Date of approval.
Date of revision.
Selegiline Metformin Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warning: Lactic acidosis
For complete black box warnings please see the [Precautions] section of the instruction manual.
1. Lactic acidosis is a rare but serious complication that can occur during treatment with this product due to accumulation of metformin. The risk of occurrence is increased in cases of sepsis, dehydration, excessive alcohol consumption, liver damage, renal damage and acute congestive heart failure.
2. Episodes are associated only with nonspecific symptoms, including general malaise, myalgia, dyspnea, increased drowsiness, and nonspecific abdominal discomfort. Laboratory test abnormalities include decreased pH, increased anion gap, and elevated blood lactate levels.
3. Once acidosis is suspected, the patient should be discontinued from the product and hospitalized immediately.
Drug Name]
Generic name: Selegiline Metformin Tablets (II)
Sitagliptin Metformin Tablets(Ⅲ)
English Name: Sitagliptin Phosphate and Metformin Hydrochloride Tablets (Ⅱ)
Sitagliptin Phosphate and Metformin Hydrochloride Tablets (Ⅲ)
Hanyu Pinyin: Xigelieting Erjiashuanggua Pian (Ⅱ)
Xigelieting Erjiashuanggua Pian (Ⅲ)
Ingredients]
This product is a compound preparation, the components of which are sitagliptin phosphate and metformin hydrochloride.
Sitagliptin phosphate chemical name: 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolone[4,3-a]pyrazine phosphate (1:1) monohydrate
Chemical structure formula.
Molecular formula: C16H15F6N5O-H3PO4-H2O
Molecular weight: 523.32
Metformin hydrochloride chemical name: 1,1-dimethylbiguanide hydrochloride
Chemical structure formula.
Molecular formula: C4H11N5-HCl
Molecular weight: 165.63
【Properties
Sitagliptin Metformin Tablets (Ⅱ): This product is white or off-white capsule-shaped film-coated tablets with “L50” logo engraved on one side and no logo on the other side.
Sitagliptin Metformin Tablets (Ⅲ): This product is a white or off-white capsule-shaped film-coated tablet with “L72” logo engraved on one side and no logo on the other side.
【Indications】.
Adult patients with type 2 diabetes mellitus who are being treated with the combination of selegiline and metformin tablets.
Specification
Selegiline Metformin Tablets (II): Each tablet contains Selegiline phosphate 50mg (as Selegiline) and Metformin Hydrochloride 850mg.
Selegiline Metformin Tablets (Ⅲ): each tablet contains Selegiline phosphate 50mg (selegiline) and Metformin hydrochloride 1000mg.
【Dosage】.
General recommendation.
When using this product for hypoglycemic therapy, individualized doses should be given according to the patient’s current treatment regimen, the degree of effectiveness of the treatment, and the degree of tolerance to the drug, but the maximum recommended daily dose of selegiline phosphate 100 mg and metformin 2000 mg should not be exceeded.
The usual method of administration is twice daily with a meal, and the drug dose should be increased in gradual increments to minimize metformin-related gastrointestinal side effects.
Dosing Recommendations.
The initial dose of this product is determined by the patient’s current treatment regimen. Take the drug twice daily with a meal. Available drug doses are.
50 mg selegiline/ 850 mg metformin hydrochloride
50mg Selegiline/ 1000mg Metformin Hydrochloride
For patients with poor glycemic control on metformin alone.
For patients with poor glycemic control on metformin alone, the initial dose of this product should provide a selegiline dose of 50 mg twice daily (total daily dose of 100 mg) plus the dose of metformin currently being taken.
For patients who are receiving concomitant selegiline and metformin and now require a change in treatment regimen.
For patients being treated with both selegiline and metformin who now need to change treatment regimens, the initial dose of this product may be selected based on the dose of selegiline and metformin that the patient is currently taking.
(This product is available in sizes 50 mg selegiline/ 850 mg metformin hydrochloride and 50 mg selegiline/ 1000 mg metformin hydrochloride and is not indicated for other patients requiring dose adjustment, such as those with renal impairment.)
Recommendations for the use of the drug in patients with renal impairment are as follows.
Because this product contains metformin, renal function should be evaluated prior to initiating treatment with this product and should be assessed periodically after initiation of treatment.
This product is contraindicated in patients with a glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 (see Contraindications and Precautions).
Adjustment of the metformin dose according to the patient’s eGFR level is recommended. No dose adjustment is necessary for patients with eGFR ≥ 60 mL/min/1.73 m2; for patients with eGFR 45-59 mL/min/1.73 m2, dose reduction is recommended as appropriate for the patient; it is contraindicated for patients with eGFR< 45 mL/min/1.73 m2.
Discontinuation due to iodinated contrast imaging examinations.
Because it contains metformin, it needs to be discontinued on or before the iodinated contrast imaging exam in patients with eGFR ≥ 45 to <60 mL/min/1.73 m2, in patients with a history of liver disease, alcoholism or heart failure, or in patients who will be receiving intra-arterial iodinated contrast agents. Reassess eGFR 48 hours after imaging; restart this product if renal function is appropriate (see Precautions).
[Adverse Reactions] According to the literature
Clinical trial experience
Because clinical trials are conducted under different conditions, the incidence of adverse reactions observed in clinical trials for one drug cannot be directly compared with the incidence of adverse reactions in clinical trials for another drug, and the incidence of adverse reactions in clinical trials does not necessarily reflect the incidence of adverse reactions in clinical practice.
Selegiline and metformin combination therapy
Initial combination therapy
In a 24-week placebo-controlled analytic design trial in which patients were treated with an initial regimen of selegiline 50 mg twice daily in combination with metformin 500 mg or 1000 mg twice daily, the incidence of adverse reactions (regardless of the investigator’s assessment of causality) in patients in the combination treatment group at ≥5% (and at a rate greater than that in patients treated with placebo) can be seen in Table 1.
Table 1 Initial combination therapy with selegiline and metformin.
Adverse reactions occurring in ≥5% of patients in the combination treatment group (and occurring more frequently than in patients receiving placebo)
(regardless of the investigator’s assessment of causality)1 Number of patients (%) Placebo Selegiline
100 mg q.d. Metformin 500 or 1000 mg b.i.d. 2 Selegiline 50 mg b.i.d. + metformin 500 or 1000 mg b.i.d. 2 N=176N=179N=364N=372 Diarrhea7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5) Upper respiratory tract infection9 (5.1) 8 ( 4.5) 19 (5.2) 23 (6.2) Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9) Remarks: 1: Intention-to-treat population
2: Data from patients who received lower or higher doses of metformin were pooled
Combination therapy with the addition of selegiline to metformin
In a 24-week placebo-controlled trial, patients with type 2 diabetes who were still poorly controlled on metformin monotherapy were randomized to the addition of selegiline or placebo. Of these, 464 patients treated with metformin added selegiline 100 mg once daily, and 237 patients received metformin plus placebo. Sitagliptin phosphate 100 mg daily was well tolerated in patients with type 2 diabetes treated with metformin monotherapy. The overall incidence of adverse events in patients treated with selegiline and metformin was similar to that in patients treated with placebo and metformin. There were no adverse events with an incidence of ≥5% (and a higher incidence than in patients in the placebo plus metformin treatment group) in the selegiline and metformin combination group (regardless of the investigator’s assessment of causality).
