Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden
Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs
ATC code: A10BD10
Komboglyze combines two antihyperglycaemic medicinal products with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: saxagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP4 inhibitor. In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP4 enzyme activity for a 24-hour period. After an oral glucose load, this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and increased glucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptide concentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal. Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL-C and triglyceride levels.
In randomised, controlled, double-blind clinical trials (including developmental and postmarketing experience), over 17,000 patients with type 2 diabetes have been treated with saxagliptin.
The co-administration of saxagliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on metformin alone and in treatment-naive patients inadequately controlled on diet and exercise alone. Treatment with saxagliptin 5 mg once daily produced clinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and postprandial glucose (PPG) compared to placebo in combination with metformin (initial or add-on therapy). Reductions in A1c were seen across subgroups including gender, age, race, and baseline BMI. Decrease in body weight in the treatment groups given saxagliptin in combination with metformin was similar to that in the groups given metformin alone. Saxagliptin plus metformin was not associated with significant changes from baseline in fasting serum lipids compared to metformin alone.
An add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with metformin in patients with inadequate glycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided significant improvements in HbA1c, FPG, and PPG compared to placebo (n=175). Improvements in HbA1c, PPG, and FPG following treatment with saxagliptin 5 mg plus metformin were sustained up to Week 102. The HbA1c change for saxagliptin 5 mg plus metformin (n=31) compared to placebo plus metformin (n=15) was -0.8% at Week 102.
An add-on to metformin placebo-controlled study of 12-week duration was conducted to evaluate the efficacy and safety of saxagliptin 2.5 mg twice daily in combination with metformin in patients with inadequate glycaemic control (HbA1c 7-10%) on metformin alone. After 12 weeks, the saxagliptin group (n=74) had a greater HbA1c mean reduction from baseline than the placebo group (n=86) (-0.6% vs. -0.2%, respectively, difference of -0.34%, from a mean baseline HbA1c of 7.9% for the saxagliptin group and 8.0% for the placebo group), and a greater FPG reduction (-13.73 mg/dL versus -4.22 mg/dL) but without statistical significance (p=0.12, 95% CI [-21.68; 2.66]).
A 52-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (428 patients) compared with sulphonylurea (glipizide, 5 mg titrated as needed to 20 mg, mean dose of 15 mg) in combination with metformin (430 patients) in 858 patients with inadequate glycaemic control (HbA1c 6.5-10%) on metformin alone. The mean metformin dose was approximately 1900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groups had similar mean reductions from baseline in HbA1c in the per-protocol analysis (-0.7% vs. -0.8%, respectively, mean baseline HbA1c of 7.5% for both groups). The intent-to-treat analysis showed consistent results. The reduction in FPG was slightly less in the saxagliptin group and there were more discontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first 24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of patients with hypoglycaemia, 3% (19 events in 13 subjects) vs. 36.3% (750 events in 156 patients) for glipizide. Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight compared to a weight gain in patients administered glipizide (-1.1 vs. +1.1 kg).
An 18-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (403 patients), compared with sitagliptin 100 mg in combination with metformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After 18 weeks, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in both the per-protocol and the full analysis sets. The reductions from baseline in HbA1c respectively for saxagliptin and sitagliptin in the primary per-protocol analysis were -0.5% (mean and median) and -0.6% (mean and median). In the confirmatory full analysis set, mean reductions were -0.4% and -0.6% respectively for saxagliptin and sitagliptin, with median reductions of -0.5% for both groups.
A 24-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin as initial combination therapy in treatment-naive patients with inadequate glycaemic control (HbA1c 8-12%). Initial therapy with the combination of saxagliptin 5 mg plus metformin (n=306) provided significant improvements in HbA1c, FPG, and PPG compared to with either saxagliptin (n=317) or metformin (n=313) alone as initial therapy. Reductions in HbA1c from baseline to Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greater reductions observed in patients with a baseline HbA1c ≥ 10% (see Table 5). Improvements in HbA1c, PPG, and FPG following initial therapy with saxagliptin 5 mg plus metformin were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg plus metformin (n=177) compared to metformin plus placebo (n=147) was -0.5% at Week 76.
A total of 455 patients with type 2 diabetes participated in a 24-week randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin in combination with a stable dose of insulin (baseline mean: 54.2 Units) in patients with inadequate glycaemic control (HbA1c ≥7.5% and ≤11%) on insulin alone (n=141) or on insulin in combination with a stable dose of metformin (n=314). Saxagliptin 5 mg add-on to insulin with or without metformin provided significant improvements after 24 weeks in HbA1c and PPG compared with placebo add-on to insulin with or without metformin. Similar HbA1c reductions versus placebo were achieved for patients receiving saxagliptin 5 mg add-on to insulin regardless of metformin use (-0.4% for both subgroups). Improvements from baseline HbA1c were sustained in the saxagliptin add-on to insulin group compared to the placebo add-on to insulin group with or without metformin at Week 52. The HbA1c change for the saxagliptin group (n=244) compared to placebo (n=124) was -0.4% at Week 52.
