Medical Editor: John P. Cunha, DO, FACOEP
Qternmet XR (dapagliflozin, saxagliptin, and metformin hydrochloride) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and a biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Common side effects of Qternmet XR include:
- upper respiratory tract infection,
- urinary tract infection (UTI),
- high levels of fats in the blood (dyslipidemia),
- back pain,
- genital infections, and
- joint pain
For patients not currently taking dapagliflozin, the recommended starting total daily dose of Qternmet XR is a 5 mg dapagliflozin/5 mg saxagliptin/1000 mg or 2000 mg metformin hydrochloride (HCl) once daily. The maximum recommended daily dose is 10 mg dapagliflozin, 5 mg saxagliptin and 2000 mg metformin HCl. Qternmet XR may interact with ketoconazole, HIV medications, antibiotics, carbonic anhydrase inhibitors, some antidepressants, ranolazine, vandetanib, cimetidine, alcohol, insulin or insulin secretagogues, diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. Tell your doctor all medications and supplements you use. Qternmet XR is not recommended during the second and third trimesters of pregnancy; it may harm a fetus. Metformin passes into breast milk. It is unknown if dapagliflozin or saxagliptin pass into breast milk. Because of the potential for serious adverse reactions in a breastfed infant, breastfeeding is not recommended while using Qternmet XR.
Our Qternmet XR (dapagliflozin, saxagliptin, and metformin hydrochloride) Extended-Release Tablets, for Oral Use Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
The following important adverse reactions are described below or elsewhere in the labeling:
- Lactic Acidosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Pancreatitis [see WARNINGS AND PRECAUTIONS]
- Heart Failure [see WARNINGS AND PRECAUTIONS]
- Hypotension [see WARNINGS AND PRECAUTIONS]
- Ketoacidosis [see WARNINGS AND PRECAUTIONS]
- Acute Kidney Injury and Impairment in Renal Function [see WARNINGS AND PRECAUTIONS]
- Urosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS]
- Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see WARNINGS AND PRECAUTIONS]
- Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Vitamin B12 Concentrations [see WARNINGS AND PRECAUTIONS]
- Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS]
- Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see WARNINGS AND PRECAUTIONS]
- Bladder Cancer [see WARNINGS AND PRECAUTIONS]
- Severe and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS]
- Bullous Pemphigoid [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of combined use of 10 mg dapagliflozin and 5 mg saxagliptin has been evaluated in adult subjects with type 2 diabetes in a pooled safety analysis of three phase 3 active/placebo-controlled clinical trials with a median exposure of 51 weeks. The pooled safety analysis included a total of 1169 adults: 492 patients in the combination of saxagliptin and dapagliflozin plus metformin group, 341 patients in the dapagliflozin plus metformin group, 336 patients the saxagliptin plus metformin group. The mean age of these subjects was 54 years, 0.8% were 75 years or older and 53.7% were female. The population was 80.9% White, 8.3% Black or African American, 3.7% Asian, and 6.6% Other race. At baseline the population had diabetes for an average of 7.5 years and a mean HbA1c of 8.4%. The mean eGFR at baseline was 94.4 mL/min/1.73 m².
The common adverse reactions were based on the pooled analyses of these studies as shown in Table 1.
Table 1: Adverse Reactions Reported in ≥2% of
Subjects Treated with 10 mg Dapagliflozin and 5 mg Saxagliptin plus Metformin
|Adverse Reaction Preferred Term*||Frequency %|
|Upper respiratory tract infection*||13.6|
|Urinary tract infection*||5.7|
|* Adverse reactions that are medically related were grouped to a single preferred term.|
Additionally, adverse reactions reported in <5% and ≥2% from the dapagliflozin development program and ≥1% more frequently compared to placebo included increased urination and discomfort with urination.
In placebo-controlled monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release.
In the pooled analysis, the incidences of hypoglycemia (defined as blood glucose <54 mg/dL regardless of the presence or absence of symptoms) and severe hypoglycemia (events requiring assistance due to neuroglycopenia, characterized by altered mental and/or physical status) were 1% and 0.2%, respectively.
Genital Mycotic Infections
Genital mycotic infections were reported in 15 subjects (3%) treated with combination plus metformin therapy. Reported adverse reactions by frequency included vulvovaginal mycotic infection, balanoposthitis, genital fungal infection, vaginal infection, and vulvovaginitis. The majority of subjects (84.2%) who experienced genital infection adverse reactions were females.
