Approval date: 09/29/2017
Instructions for Cargolizine Tablets
Please read the instructions carefully and use under the guidance of your physician.
Warnings
Amputations in the mid-foot region of the lower extremity (99 of 140 amputations in two trials received this product) were the most common.
However, amputations of the leg above or below the knee were also observed (41 of 140 amputees treated with this product in two trials
). A small number of patients had multiple amputations or involved both lower limbs:
– In two large, randomized, placebo-controlled trials (CANVAS and CANVAS-R) in patients with type 2 diabetes with a prior history of cardiovascular disease (CVD) or risk factors for CVD, an approximately doubled risk of lower extremity amputation was observed with this product.
– Toe and midfoot amputations were the most common; however, leg amputations were also observed. A small number of patients had multiple amputations or involved both lower extremities.
– Factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease and neuropathy, and diabetic foot ulcers, should be considered before starting the drug.
– Patients taking this product should be monitored for the development of lower extremity site infections, new onset pain or tenderness in the lower extremities, sores or ulcers, and discontinued if these complications occur (see [Precautions]).
Drug Name]
Generic name: Cargolizine Tablets
Trade Name: Ecolab
English Name: Canagliflozin Tablets
Hanyu Pinyin: Kageliejing Pian
Ingredients
Main ingredients: Kageliejing
Chemical name: (1S)-1,5-anhydro-1-C-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-D-glucitol
Chemical structure formula.
Molecular Formula.
C24H25FO5S1/2 H2O Molecular Weight: 453.53
Properties
This product is yellow capsule-shaped film-coated tablet (100mg specification) or white to off-white capsule-shaped film-coated tablet (300mg specification), which should appear white after removing the coating.
Indications
Combination of metformin and metformin: When the glycemic control of metformin alone is not good, it can be used in combination with metformin to improve the glycemic control of adult type 2 diabetic patients with diet and exercise.
Combination with metformin and sulfonylurea: When the combination of metformin and sulfonylurea is not good for blood glucose control, it can be used in combination with metformin and sulfonylurea, together with diet and exercise to improve blood glucose control in adults with type 2 diabetes.
This product is not recommended for the treatment of type 1 diabetic patients or diabetic ketoacidosis (patients).
【Specifications】.
(1) 100mg; (2) 300mg (based on C24H25FO5S anhydrous substance)
Dosage]
The recommended starting dose of this product is 100mg once a day before the first meal of the day. For those who tolerate 100 mg once daily, the estimated glomerular filtration rate (eGFR)
≥60 mL/min/1.73 m2 and who require additional glycemic control, the dose may be increased to 300 mg once daily (see [Precautions], [Pharmacology and Toxicology]). In patients with hypovolemia, correction of this condition is recommended prior to initiating treatment with this product (see [Precautions], [Geriatric Use]).
Patients with renal impairment
Assessment of renal function is recommended prior to initiation of this product and periodically after the start of therapy.
No dose adjustment is required in patients with mild renal impairment (eGFR ≥ 60 mL/min/1.73 m2).
For patients with moderate renal impairment (eGFR ≥ 45 to < 60 mL/min/1.73 m2), the dose of this product is limited to 100 mg once daily.
For patients with eGFR < 45 mL/min/1.73 m2, this product is not recommended.
This product is not recommended when eGFR is consistently below 45 mL/min/1.73 m2 (see [Precautions]).
This product is contraindicated in patients with eGFR below 30 mL/min/1.73 m2 (see [Precautions]).
Patients with hepatic impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment. No clinical studies have been conducted in patients with severe liver impairment; therefore, this product is not recommended for use in patients with severe liver impairment.
Combination with UDP-glucuronosyltransferase (UGT) inducers
If a UGT inducer (e.g., rifampin, phenytoin, phenobarbital, and ritonavir) is used in combination with this product, consider increasing the dose to 300 mg once daily for patients who currently tolerate a dose of 100 mg once daily, have an eGFR ≥60 mL/min/1.73 m2, and require additional glycemic control (see [Drug Interactions]).
For patients with an eGFR of ≥45 to <60 mL/min/1.73 m2 who are on a combination of UGT inducers, another hypoglycemic agent may be considered.
[Adverse Reactions].
The following important adverse reactions are discussed in other sections of the instruction.
Lower extremity amputation (see [Precautions]).
Hypotension (see [Precautions]).
Ketoacidosis (see [Precautions]).
Acute kidney injury and impaired renal function (see [Precautions]).
Hyperkalemia (see [Precautions]).
Urinary sepsis and pyelonephritis (see [Precautions]).
Hypoglycemia and combined use of insulin or insulin stimulants (see [Precautions]).
Genital fungal infections (see [Precautions]).
Allergic reactions (see [Precautions])
Bone fracture (see [Precautions])
Elevated low-density lipoprotein cholesterol (LDL-C) (see [Precautions]).
Clinical trial data
Due to the varying conditions under which clinical trials are conducted, the rate of adverse reactions in one clinical trial is not directly comparable to the incidence in another clinical trial and may not reflect the actual incidence in clinical practice.
Summary of Placebo-Controlled Trials
The data in Table 1 are from four 26-week placebo-controlled trials. In one trial, the product was used as a monotherapy drug; in the other 3 trials, the product was used as a combination therapy. These data reflect exposure to this product in 1667 patients and the mean duration of 24-week exposure to cardigliptin. Patients were treated with 100 mg of this product (N=833), 300 mg of this product (N=834), or placebo (N=646) once daily. The mean age of the population was 56 years, with 2% of patients over 75 years of age. The population was 50% male, 72% Caucasian, 12% Asian, and 5% Black or African American. The mean length of time patients had diabetes at baseline was 7.3 years, the mean HbA1C was 8.0%, and 20% had established diabetic microvascular complications. Baseline renal function was normal or mildly impaired (mean eGFR of 88 mL/min/1.73 m2).
Table 1 lists the common adverse reactions associated with this product. These adverse reactions were not present at baseline and occurred more frequently with this product than with placebo and occurred in at least 2% of patients treated with either 100 mg of this product or 300 mg of this product.
Table 1 Summary of adverse reactions reported in ≥ 2% of patients treated with this product in four 26-week placebo-controlled studies
Adverse reactions Placebo
N= 646 This product
100 mg
N= 833 Benadryl
300 mg
N= 834 Various urinary tract infections (2) 3.8% 5.9% 4.4% Increased urination (3) 0.7% 5.1% 4.6% Thirst (5) 0.1% 2.8% 2.4% Constipation 0.9% 1.8% 2.4% Nausea 1.6% 2.1% 2.3% Female N= 312 N= 425 N= 430 Female genital fungal infection (1) 2.8% 10.6% 11.6% Vulvovaginal itching 0.0% 1.6% 3.2% Male N=334 N=408 N=404 Male genital fungal infection (4) 0.7% 4.2% 3.8%
(1)
Genital fungal infections in females include the following adverse reactions: vulvovaginal candidiasis, vulvovaginal fungal infection, vulvovaginitis, vaginal infection, vulvovaginitis and genital fungal infection.
(2)
Urinary tract infections include the following adverse reactions: urinary tract infections, cystitis, renal infections and urinary sepsis.
(3)
Increased urination includes the following adverse reactions: polyuria, dysuria, increased urine volume, urinary urgency and nocturia.
(4)
Fungal infections of the male genitalia include the following adverse reactions: glansitis or prepuce glansitis, candidal glansitis and fungal infections of the genital tract.
(5)
Thirst includes the following adverse reactions: thirst, dry mouth, and irritability.
Note: Percentages are weighted means across studies. Study weights are proportional to the summed mean of the sample sizes of the three treatment groups.
