Date of approval.
Instructions for Englestrin Tablets
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Englestrin Tablets
Trade name: Jardiance®/Ortanjeong®
English Name: Empagliflozin Tablets
Hanyu Pinyin: Engeliejing Pian
Ingredients
Active ingredient: Engeliejing.
Chemical name: (1S)-1, 5-anhydrous-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy] phenyl] methyl] phenyl]- D-glucitol.
Chemical structure formula.
Molecular formula: C23H27ClO7
Molecular weight: 450.9
Characteristic】.
This product is a light yellow film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product is suitable for the treatment of type 2 diabetes mellitus.
Monotherapy
This product is used in combination with diet control and exercise to improve glycemic control in patients with type 2 diabetes.
Combined with Metformin Hydrochloride
When metformin hydrochloride alone still cannot effectively control blood sugar, this product can be used in combination with metformin hydrochloride to improve blood sugar control in patients with type 2 diabetes based on diet and exercise.
Combined use with metformin hydrochloride and sulfonylureas
When the combination of metformin hydrochloride and sulfonylurea is not effective in controlling blood glucose, this product can be used in combination with metformin hydrochloride and sulfonylurea to improve blood glucose control in patients with type 2 diabetes based on diet and exercise.
Dosing restrictions
This product is not recommended for use in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
【Specifications】.
(1) 10 mg; (2) 25 mg.
Dosage]
Recommended Dose
The recommended dose of this product is 10 mg once a day in the morning, administered on an empty stomach or after a meal. The dose can be increased to 25 mg in patients who tolerate this product (see [Clinical Trials]).
In patients with hypovolemia, correction of hypovolemia is recommended prior to initiation of this product (see [Precautions]).
Patients with renal impairment
Evaluation of renal function is recommended prior to initiation of this product and should be assessed periodically thereafter.
This product should not be used in patients with an eGFR below 45 mL/min/1.73 m2.
Patients with eGFR greater than or equal to 45 mL/min/1.73 m2 do not require dose adjustment.
This product should be discontinued if eGFR is consistently below 45 mL/min/1.73 m2 (see [Precautions]).
Patients with hepatic impairment
Dose adjustment is not required in patients with hepatic impairment. Increased exposure to engramine in patients with severe liver impairment. Experience with the treatment of patients with severe liver impairment is limited; therefore, use in this population is not recommended.
Adverse reactions]
Please also see [Precautions] for the following important adverse reactions.
Hypotension
Ketoacidosis
Acute kidney injury and renal impairment
Urinary sepsis and pyelonephritis
Hypoglycemia associated with the combination of insulin and insulin secretion enhancers
Genital fungal infections
Elevated low-density lipoprotein cholesterol (LDL-C)
Clinical trial experience
Because clinical trials are conducted under a variety of different circumstances, it is not possible to directly compare the incidence of adverse reactions observed in clinical trials of two different drugs, and they may not reflect the incidence in clinical practice.
Summary of placebo-controlled trials evaluating engramine 10 mg and 25 mg
The data in Table 1 are derived from a pooling of data from multiple placebo-controlled trials. Trials in which engramlizine was used as monotherapy or as add-on therapy (see [Clinical Trials]).
These data reflect engramlizine exposure in 1976 patients with a mean duration of exposure of approximately 23 weeks. Patients received placebo (N=995), engramlizine 10 mg (N=999), or engramlizine 25 mg (N=977) once daily. The mean age of the population was 56 years, and 3% of patients were older than 75 years. More than half of the patients in the population (55%) were male, 46% were white, 50% were Asian, and 3% were black or African American. At baseline, 57% of the population had diabetes for more than 5 years and had a mean hemoglobin A1c (HbA1c) of 8%. Diabetic microvascular complications diagnosed at baseline included diabetic nephropathy (7%), retinopathy (8%), or neuropathy (16%). 91% of patients had normal or mildly impaired baseline renal function and 9% had moderate impairment (mean eGFR 86.8 mL/min/1.73 m2).
Table 1 shows the common adverse reactions (excluding hypoglycemia) associated with engramine use. That is, adverse reactions that were not seen at baseline but occurred at an incidence of ≥2% and were proportionately higher with engramlizine than with placebo.
Table 1 Adverse reactions reported in ≥2% of engramlizine treated patients in placebo-controlled combined clinical studies of engramlizine monotherapy or combination therapy with a higher incidence than placebo
Number of patients (%) Placebo
N=995 engramlizine 10 mg
N=999 engramlizine 25mg
N=977 Urinary tract infectionsa7.6% 9.3% 7.6% Female genital fungal infectionsb1.5% 5.4% 6.4% Upper respiratory tract infections3.8% 3.1% 4.0% Increased urinationc1.0% 3.4% 3.2% Dyslipidemia3.4% 3.9% 2.9% Arthralgia2.2% 2.4% 2.3% Male genital fungal infectionsd0.4% 3.1% 1.6% Nausea 1.4% 2.3% 1.1% Predefined groupings of adverse events including, but not limited to, urinary tract infections, asymptomatic bacteriuria, cystitis
Female genital fungal infections included the following adverse events: vulvovaginal fungal infection, vaginal infection, vulvovaginitis, vulvovaginal candidiasis, genital tract infection, genital tract candidiasis, genital fungal infection, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital fungal infection, bacterial vaginitis. Percentages were calculated using the number of female subjects in each group as the denominator: placebo (N=481), engramine 10 mg (N=443), and engramine 25 mg (N=420).
Predefined groupings of adverse events, including, but not limited to, polyuria, dysuria, and nocturia.
Male genital fungal infections included the following adverse events: priapism, priapism, genital fungal infection, genitourinary tract infection, penile head candidiasis, scrotal abscess, and penile infection. Percentages were calculated using the number of male subjects in each group as the denominator: placebo (N=514), engramine 10 mg (N=556), and engramine 25 mg (N=557).
Thirst (including excessive drinking) was reported by 0%, 1.7% and 1.5% of patients on placebo, engramine 10 mg and engramine 25 mg, respectively.
Blood volume deficit
This product may lead to osmotic diuresis, which may result in a decrease in blood volume and adverse reactions associated with hypovolemia. In a pooled analysis of placebo-controlled clinical trials, 0.3%, 0.5%, and 0.3% of patients treated with placebo, engramine 10 mg, and engramine 25 mg, respectively, reported hypovolemia-related adverse reactions (e.g., decreased blood pressure (dynamic), decreased systolic blood pressure, dehydration, hypotension, hypovolemia, postural hypotension, and syncope). In patients at risk for decreased blood volume, this product may increase the risk of hypotension (see [Precautions]).
