There are no data from the use of saxagliptin and dapagliflozin in pregnant women. Studies in animals with saxagliptin have shown reproductive toxicity at high doses. Studies with dapagliflozin in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy. Therefore, saxagliptin/dapagliflozin should not be used during pregnancy. If pregnancy is detected, treatment with saxagliptin/dapagliflozin should be discontinued.
It is unknown whether saxagliptin and dapagliflozin and/or its metabolites are excreted in human milk. Animal studies have shown excretion of saxagliptin and/or metabolite in milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in breast-feeding offspring. A risk to the newborns/infants cannot be excluded. Saxagliptin/dapagliflozin should not be used while breast-feeding.
The effect of saxagliptin and dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. Effects on fertility were observed using saxagliptin in male and female rats at high doses producing overt signs of toxicity.
Saxagliptin/dapagliflozin combination has no or negligible influence on the ability to drive and use machines. When driving or using machines, it should be taken into account that dizziness has been reported in studies with combined use of saxagliptin and dapagliflozin. In addition, patients should be alerted to the risk of hypoglycaemia if used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. sulphonylureas).
The combination of saxagliptin 5 mg and dapagliflozin 10 mg in 1169 adults with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control on metformin has been evaluated in three Phase 3, randomised, double-blind, active/placebo-control, parallel group, multi-centre clinical trials for up to 52 weeks. The pooled safety analysis comprised 3 treatment groups: saxagliptin plus dapagliflozin plus metformin (492 subjects), saxagliptin plus metformin (336 subjects), and dapagliflozin plus metformin (341 subjects). The safety profile of the combined use of saxagliptin plus dapagliflozin plus metformin was comparable to the adverse reactions identified for the respective mono-components.
The most frequently reported adverse reactions associated with saxagliptin/dapagliflozin are upper respiratory tract infections (very common), hypoglycaemia when used with SU (very common), and urinary tract infections (common). Diabetic ketoacidosis may occur rarely.
The adverse reactions are presented in the talbe below. The safety profile is based on the summarized data from the saxagliptin/dapagliflozin combination clinical trials pooled safety data, and also clinical trials, post-authorisation safety studies and post-marketing experience with the mono-components. The adverse reactions are listed by system organ class (SOC) and frequency. Frequency categories were defined according to very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and not known (cannot be estimated from the available data).
Compilation of reported adverse reactions:
| System organ class | Very common | CommonA | UncommonB | Rare | Very rare | Not known |
|---|---|---|---|---|---|---|
| Infections and infestations | Upper respiratory tract infection1 | Urinary tract infection2, vulvovaginitis, balanitis and related genital infection3, gastroenteritisD | Fungal infection | Necrotising fasciitis of the perineum (Fournier’s gangrene)C,F | ||
| Immune system disorders | Hypersensitivity | |||||
| Anaphylactic reactions including anaphylactic shockC | ||||||
| Metabolism and nutrition disorders | HypoglycaemiaD (when used with SU) | Dyslipidaemia4 | Volume depletionF, thirst | Diabetic ketoacidosisF,G | ||
| Nervous system disorders | Headache, | |||||
| Gastrointestinal disorders | Abdominal painC, diarrhoea, dyspepsiaD, gastritisD, nauseaC, vomitingD | Constipation, dry mouth, pancreatitisC | ||||
| Skin and subcutaneous tissue disorders | Rash5 | DermatitisC, pruritusC, urticariaC | AngioedemaC | Bullous pemphigoidC | ||
| Musculoskeletal and connective tissue disorders | Arthralgia, back pain, myalgiaD | |||||
| Renal and urinary disorders | Dysuria, | |||||
| Nocturia | ||||||
| Reproductive system and breast disorders | Erectile dysfunction, pruritus genital, vulvovaginal pruritus | |||||
| General disorders and administration site conditions | FatigueD, oedema peripheralD | |||||
| Investigations | Creatinine renal clearance decreased during initial treatmentF, haematocrit increasedE | Blood creatinine increased during initial treatmentF, blood urea increased, weight decreased |
A Adverse reactions reported in ≥2% of subjects treated with the combined use of saxagliptin + dapagliflozin in the pooled safety analysis, or if reported in <2% in the pooled safety analysis, they were based on the individual mono-components data.
B Frequencies of all uncommon adverse reactions were based on the individual mono-components data.
C Adverse reaction originates from saxagliptin or dapagliflozin post-marketing surveillance data.
D Adverse reactions were reported in ≥2% of subjects with either mono-component and ≥1% more than placebo, but not in the pooled analysis.
E Haematocrit values >55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% of placebo subjects.
F Frequency is based on events in the dapagliflozin clinical programme.
G Reported in the dapagliflozin cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency is based on annual rate.
1 Upper respiratory tract infection includes the following preferred terms: nasopharyngitis, influenza, upper respiratory tract infection, pharyngitis, rhinitis, sinusitis, pharyngitis bacterial, tonsillitis, acute tonsillitis, laryngitis, viral pharyngitis, and viral upper respiratory tract infection.
2 Urinary tract infection includes the following preferred terms: urinary tract infection, Escherichia urinary tract infection, pyelonephritis, and prostatitis.
3 Vulvovaginitis, balanitis and related genital infection include the following preferred terms: vulvovaginal mycotic infection, balanoposthitis, genital infection fungal, vaginal infection, and vulvovaginitis.