Abdominal pain was also reported more frequently in the 100 mg of this product (1.8%) and 300 mg of this product treatment groups (1.7%) than in the placebo group (0.8%).
Summary of Placebo and Positive Control Trials
The incidence of adverse reactions to this product was also evaluated in the larger pooled patient population enrolled in the placebo and positive control trials.
Data from eight clinical trials were pooled that reflected exposure to this product in 6,177 subjects. The mean duration of exposure was 38 weeks, with 1832 individuals exposed for more than 50 weeks. Patients received 100 mg of this product (N=3092), 300 mg of this product (N=3085), or a positive control (N=3262) once daily. The mean age of the population was 60 years, with 5% of patients over 75 years of age. The population was 58% male, 73% Caucasian, 16% Asian, and 4% Black or African American. At baseline, the population had a mean duration of diabetes of 11 years, a mean HbA1C of 8.0%, and 33% had established diabetic microvascular complications. Baseline renal function was normal or mildly impaired (mean eGFR of 81 mL/min/1.73 m2).
The types and frequencies of common adverse reactions observed in the eight clinical trials pooled were consistent with those listed in Table 1. Percentages are weighted means across studies. Study weights are proportional to the summed mean of the sample sizes of the three treatment groups. Adverse reactions associated with this product in this pooled data also included fatigue (1.8 % in the control group, 2.2 % in the 100 mg group and 2.0 % in the 300 mg group) and loss of physical strength or energy (i.e., weakness) (0.6 % in the control group, 0.7 % in the 100 mg group and 1.1 % in the 300 mg group).
The incidence of pancreatitis (acute or chronic) in the control, 100 mg, and 300 mg groups was 0.1%, 0.2%, and 0.1% in the pooled 8 clinical trials.
The incidence of allergy-related adverse reactions (including erythema, rash, pruritus, urticaria and angioedema) in the pooled 8 clinical trials was 3.0% in the control drug group, 3.8% in the 100 mg group and 4.2% in the 300 mg group. 5 patients developed severe allergic reactions associated with treatment with this product, including 4 cases of urticaria and 1 case of diffuse rash and urticaria, which occurred within a few hours of exposure to this product. Two of these patients discontinued the product and one patient with urticaria relapsed after restarting treatment with the product.
The incidence of photosensitivity-related adverse reactions (including photosensitivity reactions, polymorphic sun rash, and sunburn) was 0.1% in the control group, 0.2% in the 100 mg group, and 0.2% in the 300 mg group.
Other adverse reactions that were more common with this product than the control drug group included
Lower extremity amputation
In two large, randomized, placebo-controlled trials (CANVAS and CANVAS-R) in patients with type 2 diabetes with a prior history of cardiovascular disease (CVD) or risk factors for CVD, an approximately doubled risk of lower extremity amputation was observed with CANVAS and CANVAS-R. The mean follow-up time was 5.7 and 2.1 years for CANVAS and CANVAS-R patients, respectively. Please see Tables 2 and 3 for CANVAS and CANVAS-R amputation data, respectively (see [Caution]).
Table 2: Amputations in CANVAS
Placebo group
N=1441 this product
100 mg group N=1445 this product
300 mg group N=1441
(Summary)
N=2886 Number of patients with amputation, n (%) 22 (1.5)50 (3.5)45 (3.1)95 (3.3) Total number of amputation events 338379162 Incidence of amputation (per 1000 patient-years) 2.86.25.55.9 Risk ratio (95% CI) – 2.24 (1.36, 3.69)2.01 (1.20, 3.34) 2.12 (1.34, 3.38) (1) Incidence was calculated based on the number of patients who had undergone at least one amputation, rather than the total number of amputation events.
(2) Patient follow-up was calculated from day 1 to the date of the first amputation event. Some patients had more than 1 amputation.
Table 3: CANVAS-R amputations
Placebo group N=2903 Benadryl 100 mg group
(titrated up to 300 mg) N=2904 Number of patients with amputations, n (%) 25 (0.9)45 (1.5) Total amputation events 3659 Amputation incidence (per 1000 patient-years) 4.27.5 Risk ratio (95% CI) – 1.80 (1.10, 2.93) (1) Based on the number of patients who had received at least one amputation, not the total number of amputation events incidence was calculated.
(2) Patient follow-up was calculated from day 1 to the date of the first amputation event. Some patients had more than 1 amputation.
Adverse reactions associated with hypovolemia
This product causes osmotic diuresis, which can lead to a decrease in blood volume. In clinical studies, treatment with this product has caused a dose-dependent increase in the incidence of adverse reactions associated with hypovolemia (e.g., hypotension, postural dizziness, upright hypotension, syncope, and dehydration). An increased incidence was observed in patients in the 300 mg dose group. The three major factors that caused a greater increase in the incidence of adverse reactions associated with hypovolemia were the use of tab diuretics, moderate renal impairment (eGFR of 30 to <60 mL/min/1.73 m2), and age 75 years or older (see Table 4, [Dosage], [Precautions], and [Geriatric Use]).
Table 4 Proportion of patients with at least 1 adverse reaction related to hypovolemia (pooled results from 8 clinical trials)
Baseline characteristics control drug group
(1)
% Benadryl 100mg
% Benadryl 300 mg
% overall population 1.5% 2.3% 3.4% 75 years and older (2) 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2 (2) 2.5% 4.7% 8.1% Use of tab diuretics (2) 4.7% 3.2% 8.8% (1) Includes placebo and positive controls
(2)
Patients may have more than 1 risk factor (including: use of tab diuretics, moderate renal impairment, age greater than or equal to 75 years)
Falls
In the nine clinical trials pooled, the mean exposure time to this product was 85 weeks, and the percentage of patients who experienced falls in the control, the 100 mg group and the 300 mg group of this product was 1.3%, 1.5% and 2.1%, respectively. A higher risk of falls was observed in patients during the first weeks of treatment with Cargolizine.
Renal impairment
The product caused a dose-dependent increase in serum creatinine accompanied by a decrease in eGFR (see Table 5). Patients with moderate renal impairment at baseline had a greater mean change.
Table 5 Changes in serum creatinine and eGFR associated with this product in a pooled analysis of four placebo-controlled trials and trials with moderate renal impairment
Placebo
N= 646 Benadryl 100 mg
N= 833 Benadryl 300 mg
N= 8344 placebo-controlled trials pooled baseline creatinine (mg/dL) 0.84 0.82 0.82 eGFR (mL/min/1.73 m2) 87.0 88.3 88.8 Week 6 change creatinine (mg/dL) 0.01 0.03 0.05 eGFR (mL/min/1.73 m2) -1.6 -3.8 -5.0 Treatment End
Change (1) Creatinine (mg/dL) 0.01 0.02 0.03 eGFR (mL/min/1.73 m2)-1.6 -2.3 -3.4 Placebo
N= 90 Benadryl 100mg
N= 90 Benadryl 300mg
N= 89 Moderate renal impairment test baseline creatinine (mg/dL) 1.61 1.62 1.63 eGFR (mL/min/1.73 m2) 40.1 39.7 38.5 Change at week 3 creatinine (mg/dL) 0.03 0.18 0.28 eGFR (mL/min/1.73 m2) -0.7 -4.6 -6.2 End of treatment
Change (1) creatinine (mg/dL) 0.07 0.16 0.18 eGFR (mL/min/1.73 m2)-1.5 -3.6 -4.0 (1) mITT population end of week 26 subobservation carryover method
In the four placebo-controlled trials (patients with normal or mildly impaired renal function at baseline), the proportion of patients with at least one event of significant renal function decline (defined as eGFR less than 80 mL/min/1.73 m2 and more than 30% reduction from baseline values) was 2.1% in the placebo group, 2.0% in the Benadryl 100 mg group, and 4.1% in the Benadryl 300 mg group. At the end of treatment, the proportion of events with significant renal decline was 0.5% in the placebo group, 0.7% in the Benadryl 100 mg group, and 1.4% in the Benadryl 300 mg group.