Hypoglycemia and Gastrointestinal Adverse Events
Two placebo-controlled trials studied selegiline and metformin combination therapy.
The incidence of hypoglycemia reported by patients in the combination treatment group (regardless of the investigator’s assessment of the cause of the occurrence of hypoglycemia) was similar to that of patients in the metformin + placebo treatment group. Hypoglycemic adverse events in the study were determined based on all reports of symptomatic hypoglycemia; concomitant measurement of blood glucose levels was not required. See Table 2.
The incidence of scheduled gastrointestinal adverse events in patients treated with the combination of selegiline and metformin was similar to that in patients treated with metformin monotherapy. See Table 2.
Table 2 Hypoglycemia and scheduled gastrointestinal adverse events reported by patients in the combination treatment group
(regardless of the investigator’s assessment of causality)1 Number of patients (%) Studies in which selegiline + metformin was the initial treatment Studies in which selegiline was added to metformin treatment Placebo selegiline
100 mg q.d. metformin 500 or 1000 mg b.i.d. 2 selegiline 50 mg b.i.d. + metformin 500 or 1000 mg b.i.d. 2 placebo + metformin ≥ 1500 mg/day selegiline
100 mg q.d. + metformin ≥ 1500 mg/day N=176N=179N=364N=372N=237N=464 Hypoglycemia1 (0.6) 1 (0.6) 3 (0.8) 6 (1.6) 5 (2.1) 6 (1.3) Diarrhea7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5) 6 (2.5) 11 ( 2.4) nausea 2 (1.1) 2 (1.1) 20 (5.5) 18 (4.8) 2 (0.8) 6 (1.3) vomiting 1 (0.6) 0 (0.0) 2 (0.5) 8 (2.1) 2 (0.8) 5 (1.1) abdominal pain 14 (2.3) 6 (3.4) 14 (3.8) 11 (3.0) 9 (3.8) 10 (2.2) Remarks: 1: In the studies with initial treatment, patients’ abdominal pain symptoms included abdominal discomfort.
2: Data from patients receiving lower or higher doses of metformin were pooled.
Selegiline in combination with metformin and glimepiride
In a 24-week placebo-controlled trial, patients with type 2 diabetes treated with glimepiride ≥4 mg/day and metformin ≥1500 mg/day but with poor glycemic control were randomized to the addition of selegiline 100 mg/day and placebo treatment (selegiline phosphate, N=116; placebo, N=113). Adverse reactions that occurred in ≥5% of patients treated with sitagliptin phosphate (and were more common than in patients receiving placebo) (regardless of the investigator’s assessment of causality) were: hypoglycemia (Table 3) and headache (6.9%, 2.7%).
Selegiline in combination with metformin and rosiglitazone
In a placebo-controlled study, sitagliptin phosphate 100 mg was used as add-on therapy in patients with type 2 diabetes treated with metformin and rosiglitazone but with poor glycemic control (sitagliptin phosphate, N=181; placebo, N=97). At week 18, adverse reactions (regardless of the investigator’s assessment of causality) that were reported to occur ≥5% of patients in the sitagliptin-treated group (N=170) and were more common than in patients receiving placebo (N=92) were: upper respiratory tract infection (sitagliptin phosphate, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). At week 54, adverse reactions reported at an incidence of ≥5% among patients in the sitagliptin-treated group and more common than among patients receiving placebo (regardless of the investigator’s assessment of causality) were: upper respiratory tract infection (sitagliptin phosphate, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache ( 5.5%, 4.1%).
Sitagliptin in combination with metformin and insulin
In a 24-week placebo-controlled study, sitagliptin phosphate 100 mg was used as add-on therapy in patients with type 2 diabetes treated with metformin (≥1500 mg/day) and stable doses of insulin but with poor glycemic control. The adverse effect (regardless of the investigator’s assessment of causality) that occurred in ≥5% of patients treated with sitagliptin phosphate and was more common than in patients receiving placebo (N=233) was hypoglycemia (see Table 3). In another 24-week study of selegiline as add-on therapy with concomitant insulin intensification (with or without metformin), the only adverse effect that occurred at an incidence of ≥1% and was higher in the selegiline combined with metformin treatment group than in the placebo combined with metformin treatment group was vomiting (selegiline combined with metformin treatment group, 1.1%; placebo combined with metformin treatment group, 0.4% ).
Hypoglycemia
When selegiline phosphate and metformin were given in combination with sulfonylurea or insulin, the percentage of patients reporting at least one hypoglycemic adverse reaction (regardless of the investigator’s assessment of causality) was higher than the percentage observed with placebo and metformin given concomitantly with sulfonylurea or insulin (see Table 3).
Table 3 Incidence and proportion of hypoglycemia in placebo-controlled clinical studies of selegiline phosphate and metformin in combination with concomitant administration of glimepiride or insulin1 (regardless of the investigator’s assessment of causality) added to glimepiride + metformin (24 weeks) Selegiline phosphate 100 mg + metformin + glimepiride Placebo + metformin + glimepiride N=116N=113 Overall (%) 19 (16.4) 1 (0.9) Incidence (events/patient-year) 20.820.02 Severe (%) 0 (0.0) 0 (0.0) Add to insulin + metformin (24 weeks) Selegiline phosphate 100 mg + metformin + insulin placebo + metformin + insulin N=229N=233 Overall (%) 35 (15.3) 19 ( 8.2) Incidence (events/patient-year) 20.980.61 Severe (%) 1 (0.4) 1 (0.4) Remarks: 1: Adverse effects of hypoglycemia were reported based on total symptomatic hypoglycemia; contemporaneous glucose measurements were not required: intention-to-treat population.
2: Based on the total number of events (i.e., one patient may have multiple events). § A severe hypoglycemic event is defined as an event requiring medical support or the presence of a decreased level of consciousness or unconsciousness or seizure.
In the study of the combination of selegiline phosphate and metformin and rosiglitazone, the overall incidence of hypoglycemia in patients was 2.2% during the 18-week treatment period with the addition of selegiline phosphate and 0.0% in patients with the addition of placebo. During the 54-week period, the overall incidence of hypoglycemia was 3.9% in patients who added sitagliptin phosphate and 1.0% in patients who added placebo.