4 Dyslipidaemia includes the following preferred terms: dyslipidaemia, hyperlipidaemia, hypercholesterolaemia, and hypertriglyceridaemia.
5 Rash was reported during the post-marketing use of saxagliptin and dapagliflozin. Preferred terms reported in dapagliflozin clinical trials included in order of frequency: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous.
6 Polyuria includes the following preferred terms: polyuria, and pollakiuria.
SU = sulphonylurea
Saxagliptin/dapagliflozin combination: The reported adverse events of vulvovaginitis, balanitis and related genital infections from pooled safety analysis were reflective of the safety profile of dapagliflozin. Adverse events of genital infection were reported in 3.0% in the saxagliptin plus dapagliflozin plus metformin group, 0.9% of saxagliptin plus metformin group and 5.9% of subjects in the dapagliflozin plus metformin group. The majority of the genital infection adverse events were reported in females (84% of subjects with a genital infection), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.
In the pooled safety analysis, the overall incidence of hypoglycaemia (all reported events including those with central laboratory FPG ≤3.9 mmol/L) was 2.0% in subjects treated with saxagliptin 5 mg plus dapagliflozin 10 mg plus metformin (combination therapy), 0.6% in the saxagliptin plus metformin group, and 2.3% in the dapagliflozin plus metformin group.
In a 24-week study comparing the combination of saxagliptin and dapagliflozin plus metformin with or without SU, with insulin plus metformin with or without SU, the overall incidence rates for hypoglycaemia in patients without a background treatment of SU, were 12.7% for the combination compared to 33.1% for insulin. The overall incidence rates of hypoglycaemia in two 52-week studies comparing the combination therapy to glimepiride (SU) were: for the 1st study, 4.2% for the combination therapy versus 27.9% for glimepiride plus metformin versus 2.9% for dapagliflozin plus metformin; for the 2nd study, 18.5% for the combination therapy versus 43.1% for glimepiride plus metformin.
Events suggestive of volume depletion (hypotension, dehydration, and hypovolaemia) were reported in two subjects (0.4%) in the saxagliptin plus dapagliflozin plus metformin group (serious adverse event [SAE] of syncope and an AE of urine output decreased), and 3 subjects (0.9%) in the dapagliflozin plus metformin group (2 AEs of syncope and 1 of hypotension).
In the pooled safety analysis, the incidence of adverse events related to decreased renal function was 2.0% subjects in the saxagliptin plus dapagliflozin plus metformin group, 1.8% subjects in the saxagliptin plus metformin group, and 0.6% subjects in the dapagliflozin plus metformin group. Subjects with adverse events of renal impairment had lower mean eGFR values at baseline of 61.8 mL/min/1.73m² compared to 93.6 mL/min/1.73m² in the overall population. The majority of events were considered non-serious, mild or moderate in intensity, and resolved. The change in mean eGFR from baseline at week 24 was -1.17 mL/min/1.73m² in the saxagliptin plus dapagliflozin plus metformin group, -0.46 mL/min/1.73 m² in saxagliptin plus metformin, and 0.81 mL/min/1.73m² in dapagliflozin plus metformin.
Adverse reactions related to increased creatinine have been reported for dapagliflozin as a mono-component. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.
Cases of Fournier’s gangrene have been reported post-marketing in patients taking SGLT2 inhibitors, including dapagliflozin.
In the dapagliflozin cardiovascular outcomes study (DECLARE) with 17 160 type 2 diabetes mellitus patients and a median exposure time of 48 months, a total of 6 cases of Fournier’s gangrene were reported, one in the dapagliflozin-treated group and 5 in the placebo group.
In the dapagliflozin cardiovascular outcomes study (DECLARE), with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population.
In the pooled safety analysis, urinary tract infections (UTIs) were balanced across the 3 treatment groups: 5.7% in the saxagliptin plus dapagliflozin plus metformin group, 7.4% in the saxagliptin plus metformin group and 5.6% in the dapagliflozin plus metformin group. One patient in the saxagliptin plus dapagliflozin plus metformin group experienced an SAE of pyelonephritis and discontinued treatment. The majority of the urinary tract infection adverse events were reported in females (81% of subjects with UTI), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.
Saxagliptin: In a pool of 5 placebo-controlled studies, a small decrease in absolute lymphocyte count was observed, approximately 100 cells/microl relative to placebo. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. This decrease in mean absolute lymphocyte count was not associated with clinically relevant adverse reactions.
Saxagliptin/dapagliflozin combination: Data from the saxagliptin plus dapagliflozin plus metformin treatment arms of 3 Phase 3 trials, demonstrated trends of mean percent increases from baseline (rounded to the nearest tenth) in total cholesterol (Total C), (ranging from 0.4% to 3.8%), LDL-C (ranging from 2.1% to 6.9%) and HDL-C (ranging 2.3% to 5.2%) along with mean percent decreases from baseline in triglycerides (ranging from -3.0% to -10.8%).
Of the 1169 subjects treated in the pooled safety data from the 3 clinical trials, 1007 subjects (86.1%) were aged <65 years, 162 subjects (13.9%) were aged ≥65 years, and 9 subjects (0.8%) were aged ≥75 years. Generally, the most common adverse events reported in ≥65 years old were similar to <65 years old. Therapeutic experience in patients 65 years and older is limited, and very limited in patients 75 years and older.
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