The results of a trial in patients with moderate renal impairment (baseline eGFR of 30 to <50 mL/min/1.73 m2 and mean baseline eGFR of 39 mL/min/1.73 m2) showed that the proportion of patients with at least 1 event of significant renal decline (defined as a reduction of more than 30% from baseline values) was 6.9% in the placebo group, 6.9% in the Benadryl 100 mg group 18%, and 22.5% in the Benadryl 300 mg group. At the end of treatment, the proportion of patients with significant renal decline events was 4.6% in the placebo group, 3.4% in the Benadryl 100 mg group, and 2.2% in the Benadryl 300 mg group.
In the pooled population of patients with moderate renal impairment (baseline eGFR of 30 to <60 mL/min/1.73 m2 and mean baseline eGFR of 48 mL/min/1.73 m2) (N=1085), the overall incidence of these events was lower than in the above-specific trials, but a dose-dependent increase in the number of significant renal function decline events compared to the placebo group was still observed. dependent increase.
The use of this product was associated with an increased incidence of renal function-related adverse reactions (e.g., elevated creatinine, decreased glomerular filtration rate, renal impairment, acute renal failure), particularly in patients with moderate renal impairment.
In a pooled analysis of patients with moderate renal impairment, the incidence of renal function-related adverse reactions was 3.7% in the placebo group, 8.9% in the 100 mg group, and 9.3% in the 300 mg group of this product. The incidence of discontinuation due to renal function-related adverse reactions was 1.0% in the placebo group, 1.2% in the 100 mg group, and 1.6% in the 300 mg group (see [Precautions]).
Genital fungal infections
In a pooled analysis of four placebo-controlled clinical trials, the incidence of female genital fungal infections (e.g., mycosis fungoides, vulvovaginal candidiasis, vulvovaginitis) was 2.8%, 10.46%, and 11.46% in the placebo, 100 mg, and 300 mg groups, respectively. Patients with a history of genital fungal infections were more likely to develop genital fungal infections when treated with this product. Women with previous genital fungal infections are more likely to have recurrences when treated with this product and require treatment with oral or topical antifungal and antimicrobial agents. The proportion of female patients who discontinued drug therapy for genital fungal infections was 0% and 0.7% in the placebo and this product groups, respectively (see [Precautions]).
In a pooled analysis of four placebo-controlled clinical trials, the incidence of genital fungal infections (e.g., candidiasis, glans vulgaris) in men was 0.7% in the placebo group, 4.2% in the 100 mg group, and 3.8% in the 300 mg group. Fungal infections of the male genitalia occurred more frequently in uncircumcised men and in men with a previous history of glansitis or glansitis. Compared with the control drug group, men with previous genital fungal infections were more likely to have recurrent infections when treated with this product (22% in the product group and none in the placebo group), requiring treatment with oral or topical antifungal and antimicrobial agents. Among male patients, discontinuation of drug therapy for genital fungal infections was 0% in the placebo and 0.5% in the Benadryl group. In a pooled analysis of 8 controlled trials, 0.3% of uncircumcised patients treated with cagliflozin reported circumcision, of which 0.2% required circumcision to treat circumcision (see [Precautions]).
Hypoglycemia
In all clinical trials, hypoglycemia was defined as any event documented as biochemical hypoglycemia (any blood glucose value equal to or less than 70 mg/dL), regardless of symptoms.
Severe hypoglycemia was defined as an event such as the occurrence of a patient with hypoglycemia requiring the assistance of another person for recovery, loss of consciousness, or the occurrence of a seizure (regardless of whether a biochemically documented hypoglycemic value had been obtained). In individual clinical trials, the incidence of hypoglycemia was increased when this product was used in combination with insulin or sulfonylureas (see Table 6 and [Caution]).
Table 6 Incidence of hypoglycemia in controlled clinical studies
(1)
Monotherapy
(26 weeks) Placebo
(N= 192) This product
100 mg
(N= 195) Benadryl
300mg
(N= 197) Total [N (%)]5 (2.6) 7 (3.6) 6 (3.0) Combination
Metformin
(26 weeks) Placebo + metformin
(N= 183) Benadryl 100 mg + metformin
(N= 368) Benadryl 300mg + metformin (N=367) Total [N (%)]3 (1.6) 16 (4.3)17 (4.6) Severe [N (%)] (2)0 (0) 1 (0.3) 1 (0.3) Combined
Metformin
(52 weeks) Glimepiride + Metformin
(N= 482) This product 100mg + Metformin
(N= 483) Benadryl 300mg + Metformin (N= 485) Overall [N (%)] 165 (34.2) 27 (5.6) 24 (4.9) Severe [N (%)] (2) 15 (3.1) 2 (0.4) 3 (0.6) Combined
Sulfonylurea
(18 weeks) Placebo
+ sulfonylurea
(N= 69) This product 100mg
+ sulfonylurea
(N= 74) 300mg of this product
+ sulfonylurea
(N= 72) Overall [N (%)]4 (5.8) 3 (4.1) 9 (12.5) Combined metformin + sulfonylurea
(26 weeks) Placebo + metformin + sulphonylurea (N=156) Benadryl 100mg + metformin
+ sulfonylurea
(N= 157) Benadryl 300mg + metformin + sulfonylurea
(N= 156) Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) Severe [N (%)] (2) 1 (0.6) 1 (0.6)0 Combined metformin + sulfonylurea
(52 weeks) Sitagliptin + Metformin + Sulfonylurea (N=378) This product 300mg + Metformin + Sulfonylurea
(N=377) Overall [N (%)] 154 (40.7) 163 (43.2) Severe [N (%)] (2) 13 (3.4) 15 (4.0) Combined metformin + pioglitazone (26 weeks) Placebo + metformin + pioglitazone (N=115) Benadryl 100 mg + metformin
+ pioglitazone
(N= 113) Benadryl 300mg + metformin + pioglitazone (N= 114) Overall [N (%)]3 (2.6) 3 (2.7) 6 (5.3) Combination
insulin
(18 weeks)
Placebo
(N= 565) 100 mg of this product
(N= 566) Benadryl 300mg
(N= 587) Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Severe [N (%)] (2) 14 (2.5) 10 (1.8) 16 (2.7) (1) Number of patients in the intention-to-treat population with at least 1 biochemically-based documented hypoglycemic or severe hypoglycemic event
(2)
Severe hypoglycemic episodes were defined as events such as needing assistance from others to recover, losing consciousness, or having a seizure in patients with hypoglycemia (regardless of whether biochemically documented hypoglycemic values were obtained)
Fractures
The incidence of fractures was evaluated in a pooled manner in 9 clinical trials with a mean exposure time of 85 weeks for this product. The incidence of proven fractures was 1.1, 1.4 and 1.5 per 100 patient-years of exposure in the control, 100 mg group and 300 mg group of this product, respectively. Fractures were observed as early as 12 weeks after initiation of treatment and were mostly low trauma fractures (e.g., falls on level ground) and upper extremity fractures (see [Precautions]).
Laboratory and imaging studies
Elevated serum potassium
In pooled patients with moderately impaired renal function (eGRF of 45 to less than 60 mL/min/1.73 m2) (N
=723), the number of patients with elevated blood potassium greater than 5.4 mEq/L and a change of more than 15% from baseline values was 5.3%, 5.0%, and 8.8% in the placebo, 100 mg, and 300 mg groups, respectively. The number of patients with severely elevated blood potassium (i.e., at or above 6.5 mEq/L) was 0.4% in the placebo group, none in the 100 mg group, and 1.3% in the 300 mg group.