Pancreatitis
In a pooled analysis of 19 double-blind clinical trials containing data from 10246 patients randomized to selegiline 100 mg daily (N=5429) or the corresponding (active or placebo) control (N=4817) treatment, the incidence of non-adjudicated acute pancreatitis events was 0.1/100 patient-years in each treatment group (4708 patient-years total in the selegiline treatment group) out of 4 patients with one adverse event and 4 patients with one adverse event out of a total of 3942 patient-years in the control group). See also the TECOS cardiovascular safety study below. (See Precautions, Pancreatitis).
No clinically meaningful changes in vital signs or electrocardiogram (including QTc interval) were observed with the combination of selegiline and metformin.
Adverse reactions of each active ingredient in the selegiline metformin combination
Reported adverse reactions to selegiline
The adverse event that occurred in ≥5% of patients treated with selegiline monotherapy and was more common than in patients receiving placebo (without regard to the investigator’s assessment of causality) was nasopharyngitis.
Reported Adverse Reactions with Metformin*
Reported adverse reactions with an incidence >5% in patients treated with metformin and more common than in patients receiving placebo (regardless of causality) were diarrhea, nausea/vomiting, flatulence, abdominal discomfort, dyspepsia, debility, and headache. Other rare ones are abnormal stools, hypoglycemia, myalgia, dizziness, abnormal nails, rash, increased sweating, abnormal taste, chest discomfort, chills, flu-like symptoms, hot flashes, palpitations, and weight loss. Metformin may reduce vitamin B12 absorption, but rarely causes anemia. It is rare to cause lactic acidosis in the therapeutic dose range.
TECOS cardiovascular safety studies
In the Evaluation of Selegiline Cardiovascular Clinical Outcomes Trial (TECOS), 7332 patients in the intention-to-treat population received selegiline 100 mg once daily (50 mg once daily if baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min/1.73 m2) and 7339 patients in the intention-to-treat population received placebo. Both study treatments were supplemented with conventional therapy aimed at improving glycated hemoglobin (HbA1c) and cardiovascular (CV) risk factors. The study population consisted of 2004 patients ≥75 years of age (970 treated with sitagliptin and 1034 treated with placebo). The overall incidence of serious adverse events among selegiline treated patients was similar to that of placebo treated patients. A prespecified assessment of diabetes-related complications showed similar rates between treatment groups, including infections (18.4% and 17.7% in selegiline and placebo-treated patients, respectively) and renal failure (1.4% and 1.5% in selegiline and placebo-treated patients, respectively). The characteristics of adverse events among patients ≥75 years of age were broadly similar to the overall population.
In the intention-to-treat population, the incidence of severe hypoglycemia was 2.7% and 2.5% in selegiline and placebo-treated patients, respectively, among patients using insulin and/or sulfonylurea at baseline, and 1.0% and 0.7% among selegiline and placebo-treated patients not using insulin and/or sulfonylurea at baseline. The incidence of adjudicated confirmed pancreatitis events was 0.3% and 0.2% in selegiline and placebo-treated patients, respectively. The incidence of adjudication-confirmed malignancy events was 3.7% and 4.0% in selegiline and placebo-treated patients, respectively.
Postmarketing Experience.
Additional adverse reactions have been reported following the marketed use of this product or one of its components, sitagliptin, as described below. These adverse reactions were seen with monotherapy with this product or selegiline and/or in combination with other hypoglycemic agents. Because these reactions are spontaneously reported by an indeterminate number of people, it is usually not possible to reliably estimate their frequency or to establish a causal relationship with drug exposure.
Allergic reactions, including anaphylaxis, angioedema, rash, rubella, cutaneous vasculitis, and exfoliative skin lesions, including Stevens-Johnson syndrome (see Contraindications and Precautions, Sitagliptin Phosphate, Allergic Reactions); acute pancreatitis, including lethal and nonlethal hemorrhagic and necrotizing pancreatitis (see Precautions, Pancreatitis); worsening renal function, including acute renal failure (sometimes requiring dialysis) (see Contraindications and Precautions); herpetic aspergillosis (see Precautions, Herpetic Aspergillosis); upper respiratory tract infections; elevated liver enzyme levels; constipation; vomiting; headache; severe and disabling arthralgia; myalgia; limb pain; back pain; pruritus; oral ulcers, stomatitis; cholestatic, hepatocellular, and mixed hepatocellular liver injury.
Laboratory tests
Sitagliptin phosphate
The incidence of adverse laboratory reactions in patients treated with selegiline and metformin (7.6%) was similar to that in patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell counts was observed due to a small increase in neutrophils (a difference of approximately 200 cells/μL relative to placebo; the baseline mean for white blood cells was approximately 6600 cells/μL). Changes in laboratory parameters were not considered clinically significant.
Metformin hydrochloride
In a 29-week controlled trial of metformin, a decrease in previously normal vitamin B12 serum concentrations to below normal levels was observed in approximately 7% of patients without clinical manifestations. This decrease in vitamin B12 levels may be due to metformin interfering with the uptake of B12 by the B12-internal factor complex; however, the phenomenon is very rarely accompanied by anemia. It resolves quickly after discontinuation of metformin or vitamin B12 supplementation (see Precautions – Metformin Hydrochloride).
Contraindications
Contraindications to this product (sitagliptin phosphate/metformin hydrochloride) include.
1Severe renal impairment (eGFR < 45 mL/min/1.73 m2) due to the presence of metformin in this product (see Precautions, Metformin Hydrochloride, Renal Impairment).
2 Known hypersensitivity to sitagliptin phosphate, metformin hydrochloride, or any other component of this product (see PRECAUTIONS, Sitagliptin Phosphate, Allergic Reactions and Adverse Reactions, Postmarketing Experience).
3 Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
Treatment with this product should be temporarily discontinued in patients undergoing imaging studies requiring intravascular injection of iodine-containing contrast agents, as such contrast agents may cause acute renal function changes (see PRECAUTIONS: Metformin Hydrochloride).
Precautions]
This product
This product should not be used in patients with type 1 diabetes or diabetic ketoacidosis.
Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been reported in patients treated with selegiline in post-marketing experience (see ADVERSE REACTIONS). Patients must be carefully monitored for signs and symptoms after initiation of selegiline metformin therapy. If pancreatitis is suspected, the product must be discontinued immediately and treated accordingly. Selegiline metformin has not been studied in patients with a previous history of pancreatitis. It is not clear whether the use of selegiline metformin in patients with a history of prior pancreatitis increases the risk of pancreatitis. Patients must be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain.
