCss and 8% lower Cmax,ss for ligagliptin compared to healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure to healthy subjects based on AUC0-24 ligliptin and approximately 23% lower Cmax than healthy subjects. Reductions in pharmacokinetic parameters in patients with hepatic impairment do not result in a reduction in DPP-4 inhibition.
Metformin hydrochloride
Pharmacokinetic studies of metformin have not been performed in patients with hepatic impairment.
Body mass index (BMI)/weight
Ligliptin
Based on population pharmacokinetic analysis, BMI/body weight had no clinically meaningful effect on the pharmacokinetics of ligliptin.
Gender
Ligagliptin
Based on population pharmacokinetic analysis, there was no clinically meaningful effect of gender on the pharmacokinetics of ligliptin.
Metformin hydrochloride
When analyzed according to gender, there were no significant differences in the pharmacokinetic parameters of metformin between healthy subjects and type 2 diabetic patients. Similarly, in controlled clinical studies in patients with type 2 diabetes, the glucose-lowering effect of metformin was comparable in men and women.
Geriatric population
Studies on the pharmacokinetic characteristics of ligliptin and metformin following administration of this product have not been conducted in elderly patients.
Ligliptin
Based on population pharmacokinetic analysis, there is no clinically meaningful effect of age on the pharmacokinetics of ligliptin.
Metformin hydrochloride
Limited data from a controlled pharmacokinetic study of metformin in healthy elderly subjects showed decreased total plasma clearance, prolonged half-life, and increased Cmax of metformin compared to healthy younger subjects. From these data, it appears that the changes in metformin pharmacokinetics with age are primarily due to changes in renal function.
Children
Studies on the pharmacokinetic profile of ligliptin and metformin following administration of this product have not been performed in pediatric patients.
Ethnicity
Ligliptin
Based on the available pharmacokinetic data, ethnicity (including Caucasian, Hispanic, Black, and Asian) does not have a clinically meaningful effect on the pharmacokinetics of ligliptin.
Metformin hydrochloride
The pharmacokinetic parameters of metformin have not been studied based on ethnicity. In controlled clinical studies of metformin in patients with type 2 diabetes, the hypoglycemic effects were comparable in whites (n=249), blacks (n=51), and Latinos (n=24).
Drug Interactions
Drug interactions have not been studied for the pharmacokinetics of this product; however, the individual components of this product (ligliptin and metformin hydrochloride) have been studied.
Ligliptin
In vitro evaluation of drug interactions
Linagliptin 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 isozymes (including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11).
Ligliptin is a P-glycoprotein (P-gp) substrate that inhibits P-gp-mediated digoxin transport at high concentrations. Based on these results and in vivo drug interaction studies, ligagliptin is considered unlikely to interact with other P-gp substrates at therapeutic concentrations.
In vivo evaluation of drug interactions
CYP3A4 or strong inducers of P-gp (e.g., rifampin) can reduce the exposure of ligagliptin to less than therapeutic concentrations and possibly to ineffective concentrations. Replacement of ligliptin is strongly recommended for patients requiring such agents. In vivo studies have shown a reduced propensity for drug interactions in the presence of CYP3A4, CYP2C9, CYP2C8, P-gp, and OCT substrates. Based on the results of the pharmacokinetic studies described, no dose adjustment of ligliptin is recommended.
Table 2 Effect of combination dosing on systemic exposure to ligliptin
Co-administration Co-administration dose*Liglitazar dose*Geometric mean ratio
(Ratio with/without co-administration)
Ineffective=1.0 AUC †Cmax Metformin 850 mg TID10 mg QD 1.201.03 Glibenclamide**1.75 mg#5 mg QD1.021.01 Pioglitazone 45 mg QD10 mg QD1.131.07 Ritonavir 200 mg BID5 mg#2.012.96 Rifampin***600 mg QD5 mg QD0.600.56* Multiple dose administration (steady state) unless otherwise indicated.
** Concomitant administration of this product with an insulinotropic agent (e.g., sulfonylurea) or insulin may require a lower dose of insulinotropic agent or insulin to reduce the risk of hypoglycemia.