In these patients, elevated blood potassium was more commonly seen in patients who had elevated blood potassium at baseline. In patients with moderate renal impairment, approximately 84% were on medications that interfere with potassium excretion, such as potassium-preserving diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers (see [Precautions]).
Increased serum magnesium
A dose-related increase in serum magnesium was observed in the early phase (within 6 weeks) of initiation of treatment with this product and continued to be elevated over the course of this treatment. In a pooled analysis of four placebo-controlled trials, the mean percentage change in serum magnesium levels was 8.1% and 9.3% in the 100 mg and 300 mg groups of Benadryl, respectively, compared with -0.6% in the placebo group. In the trial in patients with moderate renal impairment, serum magnesium levels increased by 0.2% in the placebo group, 9.2% in the 100 mg group, and 14.8% in the 300 mg group.
Increase in serum phosphorus
A dose-related increase in serum phosphorus was observed in this treatment. In a pooled analysis of four placebo-controlled trials, the mean percentage change in serum phosphorus levels was 3.6% and 5.1% in the 100 mg and 300 mg groups, respectively, and 1.5% in the placebo group. In the trial of patients with moderate renal impairment, mean serum phosphorus levels increased by 1.2% in the placebo group, 5.0% in the 100 mg group and 9.3% in the 300 mg group.
Elevated low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non–HDL-C)
In a pooled analysis of four placebo-controlled trials, a dose-related increase in LDL-C was observed in patients treated with this product. The mean change (percent change) from baseline in LDL-C was 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) in the 100 mg and 300 mg groups, respectively, compared with the placebo group. Mean baseline LDL-C levels in all treatment groups ranged from 104 to 110 mg/dL (see [Precautions]).
Dose-related non-HDL-C elevations were observed with this product treatment. The mean change (percent change) from baseline in non-HDL-C was 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) in the 100 mg and 300 mg groups, respectively, compared with the placebo group. Mean baseline non-HDL-C levels in all treatment groups ranged from 140 to 147 mg/dL.
Elevated hemoglobin
In the pooled analysis of the four placebo-controlled trials, the mean change in hemoglobin from baseline (percent change) was -0.18 g/dL (-1.1%) in the placebo group, 0.47 g/dL (3.5%) in the 100 mg group, and 0.51 g/dL (3.8%) in the 300 mg group. The mean baseline hemoglobin level in all treatment groups was approximately 14.1 g/dL, and the percentage of patients with hemoglobin levels above the upper limit of normal at the end of treatment was 0.8% in the placebo group, 4.0% in the 100 mg group, and 2.7% in the 300 mg group.
Reduced bone mineral density
In a clinical trial conducted in 714 elderly patients (mean age 64 years), reduction in bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Over a 2-year period, total hip BMD was reduced by 0.9% and 1.2% in the 100 mg group and 0.3% and 0.7% in the 300 mg group, respectively, and lumbar spine BMD was reduced compared to the placebo group. In addition, there was a 0.1% reduction in femoral neck BMD in both dose groups and a 0.4% reduction in distal forearm BMD in the 300 mg group compared to the placebo group, while there was no change in distal forearm BMD in the 100 mg group.
Postmarketing Experience
Additional adverse reactions were identified during post-approval use of this product. Because these adverse reactions were spontaneously reported and reported from an uncertain population size, their incidence cannot usually be accurately estimated or their causal relationship to drug exposure determined.
Ketoacidosis (see [Precautions])
Acute kidney injury and impaired renal function (see [Precautions])
Allergic reactions, angioedema (see [Precautions])
Urinary sepsis and pyelonephritis (see [Precautions])
[Contraindication].
People with a history of severe allergic reactions to this product, such as anaphylactic reactions or angioedema (see [Precautions])
Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), patients with advanced renal disease (ESRD), or patients on dialysis (see [Precautions], [Dosage])
[Precautions].
Lower extremity amputation
In two large, randomized, placebo-controlled trials (CANVAS and CANVAS-R) in type 2 diabetic patients with a prior history of cardiovascular disease (CVD) or risk factors for CVD, an approximately doubled risk of lower extremity amputation was observed with administration of this product. In the CANVAS trial, the number of amputations per year was 5.9 and 2.8 per 1,000 patients in patients treated with this product and in patients treated with placebo, respectively. In the CANVAS-R trial, the number of amputations per year was 7.5 per 1,000 patients treated with CANVAS and 4.2 per 1,000 patients treated with placebo. The risk of lower extremity amputation was observed for both the 100 mg and 300 mg once-daily dosing regimens, and amputation data for CANVAS and CANVAS-R are shown in Tables 2 and 3, respectively (see [Adverse Reactions]).
Amputations at the toe and midfoot sites (99 of 140 amputations in both trials were treated with this product) were the most common.
However, leg amputations above or below the knee were also observed (41 of 140 amputees treated in both trials
). A small number of patients had multiple amputations or involved both lower limbs.
Lower extremity infections, gangrene, and diabetic foot ulcers were the most common predisposing medical events leading to amputation. Subjects with a prior history of amputation, peripheral vascular disease and neuropathy were at highest risk for amputation.
Factors in the patient’s medical history that may increase the risk of amputation, such as prior history of amputation, peripheral vascular disease and neuropathy, and diabetic foot ulcers, should be considered prior to initiation of this medication. The importance of taking routine preventive foot care needs to be emphasized (or explained) to the patient. Monitor patients taking this product for the following signs and symptoms: infection (including osteomyelitis) in the lower extremity area, new onset of pain or tenderness in the lower extremity, sores or ulcers, and discontinue the product if these complications occur.
Hypotension
This product may cause a decrease in blood volume. Symptomatic hypotension may occur in patients after initiation of therapy with this product (see [Adverse Reactions]), especially in patients with renal impairment (eGFR < 60 mL/min/1.73m2), in elderly patients, in patients receiving diuretics or using drugs that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARB ]), or patients with low systolic blood pressure. Patients with one or more of these characteristics should have their blood volume status assessed and corrected prior to initiation of therapy with this product. Monitor for signs and symptoms after initiation of therapy.
Ketoacidosis
Ketoacidosis is a serious life-threatening condition that requires urgent hospitalization. Post-marketing drug monitoring has identified reports of ketoacidosis in patients with type 1 and type 2 diabetes treated with sodium-glucose co-transporter protein 2 (SGLT2) inhibitors, including this product. Deaths from ketoacidosis have been reported in patients using this product. This product is not indicated for the treatment of patients with type 1 diabetes mellitus.
The possibility of ketoacidosis should be evaluated in patients treated with this product who have signs and symptoms consistent with severe metabolic acidosis, regardless of their blood glucose level, because ketoacidosis associated with this product may exist even if blood glucose levels are below 250 mg/dL. If ketoacidosis is suspected, the product should be discontinued and the patient should be evaluated, and treatment should be administered immediately. Treatment of ketoacidosis may require the use of insulin, fluids, and carbohydrate replacement.
In many post-marketing reports, particularly in patients with type 1 diabetes, ketoacidosis was not immediately diagnosed because the patient’s blood glucose levels were below the values generally expected for diabetic ketoacidosis (often below 250 mg/dL), resulting in a delay in treatment. Signs and symptoms of ketoacidosis are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, general malaise, and shortness of breath. Susceptibility factors for ketoacidosis found in some, but not all, cases include 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, history of pancreatitis, or history of pancreatic surgery), and alcohol abuse.