Heart Failure: An association between DPP-4 inhibitor therapy and heart failure was found in cardiovascular safety studies of two other DPP-4 inhibitors. These studies evaluated patients with type 2 diabetes and atherosclerotic cardiovascular disease.
In patients at high risk for heart failure, risks and benefits should be assessed prior to initiating therapy, such as a history of prior heart failure and renal impairment, and patients should be observed for signs and symptoms during therapy. Patients should be informed of the typical symptoms of heart failure and reported to the physician immediately upon the onset of appropriate symptoms. If heart failure occurs, treatment should be evaluated according to current treatment criteria and discontinuation should be considered.
The Evaluation of Selegiline Cardiovascular Clinical Outcomes Trial (TECOS) is a randomized study of 14,671 patients in the intention-to-treat population with HbA1c ≥6.5 to 8.0% and established CV disease. After a median follow-up of 3 years, supplementing selegiline dosing with conventional therapy did not increase the risk of major adverse cardiovascular events or the risk of hospitalization for heart failure compared with patients with type 2 diabetes who received conventional therapy only and did not receive selegiline dosing.
Monitoring renal function: Both metformin and selegiline are known to be excreted primarily through the kidneys. As the degree of renal impairment increases, the risk of accumulation of metformin in the body and the development of lactic acidosis increases accordingly. This product contains metformin and is contraindicated in patients with severe renal impairment (eGFR <45mL/min/1.73 m2) (see Dosage, Contraindications and Precautions, Metformin Hydrochloride, Lactic Acidosis).
There have been post-marketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. Patients’ renal function should be evaluated prior to initiating treatment with this product and checked at least once a year after starting the drug. In patients whose renal function is estimated to be deteriorating, especially in the elderly, renal function should be checked frequently and treatment with this product should be discontinued as soon as renal impairment is detected.
Sitagliptin phosphate
Allergic reactions: There have been post-marketing reports of serious allergic reactions in patients treated with one of the components of this product, sitagliptin. These adverse reactions include anaphylaxis, angioedema, and exfoliative skin lesions, including Stevens-Johnson syndrome. Because these reactions are spontaneously reported by an indeterminate number of people, it is usually not possible to reliably estimate their frequency or to establish a causal relationship with drug exposure. These adverse reactions occur within 3 months after initiation of selegiline therapy, with some of these reports seen after the first dose. If an allergic reaction is suspected, treatment with this product must be discontinued, other potential causes of the adverse event evaluated and other therapy for diabetes must be initiated (see Contraindications and Adverse Reactions, Postmarketing Experience).
Herpetiform aspergillosis: Cases of herpetiform aspergillosis requiring hospitalization have been reported in the post-marketing phase with the use of DPP-4 inhibitors. In such reported cases, patients usually resolved after topical topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor medication. Patients must be informed to report the presence of blisters or breakouts while receiving this product. If herpetiform aspergillosis is suspected, discontinue the drug and consider referral to a dermatologist for diagnosis and appropriate treatment.
Severe and disabling arthralgia: There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time interval between initiation of drug therapy and the onset of symptoms varies from one day to several years. Patients have experienced relief of symptoms after discontinuation of the drug. Some patients experience a recurrence of symptoms upon re-treatment with the same drug or other DPP-4 inhibitors. If appropriate, DPP-4 inhibitors should be considered as the cause of severe joint pain and discontinued.
Metformin hydrochloride
Lactic acidosis: Lactic acidosis is a rare but serious metabolic complication that can occur during treatment with this product (sitagliptin phosphate/metformin hydrochloride) due to accumulation of metformin; when it occurs, the lethality rate is around 50%. The development of lactic acidosis is also associated with many pathophysiologic conditions, including diabetes mellitus and any condition that causes severe tissue hypoperfusion and hypoxia. The clinical features of lactic acidosis are elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/acetone ratio. If the cause of lactic acidosis is metformin, then metformin plasma levels will typically be >5 μg/mL.
The incidence of lactic acidosis in patients treated with metformin hydrochloride has been documented to be very low (approximately 0.03 cases/1000 patients/year, with approximately 0.015 deaths/1000 patients/year). More than 20,000 patients per year were treated with metformin in clinical trials and no cases of lactic acidosis were reported. The reported cases of lactic acidosis occurred primarily in diabetic patients with severe renal impairment, including patients with renal per se disease and renal hypoperfusion, and these patients often also had other medical/surgical conditions and were taking multiple concomitant medications (see Dosage and Administration, Recommended Doses for Patients with Renal Impairment). Patients with congestive heart failure requiring drug therapy are at increased risk of lactic acidosis, especially those with unstable or acute congestive heart failure, and these patients have a higher than usual risk of tissue hypoperfusion and hypoxemia. The more severe the degree of renal damage and the older the patient, the higher the risk of lactic acidosis. Therefore, if the renal function of patients taking metformin is regularly monitored and metformin is adjusted to the lowest effective dose, the risk of lactic acidosis in patients will be significantly reduced. Geriatric patients in particular should be monitored for changes in renal function during treatment (see Geriatric Dosing, Metformin Hydrochloride). In addition, metformin therapy should be discontinued as soon as the patient develops any clinical signs associated with hypoxemia, dehydration, or sepsis. Because impaired liver function can severely impair lactate clearance in patients, metformin should be avoided if clinical signs of liver disease or evidence of laboratory tests are present. Physicians should also caution patients taking metformin to avoid excessive alcohol consumption (either short-term or long-term heavy drinking), as alcohol enhances the effects of metformin hydrochloride on lactate metabolism. In addition, patients should temporarily discontinue metformin therapy before undergoing any imaging studies with intravascular contrast or any surgery.
The onset of lactic acidosis is often very insidious and patients usually have only a few nonspecific symptoms such as general malaise, myalgia, dyspnea, drowsiness, and nonspecific abdominal discomfort. Further progression of acidosis may be associated with hypothermia, hypotension, and intractable bradycardia. Both the patient and the physician must be aware of the potential dangers behind these symptoms, and the patient should inform the physician as soon as they occur. If lactic acidosis occurs, metformin therapy should be discontinued until the condition is resolved. Measuring the patient’s electrolytes, ketone bodies, and blood glucose may be helpful in the diagnosis of lactic acidosis, as well as measuring the patient’s blood pH, lactate concentration, and even blood metformin levels, if needed. It is unlikely that the gastrointestinal symptoms that occur after a patient takes a stable dose of metformin are drug-related; such gastrointestinal symptoms are common during the initial phase of treatment. Gastrointestinal symptoms that occur later in treatment are likely to be caused by lactic acidosis or other serious illness.