A total of 257 patients with type 2 diabetes participated in a 24-week randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin (5 mg once daily) in combination with metformin plus sulphonylurea (SU) in patients with inadequate glycaemic control (HbA1c ≥7% and ≤10%). Saxagliptin (n=127) provided significant improvements in HbA1c and PPG compared with the placebo (n=128). The HbA1c change for saxagliptin compared to placebo was -0.7% at Week 24.
A 24-week randomised, double-blind, placebo-controlled study conducted in patients with type 2 diabetes mellitus compared saxagliptin 5 mg with placebo as add-on therapy in individuals with HbA1c 7-10.5% treated with dapagliflozin (SGLT2-inhibtor) and metformin. Patients who completed the initial 24-week study period were eligible to enter a controlled 28-week long-term study extension (52 weeks).
Individuals treated with saxagliptin added to dapagliflozin and metformin (n=153) achieved statistically significantly (p-value <0.0001) greater reductions in HbA1c versus the group with placebo added to dapagliflozin plus metformin (n=162) at 24 weeks (see Table 5). The effect on HbA1c observed at Week 24 was sustained at Week 52. The safety profile of saxagliptin added to dapagliflozin plus metformin in the long-term treatment period was consistent with that observed in the 24-week treatment period in this study and in the trial in which saxagliptin and dapagliflozin were given concomitantly as add-on therapy to patients treated with metformin (described below).
The proportion of patients achieving HbA1c <7% at Week 24 was higher in the saxagliptin 5 mg plus dapagliflozin plus metformin group 35.3% (95% CI [28.2, 42.4]) compared to the placebo plus dapagliflozin plus metformin group 23.1% (95% CI [16.9, 29.3]). The effect in HbA1c observed at Week 24 was sustained at Week 52.
Table 5. Key efficacy results in placebo-controlled, combination therapy studies of saxagliptin and metformin:
| Mean baseline HbA1c (%) | Mean change1 from baseline HbA1c (%) | Placebo-corrected mean change in HbA1c ( % ) (95% CI) | |
|---|---|---|---|
| Add-on/initial combination with metformin studies | |||
| 24-weeks | |||
| Saxa 5 mg daily add-on to metformin; Study CV181014 (n=186) | 8,1 | -0,7 | -0,8 (-1,0, -0,6)2 |
| Saxa 5 mg daily initial combination with metformin; Study CV1810393 | |||
| Overall population (n=306) | 9,4 | -2,5 | -0,5 (-0,7, -0,4)4 |
| Baseline HbA1c ≥10% stratum (n=107) | 10,8 | -3,3 | -0,6 (-0,9, -0,3)5 |
| 12-weeks | |||
| Saxa 2.5 mg twice daily add-on to metformin; Study CV181080 (n=74) | 7,9 | -0,6 | -0,3 (-0,6,-0,1)6 |
| Add-on/combination studies with additional therapies | |||
| Add-on to insulin (+/- metformin) | |||
| Saxa 5 mg daily, Study CV181057: Overall population (n=300) | 8,7 | -0,7 | -0.4 (-0,6, -0,2)2 |
| 24-weeks | |||
| Saxa 5 mg daily add-on to metformin plus sulphonylurea; | |||
| Study D1680L00006 (n=257) | 8,4 | -0,7 | -0,7 (-0,9, -0,5)2 |
| Saxa 5 mg daily add-on to metformin plus dapagliflozin | |||
| Study CV181168 (n=315) | 7,9 | -0,5 | -0,4 (-0,5, -0,2)7 |
n = Randomised patients
1 Adjusted mean change from baseline adjusted for baseline value (ANCOVA).
2 p <0.0001 compared to placebo.
3 Metformin was uptitrated from 500 to 2000 mg per day as tolerated.
4 Mean HbA1c change is the difference between the saxagliptin 5 mg + metformin and metformin alone groups (p <0.0001).
5 Mean HbA1c change is the difference between the saxagliptin 5 mg + metformin and metformin alone groups.
6 p-value = 0.0063 (between group comparisons significant at α = 0.05).
7 Mean HbA1c change is the difference between the saxagliptin 5 mg + dapagliflozin + metformin and dapagliflozin + metformin groups (p <0.0001).
A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone (HbA1c 8%-12%), participated in this 24-week randomised, double-blind, active comparator-controlled trial to compare the combination of saxagliptin and dapagliflozin added concurrently to metformin, versus saxagliptin or dapagliflozin added to metformin. Patients were randomised to one of three double-blind treatment groups to receive saxagliptin 5 mg and dapagliflozin 10 mg added to metformin, saxagliptin 5 mg and placebo added to metformin, or dapagliflozin 10 mg and placebo added to metformin.