The presence of ketoacidosis susceptibility factors in the patient’s medical history, including any cause of pancreatic insulin deficiency, caloric restriction, and alcohol abuse, should be considered prior to initiating treatment with this product. In patients treated with this product who have a clinical condition known to predispose them to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery), monitoring for ketoacidosis should be considered and treatment should be suspended if necessary.
Acute renal injury and impaired renal function
This product may cause a reduction in intravascular blood volume (see [Precautions]). There have been post-marketing reports of acute kidney injury in patients receiving this product, some of whom required hospitalization and dialysis; some of the patients reported were younger than 65 years of age.
Factors that may cause acute kidney injury in patients should be considered before initiating treatment with this product, including hypovolemia, chronic renal insufficiency, congestive heart failure, and comorbid medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider suspension of this product if decreased transoral feeding (e.g., acute illness or fasting) or fluid loss (e.g., gastrointestinal illness or exposure to heat) occurs; monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue the product immediately and treat accordingly.
This product may increase serum creatinine levels and decrease eGFR. Patients may experience abnormal renal function after initiation of this product (see [ADVERSE REACTIONS]). Renal function should be assessed prior to initiation of this product and periodically after the start of therapy. More frequent renal function monitoring is recommended for patients with eGFR below 60 mL/min/1.73 m2. This product is not recommended if eGFR is below or consistently below 45 mL/min/1.73 m2. eGFR below 30 mL/min/1.73 m2 is contraindicated in patients (see [Dosage], [Contraindications]).
Hyperkalemia
This product may cause hyperkalemia. The use of drugs that interfere with potassium excretion (e.g., potassium-protective diuretics) or drugs that interfere with the renin-angiotensin-aldosterone system in patients with moderate renal impairment may increase the risk of hyperkalemia (see [ADVERSE REACTIONS]).
Monitor serum potassium levels regularly after initiating treatment with this product in patients with renal impairment and in patients predisposed to hyperkalemia due to medications or other medical conditions.
Urinary sepsis and pyelonephritis
Post-marketing surveillance data indicate that serious urinary tract infections, including urinary sepsis and pyelonephritis requiring hospitalization, have been reported in patients treated with SGLT2 inhibitors, including this product. Treatment with SGLT2 inhibitors may increase the risk of urinary tract infections. Patients should be evaluated for signs and symptoms of urinary tract infection and, if present, should be treated immediately (see [Adverse Reactions]).
Hypoglycemia and the combination of insulin and insulin stimulants
Insulin and insulin stimulants are known to cause hypoglycemia. When used in combination with insulin and insulinotropic agents, this product may increase the risk of hypoglycemia (see [ADVERSE REACTIONS]). Therefore, when co-administered with this product, a lower dose of insulin or insulinotropic agent should be considered to reduce the risk of hypoglycemia.
Genital fungal infections
This product increases the risk of genital fungal infections. Patients with a history of genital fungal infections or uncircumcised men are more likely to develop genital fungal infections (see [Adverse Reactions]). Perform appropriate monitoring and treatment.
Allergic reactions
Allergic reactions (including angioedema and anaphylactic reactions) have been reported in patients treated with this product; these reactions usually occur within a few hours to a few days after initiation of treatment with this product. If an allergic reaction occurs, discontinue the product, give treatment and monitor until signs and symptoms subside (see [Adverse Reactions], [Contraindications]).
Bone fractures
Given that an increased risk of fracture has been observed in patients using this product and occurred as early as 12 weeks after initiation of treatment, factors that may increase the risk of fracture should be considered before initiating treatment with this product (see [ADVERSE REACTIONS]).
Elevated low-density lipoprotein cholesterol (LDL-C)
A dose-related increase in LDL-C has been observed with this product (see [ADVERSE REACTIONS]). After starting this product, LDL-C levels should be monitored and treatment given when appropriate.
Large vessel lesion outcomes
There is no clear evidence from clinical studies that this product reduces the risk of macroangiopathy.
Please keep it out of the reach of children.
Pregnant women and nursing mothers
Pregnancy
Risk Summary
Based on data from animal studies showing renal adverse effects, the use of this product in mid to late pregnancy is not recommended.
Data on pregnant women treated with this product are limited to confirm whether the risk of major birth defects or miscarriage is drug-related. Poor control of diabetes during pregnancy poses a risk to the mother and fetus.
In animal studies, irreversible adverse reactions renal pelvis and tubular dilatation were observed in rats during renal development (equivalent to mid to late human gestation) when cabergoline was administered (exposure 0.5 times the clinical dose of 300 mg, based on AUC).
The predicted background risk of major birth defects is 6-10% in women with preexisting diabetes and HbA1c >7%. up to 20-25% predicted background risk is reported in women with HbA1c >10%. The predicted background risk of miscarriage in the indication population is unknown. In the general US population, the predicted background risks for clinically identified major birth defects and miscarriage in pregnant women are 2-4% and 15-20%, respectively.
Clinical considerations
Maternal and/or embryonic/fetal disease-related risks
Poorly controlled diabetes during pregnancy increases the risk of maternal diabetic ketoacidosis, pre-eclampsia, spontaneous abortion, early delivery, stillbirth, and complications of labor and delivery. Poorly controlled diabetes increases the risk of major birth defects, stillbirth, and macrosomia-related disorders in the fetus.
Animal Data
Juvenile rats receiving directly postnatal (PND) day 21 to day 90 administration of cabergoline 4, 20, 65 or 100 mg/kg showed increased renal weight at all dose levels, along with a dose-dependent increase in the incidence and severity of renal pelvis and tubular dilatation. Exposure at the lowest dose was greater than or equal to 0.5 times the clinical dose of 300 mg, as calculated by AUC. These results occurred with drug exposure in the developing rat kidney (equivalent to the middle to late stages of human kidney development). The dilated renal pelvis observed in juvenile rats was not completely reversed during a 1-month recovery period.
In embryo-fetal development studies in rats and rabbits, the interval of cabergoline administration was consistent with the early gestation period of human organogenesis. Developmental toxicity events associated with maternal toxicity were observed when gestating rats and pregnant rabbits were administered capagliflozin at doses of 100 mg/kg and 160 mg/kg, respectively, during embryonic organogenesis, or in a study in which maternal rats were given capagliflozin at an exposure of approximately 19 times the clinical dose of 300 mg (based on AUC) from day 6 of gestation (GD) to day 21 of PND .
Lactation
Risk Summary
No information is available on the presence of this product in human milk, its effect on breastfed infants, or its effect on lactation. Cargolizine is present in milk secreted by lactating rats. Given that kidney maturation in humans occurs in utero and during the first two years of life, this product may pose a risk to human kidney development by causing drug exposure to infants through breastfeeding at this time.
Because of the potential for serious adverse reactions in breastfed infants, it is recommended that this product not be used during breastfeeding.
Animal Data
On postnatal day 13, the milk/plasma ratio in lactating rats receiving radiolabeled administration of cabergoline was 1.40, indicating that the concentrations of cabergoline and its metabolites in milk were comparable to those in plasma. Data from juvenile rats directly exposed to cabergoline show a risk to the developing kidney during maturation (dilated renal pelvis and tubules).
[Pediatric Dosage].
The safety and efficacy of this product in pediatric patients under 18 years of age have not been established.
[Geriatric Use].
In nine relevant clinical studies, a total of 2034 patients aged 65 years and older and 345 patients aged 75 years and older were exposed to this product.
In patients treated with this product, the incidence of adverse reactions (e.g., hypotension, postural dizziness, upright hypotension, syncope, dehydration) associated with reduced intravascular blood volume was higher in patients 65 years of age and older compared to younger patients, especially in the 300 mg daily dose group; the incidence of adverse reactions increased more significantly in patients 75 years of age and older (see [Dosage], [Adverse Reactions]). The reduction of HbA1C in the placebo group was smaller in older patients (65 years and older; -0.61% in the 100 mg group and -0.74% in the 300 mg group) than in younger patients (-0.72% in the 100 mg group and -0.87% in the 300 mg group).