Increased urination
In a pooled analysis of placebo-controlled clinical trials, increased urination adverse reactions (e.g., polyuria, dysuria, and nocturia) were more common in patients receiving this product than in patients receiving placebo (see Table 1). Nocturia, in particular, was reported at a population rate of 0.4%, 0.3%, and 0.8% in patients treated with placebo, engramine 10 mg, and engramine 25 mg, respectively.
Acute Renal Impairment
Use of this product was associated with elevated serum creatinine and reduced eGFR (see Table 2). In particular, the mean change in creatinine and eGFR was greater in patients with moderate renal impairment at baseline on this product (see [Precautions]).
In a long-term cardiovascular outcomes trial, acute renal impairment was observed to be reversible after discontinuation of treatment, suggesting a role for acute hemodynamic changes in engramlin-induced changes in renal function.
Table 2 Changes in serum creatinine and eGFRa from baseline in the pooled analysis of 24-week placebo-controlled and renal impairment studies
24-week placebo-controlled study summary placebo engramlizine 10 mg engramlizine 25 mg baseline mean N 825830 822 creatinine (mg/dL) 0.84 0.85 0.85 eGFR (mL/min/1.73 m2) 87.3 87.1 87.8 Week 12 change N 771 797 783 creatinine (mg/dL) 0.00 0.02 0.01 eGFR (mL/min/1.73 m2) -0.3 -1.3 -1.4 Week 24 changeN 708 769 754 Creatinine (mg/dL) 0.00 0.01 0.01 eGFR (mL/min/1.73 m2) -0.3 -0.6 -1.4 Moderate renal impairmentb Placebo Englestrin 25 mg baseline meanN 187 —187 Creatinine (mg/dL) 1.49 —1.46 eGFR (mL/min/1.73 m2) 44.3 —45.4 Change at Week 12N 176 —179 Creatinine (mg/dL) 0.01 —0.12 eGFR (mL/min/1.73 m2) 0.1 —3.8 Change at Week 24N 170 — 171 Creatinine (mg/dL) 0.01 —0.10 eGFR (mL/min/1.73 m2) 0.2 —3.2 Change at Week 52N 164 —162 Creatinine (mg/dL) 0.02 —0.11 eGFR (mL/min/1.73 m2) —0.3 —2.8 Change after treatmentcN 98 —103 Creatinine ( mg/dL) 0.03 — 0.02 eGFR (mL/min/1.73 m2) 0.16 — 1.48a Observed cases on treatment.
bSubset of patients with eGFR of 30 mL/min/1.73 m2 to <60 mL/min/1.73 m2 in the renal impairment study
cAt approximately 3 weeks after the end of treatment.
Hypoglycemia
The incidence of hypoglycemia in each study can be seen in Table 3. The incidence of hypoglycemia was increased when this product was given concomitantly with insulin or a sulfonylurea (see [Precautions]).
Table 3 Incidence of alla and severeb hypoglycemic events in placebo-controlled clinical studiesc
Monotherapy (24 weeks) Placebo (n=229) Englestrin 10 mg (n=224) Englestrin 25 mg (n=223) All (%) 0.4% 0.4% 0.4% Severe (%) 0% 0% 0% Co-administered with metformin
(24 weeks) Placebo + metformin (n=206) Englestrin 10 mg + metformin (n=217) Englestrin 25 mg + metformin (n=214) All (%) 0.5% 1.8% 1.4% Severe (%) 0% 0% 0% Co-administered with metformin + sulfonylurea (24 weeks) Placebo (n=225) Englestrin 10 mg + metformin Guanidine + sulfonylurea (n=224) Englestrin 25 mg + metformin + sulfonylurea (n=217) All (%) 8.4% 16.1% 11.5% Severe (%) 0% 0% 0% Co-administered with pioglitazone +/- metformin (24 weeks) Placebo (n=165) Englestrin 10 mg + pioglitazone +/- metformin (n=165) Englestrin Engeletin 25 mg + pioglitazone +/- metformin (n=168) All (%) 1.8% 1.2% 2.4% Severe (%) 0% 0% 0% Coadministration with basal insulin +/- metformin (18 weeksd) Placebo (n=170) Engeletin 10 mg (n=169) Engeletin 25 mg (n=155) All (%) 20.6% 19.5% 28.4% Severe (%) 0% 0% 1.3% Co-administration with MDI insulin +/- metformin (18 weeks d) placebo (n=188) engramliptin 10 mg (n=186) engramliptin 25 mg (n=189) All (%) 37.2% 39.8% 41.3% Severe (%) 0.5% 0.5% 0.5% 0.5% All hypoglycemia Event: plasma or capillary blood glucose less than or equal to 70 mg/dL
Severe hypoglycemic events: needing help regardless of blood glucose level
Treatment set (patients who have received at least one dose of study drug)
No insulin dose adjustment during the initial 18 weeks of treatment
Genital fungal infection
In a pooled analysis of placebo-controlled clinical trials, the incidence of genital fungal infections (e.g., vaginal fungal infections, vaginal infections, genital fungal infections, vulvovaginal candidiasis, and vulvodynia) was increased in patients treated with this product compared with those receiving placebo, with 0.9%, 4.1%, and 3.7% of patients randomly assigned to placebo, engramine 10 mg, and engramine 25 mg, respectively. 0% of placebo-treated patients and 0.2% of engramlizine 10 mg or 25 mg-treated patients withdrew from the study due to genital infections.
Genital fungal infections were more common in female patients than in male patients (see Table 1).
Genital infections were more common in male patients treated with engramlizine 10 mg (less than 0.1%) and engramlizine 25 mg (0.1%) than in patients receiving placebo (0%).
Urinary tract infections
In a pooled analysis of placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infections, asymptomatic bacteriuria, and cystitis) was increased in patients treated with this product compared with those receiving placebo (see Table 1). Patients with a history of chronic or recurrent urinary tract infections were more likely to develop urinary tract infections. Treatment was discontinued due to urinary tract infection in 0.1%, 0.2%, and 0.1% of patients in the placebo group, the engramine 10 mg group, and the engramine 25 mg group, respectively.
Urinary tract infections were more common in female patients. The incidence of urinary tract infections was 16.6%, 18.4%, and 17.0% among female patients in the placebo group, the engramine 10 mg group, and the engramine 25 mg group, respectively, compared with 3.2%, 3.6%, and 4.1% among male patients (see [Precautions]).