In patients taking metformin, a fasting venous lactate level above the upper limit of normal but less than 5 mmol/L does not necessarily indicate that the patient is about to develop lactic acidosis and may be explained by other mechanisms, such as poor diabetic control, obesity, strenuous physical activity, or technical problems occurring during specimen processing.
The possibility of lactic acidosis should be suspected in any diabetic patient who develops metabolic acidosis but lacks evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is an emergency and must be treated in hospital. Patients taking metformin should discontinue metformin therapy immediately in the event of lactic acidosis and be given prompt systemic supportive therapy measures. Because metformin hydrochloride is cleared by dialysis (hemodynamically stable clearance of 170 mL/min), hemodialysis may be recommended for patients with lactic acidosis to relieve the acidosis and clear the metformin accumulation. Rapid reversal of the patient’s symptoms can often be achieved with this therapeutic measure to help the patient heal (see contraindications).
Hypoglycemia: Hypoglycemia does not usually occur in patients receiving metformin monotherapy. Hypoglycemia often occurs with inadequate energy intake, lack of timely energy replacement after strenuous exercise, concurrent treatment with other hypoglycemic agents (e.g., sulfonylureas and insulin), or alcohol consumption. Elderly, frail, and malnourished patients, as well as patients with adrenal or pituitary insufficiency and alcoholism, are particularly susceptible to hypoglycemia. Hypoglycemia is often difficult to detect when it occurs in the elderly and in patients treated with beta-adrenoceptor blockers.
Administration of other drugs that may affect renal function or metformin metabolism: These drugs should be taken with caution because they can affect renal function, or cause changes in hemodynamic status, or affect metformin metabolism, such as cationic drugs cleared by renal tubular excretion (see Drug Interactions – Metformin Hydrochloride).
Imaging involving intravascular injection of iodine contrast (e.g., intravenous urography, intravenous cholangiography, angiography, computed tomography [CT] with intravenous contrast injection): imaging with intravascular injection of iodine contrast may result in acute renal function changes and has been associated with the development of lactic acidosis in patients treated with metformin (see Contraindications). Because it contains metformin, it should be temporarily discontinued in patients with an eGFR ≥ 45 to <60 mL/min/1.73 m2, a history of liver disease, alcoholism, or heart failure, or in patients who will be receiving intra-arterial iodinated contrast, and should not be taken for 48 hours after completion of the examination until renal function is confirmed to be acceptable by reexamination before reintroduction of Treatment (see Dosage and Administration).
Hypoxia: Circulatory collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions causing hypoxemia from any cause may cause lactic acidosis and may also cause prerenal azotemia. Once these events occur in patients receiving this product, the drug should be discontinued immediately.
Surgery: Patients should temporarily discontinue treatment prior to any surgery (except minor surgery without restriction of food and fluid intake) and should not restart treatment until the patient is able to eat again and renal function has been reviewed as acceptable (see Dosage and Administration).
Alcohol consumption: Alcohol consumption is known to enhance the effects of metformin on lactate metabolism. Therefore, physicians should caution patients receiving this product to avoid excessive alcohol consumption, either short-term or long-term in large quantities.
Impaired liver function: Because several cases of lactic acidosis associated with impaired liver function have occurred, this product should be avoided in any patient with clinical manifestations or laboratory evidence of liver disease.
Vitamin B12 levels: In a 29-week clinical trial of metformin, it was observed that approximately 7% of patients with previously normal blood vitamin B12 levels had a decrease in vitamin B12 levels below the normal range after administration of the drug without clinical symptoms. This decrease in vitamin B12 levels may be due to metformin interfering with the absorption of vitamin B12 by the vitamin B12-internal factor complex, but patients in whom this occurs are rarely anemic and resolve quickly after discontinuation of metformin or vitamin B12 supplementation. Patients taking this product are advised to have their hematological parameters checked annually, and any apparent abnormalities in the parameters should be carefully followed and treated accordingly.
Some individuals (with inadequate intake or absorption of vitamin B12 or calcium) appear to be more prone to lower than normal vitamin B12 levels. It may be beneficial to routinely check blood vitamin B12 levels every 2-3 years in such patients.
Patients with type 2 diabetes who have previously had good glycemic control but have recently experienced a change in clinical status: Patients with type 2 diabetes whose disease has been well controlled with previous treatment with this product should be checked immediately for ketoacidosis or lactic acidosis if they develop abnormal laboratory tests or develop clinical symptoms (especially vague and difficult to define symptoms). Tests include measuring the patient’s electrolytes, ketone bodies, blood glucose, and if needed, blood pH, lactate, pyruvate, and metformin levels. In the event of any of these acidosis, the patient should immediately discontinue treatment with this product and be given appropriate therapeutic measures.
Poor glycemic control: Patients who have previously had good glycemic control may experience temporary poor glycemic control in the event of stress such as fever, trauma, infection or surgery. In this case, it is necessary to stop the treatment of this product and give insulin treatment temporarily. After the acute period, the treatment can be restarted.
[For pregnant and lactating women].
Pregnant women.
This product
There are no adequate controlled studies on the use of this product or its ingredients in pregnant women, so the safety of this product in pregnant women is not known. As with other oral hypoglycemic drugs, it is not recommended that women take this product during pregnancy.
No animal studies have been conducted on the effects of this product on fertility. The following are findings from studies of selegiline or metformin alone
Lactating women.
No studies have been conducted on this product in lactating animals. From studies of each individual component, it appears that both selegiline and metformin are secreted through the milk of lactating rats. It is not known whether selegiline is secreted into human milk. Therefore, lactating women should not take this product.
Pediatric Dosage]
Studies on the efficacy and safety of selegiline have not been conducted in pediatric patients under 18 years of age.
Geriatric use
This product
Because selegiline and metformin are primarily excreted through the kidneys, and aging is associated with declining renal function, this product should be taken with caution as patients age. Physicians should carefully and regularly monitor the patient’s renal function and choose the drug dose carefully on this basis (see PRECAUTIONS – Renal Function Monitoring).
Sitagliptin phosphate
Results of clinical trials have shown that the safety and efficacy of sitagliptin in the elderly population (≥65 years) are comparable to those in younger patients (<65 years).
Metformin Hydrochloride
Controlled clinical trials of metformin did not enroll sufficient numbers of older patients to measure whether older patients respond differently to the drug than younger patients, although from other clinical reports that have been obtained, no differences in response to the drug between older and younger patients have been found.
[Drug Interactions] According to the literature
Sitagliptin and metformin
In patients with type 2 diabetes, multiple dose co-administration of selegiline (50 mg twice daily) and metformin (1000 mg twice daily) does not significantly alter the pharmacokinetics of each component drug.