Urinary Tract Infections
Urinary tract infections were reported in 28 subjects (5.7%) treated with combination plus metformin therapy. Reported adverse reactions by frequency included urinary tract infection, Escherichia urinary tract infection, prostatitis, and pyelonephritis. The majority of subjects (80.6%) who experienced urinary tract infection adverse reactions were females.
Dapagliflozin causes an osmotic diuresis, which may lead to reductions in intravascular volume. Events related to volume depletion (hypotension, dehydration, and hypovolemia) were reported in 2 subjects (0.4%) treated with dapagliflozin, saxagliptin and metformin combination therapy.
Impairment Of Renal Function
Dapagliflozin And Saxagliptin Plus Metformin
Adverse reactions related to decreased renal function were reported in 10 subjects (2.0%) treated with combination plus metformin therapy. The reported adverse reactions included decreased glomerular filtration rate, renal impairment, increased blood creatinine, acute renal failure, and decreased urine output. None of the adverse reactions were reported as serious and all but one were mild to moderate in intensity. Three subjects discontinued due to decreased eGFR. Subjects with AEs of renal impairment had lower mean eGFR values at baseline of 64.4 mL/min/1.73 m² compared to 94.4 mL/min/1.73 m² in overall population treated with combination plus metformin therapy.
Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 2). In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24. Renal-related adverse reactions, including renal failure and blood creatinine increase, were more frequent in patients treated with dapagliflozin (see Table 3). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions (see Table 3). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²). QTERNMET XR is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m².
Table 2: Changes in Serum Creatinine and eGFR
Associated with Dapagliflozin in the Pool of 12 Placebo-Controlled Studies and
Moderate Renal Impairment Studies
|Pool of 12 Placebo-Controlled Studies|
|5 mg Dapagliflozin
|10 mg Dapagliflozin
|Baseline Mean||Serum Creatinine (mg/dL)||0.853||0.860||0.847|
|eGFR (mL/min/1.73 m²)||86.0||85.3||86.7|
|Week 1 Change||Serum Creatinine (mg/dL)||-0.003||0.029||0.041|
|eGFR (mL/min/1.73 m²)||0.4||-2.9||-4.1|
|Week 24 Change||Serum Creatinine (mg/dL)||-0.005||-0.001||0.001|
|Baseline Mean||Serum Creatinine (mg/dL)||1.46||1.53||1.52|
|eGFR (mL/min/1.73 m²)||45.6||44.2||43.9|
|Moderate Renal Impairment Study* (eGFR 30 to less than 60 mL/min/1.73 m²)|
|Placebo N=84||5 mg Dapagliflozin N=83||10 mg Dapagliflozin N=85|
|Week 1 Change||Serum Creatinine (mg/dL)||0.01||0.13||0.18|
|eGFR (mL/min/1.73 m²)||0.5||-3.8||-5.5|
|Week 24 Change||Serum Creatinine (mg/dL)||0.02||0.08||0.16|
|eGFR (mL/min/1.73 m²)||0.03||-4.0||-7.4|
|Week 52 Change||Serum Creatinine (mg/dL)||0.10||0.06||0.15|
|eGFR (mL/min/1.73 m²)||-2.6||-4.2||-7.3|
|Moderate Renal Impairment Study (eGFR 45 to less than 60 mL/min/1.73 m²)|
|10 mg Dapagliflozin
|Baseline Mean||Serum Creatinine (mg/dL)||1.25||1.25|
|eGFR (mL/min/1.73 m²)||53.6||53.3|
|Week 4 Change||Serum Creatinine (mg/dL)||-0.02||0.09|
|eGFR (mL/min/1.73 m²)||1.3||-3.8|
|Week 12 Change||Serum Creatinine (mg/dL)||-0.02||0.08|
|eGFR (mL/min/1.73 m²)||1.5||-3.2|
|Week 24 Change||Serum Creatinine (mg/dL)||-0.003||0.06|
|eGFR (mL/min/1.73 m²)||0.8||-2.0|
|* QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m².|
Table 3: Proportion of Patients with at Least One
Renal Impairment-Related Adverse Reaction
|Baseline Characteristics||Pool of 6 Placebo-Controlled Studies (up to 104 weeks)*||Pool of 9 Placebo-Controlled Studies (up to 104 weeks)1.|
|Placebo||5 mg Dapagliflozin||10 mg Dapagliflozin||Placebo||10 mg Dapagliflozin|
|Patients (%) with at least one event||13 (1.7%)||14 (1.8%)||16 (1.9%)||82 (4.2%)||136 (6.7%)|
|65 years of age and older||n=190||n=162||n=159||n=655||n=620|
|Patients (%) with at least one event||4 (2.1%)||5 (3.1%)||6 (3.8%)||52 (7.9%)||87 (14.0%)|
|eGFR ≥30‡ and <60 mL/min/1.73 m²||n=77||n=88||n=75||n=249||n=251|
|Patients (%) with at least one event||5 (6.5%)||7 (8.0%)||9 (12.0%)||40 (16.1%)||71 (28.3%)|
|65 years of age and older and eGFR ≥30‡ and <60 mL/min/1.73 m²||n=41||n=43||n=35||n=141||n=134|
|Patients (%) with at least one event||2 (4.9%)||3 (7.0%)||4 (11.4%)||27 (19.1%)||47 (35.1%)|
|* Subset of patients from the pool of 12
placebo-controlled studies with long-term extensions.