Laboratory tests
Elevated low-density lipoprotein cholesterol (LDL-C)
Dose-related elevations in low-density lipoprotein cholesterol (LDL-C) have been observed in patients treated with this product. LDL-C was elevated by 2.3%, 4.6% and 6.5% in patients treated with placebo, engramine 10 mg and engramine 25 mg, respectively (see [Precautions]). The range of mean LDL-C levels at baseline between treatment groups was 90.3 mg/dL to 90.6 mg/dL.
Elevated Erythrocyte Pressure
In a pooled analysis of placebo-controlled studies, median erythrocyte pressure was reduced by 1.3% in placebo-treated patients, increased by 2.8% in engramlizine 10 mg-treated patients, and increased by 2.8% in engramlizine 25 mg-treated patients. Of the patients within the placebo, engramine 10 mg and engramine 25 mg treatment groups whose erythrocyte pressure was initially within the reference range, 0.6%, 2.7% and 3.5% of patients had values above the upper limit of the reference range at the end of treatment, respectively.
Post-marketing Experience
Other adverse reactions were identified during post-approval use of this product. Because these reactions were voluntarily reported in a population of uncertain size, it is largely unlikely that their frequency can be reliably estimated or their causal relationship to drug exposure determined.
Ketoacidosis (see [Precautions])
Urinary sepsis and pyelonephritis (see [Precautions])
[Contraindications].
History of severe hypersensitivity reactions to this product
Severe renal impairment, end-stage renal disease or dialysis
[Precautions
Hypotension
This product may cause a decrease in blood volume. Symptomatic hypotension may occur with the use of this product (see [Adverse Reactions]), especially in patients with renal impairment, in the elderly, in patients with low systolic blood pressure, and in patients receiving diuretics. Prior to initiation of this product, blood volume decreases should be assessed and volume status should be corrected if blood volume decreases. After initiation of therapy, signs and symptoms of hypotension should be monitored, and monitoring should be increased in case of clinical conditions in which a fall in blood volume can be expected to occur.
Ketoacidosis
Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been reported in post-marketing surveillance of patients with type 1 and type 2 diabetes receiving sodium-glucose cotransporter-2 (SGLT2) inhibitors, including engramine. Fatal cases of ketoacidosis have been reported in patients taking this product. This product is not indicated for the treatment of patients with type 1 diabetes mellitus.
Patients receiving this product should be evaluated for ketoacidosis if they develop signs and symptoms consistent with severe metabolic acidosis, regardless of blood glucose level. This is because this product-associated ketoacidosis may exist even if blood glucose levels are below 250 mg/dL. If ketoacidosis is suspected, the product should be discontinued, the patient should be evaluated, and treatment should be started promptly. Treatment of ketoacidosis may require insulin, infusions, and sugar replacement.
In many post-marketing reports, particularly in patients with type 1 diabetes, ketoacidosis may not be detected in a timely manner and treatment may be delayed because their blood glucose levels are below those normally expected in diabetic ketoacidosis (usually below 250 mg/dL). The disease presents with signs and symptoms consistent with dehydration and severe metabolic acidosis, including nausea, vomiting, abdominal pain, generalized weakness, and shortness of breath. In some, but not all, cases, susceptibility factors for ketoacidosis have been identified, such as reduced insulin dose, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disease suggestive of insulin deficiency (e.g., type 1 diabetes, pancreatitis, or history of pancreatic surgery), and alcohol abuse.
Possible susceptibility factors for ketoacidosis in the patient’s medical history, including inadequate pancreatic insulin secretion for any reason, caloric restriction, and alcohol abuse, should be considered prior to initiating treatment with this product. Monitoring for ketoacidosis and temporary discontinuation of this product should be considered in patients receiving this product who develop clinical conditions that are known to predispose them to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
Acute Renal Injury and Impairment of Renal Function
This product may cause a decrease in blood volume and may cause renal impairment (see [ADVERSE REACTIONS].) Acute kidney injury has been reported in patients after the introduction of SGLT2 inhibitors (including engramine), some requiring hospitalization and dialysis; some have been reported in patients younger than 65 years of age.
Factors that may predispose patients to acute kidney injury, including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs) should be considered prior to initiating this product. Consider temporary discontinuation of the product if oral intake is reduced (e.g., acute illness or fasting) or if fluid loss is present (e.g., gastrointestinal illness or heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue the product immediately and begin treatment.
This product may increase serum creatinine and decrease eGFR. patients with hypovolemia may be more likely to have these changes. Renal function abnormalities may occur after initiation of this product (see [Adverse Reactions]). Renal function should be evaluated prior to initiation of this product and monitored periodically thereafter. More frequent renal function monitoring is recommended in patients with eGFR less than 60 mL/min/1.73 m2. eGFR less than 45 mL/min/1.73 m2 persistently is not recommended and is contraindicated in patients with eGFR less than 30 mL/min/1.73 m2 (see [DOSAGE AND ADMINISTRATION], [CONTRAINDICATIONS]).
Urinary sepsis and pyelonephritis
Serious urinary tract infections, including urinary sepsis and pyelonephritis requiring hospitalization, have been reported in patients on postmarketing surveillance with SGLT2 inhibitors, including engramine, and SGLT2 inhibitor therapy may increase the risk of urinary tract infections. If indicated, patients should be evaluated for signs and symptoms of urinary tract infection and given prompt treatment (see [Adverse Reactions]).
Hypoglycemia associated with combined insulin and insulinotropic agents
Insulin and insulinotropic agents are known to cause hypoglycemia. When this product is used in combination with an insulinotropic agent (e.g., a sulfonylurea) or insulin, the risk of hypoglycemia increases (see [Adverse Reactions]). Therefore, when used in combination with this product, it may be necessary to reduce the dose of insulinotropic agents or insulin to reduce the risk of hypoglycemia.
Genital fungal infections
This product may increase the risk of genital fungal infections (see [Adverse Reactions]). Patients with a history of chronic or recurrent genital fungal infections are more likely to develop fungal genital infections. Monitor and treat as needed.
Elevated low-density lipoprotein cholesterol (LDL-C)
Elevated LDL-C can occur with this treatment (see [Adverse Reactions]). Monitor and treat as needed.
Pregnant women and nursing mothers
Pregnancy
Based on animal data showing the presence of renal adverse reactions, the use of this product in the middle and late stages of pregnancy is not recommended.
Data on the use of this product in pregnant women are limited and insufficient to determine the risk of drug-related major birth defects and miscarriage. Poorly controlled gestational diabetes poses a risk to the mother and fetus.