*** For information on clinical recommendations.
# Single-dose dosing
Collateral For single-dose therapy AUC = AUC (0-24h), for multiple-dose therapy AUC = AUC (TAU)
QD = once daily
BID = twice daily
TID = three times daily
Table 3 Effect of ligliptin on systemic exposure to co-administered drugs
Co-administration Co-administration dose * ligliptin dose * geometric mean ratio
(ratio with/without co-administration)
Ineffective = 1.0 AUC †Cmax Metformin 850 mg TID10 mg QD Metformin 1.010.89 Glibenclamide***1.75 mg#5 mg QD Glibenclamide 0.860.86 Pioglitazone 45 mg QD10 mg QD Pioglitazone
Metabolite M-III
Metabolite M-IV0.94
0.98
1.040.86
0.96
1.05 Digoxin 0.25 mg QD5 mg QD Digoxin 1.020.94 Simvastatin 40 mg QD10 mg QD Simvastatin
Simvastatin acid 1.34
1.331.10
1.21 Warfarin 10 mg#5 mg QDR-Warfarin
S-Warfarin
INR
PT0.99
1.03
0.93**
1.03**1.00
1.01
1.04**
1.15** Ethinylestradiol and levonorgestrel Ethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD5 mg QD Ethinylestradiol
Levonorgestrel 1.01
1.091.08
1.13* Multiple dose administration (steady state), unless otherwise stated
# Single dose administration
Collateral for single dose treatment AUC= AUC (0-24 h), for multi-dose treatment AUC= AUC (TAU)
**AUC=AUC (0-168) and for efficacy endpoint Cmax=Emax
***Coadministration of this product with an insulinotropic agent (e.g., sulfonylurea) or insulin may require a lower dose of insulinotropic agent or insulin to reduce the risk of hypoglycemia
INR = International Normalized Ratio
PT = prothrombin time
QD = once daily
TID = three times daily
Metformin hydrochloride
Table 4 Effect of combination dosing on systemic exposure to metformin in plasma
Co-administration Co-administration dose * metformin dose * geometric mean ratio
(Ratio with/without co-administration)
Ineffective = 1.0 AUC †Cmax glibenclamide***5mg850mg metformin 0.91‡0.93‡ nifedipine 10mg850mg metformin 1.161.21 propranolol 40mg850mg metformin 0.900.94 ibuprofen 400mg850mg metformin 1.05‡1.07‡ eliminated via renal tubular secretion Cationic drugs can reduce the elimination of metformin: should be used with caution. Cimetidine 400mg850mg Metformin 1.401.61 Carbonic anhydrase inhibitors can cause metabolic acidosis: should be used with caution. Topiramate** 100mg500mg Metformin 1.251.17* All metformin and combination drugs are single dose
Collateral
AUC = AUC (INF)
╪
Ratio of arithmetic mean
*** Concomitant administration of this product with an insulinotropic agent (e.g., sulfonylurea) or insulin may require a lower dose of insulinotropic agent or insulin to reduce the risk of hypoglycemia
** At steady state with 100 mg topiramate every 12 hours and 500 mg metformin every 12 hours: AUC = AUC (0-12h)
Table 5 Effect of metformin on systemic exposure to co-administered drugs
Co-administration co-administration dose * metformin dose * geometric mean ratio
(ratio with/without co-administration)
Ineffective = 1.0 AUC †Cmax glibenclamide** 5mg850mg §Glibenclamide 0.78‡0.63‡Furosemide 40mg850mg Furosemide 0.87‡0.69‡Nifedipine 10mg850mg Nifedipine 1.10§1.08 Propranolol 40mg850mg Propranolol 1.01§1.02 Ibuprofen 400 mg850 mg ibuprofen 0.97¶1.01¶ cimetidine*** 400 mg850 mg cimetidine 0.95§1.01* All metformin and co-administered drugs are single dose
** Concurrent administration of JENTADUETO with an insulinotropic agent (e.g., sulfonylurea) or insulin may require a lower dose of insulinotropic agent or insulin to reduce the risk of hypoglycemia
*** Drugs eliminated via renal tubular secretion may increase metformin accumulation
collateral
AUC = AUC(INF), unless otherwise stated
Ratio of the arithmetic mean of ╪, p-value of difference<0.05
§ Reported AUC (0-24 hr)
¶ Ratio of arithmetic mean
【Storage】Store airtight, not to exceed 25℃. Please keep out of reach of children.
Package】Packaged in high-density polyethylene bottle for oral solid medicine with built-in desiccant, 60 tablets/bottle, 1 bottle/box.
Expiration date】36 months
Execution Standard
Approval number】
【Drug marketing license holder
Name: Guangdong East Sunshine Pharmaceutical Co.
Address: North Industrial Zone, Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province
Postal Code: 523808
Sales telephone 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
Web address: http://pharm.hec.cn/