Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark
Pharmacotherapeutic group: Drugs used in diabetes; combinations of oral blood glucose lowering drugs
ATC code: A10BD13
Vipdomet combines two antihyperglycaemic medicinal products with complementary and distinct mechanisms of action to improve glycaemic control in patients with type 2 diabetes mellitus: alogliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor, and metformin, a member of the biguanide class.
Alogliptin is a potent and highly selective inhibitor of DPP-4, >10,000-fold more selective for DPP-4 than other related enzymes including DPP-8 and DPP-9. DPP-4 is the principal enzyme involved in the rapid degradation of the incretin hormones, glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), which are released by the intestine and levels are increased in response to a meal. GLP-1 and GIP increases insulin biosynthesis and secretion from pancreatic beta cells, while GLP-1 also inhibits glucagon secretion and hepatic glucose production. Alogliptin therefore improves glycaemic control via a glucose-dependent mechanism, whereby insulin release is enhanced and glucagon levels are suppressed when glucose levels are high.
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 3 mechanisms:
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. It also 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 cholesterol and triglyceride levels.
Clinical studies conducted to support the efficacy of Vipdomet involved the co-administration of alogliptin and metformin as separate tablets. However, the results of bioequivalence studies have demonstrated that Vipdomet film-coated tablets are bioequivalent to the corresponding doses of alogliptin and metformin co-administered as separate tablets.
The co-administration of alogliptin and metformin has been studied as dual therapy in patients initially treated with metformin alone, and as add-on therapy to a thiazolidinedione or insulin.
Administration of 25 mg alogliptin to patients with type 2 diabetes mellitus produced peak inhibition of DPP-4 within 1 to 2 hours and exceeded 93% both after a single 25 mg dose and after 14 days of once-daily dosing. Inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. When the 4-hour postprandial glucose concentrations were averaged across breakfast, lunch and dinner, 14 days of treatment with 25 mg alogliptin resulted in a mean placebo-corrected reduction from baseline of -35.2 mg/dL.
Both 25 mg alogliptin alone and in combination with 30 mg pioglitazone demonstrated significant decreases in postprandial glucose and postprandial glucagon whilst significantly increasing postprandial active GLP-1 levels at Week 16 compared to placebo (p<0.05). In addition, 25 mg alogliptin alone and in combination with 30 mg pioglitazone produced statistically significant (p<0.001) reductions in total triglycerides at Week 16 as measured by postprandial incremental AUC(0-8) change from baseline compared to placebo.
A total of 7,151 patients with type 2 diabetes mellitus, including 4,202 patients treated with alogliptin and metformin, participated in 7 phase 3 double-blind, placebo- or active-controlled clinical studies conducted to evaluate the effects of co-administered alogliptin and metformin on glycaemic control and their safety. In these studies, 696 alogliptin/metformin-treated patients were ≥65 years old.
Overall, treatment with the recommended total daily dose of 25 mg alogliptin in combination with metformin improved glycaemic control. This was determined by clinically relevant and statistically significant reductions in glycosylated haemoglobin (HbA1c) and fasting plasma glucose compared to control from baseline to study endpoint. Reductions in HbA1c were similar across different subgroups including renal impairment, age, gender and body mass index, while differences between races (e.g. White and non-White) were small. Clinically meaningful reductions in HbA1c compared to control were also observed regardless of baseline background treatment. Higher baseline HbA1c was associated with a greater reduction in HbA1c. Generally, the effects of alogliptin on body weight and lipids were neutral.
The addition of 25 mg alogliptin once daily to metformin hydrochloride therapy (mean dose = 1,847 mg) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo (Table 2). Significantly more patients receiving 25 mg alogliptin (44.4%) achieved target HbA1c levels of ≤7.0% compared to those receiving placebo (18.3%) at Week 26 (p<0.001).
The addition of 25 mg alogliptin once daily to metformin hydrochloride therapy (mean dose = 1,835 mg) resulted in improvements from baseline in HbA1c at Week 52 and Week 104. At Week 52, the HbA1c reduction by 25 mg alogliptin plus metformin (-0.76%, Table 3) was similar to that produced by glipizide (mean dose = 5.2 mg) plus metformin hydrochloride therapy (mean dose = 1,824 mg, -0.73%). At Week 104, the HbA1c reduction by 25 mg alogliptin plus metformin (-0.72%, Table 3) was greater than that produced by glipizide plus metformin (-0.59%). Mean change from baseline in fasting plasma glucose at Week 52 for 25 mg alogliptin and metformin was significantly greater than that for glipizide and metformin (p<0.001). By Week 104, mean change from baseline in fasting plasma glucose for 25 mg alogliptin and metformin was -3.2 mg/dL compared with 5.4 mg/dL for glipizide and metformin. More patients receiving 25 mg alogliptin and metformin (48.5%) achieved target HbA1c levels of ≤7.0% compared to those receiving glipizide and metformin (42.8%) (p=0.004).