Drug interactions]
UGT enzyme inducers
Rifampicin: The combination of cabergoline and rifampicin (a non-selective inducer of various UGT enzymes, including UGT1A9 and UGT2B4) was able to reduce the area under the drug-time curve (AUC) of cabergoline by 51%. The above-mentioned reduced exposure to cabergoline may reduce efficacy. If one of these UGT inducers (e.g., rifampin, phenytoin, phenobarbital, and ritonavir) must be used in combination with this product, consider increasing the dose to 300 mg once daily for patients who tolerate a dose of 100 mg once daily, have an eGFR > 60 mL/min/1.73 m2, and require additional glycemic control. For patients with an eGFR of 45 to <60 mL/min/1.73 m2, combined with UGT inducers and requiring additional glycemic control, other glucose-lowering therapy may be considered (see [Dosage], [Pharmacokinetics]).
Digoxin
Digoxin AUC and mean peak concentration (Cmax) were increased (20% and 36%, respectively) when combined with 300 mg of Digoxin (see [Pharmacokinetics]). Patients treated with the combination of this product and digoxin should be monitored appropriately.
Positive urine glucose testing
The use of urine glucose testing to monitor glycemic control is not recommended in patients receiving SGLT2 inhibitors because SGLT2 inhibitors increase urinary glucose excretion and result in positive urine glucose test results. Use other methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) assay
The 1,5-anhydroglucitol test is not recommended for monitoring glycemic control because 1,5-AG measurements are unreliable in assessing glycemic control in patients treated with SGLT2 inhibitors. Use other methods to monitor glycemic control.
[Drug overdose].
No overdose has been reported during the clinical development program for this product.
If an overdose occurs, medical personnel should be contacted promptly. Routine supportive therapy, such as removal of unabsorbed drug from the GI tract, clinical monitoring, and supportive therapy based on the patient’s clinical status, may also be used. 4 hours of hemodialysis has failed to remove almost all of the cardigliptin, and it is not expected that cardigliptin will be removed by peritoneal dialysis.
Clinical trials]
This product has been studied with metformin, metformin and sulfonylurea in patients with type 2 diabetes, and treatment with this product produced clinically and statistically significant improvements in HbA1C levels compared to placebo. HbA1C reductions were observed in age, sex, race and baseline body mass index (BMI) subgroups.
Combination therapy
Combination therapy with metformin
A total of 1284 patients with type 2 diabetes mellitus with poor glycemic control on metformin monotherapy (at or above 2000 mg/day, or at least 1500 mg/day if a higher dose was not tolerated) participated in a 26-week, double-blind, placebo and positive-controlled study to evaluate the efficacy and safety of this product in combination with metformin. Subjects had a mean age of 55 years, 47% were male, and mean baseline eGFR was 89 mL/min/1.73 m2. After completing a 2-week, single-blind, placebo introduction period, patients currently taking metformin at the required dose (N=1009) were randomized. Patients currently on metformin at less than the required dose or currently receiving metformin in combination with another glucose-lowering agent (N=275) were switched to metformin monotherapy (at the dose described above) for at least 8 weeks, followed by a 2-week, single-blind, placebo introduction period. Following the placebo introduction period, patients were randomly assigned to the 100 mg group, the 300 mg group, the selegiline 100 mg group, or the placebo group to receive once-daily dosing as an evaluation of efficacy and safety in combination with metformin.
In combination with metformin, statistically significant improvements in HbA1C levels were achieved in the 100 mg and 300 mg groups compared to the placebo group at the end of treatment (p-values <0.001 for both dose groups). Also, Benadryl 100 mg and 300 mg once daily reduced HbA1C levels to less than 7% in a greater proportion of patients, resulted in a significant reduction in fasting blood glucose (FPG), improved postprandial glucose (PPG), and reduced percent body weight (see Table 5). Systolic blood pressure was statistically significant from baseline in the 100 mg and 300 mg groups of this product compared to the placebo group (p-values <0.001 for both dose groups), and the mean change in systolic blood pressure from baseline minus the placebo effect was -5.4 mmHg and -6.6 mmHg for both dose groups, respectively.
Table 7 Results of a 26-week placebo-controlled clinical trial of the combination of this product and metformin (1)
Efficacy parameters Placebo + metformin (N= 183) Benadryl 100 mg + metformin
(N= 368) Benadryl 300mg + metformin
(N= 367) HbA1C (%) Baseline (mean) 7.967.947.95 Change from baseline (adjusted mean) -0.17 -0.79 -0.94 Difference from placebo (adjusted mean) (95% CI) (2) -0.62(3)
(-0.76; -0.48) -0.77(3)
(-0.91; -0.64) Percent of patients achieving HbA1C < 7% 3046(3)58(3) Fasting glucose (mg/dL) Baseline (mean) 164169173 Change from baseline (adjusted mean) 2-27-38 Difference from placebo (adjusted mean) (95% CI) (2) -30(3)
(-36; -24) -40(3)
(-46; -34) 2-hour postprandial glucose (mg/dL) baseline (mean) 249258262 change from baseline (adjusted mean) -10-48-57 difference from placebo (adjusted mean) (95% CI) (2) -38(3)
(-49; -27) -47(3)
(-58; -36) Weight baseline (mean), kg86.788.785.4 % change from baseline (adjusted mean) -1.2 -3.7 -4.2 Difference from placebo (adjusted mean) (95% CI)
(2) -2.5(3)
(-3.1; -1.9) -2.9(3)
(-3.5; -2.3) (1) Intent-to-treat population with end-of-trial observed values prior to the use of glucose remediation therapy
(2) Least squares means corrected for baseline values and stratification factors.
(3) p<0.001
Combination therapy with metformin and sulfonylurea
A total of 469 patients with type 2 diabetes mellitus who had poor glycemic control on a combination of metformin (at or above 2000 mg/day, or if a higher dose of at least 1500 mg/day was not tolerated,) and sulfonylurea (at or near the maximum effective dose) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of this product in combination with metformin and sulfonylurea. Subjects had a mean age of 57 years, 51% were male, and mean baseline eGFR was 89 mL/min/1.73 m2. Patients (N=372) already receiving metformin and sulfonylurea at the doses prescribed in the protocol entered a 2-week, single-blind, placebo introduction period. Other patients (N=97) were first required to receive fixed protocol-specified doses of metformin and sulfonylurea for at least 8 weeks, and then entered a 2-week introductory period. After the introductory period, patients were randomized to the 100 mg group of this product, the 300 mg group of this product, or the placebo group to receive once-daily treatment in combination with metformin and sulfonylurea.
As a combination with metformin and sulfonylurea, a statistically significant improvement in HbA1C levels was achieved at the end of treatment in the Benadryl 100 mg and 300 mg groups compared to the placebo group (p-value <0.001 for both dose groups). As a combination with metformin and sulfonylurea, Benadryl 100 mg and 300 mg once daily also reduced HbA1C levels to less than 7% in a greater proportion of patients compared to placebo, resulting in a significant reduction in fasting glucose (FPG) and a reduction in percent body weight (see Table 8).