The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c versus either the saxagliptin group or dapagliflozin group at 24 weeks (see Table 6).
Table 6. HbA1c at Week 24 in active-controlled study comparing the combination of saxagliptin and dapagliflozin added concurrently to metformin with either saxagliptin or dapagliflozin added to metformin:
| Efficacy parameter | Saxagliptin 5 mg + dapagliflozin 10 mg + metformin N=1792 | Saxagliptin 5 mg + metformin N=1762 | Dapagliflozin 10 mg + metformin N=1792 | |
|---|---|---|---|---|
| HbA1c (%) at week 241 | ||||
| Baseline (mean) | 8,93 | 9,03 | 8,87 | |
| Change from baseline (adjusted mean3) (95% Confidence interval [CI]) | −1,47 (−1,62, −1,31) | −0,88 (−1,03, −0,72) | −1,20 (−1,35, −1,04) | |
| Difference from saxagliptin + metformin (adjusted mean3) (95% CI) | −0,594 (−0,81, −0,37) | - | - | |
| Difference from dapagliflozin + metformin (adjusted mean3) (95% CI) | −0,275 (−0,48, −0,05) | - | - | |
1 LRM = Longitudinal repeated measures (using values prior to rescue).
2 Randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.
3 Least squares mean adjusted for baseline value.
4 p-value <0.0001.
5 p-value=0.0166.
In the saxagliptin and dapagliflozin combination group, 41.4% (95% CI [34.5, 48.2]) of patients achieved HbA1c levels of less than 7% compared to 18.3% (95% CI [13.0, 23.5]) of patients in the saxagliptin group and 22.2% (95% CI [16.1, 28.3]) of patients in the dapagliflozin group.
SAVOR was a CV outcome trial in 16,492 patients with HbA1c ≥6.5% and <12% (12959 with established CV disease; 3533 with multiple risk factors only) who were randomised to saxagliptin (n=8280) or placebo (n=8212) added to regional standards of care for HbA1c and CV risk factors. The study population included those ≥ 65 years (n=8561) and ≥75 years (n=2330), with normal or mild renal impairment (n=13916) as well as moderate (n=2240) or severe (n=336) renal impairment.
The primary safety (noninferiority) and efficacy (superiority) endpoint was a composite endpoint consisting of the time-to-first occurrence of any of the following major adverse CV events (MACE): CV death, nonfatal myocardial infarction, or nonfatal ischaemic stroke.
After a mean follow up of 2 years, the trial met its primary safety endpoint demonstrating saxagliptin does not increase the cardiovascular risk in patients with type 2 diabetes compared to placebo when added to current background therapy.
No benefit was observed for MACE or all-cause mortality.
Table 7. Primary and secondary clinical endpoints by treatment group in the SAVOR study*:
| Endpoint | Saxagliptin (N=8280) | Placebo (N=8212) | Hazard Ratio (95% CI)† | ||
|---|---|---|---|---|---|
| Subjects with events n (%) | Event rate per 100 patient-years | Subjects with events n (%) | Event rate per 100 patient-years | ||
| Primary composite endpoint: MACE | 613 (7,4) | 3,76 | 609 (7,4) | 3,77 | 1,00 (0,89, 1,12)‡§# |
| Secondary composite endpoint: MACE plus | 1059 (12,8) | 6,72 | 1034 (12,6) | 6,60 | 1,02 (0,94, 1,11)¶ |
| All-cause mortality | 420 (5,1) | 2,50 | 378 (4,6) | 2,26 | 1,11 (0,96, 1,27)¶ |
* Intent-to-treat population
† Hazard ratio adjusted for baseline renal function category and baseline CVD risk category.
‡ p-value <0.001 for noninferiority (based on HR <1.3) compared to placebo.
§ p-value = 0.99 for superiority (based on HR <1.0) compared to placebo.
# Events accumulated consistently over time, and the event rates for saxagliptin and placebo did not diverge notably over time.
¶ Significance not tested.
One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal statistical significance favouring placebo [HR=1.27; (95% CI 1.07, 1.51); P=0.007]. Clinically relevant factors predictive of increased relative risk with saxagliptin treatment could not be definitively identified. Subjects at higher risk for hospitalisation for heart failure, irrespective of treatment assignment, could be identified by known risk factors for heart failure such as baseline history of heart failure or impaired renal function. However, subjects on saxagliptin with a history of heart failure or impaired renal function at baseline were not at an increased risk relative to placebo for the primary or secondary composite endpoints or all-cause mortality.
Another secondary endpoint, all-cause mortality, occurred at a rate of 5.1% in the saxagliptin group and 4.6% in the placebo group (see Table 7). CV deaths were balanced across the treatment groups. There was a numerical imbalance in non-CV death, with more events on saxagliptin (1.8%) than placebo (1.4%) [HR=1.27; (95% CI 1.00, 1.62); P=0.051].