The estimated background risk of major birth defects is 6-10% in women with pre-pregnancy diabetes with HbA1c >7% and up to 20-25% in women with HbA1c >10%. The estimated background risk of miscarriage in the applicable population is unknown. In the general US population, the estimated background risks of clinically recognized major birth defects and miscarriage in pregnancy are approximately 2-4% and 15-20%, respectively.
Disease-related maternal and/or embryonic/fetal risk: Poorly controlled diabetes in pregnancy increases maternal risk of diabetic ketoacidosis, pre-eclampsia, spontaneous abortion, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the risk of major birth defects, stillbirth and morbidity associated with macrosomia in the fetus.
Lactation
No information is available on whether this product is secreted with human milk, the effect of this product on the nursing infant, or the effect on lactation. Englestrin is secreted with the milk of lactating rats. Because human kidney maturation is completed in utero and during the first 2 years of life (when lactation exposure may occur), there may be a risk to human kidney development.
Because of the risk of serious adverse reactions in nursing infants receiving this product, women should be advised that use of this product during lactation is not recommended.
[Pediatric Use].
The safety and efficacy of this product in pediatric patients less than 18 years of age have not been established.
[Geriatric Use].
Dose adjustment of this product based on age is not recommended. In studies evaluating the efficacy of engramlizine for improving glycemic control in patients with type 2 diabetes, a total of 2721 patients (32%) ≥ 65 years of age and 491 patients (6%) ≥ 75 years of age were treated with engramlizine. The hypoglycemic efficacy of this product was expected to be reduced in elderly patients with renal impairment. The risk of adverse reactions associated with hypovolemia increased to 2.1%, 2.3% and 4.4% in patients aged 75 years and older who received placebo, engramine 10 mg and engramine 25 mg. The risk of urinary tract infection increased to 10.5%, 15.7%, and 15.1% in patients aged 75 years and older in the placebo group, the engramine 10 mg group, and the engramine 25 mg group, respectively (see [Precautions], [Adverse Reactions]).
Drug Interactions]
Diuretics
Co-administration of engramine with diuretics may lead to increased urine output and frequency, which may increase the risk of hypovolemia (see [Precautions]).
Insulin or insulin stimulants
Co-administration of engramlisin with insulin or insulin stimulants may increase the risk of hypoglycemia (see [Precautions]).
Positive urine glucose test
Monitoring glycemic control by urine glucose test is not recommended for patients on SGLT2 inhibitors because SGLT2 inhibitors can increase urinary glucose excretion and will result in a positive urine glucose test result. Monitor glycemic control using other methods.
Interference with 1,5-anhydrous glucose (1,5-AG) measurement
Monitoring glycemic control using the 1,5-AG assay is not recommended because glycemic control cannot be reliably assessed by measuring 1,5-AG in patients on SGLT2 inhibitors. Use other methods to monitor blood glucose control.
[Drug overdose].
If an overdose of this product occurs, contact a poison control center. Take common supportive measures (e.g., remove unabsorbed medication from the gastrointestinal tract, perform clinical monitoring and initiate supportive therapy) as prompted by the patient’s clinical status. Removal of engramine by hemodialysis has not been studied.
[Clinical Trials].
Blood glucose control
Investigators have conducted studies of engramine monotherapy and combination therapy with metformin, sulfonylureas, etc. Englestrin has also been studied in type 2 diabetic patients with mild or moderate renal impairment.
In patients with type 2 diabetes, treatment with engramlizine reduced hemoglobin A1c (HbA1c) compared to placebo. A reduction in HbA1c was observed in the engramine group compared to the placebo group in all subgroups including gender, ethnicity, region, baseline BMI, and duration of diabetes.
Monotherapy
A total of 986 patients with type 2 diabetes were enrolled in a double-blind, placebo-controlled study to evaluate the efficacy and safety of engramine monotherapy. There were 228 cases in the placebo group, 224 cases in the engramine 10 mg group, 224 cases in the engramine 25 mg group, 223 cases in the sitagliptin group, and 87 cases in the open group.
Patients with inadequate glycemic control in the primary treatment of type 2 diabetes entered a 2-week open-label placebo introductory period. At the end of the introductory period, patients whose glycemic control remained inadequate and whose HbA1c was between 7-10% were randomly assigned to the placebo group, the engramine 10 mg group, the engramine 25 mg group, or the selegiline group.
At week 24, treatment with engramlizine 10 mg or 25 mg daily resulted in significant reductions in HbA1c (p-value <0.0001), fasting plasma glucose (FPG) and body weight compared to placebo (see Table 4 and Figure 1).
At week 24, patients in the engramine 10 mg and 25 mg groups had significantly lower systolic blood pressure compared to the placebo group, with reductions of -2.6 mmHg (placebo-corrected, p-value = 0.0231) and -3.4 mmHg (placebo-corrected, p-value = 0.0028), respectively.
Table 4 Placebo-controlled monotherapy study results for engramlizine at week 24d
Englestrin
10 mg
N=224 engramlizine
25 mg
N=224 Placebo
N=228HbA1c (%)a Baseline (mean) 7.9 7.9 7.9 Change from baseline (corrected mean) -0.7 -0.8 0.1 Difference from placebo (corrected mean) (97.5% CI) -0.7b (-0.9, -0.6) -0.9b (-1.0, -0.7) – Number of patients achieving HbA1c <7% [ n (%)] 72 (35%) 88 (44%) 25 (12%) FPG (mg/dL)c Baseline (mean) 153 153 155 Change from baseline (corrected mean) -19 -25 12 Difference from placebo (corrected mean) (95% CI) -31 (-37, -26) -36 (-42, -31) – Weight baseline (mean ) in kg 78 78 78 % change from baseline (corrected mean) -2.8 -3.2 -0.4 Difference from placebo (corrected mean) (95% CI) -2.5b (-3.1, -1.9) -2.8b (-3.4, -2.2) – modified intention-to-treat population. Missing data at week 24 were interpolated using the end-of-study observations (LOCF). At week 24, 9.4%, 9.4%, and 30.7% were interpolated for patients randomly assigned to the engramine 10 mg group, engramine 25 mg group, and placebo group, respectively.
ANCOVA p-value <0.0001 (HbA1c: ANCOVA model included baseline HbA1c, treatment, renal function, and region. (Body weight and FPG: same model as HbA1c was used but additionally included baseline body weight/baseline FPG, respectively.)