Co-administration of 12.5 mg alogliptin and 1,000 mg metformin hydrochloride twice daily resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to either 12.5 mg alogliptin twice daily alone or 1,000 mg metformin hydrochloride twice daily alone. Significantly more patients receiving 12.5 mg alogliptin and 1.000 mg metformin hydrochloride twice daily (59.5%) achieved target HbA1c levels of <7.0% compared to those receiving either 12.5 mg alogliptin twice daily alone (20.2%, p<0.001) or 1,000 mg metformin hydrochloride twice daily alone (34.3%, p<0.001) at Week 26.
The addition of 25 mg alogliptin once daily to pioglitazone therapy (mean dose = 35.0 mg, with or without metformin or a sulphonylurea) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo (Table 2). Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg alogliptin regardless of whether patients were receiving concomitant metformin or sulphonylurea therapy. Significantly more patients receiving 25 mg alogliptin (49.2%) achieved target HbA1c levels of ≤7.0% compared to those receiving placebo (34.0%) at Week 26 (p=0.004).
The addition of 25 mg alogliptin once daily to 30 mg pioglitazone in combination with metformin hydrochloride therapy (mean dose = 1,867.9 mg) resulted in improvements from baseline in HbA1c at Week 52 that were both non-inferior and statistically superior to those produced by 45 mg pioglitazone in combination with metformin hydrochloride therapy (mean dose = 1,847.6 mg, Table 3). The significant reductions in HbA1c observed with 25 mg alogliptin plus 30 mg pioglitazone and metformin were consistent over the entire 52-week treatment period compared to 45 mg pioglitazone and metformin (p<0.001 at all time points). In addition, mean change from baseline in FPG at Week 52 for 25 mg alogliptin plus 30 mg pioglitazone and metformin was significantly greater than that for 45 mg pioglitazone and metformin (p<0.001). Significantly more patients receiving 25 mg alogliptin plus 30 mg pioglitazone and metformin (33.2%) achieved target HbA1c levels of ≤7.0% compared to those receiving 45 mg pioglitazone and metformin (21.3%) at Week 52 (p<0.001).
The addition of 25 mg alogliptin once daily to insulin therapy (mean dose = 56.5 IU, with or without metformin) resulted in statistically significant improvements from baseline in HbA1c and FPG at Week 26 when compared to the addition of placebo (Table 2). Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg alogliptin regardless of whether patients were receiving concomitant metformin therapy. More patients receiving 25 mg alogliptin (7.8%) achieved target HbA1c levels of ≤7.0% compared to those receiving placebo (0.8%) at Week 26.
Table 2. Change in HbA1c (%) from baseline with alogliptin 25 mg at Week 26 by placebo-controlled study (FAS, LOCF):
| Study | Mean baseline HbA1c (%) (SD) | Mean change from baseline in HbA1c (%)† (SE) | Placebo-corrected change from baseline in HbA1c ()† (2-sided 95 CI) |
|---|---|---|---|
| Add-on combination therapy placebo-controlled studies | |||
| Alogliptin 25 mg once daily with metformin (n=203) | 7,93 (0,799) | -0,59 (0,054) | -0,48* (-0,67, -0,30) |
| Alogliptin 25 mg once daily with a sulphonylurea (n=197) | 8,09 (0,898) | -0,52 (0,058) | -0,53* (-0,73, -0,33) |
| Alogliptin 25 mg once daily with a thiazolidinedione ± metformin or a sulphonylurea (n=195) | 8,01 (0,837) | -0,80 (0,056) | -0,61* (-0,80, -0,41) |
| Alogliptin 25 mg once daily with insulin + metformin (n=126) | 9,27 (1,127) | -0,71 (0,078) | -0,59* (-0,80, -0,37) |
FAS = full analysis set
LOCF = last observation carried forward
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values
* p<0.001 compared to placebo or placebo+combination treatment
Table 3. Change in HbA1c (%) from baseline with alogliptin 25 mg by active-controlled study (PPS, LOCF):
| Study | Mean baseline HbA1c (%) (SD) | Mean change from baseline in HbA1c (%)† (SE) | Treatment-corrected change from baseline in HbA1c (%)† (1-sided CI) |
|---|---|---|---|
| Add-on combination therapy studies | |||
| Alogliptin 25 mg once daily with metformin vs a sulphonylurea + metformin | |||
| Change at Week 52 (n=382) | 7,61 (0,526) | -0,76 (0,027) | -0,03 (-infinity, 0,059) |
| Change at Week 104 (n=382) | 7,61 (0,526) | -0,72 (0,037) | -0,13* (-infinity, -0,006) |
| Alogliptin 25 mg once daily with a thiazolidinedione + metformin vs a titrating thiazolidinedione + metformin | |||
| Change at Week 26 (n=303) | 8,25 (0,820) | -0,89 (0,042) | -0,47* (-infinity, -0,35) |
| Change at Week 52 (n=303) | 8,25 (0,820) | -0,70 (0,048) | -0,42* (-infinity, -0,28) |
PPS = per protocol set
LOCF = last observation carried forward
* Non inferiority and superiority statistically demonstrated
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values
The efficacy and safety of the recommended doses of alogliptin and metformin in a subgroup of patients with type 2 diabetes mellitus and ≥65 years old were reviewed and found to be consistent with the profile obtained in patients <65 years old.