A1c was lower with saxagliptin compared to placebo in an exploratory analysis.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:
In the SAVOR study subgroups over 65 and over 75 years of age, efficacy and safety were consistent with the overall study population.
GENERATION was a 52-week glycaemic control study in 720 elderly patients, the mean age was 72.6 years; 433 subjects (60.1%) were <75 years of age, and 287 subjects (39.9%) were ≥75 years of age. Primary endpoint was the proportion of patients reaching HbA1c <7% without confirmed or severe hypoglycaemia. There appeared to be no difference in percentage responders: 37.9% (saxagliptin) and 38.2% (glimepiride) achieved the primary endpoint. A lower proportion of patients in the saxagliptin group (44.7%) compared to the glimepiride group (54.7%) achieved an HbA1c target of 7.0%. A lower proportion of patients in the saxagliptin group (1.1%) compared to the glimepiride group (15.3%), experienced a confirmed or severe hypoglycaemic event.
The European Medicines Agency has waived the obligation to submit the results of studies with Komboglyze in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
The results of bioequivalence studies in healthy subjects demonstrated that Komboglyze combination tablets are bioequivalent to co-administration of corresponding doses of saxagliptin and metformin hydrochloride as individual tablets.
The following statements reflect the pharmacokinetic properties of the individual active substances of Komboglyze.
The pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in patients with type 2 diabetes.
Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng·h/mL and 214 ng·h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%.
The inhibition of plasma DPP4 activity by saxagliptin for at least 24 hours after oral administration of saxagliptin is due to high potency, high affinity, and extended binding to the active site.
Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. Administration with food (a high-fat meal) resulted in no change in saxagliptin Cmax and a 27% increase in AUC compared with the fasted state. The time for saxagliptin to reach Cmax (Tmax) was increased by approximately 0.5 hours with food compared with the fasted state. These changes were not considered to be clinically meaningful.
The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible. Thus, changes in blood protein levels in various disease states (e.g. renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.
The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a selective, reversible, competitive DPP4 inhibitor, half as potent as saxagliptin.
The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hours and 3.1 hours respectively, and the mean t1/2 value for plasma DPP4 inhibition was 26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major metabolite, and total radioactivity respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. For the major metabolite, renal clearance values were comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed medicinal product from the gastrointestinal tract.
The Cmax and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg.
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral dose of saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (approximately GFR ≥45 to <90 mL/min), moderate (approximately GFR ≥30 to <45 mL/min), or severe (approximately GFR <30 mL/min) renal impairment. The exposures to saxagliptin were 1.2-, 1.4- and 2.1-fold higher, respectively, and the exposures to BMS-510849 were 1.7-, 2.9- and 4.5-fold higher, respectively, than those observed in subjects with normal renal function.
In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher, respectively, and the exposures to BMS-510849 were 22%, 7%, and 33% lower, respectively, than those observed in healthy subjects.
Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients (18-40 years). This is not considered clinically meaningful, therefore, no dose adjustment for this medicinal product is recommended on the basis of age alone.
After an oral dose of metformin, Tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady-state plasma concentrations are reached within 24-48 h and are generally less than 1 μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease is unknown.
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
A 3-month dog study and embryo-foetal development studies in rats and rabbits have been conducted with the combination of saxagliptin and metformin.
Co-administration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the maximum recommended human doses (RHD; 5 mg saxagliptin and 2000 mg metformin), respectively, in rats; and 249 and 1.1 times the RHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of delayed ossification (“wavy ribs”); associated maternal toxicity was limited to weight decrements of 5-6% over the course of gestation days 13 through 18, and related reductions in maternal food consumption. In rabbits, co-administration was poorly tolerated in many mothers, resulting in death, moribundity or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to foetal body weight decrements of 7%, and a low incidence of delayed ossification of the foetal hyoid.
A 3-month dog study was conducted with the combination of saxagliptin and metformin. No combination toxicity was observed at AUC exposures 68 and 1.5 times the RHDs for saxagliptin and metformin, respectively.
No animal studies have been conducted with the combination of products in Komboglyze to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with saxagliptin and metformin individually.
In cynomolgus monkeys saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (tail, digits, scrotum and/or nose) at doses ≥3 mg/kg/day. The no effect level (NOEL) for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommended human dose (RHD) of 5 mg/day.
The clinical relevance of the skin lesions is not known, however, clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.
Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes and bone marrow with no adverse sequelae have been reported in all species tested at exposures starting from 7 times the RHD.
Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD.
Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies in vitro and in vivo. No carcinogenic potential was observed in two-year carcinogenicity assays with mice and rats.
Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL 158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD). In a pre- and post-natal developmental study in rats, saxagliptin caused decreased pup weight at maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively.
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
