SYNJARDY SIDE EFFECTS
- Generic Name: empagliflozin and metformin hydrochloride tablets
- Brand Name: Synjardy
- Drug Class: Antidiabetics, Biguanides, Antidiabetics, SGLT2 Inhibitors
SIDE EFFECTS
The following important adverse reactions are described below and elsewhere in the labeling:
- Lactic Acidosis.
- Ketoacidosis
- Volume Depletion
- Urosepsis and Pyelonephritis
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
- Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
- Genital Mycotic Infections
- Hypersensitivity Reactions
- Vitamin B12 Deficiency
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 concomitantly administered empagliflozin (daily dose 10 mg and 25 mg) and metformin hydrochloride (mean daily dose of approximately 1800 mg) has been evaluated in 3456 patients with type 2 diabetes mellitus treated for 16 to 24 weeks, of which 926 patients received placebo, 1271 patients received a daily dose of empagliflozin 10 mg, and 1259 patients received a daily dose of empagliflozin 25 mg. Discontinuation of therapy due to adverse events across treatment groups was 3.0%, 2.8%, and 2.9% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
Empagliflozin Add-On Combination Therapy With Metformin
In a 24-week placebo-controlled trial of empagliflozin 10 mg and 25 mg administered once daily added to metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo.
Empagliflozin Add-On Combination Therapy With Metformin And Sulfonylurea
In a 24-week placebo-controlled trial of empagliflozin 10 mg and 25 mg administered once daily added to metformin and sulfonylurea, adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo are presented in Table 1 (see also Table 4).
Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin added on to Metformin plus Sulfonylurea and Greater than with Placebo in a 24-week Placebo Controlled Clinical Study
| Adverse Reactions | Placebo (%) n=225 |
Empagliflozin 10 mg (%) n=224 |
Empagliflozin 25 mg (%) n=217 |
| Hypoglycemia | 9.8 | 15.6 | 12.9 |
| Urinary tract infection | 6.7 | 9.4 | 6.9 |
| Nasopharyngitis | 4.9 | 8.0 | 6.0 |
Empagliflozin
The data in Table 2 are derived from a pool of four 24-week placebo-controlled trials and 18-week data from a placebo-controlled trial with basal insulin. Empagliflozin was used as monotherapy in one trial and as add-on therapy in four trials.
These data reflect exposure of 1976 patients to empagliflozin with a mean exposure duration of approximately 23 weeks. Patients received placebo (N=995), empagliflozin 10 mg (N=999), or empagliflozin 25 mg (N=977) once daily. The mean age of the population was 56 years and 3% were older than 75 years of age. More than half (55%) of the population was male; 46% were White, 50% were Asian, and 3% were Black or African American. At baseline, 57% of the population had diabetes more than 5 years and had a mean hemoglobin A1c (HbA1c) of 8%. Established microvascular complications of diabetes at baseline included diabetic nephropathy (7%), retinopathy (8%), or neuropathy (16%). Baseline renal function was normal or mildly impaired in 91% of patients and moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73m).
Table 2 shows common adverse reactions (excluding hypoglycemia) associated with the use of empagliflozin. The adverse reactions were not present at baseline, occurred more commonly on empagliflozin than on placebo and occurred in greater than or equal to 2% of patients treated with empagliflozin 10 mg or empagliflozin 25 mg.
Table 2 Adverse Reactions Reported in ≥2% of Patients Treated with Empagliflozin and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Empagliflozin Monotherapy or Combination Therapy
| Adverse Reactions | Placebo (%) N=995 |
Empagliflozin 10 mg (%) N=999 |
Empagliflozin 25 mg (% ) N=977 |
| Urinary tract infectiona | 7.6 | 9.3 | 7.6 |
| Female genital mycoticinfectionsb | 1.5 | 5.4 | 6.4 |
| Upper respiratory tract infection | 3.8 | 3.1 | 4.0 |
| Increased urinationc | 1.0 | 3.4 | 3.2 |
| Dyslipidemia | 3.4 | 3.9 | 2.9 |
| Arthralgia | 2.2 | 2.4 | 2.3 |
| Male genital mycoticinfectionsd | 0.4 | 3.1 | 1.6 |
| Nausea | 1.4 | 2.3 | 1.1 |
| aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis bFemale genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=481), empagliflozin 10 mg (N=443), empagliflozin 25 mg (N=420). cPredefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia dMale genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal, genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=514), empagliflozin 10 mg (N=556), empagliflozin 25 mg (N=557). |
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Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
Volume Depletion
Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of five placebo-controlled clinical trials, adverse reactions related to volume depletion (e.g., blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Empagliflozin may increase the risk of hypotension in patients at risk for volume contraction.