In a pooled analysis of the data from 13 studies, the overall incidences of cardiovascular death, non fatal myocardial infarction and non-fatal stroke were comparable in patients treated with 25 mg alogliptin, active control or placebo.
In addition, a prospective randomised cardiovascular outcomes safety study was conducted with 5,380 patients with high underlying cardiovascular risk to examine the effect of alogliptin compared with placebo (when added to standard of care) on major adverse cardiovascular events (MACE) including time to the first occurrence of any event in the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke in patients with a recent (15 to 90 days) acute coronary event. At baseline, patients had a mean age of 61 years, mean duration of diabetes of 9.2 years, and mean HbA1c of 8.0%.
The study demonstrated that alogliptin did not increase the risk of having a MACE compared to placebo [Hazard Ratio: 0.96; 1-sided 99% Confidence Interval: 0-1.16]. In the alogliptin group, 11.3% of patients experienced a MACE compared to 11.8% of patients in the placebo group.
Table 4. MACE Reported in cardiovascular outcomes study:
| Number of Patients (%) | ||
|---|---|---|
| Alogliptin 25 mg N=2.701 | Placebo N=2.679 | |
| Primary Composite Endpoint [First Event of CV Death, Nonfatal MI and Nonfatal Stroke] | 305 (11,3) | 316 (11,8) |
| Cardiovascular Death* | 89 (3,3) | 111 (4,1) |
| Nonfatal Myocardial Infarction | 187 (6,9) | 173 (6,5) |
| Nonfatal Stroke | 29 (1,1) | 32 (1,2) |
* Overall there were 153 subjects (5.7%) in the alogliptin group and 173 subjects (6.5%) in the placebo group who died (all-cause mortality)
There were 703 patients who experienced an event within the secondary MACE composite endpoint (first event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and urgent revascularization due to unstable angina). In the alogliptin group, 12.7% (344 subjects) experienced an event within the secondary MACE composite endpoint, compared with 13.4% (359 subjects) in the placebo group [Hazard Ratio = 0.95; 1-sided 99% Confidence Interval: 0-1.14].
In a pooled analysis of the data from 12 studies, the overall incidence of any episode of hypoglycaemia was lower in patients treated with 25 mg alogliptin than in patients treated with 12.5 mg alogliptin, active control or placebo (3.6%, 4.6%, 12.9% and 6.2%, respectively). The majority of these episodes were mild to moderate in intensity. The overall incidence of episodes of severe hypoglycaemia was comparable in patients treated with 25 mg alogliptin or 12.5 mg alogliptin, and lower than the incidence in patients treated with active control or placebo (0.1%, 0.1%, 0.4% and 0.4%, respectively). In the prospective randomised controlled cardiovascular outcomes study, investigator reported events of hypoglycemia were similar in patients receiving placebo (6.5%) and patients receiving alogliptin (6.7%) in addition to standard of care.
In a clinical trial of alogliptin as mono-therapy, the incidence of hypoglycaemia was similar to that of placebo, and lower than placebo in another trial as add-on to a sulphonylurea.
Higher rates of hypoglycaemia were observed with triple therapy with a thiazolidinedione and metformin and in combination with insulin, as observed with other DPP-4 inhibitors.