Table 8 Results of a 26-week placebo-controlled clinical trial of this product in combination with metformin and sulfonylurea (1)
Efficacy parameters Placebo + metformin and sulfonylurea (N=156) Benadryl 100 mg + metformin
and sulfonylurea
(N= 157) Benadryl 300 mg + metformin
and sulfonylurea
(N= 156) HbA1C (%) Baseline (mean) 8.12 8.13 8.13 Change from baseline (adjusted mean) -0.13 -0.85 -1.06 Difference from placebo (adjusted mean) (95% CI) (2) -0.71(3)
(-0.90; -0.52) -0.92(3)
(-1.11; -0.73) Percent of patients achieving HbA1C < 7%18 43(3)57(3) Fasting glucose (mg/dL) Baseline (mean) 170 173 168 Change from baseline (adjusted mean)4 -18 -31 Difference from placebo (adjusted mean) (95% CI) (2) -22(3)
(-31, -13) -35(3)
(-44; -25) Weight baseline (mean), kg90.8 93.5 93.5 % change from baseline (adjusted mean) -0.7 -2.1 -2.6 Difference from placebo (adjusted mean) (95% CI) (2) -1.4(3)
(-2.1; -0.7) -2.0(3)
(-2.7; -1.3) (1) Intent-to-treat population with end-of-trial observed values prior to the use of glucose remediation therapy
(2) Least squares means corrected for baseline values and stratification factors.
(3) p<0.001
Clinical studies conducted in special populations
Elderly patients (adults aged 55 to 80 years)
A total of 714 elderly patients with type 2 diabetes mellitus who were receiving current diabetes therapy (diet and exercise control alone or in combination with oral or parenteral hypoglycemic agents) with poor glycemic control participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of this product in combination with current diabetes therapy. The mean age of the subjects was 64 years, 55% were male, and the mean baseline eGFR was 77 mL/min/1.73 m2. Patients were randomized to receive either 100 mg of this product, 300 mg of this product, or placebo once daily.
At the end of treatment, subjects receiving either 100 mg or 300 mg of Benadryl once daily achieved a statistically significant improvement in HbA1C levels from baseline compared to the placebo group (p-value <0.001 for both dose groups), with -0.57% (95% CI: -0.71; -0.44) in the Benadryl 100 mg group and – 0.70% (95% CI: -0.84; -0.57). Statistically significant improvements in fasting blood glucose (FPG) and body weight from baseline were also achieved in the 100 mg and 300 mg groups (p-values <0.001 for both dose groups) (see [Geriatric Dosing]).
Moderate renal impairment
A total of 269 patients with type 2 diabetes (concurrent eGFR of 30 mL/min/1.73 m2 to less than 50 mL/min/1.73 m2) who were receiving current diabetes therapy with poor glycemic control participated in a 26-week, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of this product in combination with current diabetes therapy. The mean age was 68 years, 61% of the patients were male, and the mean baseline eGFR was 39 mL/min/1.73 m2. Patients were randomized to receive either 100 mg of this product, 300 mg of this product, or placebo once daily.
At the end of treatment, subjects receiving 100 mg or 300 mg once daily had a greater reduction in HbA1C levels compared to the placebo group, with -0.30% (95% CI: -0.53; -0.07) in the 100 mg group and -0.40%, (95% CI: -0.64; -0.17) in the 300 mg group (see [ Precautions], [Adverse Reactions], [Dosage]).
Pharmacology and Toxicology
Pharmacological effects
Cagliflozin is a sodium-glucose co-transport protein (SGLT2) inhibitor. Glucose filtrated by the tubular lumen of the kidney is mainly reabsorbed by SGLT2 expressed in the proximal tubule. By inhibiting SGLT2, Cargrelin reduces the reabsorption of filtered glucose by the kidney, decreases the renal glucose threshold (RTG), increases urinary glucose excretion, and thus lowers blood glucose.
Toxicological studies
Genotoxicity
Negative results in the Ames test and positive results in the in vitro mouse lymphoma test with metabolic activation and negative results in the test without metabolic activation. In vivo micronucleus test and comet test results were negative in rats.
Reproductive toxicity
Oral administration of 100 mg/kg of kaglegiline to rats (14 and 18 times the clinically recommended dose of 300 mg in male and female rats, respectively) caused slight changes in reproductive parameters, including decreased sperm motility, increased number of abnormal sperm, slight decrease in the number of corpus luteum, decreased number of fertility, and decreased number of litters per litter. No significant effects on fertility were observed.
No renal developmental toxicity was observed in rats administered orally from day 6 of gestation to lactation (day 21 after the birth of the litter). In the rat and rabbit embryo-fetal toxicity assays, only a mild increase in the number of ossified fetuses was observed at maternal toxicity doses (exposure approximately 19 times the clinically recommended dose of 300 mg), and no other maternal or fetal toxicity reactions were observed at NOAELs of 100 mg/kg/day and 160 mg/kg/day, respectively.
In a 10-week repeated dosing toxicity study in rats, rats were given orally from postnatal days 21 to 90 at doses of 4, 20, 65, and 100 mg/kg, and increased urine output with increased glucose and calcium secretion, increased kidney weight, and dose-related renal pelvis and tubular dilatation were observed in all dose groups, and renal pelvis dilatation did not fully recover at the end of the 1-month recovery period. Exposure in animals at the lowest dose was greater than 0.5 times the clinically recommended dose of 300 mg.
Cargolizine can be secreted into rat milk, and the level in milk is 1.4 times higher than the maternal plasma level.
Carcinogenicity
In a 2-year oral carcinogenicity study in mice and rats, doses of 10, 30, and 100 mg/kg/d were administered to mice, and no increase in tumor incidence associated with administration was observed at the 100 mg/kg/d dose (exposure less than 14 times the clinically recommended dose of 300 mg). The incidence of testicular mesenchymal cell tumors was significantly increased in male rats at all doses, and the incidence of renal tubular adenomas and carcinomas and adrenal pheochromocytomas was increased in male and female rats at 100 mg/kg, with a significant increase in adrenal pheochromocytomas in males compared to females. Preclinical mechanistic studies suggest that the development of testicular mesenchymal cell tumors in male rats is associated with elevated luteinizing hormone (LH) levels in kaglegiline, and that renal and adrenal tumors in rats are associated with carbohydrate malabsorption due to high doses of kaglegiline, but neither elevated LH levels nor impaired carbohydrate absorption were seen in clinical trials.
Pharmacokinetics]
The pharmacokinetics of this product were similar in healthy subjects and type 2 diabetic patients. Peak blood concentrations (median Tmax) were reached 1-2 hours after a single oral dose of 100 mg and 300 mg of this product. The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady state is achieved after 4-5 days of once-daily administration of 100 mg to 300 mg of this product. The pharmacokinetics of this product are not time-dependent, with plasma accumulation reaching 36% after multiple doses of 100 mg and 300 mg.
Absorption
The mean absolute oral bioavailability of this product is approximately 65%. A high-fat diet has no effect on the pharmacokinetics of this product; therefore, it can be taken with or without food. However, due to delayed intestinal glucose absorption that may reduce postprandial glucose fluctuations, it is best taken before the first meal of the day (see [Dosage]).
Distribution
The mean steady-state volume of distribution of this product after a single intravenous dose in healthy subjects was 83.5 L, indicating a wide tissue distribution. The product is extensively bound to plasma proteins (99%), primarily to albumin. Protein binding is not dependent on the blood concentration of Cargolizine. Changes in plasma protein binding in patients with renal or hepatic impairment are not significant.
Metabolism
O-glucuronidation is the major metabolic elimination pathway for this product, and glucuronidation occurs primarily via UGT1A9 and UGT2B4 to generate two inactive O-glucuronide metabolites.
CYP3A4-mediated (oxidative) metabolism of cagliflozin accounts for a relatively small proportion (~7%) in humans.
Excretion
Following a single oral dose of [14C]-labeled kaglegiline in healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radiopharmaceutical dose of kaglegiline prodrug, hydroxyl metabolite, and O-glucuronide metabolite, respectively, were recovered from the feces. Hepatic and intestinal circulation of this product was negligible.