FPG (mg/dL); for enagliptin 10 mg, n=223, for enagliptin 25 mg, n=223 and for placebo, n=226
Results for the selegiline and open groups are not shown in the table
Figure 1 Mean change in corrected HbA1c at each time point (completers) and at week 24 (mITT population) – LOCF
Mean change from baseline in HbA1c (%)*
Weeks* for baseline HbA1c, region and eGFR corrected mean change from baseline at baseline.
Engeletin combined with metformin treatment
A total of 637 patients with type 2 diabetes were enrolled in a double-blind, placebo-controlled study to evaluate the efficacy and safety of the combination of engramine and metformin.
Patients with type 2 diabetes who received at least 1500 mg/day of metformin and had inadequate glycemic control entered an open-label 2-week placebo introductory period. At the end of the introductory period, patients whose glycemic control remained inadequate and whose HbA1c was between 7-10% were randomized to the placebo group, the engramine 10 mg group, or the engramine 25 mg group.
At week 24, treatment with engramlizine 10 mg or 25 mg daily resulted in significant reductions in HbA1c (p value <0.0001), FPG and body weight compared to placebo (see Table 5).
At week 24, patients in the engramine 10 mg and 25 mg groups had significantly lower systolic blood pressure compared to the placebo group, with reductions of -4.1 mmHg (placebo-corrected, p-value <0.0001) and -4.8 mmHg (placebo-corrected, p-value <0.0001), respectively.
Table 5 Placebo-controlled study results for the combination of engramlizine and metformin at week 24
Englestrin 10 mg + metformin N=217 Englestrin 25 mg + metformin N=213 Placebo + metformin N=207 HbA1c (%)
a Baseline (mean) 7.9 7.9 7.9 Change from baseline (corrected mean) -0.7 -0.8 -0.1 Difference from placebo + metformin (corrected mean) (95% CI) -0.6b (-0.7, -0.4) -0.6b (-0.8, -0.5) – Number of patients achieving HbA1c <7% [n (%)] 75 ( 38%) 74 (39%) 23 (13%) FPG (mg/dL)
cBaseline (mean) 155 149 156 Change from baseline (corrected mean) -20 -22 6 Difference from placebo + metformin (corrected mean) -26 -29 –Baseline mean weight in kg 82 82 80 Change from baseline % (corrected mean) -2.5 -2.9 -0.5 Difference from placebo (corrected mean) (95% CI) -2.0b (-2.6, -1.4) -2.5b (-3.1, -1.9) – Modified intention-to-treat population. Missing data at week 24 were interpolated using the end-of-study observations (LOCF). At week 24, 9.7%, 14.1% and 24.6% were interpolated for patients randomly assigned to the engramine 10 mg group, engramine 25 mg group and placebo group, respectively.
ANCOVA p value <0.0001 (HbA1c: ANCOVA model included baseline HbA1c, treatment, renal function and region. (Body weight and FPG: same model as HbA1c was used but additionally included baseline body weight/baseline FPG, respectively.)
FPG (mg/dL); for engramlizine 10 mg, n=216, for engramlizine 25 mg, n=213, for placebo, n=207
Combination of engramine with metformin and sulfonylureas
A total of 666 patients with type 2 diabetes were enrolled in a double-blind, placebo-controlled study to evaluate the efficacy and safety of the combination of engramine with metformin and sulfonylureas.
Patients with type 2 diabetes who received at least 1500 mg/day of metformin and a sulfonylurea with inadequate glycemic control entered a 2-week open-label placebo introductory period. At the end of the introductory period, patients whose glycemic control remained inadequate and whose HbA1c was between 7-10% were randomly assigned to the placebo group, the engramine 10 mg group, or the engramine 25 mg group.
At week 24, treatment with engramine 10 mg or 25 mg daily resulted in significant reductions in HbA1c (p-value <0.0001), FPG and body weight compared to placebo (see Table 6).
Table 6 Results of placebo-controlled study of engramine in combination with metformin and sulfonylurea at week 24
Enagliflozin 10 mg
+ Metformin
+ SU
N=225 engramlizine 25mg
+ Metformin
+ SUN=216 Placebo
+ Metformin + SU
N=225HbA1c (%)a Baseline (mean) 8.1 8.1 8.2 Change from baseline (corrected mean) -0.8 -0.8 -0.2 Difference from placebo (corrected mean) (95% CI) -0.6b (-0.8, -0.5) -0.6b (-0.7, -0.4) – Number of patients achieving HbA1c <7% [n (%)] 55 (26%) 65 (32%) 20 (9%) FPG (mg/dL)c Baseline (mean) 151 156 152 Change from baseline (corrected mean) -23 -23 6 Difference from placebo (corrected mean) -29 -29 – – Weight Baseline mean in kg 77 78 76 % change from baseline (corrected mean) – 2.9 -3.2 -0.5 Difference from placebo (corrected mean) (95% CI) -2.4b (-3.0, -1.8) -2.7b (-3.3, -2.1) – Modified intention-to-treat population. Missing data at week 24 were interpolated using the end-of-study observations (LOCF). At week 24, 17.8%, 16.7%, and 25.3% were interpolated for patients randomly assigned to the engramine 10 mg group, engramine 25 mg group, and placebo group, respectively.
ANCOVA p-value <0.0001 (HbA1c: ANCOVA model included baseline HbA1c, treatment, renal function, and region. (Body weight and FPG: same model as HbA1c was used but additionally included baseline body weight/baseline FPG, respectively.)
FPG (mg/dL); for engramine 10 mg, n=225, for engramine 25 mg, n=215, for placebo, n=224
Renal impairment
A total of 738 patients with type 2 diabetes with baseline eGFR below 90 mL/min/1.73 m2 were enrolled in a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of engramine in patients with type 2 diabetes with renal impairment. The trial population consisted of 290 patients with mild renal impairment (eGFR 60 mL/min/1.73 m2 to <90 mL/min/1.73 m2; after randomization, 95 patients received placebo, 98 patients received engramine 10 mg, and 97 patients received engramine 25 mg), 374 patients with moderate renal impairment (eGFR 30 mL/min/1.73 m2 to <60 mL/min/1.73 m2; after randomization, 95 patients received placebo, 98 patients received engramine 10 mg, and 97 patients received engramine 25 mg), and 374 patients with moderate renal impairment (eGFR 30 mL/min/ 1.73 m2 to <60 mL/min/1.73 m2; after randomization, 187 patients received placebo and 187 patients received engramlizine 25 mg) and 74 patients with severe renal impairment (eGFR <30 mL/min/1.73 m2; after randomization, 37 patients received placebo and 37 patients received engramlizine 25 mg). Of these patients with moderate renal impairment, 194 had a baseline eGFR of 30 mL/min/1.73 m2 to <45 mL/min/1.73 m2 and 180 had a baseline eGFR of 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2.