Patients (≥65 years old) with type 2 diabetes mellitus are considered more susceptible to episodes of hypoglycaemia than patients <65 years old. In a pooled analysis of the data from 12 studies, the overall incidence of any episode of hypoglycaemia was similar in patients ≥65 years old treated with 25 mg alogliptin (3.8%) to that in patients <65 years old (3.6%).
The European Medicines Agency has waived the obligation to submit the results of studies with Vipdomet in all subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
The results of bioequivalence studies in healthy subjects demonstrated that Vipdomet film-coated tablets are bioequivalent to the corresponding doses of alogliptin and metformin co-administered as separate tablets.
Co-administration of 100 mg alogliptin once daily and 1,000 mg metformin hydrochloride twice daily for 6 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin or metformin.
Administration of Vipdomet with food resulted in no change in total exposure (AUC) to alogliptin or metformin. However, mean peak plasma concentrations of alogliptin and metformin were decreased by 13% and 28% when Vipdomet was administered with food, respectively. There was no change in the time to peak plasma concentration (Tmax) for alogliptin, but there was a delayed Tmax for metformin of 1.5 hours. These changes are not likely to be clinically significant (see below).
Vipdomet should be taken twice daily because of the pharmacokinetics of its metformin component. It should also be taken with meals to reduce the gastrointestinal undesirable effects associated with metformin (see section 4.2).
The pharmacokinetics of Vipdomet in children and adolescents <18 years old has not been established. No data are available (see section 4.2).
The following section outlines the pharmacokinetic properties of the individual components of Vipdomet (alogliptin/metformin) as reported in their respective Summary of Product Characteristics.
The pharmacokinetics of alogliptin has been shown to be similar in healthy subjects and in patients with type 2 diabetes mellitus.
The absolute bioavailability of alogliptin is approximately 100%.
Administration with a high-fat meal resulted in no change in total and peak exposure to alogliptin. Alogliptin may, therefore, be administered with or without food.
After administration of single oral doses of up to 800 mg in healthy subjects, alogliptin was rapidly absorbed with peak plasma concentrations occurring 1 to 2 hours (median Tmax) after dosing.
No clinically relevant accumulation after multiple dosing was observed in either healthy subjects or in patients with type 2 diabetes mellitus.
Total and peak exposure to alogliptin increased proportionately across single doses of 6.25 mg up to 100 mg alogliptin (covering the therapeutic dose range). The inter-subject coefficient of variation for alogliptin AUC was small (17%).
Following a single intravenous dose of 12.5 mg alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L indicating that the active substance is well distributed into tissues.
Alogliptin is 20-30% bound to plasma proteins.
Alogliptin does not undergo extensive metabolism, 60-70% of the dose is excreted as unchanged active substance in the urine.
Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, N-demethylated alogliptin, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite and is a highly selective inhibitor of DPP-4 similar to alogliptin; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.
In vitro studies indicate that alogliptin does not induce CYP1A2, CYP2B6 and CYP2C9 and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at concentrations achieved with the recommended dose of 25 mg alogliptin. Studies in vitro have shown alogliptin to be a mild inducer of CYP3A4, but alogliptin has not been shown to induce CYP3A4 in studies in vivo.
In studies in vitro, alogliptin was not an inhibitor of the following renal transporters; OAT1, OAT3 and OCT2.
Alogliptin exists predominantly as the (R)-enantiomer (>99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at therapeutic doses.
Alogliptin was eliminated with a mean terminal half-life (T1/2) of approximately 21 hours.
Following administration of an oral dose of [14C] alogliptin, 76% of total radioactivity was eliminated in the urine and 13% was recovered in the faeces.
The average renal clearance of alogliptin (170 mL/min) was greater than the average estimated glomerular filtration rate (approx. 120 mL/min), suggesting some active renal excretion.
Total exposure (AUC) to alogliptin following administration of a single dose was similar to exposure during one dose interval (AUC) after 6 days of once daily dosing. This indicates no time-dependency in the kinetics of alogliptin after multiple dosing.
A single dose of 50 mg alogliptin was administered to 4 groups of patients with varying degrees of renal impairment (CrCl using the Cockcroft-Gault formula): mild (CrCl = >50 to ≤80 mL/min), moderate (CrCl = ≥30 to ≤50 mL/min), severe (CrCl = <30 mL/min) and end-stage renal disease on haemodialysis.
An approximate 1.7-fold increase in AUC for alogliptin was observed in patients with mild renal impairment. However, as the distribution of AUC values for alogliptin in these patients was within the same range as control subjects, no dose adjustment of alogliptin for patients with mild renal impairment is necessary (see section 4.2).