Approximately 33% of the administered radiopharmaceutical dose was excreted in the urine, primarily in the form of O-glucuronide metabolites (30.5%). Less than 1% of the original form of the drug is excreted in the urine. The range of variation in renal clearance for 100 mg and 300 mg of this product is 1.30 to 1.55 mL/min.
The mean systemic clearance of this product after intravenous administration in healthy subjects was approximately 192 mL/min.
Special Populations
Renal impairment
A single-dose, open trial compared the pharmacokinetics of Cargolizine 200 mg in subjects with varying degrees of renal impairment (classified using the MDRD-eGFR equation) and healthy subjects.
Renal impairment did not affect the Cmax of this product. compared to healthy subjects (N=3; eGFR at or above 90 mL/min/1.73 m2), mild (N=10), moderate (N=9), and severe (N=10) renal impairment (eGFR of 60 to <90, 30 to <60, and 15 to <30 mL/min/1.73 m2) subjects increased the plasma AUC of this product by approximately 15%, 29% and 53%, respectively, but end-stage renal disease (ESRD) subjects (N=8) were similar to healthy subjects.
The magnitude of the increase in AUC of this product was not clinically significant. The pharmacodynamic effect of this product decreases as the severity of renal impairment increases (see [Contraindications], [Precautions]).
This product is barely cleared by hemodialysis.
Hepatic impairment
Compared to subjects with normal liver function, the geometric mean ratios of Cmax and AUC∞ in subjects with Child-Pugh rating A (mild hepatic impairment) were 107% and 110%, respectively, and the geometric mean ratios of Cmax and AUC∞ in subjects with Child-Pugh rating B (moderate hepatic impairment) were 96% and 111%.
These differences are generally not considered clinically significant. There is no clinical experience in patients with Child-Pugh grade C (severe) liver impairment (see [DOSAGE AND ADMINISTRATION]).
Pharmacokinetic Effects of Age, Body Mass Index (BMI)/Weight, Gender, and Race
Based on a population PK analysis of data from 1526 subjects, there were no clinically meaningful effects of age, body mass index (BMI)/weight, gender, or race on the pharmacokinetics of this product (see [Geriatric Use]).
Children
Pharmacokinetic trials of this product have not been conducted in pediatric patients.
Drug Interaction Studies
In vitro evaluation of drug interactions
This product does not induce the expression of CYP450 enzymes (3A4, 2C9, 2C19, 2B6 and 1A2) in human hepatocyte cultures. Based on in vitro assays with human liver microsomes, it does not inhibit CYP450 isozymes (1A2, 2A6, 2C19, 2D6 or 2E1) and weakly inhibits CYP2B6, CYP2C8, CYP2C9 and CYP3A4. It is a weak inhibitor of P-gp.
It is also a substrate for the drug transport proteins P-glycoprotein (P-gp) and MRP2.
In vivo assessment of drug interactions
Table 9 Effect of concomitant dosing on systemic exposure to this product
Concomitant dosing Concomitant dosing (1) Dose of this product (1) Geometric mean ratio
(ratio with/without concomitant dosing)
No effect = 1.0 AUC(2)
(90% CI) Cmax
(90% CI) For clinical relevance of the following drugs, see [Drug Interactions] Rifampicin 600 mg QD
8 days 300 mg 0.49
(0.44; 0.54) 0.72
(0.61; 0.84) No dose adjustment is required for the following: cyclosporine 400 mg 300 mg QD
8 days 1.23
(1.19; 1.27) 1.01
(0.91; 1.11) Ethinylestradiol and levonorgestrel 0.03 mg ethinylestradiol and
0.15 mg levonorgestrel 200 mg QD
6 days 0.91
(0.88; 0.94) 0.92
(0.84; 0.99) Hydrochlorothiazide 25 mg QD
35 days 300 mg QD
7 days 1.12
(1.08; 1.17) 1.15
(1.06; 1.25) Metformin
2,000 mg 300mg QD
1.10 for 8 days
(1.05; 1.15) 1.05
(0.96; 1.16) Propofol 500 mg BID
3 days 300 mg QD
17 days 1.21
(1.16; 1.25) 1.13
(1.00; 1.28) (1) Single dose, unless otherwise indicated
(2) AUCinf for single dosing , AUC24h for multiple dosing.
QD = once daily; BID = twice daily
Table 10 Effect of this product on concomitant dosing systemic exposure
Concomitant dosing Concomitant dosing (1) Dose of this product (1) Geometric mean ratio
(ratio with/without concomitant dosing) No effect = 1.0 AUC(2)
(90% CI) Cmax
(90% CI) For clinical relevance of the following drugs, see [Drug Interactions] Digoxin 0.5 mg once daily on day 1, followed by 0.25 mg once daily for 6 days 300 mg once daily for 7 days Digoxin 1.20
(1.12; 1.28) 1.36
(1.21; 1.53) No concomitant dose adjustment required for the following: acetaminophen 1000 mg 300 mg BID 25 days acetaminophen 1.06(3)
(0.98; 1.14) 1.00
(0.92; 1.09) Ethinylestradiol and levonorgestrel 0.03 mg Ethinylestradiol, 0.15 mg Levonorgestrel 200 mg QD
6 days Ethinylestradiol 1.07
(0.99; 1.15) 1.22
(1.10; 1.35) levonorgestrel 1.06
(1.00; 1.13) 1.22
(1.11; 1.35) Glibenclamide 1.25 mg 200 mg QD
6 days glibenclamide 1.02
(0.98; 1.07) 0.93
(0.85; 1.01) 3-cis-hydroxy-glibenclamide 1.01
(0.96; 1.07) 0.99
(0.91; 1.08) 4-trans-hydroxy-glibenclamide1.03
(0.97; 1.09) 0.96
(0.88; 1.04) Hydrochlorothiazide 25 mg QD
35 days 300 mg QD
7 days hydrochlorothiazide 0.99
(0.95; 1.04) 0.94
(0.87; 1.01) Metformin 2000 mg 300 mg QD
8 days Metformin 1.20
(1.08; 1.34) 1.06
(0.93; 1.20) Simvastatin 40 mg 300mg QD
7 days Simvastatin 1.12
(0.94; 1.33) 1.09
(0.91; 1.31) Simvastatin acid 1.18
(1.03; 1.35) 1.26
(1.10; 1.45) Warfarin 30 mg 300 mg QD
12 days (R)-warfarin 1.01
(0.96; 1.06) 1.03
(0.94; 1.13) (S)-warfarin 1.06
(1.00; 1.12) 1.01
(0.90; 1.13) INR1.00
(0.98; 1.03) 1.05
(0.99; 1.12) (1)
Single dose, unless otherwise stated
(2) AUCinf for single dosing and AUC24h for multiple dosing.
(3) AUC0-12h
QD = once daily; BID = twice daily; INR = International Normalized Ratio
[Storage].
Store at no more than 25°C.
Allowed to be stored at 15~30°C for a short period of time.
Package】
Polyvinyl chloride (PVC)/aluminum foil blister pack. 10 tablets/plate/box.
Expiration date
24 months
Execution Standard
Imported drug registration standard JX20150364
【Imported drug registration certificate
100mg: H20170375
300mg: H20170374
【Manufacturing Company
Company name: Janssen Ortho, LLC
Production Address: State Road 993, Km 0.1, Mamey Ward,Gurabo, Puerto Rico 00778, USA
Domestic Contact Information
Name: Xi’an Janssen Pharmaceutical Co.
Address: No. 34, Wanshou North Road, Xincheng District, Xi’an City, Shaanxi Province, China
Postal Code: 710043
Telephone number: 400 888 9988
Fax number: (029)82576616