At week 24, there was a significant reduction in HbA1c with engramine 25 mg versus placebo in patients with mild to moderate renal impairment (see Table 7). Significant reductions in HbAlc relative to placebo were observed in patients with either mild or moderate renal impairment (mild: [-0.7 (95% CI: -0.9, -0.5)]; moderate: [-0.4 (95% CI: -0.6, -0.3)]).
A significant reduction in HbAlc with engramine 10 mg versus placebo was observed in patients with mild renal impairment [-0.5 (95% CI: -0.7, -0.3)].
Table 7 Results of the placebo-controlled study of engramine in patients with type 2 diabetes mellitus with renal impairment at week 24 (LOCF)
Mild and moderate renal impairmentb Engeletin 25 mg HbA1c Number of patient cases n=284 vs placebo (corrected mean) (95% CI) -0.5a (-0.6, -0.4) p-value<0.0001 (HbA1c: ANCOVA model including baseline HbA1c, treatment, renal function and background medication).
eGFR 30 mL/min/1.73 m2 to <90 mL/min/1.73 m2-modified intention-to-treat population. Missing data at week 24 were interpolated using the end-of-study observation (LOCF) values. At week 24, 24.6% and 26.2% were interpolated for patients randomly assigned to the engramine 25 mg group and the placebo group, respectively.
In the mild to moderate range, the glucose-lowering efficacy of engramine 25 mg decreased with decreasing levels of renal function, as detailed in Table 8.
Table 8 Glucose-lowering efficacy of engramine 25 mg in diabetic patients with mild to moderate renal impairment in different eGFR ranges
Least squares mean change in HbA1c at week 24 of the eGFR range Empagliflozin 25 mg group Placebo group 60 mL/min/1.73 m2 to <90 mL/min/1.73 m2 -0.6% 0.1% 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2 -0.5% -0.1% 30 mL/min/ 1.73 m2 to <45 mL/min/1.73 m2-0.2% 0.2%
In patients with severe renal impairment, analysis of changes in HbA1c and FPG showed no significant therapeutic effect of engramine 25 mg over placebo (see [Dosage]).
Cardiovascular outcomes in patients with type 2 diabetes and atherosclerotic cardiovascular disease
The effect of this product on cardiovascular risk in adult patients with type 2 diabetes and diagnosed stable atherosclerotic cardiovascular disease was evaluated in the EMPA-REG OUTCOME (Englestrin Cardiovascular Outcomes) study, a multicenter, multinational, randomized, double-blind, parallel-group trial. The study compared the risk of major adverse cardiovascular events (MACE) when engramine was added to and used in conjunction with standard therapy for diabetes and atherosclerotic cardiovascular disease with placebo. During the first 12 weeks of the trial, the combined glucose-lowering medications remained stable. Thereafter, glucose-lowering drugs and atherosclerotic therapy could be adjusted at the discretion of the investigator to ensure that participants were treated according to standard medical treatment for these conditions.
A total of 7020 patients were treated (engramine 10 mg = 2345; engramine 25 mg = 2342; placebo = 2333) and followed up for a median of 3.1 years. Approximately 72% of the study population was Caucasian, 22% was Asian, and 5% was black. The mean age was 63 years and approximately 72% were men.
All patients in this study had poorly controlled type 2 diabetes (HbA1c greater than or equal to 7%) at baseline. The mean baseline HbA1c was 8.1%, and 57% of participants had diabetes for more than 10 years. Approximately 31%, 22% and 20% of participants reported to the investigator a past history of neuropathy, retinopathy and nephropathy, respectively, with a mean eGFR of 74 mL/min/1.73 m2. At baseline, patients were receiving one (approximately 30%) or more (approximately 70%) glucose-lowering medications, including metformin (74%), insulin (48%) and sulfonylureas (43%) .
All patients had a confirmed diagnosis of atherosclerotic cardiovascular disease at baseline, including one (82%) or more (18%) of the following: documented history of coronary artery disease (76%), stroke (23%), or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, patients were treated for stable atherosclerotic cardiovascular disease according to local medical practice, including renin angiotensin system inhibitors, beta-blocker therapy, diuretics, statins, and antiplatelet agents.
The primary endpoint of EMPA-REG OUTCOME is the time to the first major adverse cardiovascular event (MACE). A major adverse cardiovascular event (MACE) was defined as the occurrence of cardiovascular death or non-fatal myocardial infarction (MI) or non-fatal stroke. This product significantly reduced the risk of MACE (HR: 0.86; 95% CI 0.74, 0.99). The treatment effect resulted primarily from a significant reduction in the risk of cardiovascular death in subjects receiving engramlizine (HR: 0.62; 95% CI 0.49, 0.77), while the risk of non-fatal myocardial infarction or non-fatal stroke was unchanged (see Table 9, Figures 2 and 3). results for the 10 mg and 25 mg engramlizine doses were consistent with those for the combined dose group.
The efficacy of engramlizine on cardiovascular mortality was broadly consistent across major demographic and disease subgroups.
Table 9 Treatment effects for the primary composite endpoint and its componentsa
Placebo
N = 2333 Englestradiol
N = 4687 Risk ratio compared with placebo
(95% CI) Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke composite (to time of first occurrence)b
282 (12.1%) 490 (10.5%) 0.86 (0.74, 0.99) Nonfatal myocardial infarctionc121 (5.2%) 213 (4.5%) 0.87 (0.70, 1.09) Nonfatal strokec60 (2.6%) 150 (3.2%) 1.24 (0.92, 1.67) Cardiovascular deathc137 ( (5.9%) 172 (3.7%) 0.62 (0.49, 0.77) aTreatment set (patients treated with at least one dose of study drug)
bEfficacy p-value (bilateral) was 0.04. The statistical analysis plan prespecified that the 10 mg and 25 mg doses would be combined. Non-inferiority was tested using a Cox proportional risk model with a pre-specified risk threshold of 1.3 for the MACE risk ratio, and if non-inferiority was demonstrated, superiority was tested with respect to MACE. A cascade testing strategy was used to control for Type 1 error in multiple testing.
cTotal number of events
Figure 2 Estimated cumulative incidence of first MACEa
a statistical analysis plan prespecified that the 10 mg and 25 mg doses would be combined.