In patients with moderate or severe renal impairment, or end-stage renal disease on haemodialysis, an increase in systemic exposure to alogliptin of approximately 2- and 4-fold was observed, respectively. (Patients with end-stage renal disease underwent haemodialysis immediately after alogliptin dosing. Based on mean dialysate concentrations, approximately 7% of the active substance was removed during a 3-hour haemodialysis session.) Therefore, in order to maintain systemic exposures to alogliptin that are similar to those observed in patients with normal renal function, lower doses of alogliptin should be used in patients with moderate or severe renal impairment, or end-stage renal disease requiring dialysis (see above and section 4.2).
Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment compared to control subjects. The magnitude of these reductions was not considered to be clinically relevant. Therefore, no dose adjustment of alogliptin is necessary for patients with mild to moderate hepatic impairment (Child-Pugh scores of 5 to 9). Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh score >9).
Age (65-81 years old), gender, race (white, black and Asian) and body weight did not have any clinically relevant effect on the pharmacokinetics of alogliptin. No dose adjustment is necessary (see section 4.2).
The pharmacokinetics of alogliptin in children and adolescents <18 years old has not been established. No data are available (see section 4.2 and above).
After an oral dose of metformin, the maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (Tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride 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 recommended metformin doses and dosing schedules, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 microgram/mL. In controlled clinical studies, maximum metformin plasma levels (Cmax) did not exceed 4 microgram/mL even at maximum doses.
Food slightly delays and decreases the extent of the absorption of metformin. Following oral administration of an 850 mg metformin hydrochloride tablet, the peak plasma concentration was 40% lower, AUC was decreased by 25% and the time to peak plasma concentration (Tmax) was prolonged by 35 minutes. The clinical relevance of these findings 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 volume of distribution (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 hours.
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 the plasma.
Due to its metformin component, Vipdomet should not be used in patients with severe renal impairment, or end-stage renal disease requiring dialysis (see section 4.2).
Vipdomet should not be used in patients with hepatic impairment (see section 4.2).
Concomitant treatment with alogliptin and metformin did not produce new toxicities and no effects on the toxicokinetics of either compound were observed.
In rats no treatment-related foetal abnormalities occurred following concomitant administration at exposure margins of approximately 28- to 29-fold for alogliptin and 2- to 2.5-fold for metformin at the maximum recommended human dose of 25 mg/day and 2,000 mg/day, respectively. The combination revealed teratogenic potential in small numbers of foetuses (microphthalmia, small eye bulge and cleft palate) at higher doses of metformin (exposure margins of approximately 20-fold and 5- to 6-fold the maximum recommended human dose for alogliptin and metformin, respectively).
The following data are findings from studies performed with alogliptin or metformin individually.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and toxicology.
The no-observed-adverse-effect level (NOAEL) in the repeated dose toxicity studies in rats and dogs up to 26- and 39-weeks in duration, respectively, produced exposure margins that were approximately 147- and 227-fold, respectively, the exposure in humans at the recommended total daily dose of 25 mg alogliptin.
Alogliptin was not genotoxic in a standard battery of in vitro and in vivo genotoxicity studies.
Alogliptin was not carcinogenic in 2-year carcinogenicity studies conducted in rats and mice. Minimal to mild simple transitional cell hyperplasia was seen in the urinary bladder of male rats at the lowest dose used (27 times the human exposure) without establishment of a clear NOEL (no observed effect level).
No adverse effects of alogliptin were observed upon fertility, reproductive performance, or early embryonic development in rats up to a systemic exposure far above the human exposure at the recommended dose. Although fertility was not affected, a slight, statistical increase in the number of abnormal sperm was observed in males at an exposure far above the human exposure at the recommended dose.
Placental transfer of alogliptin occurs in rats.
Alogliptin was not teratogenic in rats or rabbits with a systemic exposure at the NOAELs far above the human exposure at the recommended dose. Higher doses of alogliptin were not teratogenic but resulted in maternal toxicity, and were associated with delayed and/or lack of ossification of bones and decreased foetal body weights.
In a pre- and postnatal development study in rats, exposures far above the human exposure at the recommended dose did not harm the developing embryo or affect offspring growth and development.
Higher doses of alogliptin decreased offspring body weight and exerted some developmental effects considered secondary to the low body weight.
Studies in lactating rats indicate that alogliptin is excreted in milk.
No alogliptin-related effects were observed in juvenile rats following repeat-dose administration for 4 and 8 weeks.
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and 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.