No studies have evaluated the pharmacokinetic drug interactions of this product, however, studies have evaluated selegiline and metformin as separate components of this product.
Sitagliptin phosphate
Trials investigating drug interactions have shown that selegiline does not have a clinically meaningful effect on the pharmacokinetics of metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, and oral contraceptives. These data indicate that selegiline does not inhibit the CYP coenzymes CYP3A4, 2C8, or 2C9. Results from in vivo trials also indicate that selegiline does not inhibit the CYP coenzymes CYP2D6, 1A2, 2C19, or 2B6, nor does it induce production of CYP3A4.
Studies have been conducted to analyze the population pharmacokinetic characteristics of patients with type 2 diabetes. It was found that other drugs taken by these patients did not produce clinically meaningful effects on the pharmacokinetics of sitagliptin. These were mainly drugs that are frequently taken by patients with type 2 diabetes, including cholesterol-lowering drugs (e.g., statins, fibrates, ezetimibe), antiplatelet agents (e.g., clopidogrel), antihypertensive agents (e.g., angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and nonsteroidal anti-inflammatory drugs (e.g., naproxen, diclofenac , celecoxib), antidepressants (e.g., butalbital, fluoxetine, sertraline), antihistamines (e.g., cetirizine), proton pump inhibitors (e.g., omeprazole, lansoprazole), and drugs for erectile dysfunction (e.g., sildenafil).
When digoxin is combined with selegiline, there is a mild increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of the selegiline pharmacokinetic curve. The extent of this increase is not considered clinically significant at this time. Nonetheless, patients receiving digoxin therapy should be monitored appropriately. When patients were given 100 mg of selegiline and 600 mg of cyclosporine (a potent p-glycoprotein inhibitor) concomitantly, the AUC and Cmax of the selegiline pharmacokinetic profile increased by about 29% and 68%, respectively. However, the above pharmacokinetic changes in selegiline are not considered to be clinically significant.
Metformin hydrochloride
Glibenclamide: A trial in patients with type 2 diabetes studied the interaction between single doses of the drug. The results showed that combined treatment with metformin and glibenclamide did not cause any effect on the pharmacokinetics or pharmacodynamics of metformin. A decrease in the AUC and a decrease in the Cmax of the glibenclamide pharmacokinetic profile could also be observed in the study, but there was no fixed trend. The clinical significance of this drug interaction observed was not significant because it was a single dose drug trial and there was no correlation between the blood concentration of glibenclamide and its pharmacodynamics.
Furosemide: A clinical trial with healthy subjects investigated the interaction between single doses of metformin and furosemide. The results of the study showed that the combination treatment had an effect on the respective pharmacodynamic parameters of both drugs. Furosemide resulted in a 22% increase in blood Cmax and a 15% increase in AUC values for metformin, but no significant change in renal clearance. In contrast, metformin decreased the Cmax value of furosemide by 31%, the AUC value by 12%, and the terminal half-life of the drug by 32% compared with the drug alone, but there was no significant change in renal clearance. No interactions between metformin and furosemide have been documented in the literature regarding their long-term coadministration.
Nifedipine: A clinical trial in healthy subjects investigated the interaction between a single dose of metformin and nifedipine. The results of the study showed that the combination with nifedipine increased the Cmax of metformin by 20%, increased the AUC by 9%, and increased the excretion of metformin in the urine. The Tmax and half-life of metformin were not affected. Nifedipine also appears to increase the absorption of metformin. The effect of metformin on nifedipine was minimal.
Drugs that reduce metformin clearance: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cation transport protein-2 [OCT2] / multidrug and toxin efflux protein [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase systemic metformin exposure and may increase the lactic acidosis risk. The benefits and risks of concomitant medications need to be considered.
Other medications: Some medications tend to cause hyperglycemia, which can lead to poor glycemic control in patients. Such medications include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid medications, estrogens, oral contraceptives, phenytoin, niacin, sympathomimetics, calcium channel blockers, and isoniazid. If a patient receiving this product is also taking any of these medications, the physician should closely monitor the patient’s blood glucose to ensure that it is well controlled.
Trials conducted in healthy subjects have shown that metformin and propranolol and metformin and ibuprofen do not interact with each other in their respective pharmacokinetics when given as a single dose.
Unlike sulfonylureas, which bind extensively to serum proteins, metformin barely binds to plasma proteins, so interactions between drugs with high protein binding and metformin are less likely to occur, including salicylates, amisulpride, chloroacetic acid, and propoxur.
Drug overdose】According to the literature
Sitagliptin phosphate
Controlled clinical trials with healthy subjects have shown that a single dose of selegiline 800 mg is usually well tolerated. In a trial with a selegiline dose of 800 mg, a mild prolongation of QTc was observed in some patients, but this change was not clinically significant (see Clinical Pharmacology, Pharmacodynamics, Cardiac Electrophysiology). Experience with doses greater than 800 mg has not been obtained in clinical studies. In Phase I multiple-dose studies, no dose-related clinical adverse reactions occurred when the maximum dose of selegiline was 600 mg daily for up to 10 days and 400 mg daily for up to 28 days.
In the event of an overdose, physicians should take the usual adjunctive measures for symptomatic management, such as removal of unabsorbed drug from the gastrointestinal tract, use of clinical monitoring equipment (including measurement of electrocardiogram), and appropriate adjunctive therapy if necessary.
Sitagliptin can be moderately cleared by dialysis. In clinical trials, approximately 13.5% of the drug dose was cleared after 3-4 hours of hemodialysis. The duration of hemodialysis may also be extended if necessary depending on the clinical situation. It is not known whether selegiline can be cleared by peritoneal dialysis.
Metformin hydrochloride
Clinical events have occurred in which patients have overdosed on metformin hydrochloride, even including doses exceeding 50 g. Hypoglycemia has been reported in approximately 10% of patients taking metformin, but no causal relationship has been found between hypoglycemia and metformin hydrochloride administration. Lactic acidosis was reported in approximately 32% of metformin overdose cases (see PRECAUTIONS – Metformin Hydrochloride). Metformin is cleared by dialysis at rates of up to 170 mL/min in good hemodynamics; therefore, hemodialysis may help to clear the drug accumulated in patients who have overdosed on metformin.
Pharmacology and Toxicology
Pharmacological effects
This product is a compound preparation of sitagliptin and metformin.