Figure 3 Estimated cumulative incidence of cardiovascular mortalitya
a Statistical analysis plan prespecified that the 10 mg and 25 mg doses would be combined.
Survival status was obtained for 99.2% of subjects in the trial. A total of 463 deaths were recorded in the EMPA-REG OUTCOME trial. The majority of these deaths were categorized as cardiovascular in nature. Non-cardiovascular deaths accounted for only a small proportion of deaths and were balanced across treatment groups (2.1% in the engramine group and 2.4% in the placebo group).
In the EMPA-REG OUTCOME cardiovascular outcomes study, there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The results of cardiovascular mortality in this subgroup were consistent with the overall results.
[Pharmacology and Toxicology].
Pharmacological effects
Sodium glucose cotransporter 2 (SGLT-2) is the main transporter protein that reabsorbs glucose from the glomerular filtrate into the circulation. Englestrin is an SGLT2 inhibitor that promotes glucose excretion from the urine by reducing glucose reabsorption in the kidney and lowering the renal glucose threshold.
Toxicological studies
Genotoxicity
The results of the Ames test, mouse lymphoma test, and rat micronucleus test for Englestrin were all negative.
Reproductive toxicity
No significant effects on fertility and early embryonic development were observed in male and female rats at a dose of 700 mg/kg/day (approximately 155 times the maximum clinical dose of 25 mg administered on an AUC basis).
In the rat and rabbit embryo-fetal development toxicity tests, no teratogenic effects were observed at 300 mg/kg/d (48 and 128 times the maximum clinically administered dose of 25 mg, respectively, based on AUC). At 700 mg/kg/d (154 and 139 times the maximum clinical dose of 25 mg, respectively, based on AUC), engramine caused maternal toxicity and fetal developmental toxicity, with increased fetal limb bone deformity in rats and increased fetal loss in rabbits.
In a perinatal toxicity test in rats, no maternal toxicity was observed in rats given 100 mg/kg/day (approximately 16 times the maximum clinical dose of 25 mg at AUC) from day 6 of gestation to lactation (day 20 of lactation), while engramine at doses ≥30 mg/kg/day (approximately 4 times the maximum clinical dose of 25 mg at AUC) could induced weight loss in the offspring.
In juvenile rats, continuous administration of engramlizine 1, 10, 30 and 100 mg/kg/d from postnatal day 21 to day 90 resulted in increased renal weight and dilated renal tubules and pelvis at a dose of 100 mg/kg/day (approximately 13 times the maximum clinical dose of 25 mg at AUC), but no such findings were observed after 13 weeks of drug withdrawal.
Englestrin can be secreted into the milk of rats, and the concentration of the drug in the milk is approximately 5 times the maternal plasma drug concentration.
Carcinogenicity
In a 2-year carcinogenicity test in mice, the incidence of tumors was not increased in female mice at a dose of 1000 mg/kg/d (62 and 45 times the maximum clinically administered dose of 25 mg in female and male mice, respectively, based on exposure), but renal tubular adenomas and carcinomas were induced in male mice. The development of renal tumors may be related to the presence of specific metabolic pathways in male mice.
In a 2-year carcinogenicity test in rats, no significant change in tumor incidence was observed in female rats at a dose of 700 mg/kg/d (72 and 42 times the maximum clinical dose of 25 mg in female and male rats, respectively, based on exposure), and a significant increase in the incidence of mesenteric hemangioma was observed in male rats.
Pharmacokinetics
Absorption
No clinically meaningful differences were observed in the pharmacokinetic profile of engramine in healthy volunteers and type 2 diabetic patients. The peak plasma concentration of engramlizine was reached at 1.5 hours after oral administration. Thereafter, plasma concentrations decreased biphasically, with a rapid distribution phase and a relatively slow terminal phase. The steady-state mean plasma AUC and Cmax were 1870 nmol-h/L and 259 nmol/L (10 mg engramlizine once daily treatment) and 4740 nmol-h/L and 687 nmol/L (25 mg engramlizine once daily treatment), respectively. Systemic exposure to engramlizine increased proportionally with dose over the therapeutic dose range. Single administration and steady-state pharmacokinetic parameters of engramlizine were similar, suggesting linear pharmacokinetics over time.
Compared to the fasted state, administration of 25 mg of engramlizine after eating a high-fat and high-calorie meal resulted in a slightly lower exposure, with an approximate 16% reduction in AUC and an approximate 37% reduction in Cmax. The observed effect of food on the pharmacokinetics of engramlizine is not considered clinically significant and engramlizine can be given after eating or on an empty stomach.
Distribution
The apparent steady-state volume of distribution was estimated from population pharmacokinetic analysis to be 73.8 L. Oral administration of [14C]-engliptin solution to healthy subjects resulted in approximately 36.8% erythrocyte partitioning and 86.2% plasma protein binding.
Metabolism
No major metabolites of engramlizine were detected in human plasma; the most abundant metabolites were the three glucosinolate conjugates (2-O-, 3-O-, and 6-O-glucosinolates). The systemic exposure of each metabolite is less than 10% of the total drug-related substances. In vitro studies have shown that the major metabolic pathway of engramine in humans is the glucuronide reaction via the uridine 5′-diphosphate-glucuronide radical transferases UGT2B7, UGT1A3, UGT1A8 and UGT1A9.
Elimination
Based on population pharmacokinetic analysis, the apparent terminal elimination half-life of engramine was estimated to be 12.4 hours, with an apparent oral clearance of 10.6 L/hour. After once-daily administration, accumulation of up to 22% relative to plasma AUC was observed at steady state, which is consistent with the half-life of engramlizine. Approximately 95.6% of drug-related radioactivity was eliminated in the feces (41.2%) or urine (54.4%) following oral administration of [14C]-englutethimide solution in healthy subjects. The vast majority of drug-associated radioactivity recovered in the feces was the parent drug prototype, and approximately half of the drug-associated radioactivity excreted in the urine was the parent drug prototype.
Special Populations
Renal impairment
In patients with mild (eGFR: 60 mL/min/1.73 m2 to <90 mL/min/1.73 m2), moderate (eGFR: 30 mL/min/1.73 m2 to <60 mL/min/1.73 m2), and severe (eGFR: <30 mL/min/1.73 m2) renal impairment and in subjects with renal failure/end-stage renal disease ( In ESRD patients, the AUC of engramine was increased by approximately 18%, 20%, 66% and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of engramine in subjects with moderate renal impairment and renal failure/ESRD were similar to those in patients with normal renal function. Plasma peak levels of engramlizine were approximately 20% higher in subjects with mild and severe renal impairment than in subjects with normal renal function. Population pharmacokinetic analysis revealed that the reduced apparent oral clearance of engramlizine, accompanied by a reduction in eGFR, leads to increased drug exposure. However, the percentage of drug prototype engramlizine excreted in the urine and urinary glucose excretion decreased with lower eGFR.