† Subset of patients from the pool of 13 placebo-controlled studies with long-term extensions.
‡ QTERNMET XR is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m².
In the pool of 12 clinical studies, a subgroup analysis assessed the safety of patients with eGFR between 30 to less than 60 mL/min/1.73 m². At Week 24, the safety of dapagliflozin was similar to that seen in the dapagliflozin clinical program, although a higher proportion of patients had at least one event related to renal impairment or failure. QTERNMET XR is contraindicated in patients with an eGFR <45 mL/min/1.73 m².
In a study of patients with eGFR 30 to less than 60 mL/min/1.73 m², 13 patients experienced bone fractures for treatment durations up to 104 weeks. No fractures occurred in the placebo group, 5 occurred in the 5 mg dapagliflozin group, and 8 occurred in the 10 mg dapagliflozin group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to 45 mL/min/1.73 m². QTERNMET XR is contraindicated in patients with an eGFR <45 mL/min/1.73 m². Ten of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the anatomic site of fracture.
Decrease In Lymphocyte Counts
A dose-related mean decrease in absolute lymphocyte count has been observed with saxagliptin. In a pool of 5 placebo-controlled studies, a mean decrease in absolute lymphocyte count of approximately 100 cells/microL relative to placebo was observed. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, and 0.4% in the 2.5 mg, 5 mg saxagliptin and placebo groups, respectively.
The clinical significance of this decrease in lymphocyte count relative to placebo is not known. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.
Increase In Hematocrit
In a pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and 2.30% in the 10 mg dapagliflozin group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of 10 mg dapagliflozin -treated patients.
Increase In Serum Inorganic Phosphorus
In a pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin-treated patients compared with placebo-treated patients (mean increase of 0.13 versus -0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL for age 17-65 years or ≥5.1 mg/dL for age ≥66 years) were reported on dapagliflozin at Week 24 (0.9% versus 1.7% for placebo and 10 mg dapagliflozin, respectively).
Increase In Low-Density Lipoprotein Cholesterol
Patients treated with combination therapy demonstrated a mean percent increase from baseline LDL-cholesterol (ranging from 2.1 to 6.9%).
Elevations In Creatine Kinase
An imbalance in the number of subjects who experienced serum creatine kinase (CK) elevations >10x the upper limit of normal (a marker of muscle injury/necrosis) was observed in 5 subjects (1%) treated with combination therapy. The elevations were transient. Rhabdomyolysis was reported for one of those subjects for which no obvious cause was identified.
Decrease In Serum Bicarbonate
In a study of concomitant therapy of 10 mg dapagliflozin with exenatide extended-release (on a background of metformin), four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the dapagliflozin and exenatide-extended release treatment groups [see WARNINGS AND PRECAUTIONS].
Vitamin B12 Concentrations
In clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.
Additional adverse reactions have been identified during post approval use of dapagliflozin, saxagliptin, and metformin. Because the following reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Acute Kidney Injury and Impairment in Renal Function
- Urosepsis and pyelonephritis
- Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)
- Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
- Severe and disabling arthralgia
- Bullous pemphigoid
- Cholestatic, hepatocellular, and mixed hepatocellular liver injury
Read the entire FDA prescribing information for Qternmet XR (Dapagliflozin, Saxagliptin, and Metformin Hydrochloride)
© Qternmet XR Patient Information is supplied by Cerner Multum, Inc. and Qternmet XR Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.