Sitagliptin phosphate
Sitagliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), an intestinal pro-insulin hormone including glucagon-like polypeptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which is released by the intestine throughout the day and its level increases after meals. Intestinal proinsulin is part of an endogenous system involved in the physiological regulation of glucose endotropic homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic β-cells via an intracellular signaling pathway involving cyclophosphatidyl adenosine. In addition, GLP-1 inhibits the secretion of glucagon by pancreatic α-cells. Decreased glucagon concentrations and increased insulin levels reduce hepatic gluconeogenesis, thereby lowering blood glucose levels.The effects of GLP-1 and GIP are glucose-dependent; when blood glucose concentrations are low, GLP-1 does not promote insulin release or inhibit glucagon secretion. When glucose levels are higher than normal concentrations, the effects of GLP-1 and GIP to promote insulin release are enhanced. In addition, GLP-1 does not impair the body’s normal glucagon release response to hypoglycemia. the activity of GLP-1 and GIP is limited by the enzyme DPP-4, which rapidly hydrolyzes enteroglucagon and produces inactive products. Sitagliptin prevents DPP-4 from hydrolyzing enteroglucagon, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By increasing active enteroglucagon levels, selegiline is able to increase insulin release and decrease glucagon levels in a glucose-dependent manner.
Metformin hydrochloride
Metformin improves glucose tolerance in patients with type 2 diabetes and can lower basal and postprandial blood glucose. It can inhibit hepatic glycogen allogenesis, reduce glucose uptake in the small intestine, and improve insulin sensitivity in peripheral tissues by increasing glucose uptake and utilization in peripheral tissues. Metformin does not generally cause hypoglycemia in patients with type 2 diabetes and normal subjects, except in special cases, and does not cause hyperinsulinemia. Although metformin treatment may reduce fasting insulin levels and insulin response throughout the day, there is usually no change in insulin secretion.
Toxicological studies
No data are available on the non-clinical safety of selegiline metformin combination; the following data are derived from the results of studies with selegiline and metformin alone.
Sitagliptin phosphate
Repeated administration: Selegiline was administered orally to dogs at 2, 10 and 50 mg/kg daily for 53 weeks, with no adverse effects seen in the trial at a dose of 10 mg/kg, which is approximately 6 times the human exposure based on the recommended adult daily dose of 100 mg. , vomiting of white foam, ataxia, tremors, reduced activity, and/or an arched back posture. Histological findings in animals in the 50 mg/kg group were suggestive of mild skeletal muscle degeneration at weeks 14-27 of the toxicity test. No skeletal muscle degeneration was observed at week 53 of the toxicity test, suggesting that this change did not recur or progress with increasing duration of administration. Systemic exposure in animals at a daily dose of 50 mg/kg was 26 times greater than human exposure.
Genotoxicity: Sitagliptin did not show genotoxicity.
REPRODUCTIVE TOXICITY: Selegiline was administered by oral gavage at 125, 250, and 1000 mg/kg to males for 4 weeks prior to mating, during mating, and during planned abortion (approximately 8 weeks total) and to females from 2 weeks prior to mating through day 7 of gestation. No adverse effects on fertility were observed in the 125 mg/kg dose group (exposure was approximately 12 times the human maximum clinically recommended dose (MRHD 100 mg/day) by AUC comparison). No dose-related increase in drug reabsorption was observed in female rats at mid- to high-dose levels (exposure was approximately 25 and 100 times greater than MRHD by AUC comparison). A mild increase in the incidence of embryonic rib malformations (missing, hypoplastic and undulating ribs) associated with drug administration was observed in rats administered orally at doses up to 1000 mg/kg/day. No teratogenic effects were seen in rats given selegiline at 250 mg/kg/day and rabbits given 125 mg/kg/day (22 times MRHD 100 mg on an AUC basis). Sitagliptin can be secreted through the milk of lactating rats.
Carcinogenicity: No increase in tumor incidence was observed in mice given selegiline 500 mg/kg/day orally for 2 years. In rats given selegiline orally for 2 years at doses of 50, 150 and 500 mg/kg/day, an increased incidence of hepatic adenoma and hepatocellular carcinoma was seen in male rats in the 500 mg/kg/day group and in female rats in the 500 mg/kg/day group. On the basis of AUC, 500 mg/kg/day was 60 times that of MRHD 100 mg, and hepatotoxicity was observed in rats at this dose. The dose at which no liver tumor-inducing effects of selegiline were observed was 150 mg/kg/day (20 times MRHD 100 mg at AUC). Since the hepatotoxicity of the drug has been found to be associated with the induction of liver tumors in rats, the increased incidence of liver tumors in rats may be secondary to the chronic hepatotoxic effects of high doses of the drug, a finding of unknown significance for human clinical use.
Metformin
Genotoxicity: Metformin Ames test, mouse lymphoma cell gene mutation test, human lymphocyte chromosome aberration test and in vivo micronucleus test in mice were all negative.
Reproductive toxicity: Fertility was not affected in male and female rats given metformin at 600 mg/kg/day, which is approximately three times the recommended maximum daily dose for humans based on body surface area.
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, which is approximately 4 times the maximum daily dose of 2000 mg recommended for humans based on body surface area. No increase in tumor incidence was seen in mice and male rats, and an increase in the incidence of small benign urinary polyps was seen in female rats at a dose of 900 mg/kg/day.
Pharmacokinetics】According to the literature
This product
An authoritative bioequivalence study in healthy subjects showed that the 50mg/500mg and 50mg/1000mg combination tablets of selegiline/metformin hydrochloride were bioequivalent to the corresponding doses of selegiline phosphate and metformin hydrochloride taken in combination.
Since bioequivalence has been demonstrated for the lowest and highest dose size combination tablets available, bioequivalence also applies to the 50 mg/850 mg fixed dose combination (FDC) tablets (selegiline/metformin).
Absorption
Sitagliptin phosphate
The absolute bioavailability of selegiline is approximately 87%. Concomitant consumption of a high-fat diet had no effect on the pharmacokinetics of selegiline.
Metformin Hydrochloride
The absolute bioavailability of the drug is about 50-60% after taking metformin hydrochloride 500 mg tablets under fasting conditions. One trial studied the absorption of single oral doses of 500-1500 mg and 850-2550 mg metformin hydrochloride tablets and found that the percentage of drug absorption did not increase with increasing drug dose, not because the clearance of the drug was altered but because the absorption of the drug was reduced. Food reduced the range of absorption of metformin and slightly delayed its absorption time, which was numerically demonstrated by a decrease in the mean peak blood concentration (Cmax) of the drug by about 40% and a decrease in the area under the curve (AUC) of blood concentration-time by 25% after food intake, and by a delay in the time to reach the peak blood concentration (Tmax) of the drug of 850 mg tablets after food intake compared to fasting. ) by 35 minutes. The clinical significance of these pharmacokinetic changes is unclear.
Distribution
Sitagliptin phosphate
The mean volume of distribution of the drug at steady state in healthy subjects receiving a single intravenous dose of selegiline 100 mg is approximately 198 liters. The proportion of selegiline that was able to bind reversibly to plasma proteins was low (38%).