Liver damage
According to Child-Pugh classification, the AUC of engramlizine was increased by approximately 23%, 47% and 75% and the Cmax by approximately 4%, 23% and 48% in subjects with mild, moderate and severe liver damage, respectively, compared to subjects with normal liver function.
Effect of age, body mass index, gender and ethnicity
Based on population PK analysis, age, body mass index (BMI), gender and ethnicity (Asian versus predominantly white) had no clinically significant effect on the pharmacokinetics of engramlizine.
Children
No studies have been performed to analyze the pharmacokinetic profile of engramlizine in pediatric patients.
Drug Interactions
In Vitro Evaluation of Drug Interactions
Englestrin does not inhibit, inactivate or induce CYP450 isoforms. In vitro data suggest that the primary metabolic pathway of engramlizine in humans is the glucuronide reaction via the uridine 5′-diphosphate-glucuronide group transferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. UGT1A3, UGT1A8, UGT1A9, and UGT2B7 are not inhibited by engramine. therefore, engramine is not expected to have an effect on the major CYP450 isoforms or UGT1A3, UGT1A8, UGT1A9, and UGT2B7 substrates given concurrently. The effect of UGT induction (e.g., induction by rifampin or any other UGT enzyme inducer) on engramlizine exposure has not been evaluated.
Englestrin is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, but does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, it is considered unlikely that engramlizine interacts with P-gp substrate drugs. Englestrin is a substrate for the human uptake transport proteins OAT3, OATP1B1 and OATP1B3, but not for OAT1 and OCT2 substrates. At clinically meaningful plasma concentrations, engramlizine does not inhibit any of these human uptake transport proteins, and engramlizine is not expected to have an effect on concomitantly administered substrates of these uptake transport proteins.
In vivo assessment of drug interactions
Based on the results of the pharmacokinetic studies described, no dose adjustment is recommended when this product is co-administered with commonly prescribed drugs. The pharmacokinetics of engramlizine were similar in healthy volunteers (with or without co-administration of diabetic drugs such as metformin and glimepiride, and warfarin, verapamil, ramipril, and simvastatin) and in patients with type 2 diabetes (with or without co-administration of hydrochlorothiazide and torsemide) (see Figure 4). Increased overall exposure (AUC) of engramlizine was observed after coadministration with gemfibrozil, rifampicin, or probenecid, but was not clinically significant.
In subjects with normal renal function, co-administration of engramlizine with probenecid resulted in a 30% reduction in the percentage of engramlizine excreted in the urine, with no effect on 24-hour urinary glucose excretion. The significance of this observation for patients with renal impairment is unclear.
Figure 4 Effect of various drugs on the pharmacokinetics of engramlizine, shown as 90% confidence interval for the geometric mean ratio of AUC and Cmax [reference line indicates 100% (80%-125%)
Geometric mean ratio (90% confidence interval)
Glucose-lowering drug metformin, 1000 mg twice dailyaAUC Cmax
Glimepiride, 1 mg, single dose
aAUC Cmax Other simvastatin, 40 mg, single dose
bAUC Cmax Warfarin, 25 mg, single dose
cAUC Cmax Verapamil, 120 mg, single dose
bAUC Cmax Ramipril, 5 mg once daily
cAUC Cmax Gemfibrozil, 600 mg twice daily
bAUC Cmax Hydrochlorothiazide, 25 mg once daily
cAUC Cmax Torasemide, 5 mg once daily
cAUC Cmax Rifampicin, 600 mg, single dose
dAUC Cmax Propofol, 500 mg twice daily
dAUC Cmax
Change relative to engramine monotherapy
a
Englestradiol, 50 mg once daily.
b
Englestrin, 25 mg, single dose.
c
Englestrin, 25 mg once daily.
d
Englestrin, 10 mg, single dose
In healthy volunteers, there was no clinically significant effect of engramlizine on the pharmacokinetics of metformin, glimepiride, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when co-administered with these drugs (see Figure 5).
Figure 5 Effect of engramlizine on the pharmacokinetics of various drugs, shown as 90% confidence intervals for the geometric mean ratios of AUC and Cmax [reference line indicates 100% (80%-125%)
Geometric mean ratio (90% confidence interval)
Glucose-lowering
Drug Metformin, 1000 mg, twice daily aAUC Cmax Glimepiride, 1 mg, single dose aAUC
Cmax Oral contraceptive ethinyl estradiol, 30 mcg, once daily
b, fAUC
Cmax levonorgestrel, 150 mcg once daily
b, fAUC Cmax
Other
Simvastatin, 40 mg, single dose
c
AUC Cmax Simvastatin acid
dAUC Cmax R-Warfarin, 25 mg, single dose
b, eAUC Cmax S-warfarin, 25 mg, single dose
b, eAUC Cmax Ramipril, 5 mg, once daily
bAUC Cmax Ramiprilat
gAUC Cmax Digoxin, 0.5 mg, single dose
bAUC Cmax Hydrochlorothiazide, 25 mg, once daily bAUC Cmax Torasemide, 5 mg, once daily bAUC Cmax
a
Englestradiol, 50 mg once daily.
b Englestradiol, 25 mg once daily
c Englestrin, 25 mg, single dose.
d Administered as simvastatin.
e Administered as a racemic mixture of warfarin.
f Administered as Microgynon®.
g As ramipril
Storage
Keep airtight, not more than 25℃.
Packaging
Aluminum – PVC blister package, 10 tablets/box.
Expiration date
36 months.
Execution Standard
Imported drug registration standard JX20150247.
Approval number
Imported drug registration certificate no.
[Manufacturer].
Company Name: Boehringer Ingelheim International GmbH
Address
Address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany
Production
Production
Plant: Boehringer Ingelheim Pharma GmbH & Co.
Location
Address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany
Domestic Affiliations
Boehringer Ingelheim Pharmaceuticals Shanghai Co.
Address: No. 1010 Longdong Avenue, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai
Zip code: 201203
Phone Number/Product Service Hotline: 400-820-5907, 800-820-5907
Fax Number: (021) 5080 1530
Website: www.boehringer-ingelheim.com.cn