Metformin hydrochloride
The mean apparent volume of distribution of metformin after a single oral dose of 850 mg of metformin hydrochloride tablets is 654 ± 358 L. The proportion of sulfonylureas bound to plasma proteins is above 90%, compared to metformin, which is rarely bound to plasma proteins. Metformin can be distributed in red blood cells and the amount of distribution is likely to be a function of time. Controlled clinical trials of metformin have shown that even at the highest doses of metformin, the maximum blood levels do not exceed 5 mcg/mL.
Metabolism
Sitagliptin phosphate
Sitagliptin is excreted primarily in its original form in the urine, and only a small fraction of it is metabolized in the body. Approximately 79% of sitagliptin is excreted in its original form in the urine.
After oral administration of [14C]-labeled selegiline, approximately 16% of the radiation is excreted as a selegiline metabolite. Six metabolites could be detected in plasma at trace levels and these metabolites were not associated with the inhibition of plasma DPP-4 by selegiline. In vitro tests showed that the enzyme associated with a small amount of the metabolic process of selegiline is mainly CYP3A4, with CYP2C8 also having an effect on this process.
Metformin hydrochloride
Single intravenous administration studies of metformin in normal subjects have shown that metformin is excreted in its original form via the urine and is neither metabolized by the liver (no metabolites were detected in humans) nor excreted via the bile.
Clearance
Sitagliptin phosphate
Oral administration of selegiline labeled with [14C] to healthy subjects resulted in the clearance of approximately 100% of the radioactive energy in the feces (13%) and urine (87%) within one week of administration. After oral administration of 100 mg of selegiline, the apparent terminal half-life of the drug was approximately 12.4 hours, and the renal clearance was approximately 350 mL/min.
The clearance of sitagliptin is primarily by renal excretion and involves active renal tubular secretion. Sitagliptin is a substrate for human organic anion transporter protein-3 (hOAT-3), a transporter protein that may be involved in the renal clearance of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport is not well understood. Selegiline is also a substrate of p-glycoprotein, a glycoprotein that may also be involved and selegiline clearance in the kidney. Nevertheless, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of selegiline.
Metformin hydrochloride
The renal clearance of metformin hydrochloride is approximately 3.5 times greater than that of creatinine, suggesting that renal tubular secretion is the major route of metformin clearance. After oral administration of metformin, approximately 90% of the absorbed drug is cleared by the renal route within 24 hours, and the plasma clearance half-life of the drug is approximately 6.2 hours. The clearance half-life of the drug in the blood is approximately 17.6 hours, suggesting that the erythrocyte collection may be a small compartment for drug distribution.
Patients with type 2 diabetes
Sitagliptin phosphate
In general, the pharmacokinetics of selegiline in type 2 diabetic patients is similar to its pharmacokinetics in healthy subjects.
Metformin hydrochloride
In the presence of normal renal function, there is no difference in the pharmacokinetics of single or multiple doses between type 2 diabetic patients and normal subjects, and no accumulation of metformin in the commonly used clinical dose range has been observed.
Patients with renal impairment
Sitagliptin phosphate
In clinical trials, it was observed that compared to healthy controls with normal renal function, the plasma AUC of selegiline was increased approximately 2-fold in patients with moderate renal impairment (eGFR between 30-45 mL/min/1.73m2) and approximately 4-fold in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) including end-stage renal disease hemodialysis. about 4-fold.
Metformin hydrochloride
The half-life of metformin in plasma and blood is prolonged and renal clearance is decreased in patients with hyperalgesia (see Contraindications and Precautions).
Liver damage
Sitagliptin phosphate
In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) after selegiline phosphate 100 mg, the mean AUC and Cmax of selegiline were 21% and 13% higher, respectively, compared to healthy subjects in the control group. It is currently believed that this difference may not be clinically significant.
No information is available on patients with severe liver damage (Child-Pugh score >9). However, since selegiline is primarily cleared by the kidneys, severe hepatic impairment should not affect the pharmacokinetics of selegiline.
Metformin hydrochloride
There are no pharmacokinetic studies of metformin in patients with hepatic impairment.
Gender
Sitagliptin phosphate
Based on a comprehensive analysis of Phase I pharmacokinetic data and a population pharmacokinetic analysis of Phase I and Phase II data, there is no clinically meaningful effect of gender on the pharmacokinetics of selegiline.
Metformin hydrochloride
Analysis by gender revealed no significant differences in metformin pharmacokinetic parameters between normal subjects and type 2 diabetic patients. Similarly, controlled clinical studies conducted in patients with type 2 diabetes showed that the anti-hyperglycemic effect of metformin was similar in male patients versus female patients.
In elderly patients
Sitagliptin phosphate
Based on a population pharmacokinetic analysis of Phase I and Phase II data, age did not have a clinically meaningful effect on the pharmacokinetics of sitagliptin. Blood concentrations of selegiline were approximately 19% higher in elderly subjects (65 to 80 years of age) than in young subjects.
Metformin hydrochloride
From the limited controlled pharmacokinetic studies of metformin in elderly healthy subjects, it appears that metformin has decreased total plasma clearance, prolonged half-life, and increased Cmax in elderly patients compared to healthy young subjects. From these data, it appears that the pharmacokinetics of metformin changes with patient age primarily because the renal function of patients changes with increasing age.
Children
No studies have been conducted on this product in pediatric patients.
Ethnicity
Sitagliptin phosphate
Based on a comprehensive analysis of Phase I pharmacokinetic data and a population pharmacokinetic analysis of Phase I and II data, there was no clinically meaningful effect of race on the pharmacokinetics of sitagliptin. Race in this context includes White, Hispanic, Black, Asian, and other races.
Metformin Hydrochloride
There are no trials examining the pharmacokinetic parameters of metformin from a racial perspective. Placebo-controlled clinical trials conducted in patients with type 2 diabetes have shown comparable anti-hyperglycemic effects of metformin in whites (n=249), blacks (n=51), and Hispanics (n=24).
Body mass index (BMI)
Sitagliptin phosphate
Based on a comprehensive analysis of phase I pharmacokinetic data and a population pharmacokinetic analysis of phase I and II data, body mass index (BMI) had no clinically meaningful effect on the pharmacokinetics of sitagliptin.
Storage
Store under 30°C in a sealed container.
Packaging
HDPE bottle, 60 tablets/box.
PVC/PVDC aluminum packaging, 14 tablets/box; 28 tablets/box.
Expiration date】 36 months
Execution Standard
Approval number】
【Drug marketing license holder
Company Name: Guangdong Dongyang 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 telephone 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
Postcode：523808
Website: http://pharm.hec.cn/