Increased Urination
In the pool of five placebo-controlled clinical trials, adverse reactions of increased urination (e.g., polyuria, pollakiuria, and nocturia) occurred more frequently on empagliflozin than on placebo (see Table 2). Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
The incidence of hypoglycemia by study is shown in Table 3. The incidence of hypoglycemia increased when empagliflozin was administered with insulin or sulfonylurea.
Table 3 Incidence of Overala and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studiesc
| Monotherapy (24 weeks) |
Placebo (n=229) |
Empagliflozin 10 mg (n=224) |
Empagliflozin 25 mg (n=223) |
| Overall (%) | 0.4 | 0.4 | 0.4 |
| Severe (%) | 0 | 0 | 0 |
| In Combination with Metformin (24 weeks) |
Placebo + Metformin (n=206) |
Empagliflozin 10 mg + Metformin (n=217) |
Empagliflozin 25 mg + Metformin (n=214) |
| Overall (%) | 0.5 | 1.8 | 1.4 |
| Severe (%) | 0 | 0 | 0 |
| In Combination with Metformin + Sulfonylurea (24 weeks) |
Placebo (n=225) |
Empagliflozin 10 mg + Metformin + Sulfonylurea (n=224) |
Empagliflozin 25 mg + Metformin + Sulfonylurea (n=217) |
| Overall (%) | 8.4 | 16.1 | 11.5 |
| Severe (%) | 0 | 0 | 0 |
| In Combination with Pioglitazone +/- Metformin (24 weeks) |
Placebo (n=165) |
Empagliflozin 10 mg + Pioglitazone +/- Metformin (n=165) |
Empagliflozin 25 mg + Pioglitazone +/- Metformin (n=168) |
| Overall (%) | 1.8 | 1.2 | 2.4 |
| Severe (%) | 0 | 0 | 0 |
| In Combination with Basal Insulin +/- Metformin (18 weeksd) |
Placebo (n=170) |
Empagliflozin 10 mg (n=169) |
Empagliflozin 25 mg (n=155) |
| Overall (%) | 20.6 | 19.5 | 28.4 |
| Severe (%) | 0 | 0 | 1.3 |
| In Combination with MDI Insulin +/-Metformin (18 weeks d) |
Placebo (n=188) |
Empagliflozin 10 mg (n=186) |
Empagliflozin 25 mg (n=189) |
| Overall (%) | 37.2 | 39.8 | 41.3 |
| Severe (%) | 0.5 | 0.5 | 0.5 |
| aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL bSevere hypoglycemic events: requiring assistance regardless of blood glucose cTreated set (patients who had received at least one dose of study drug) dInsulin dose could not be adjusted during the initial 18 week treatment period |
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Genital Mycotic Infections
In the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was increased in patients treated with empagliflozin compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either empagliflozin 10 or 25 mg.
Genital mycotic infections occurred more frequently in female than male patients (see Table 2).
Phimosis occurred more frequently in male patients treated with empagliflozin 10 mg (less than 0.1%) and empagliflozin 25 mg (0.1%) than placebo (0%).
Urinary Tract Infections
In the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with empagliflozin compared to placebo (see Table 2). Patients with a history of chronic or recurrent urinary tract infections were more likely to experience a urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was 0.1%, 0.2%, and 0.1% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 3.2%, 3.6%, and 4.1%, respectivel.
Metformin
The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.
Laboratory Tests
Empagliflozin
Increases in Serum Creatinine and Decreases in eGFR: Initiation of empagliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment, larger mean changes were observed. In a long-term cardiovascular outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m2 , respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with empagliflozin.
Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in lowdensity lipoprotein
cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.
Increase in Hematocrit: In a pool of four placebo-controlled studies, median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg-treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
Metformin
Decrease in Vitamin B12: In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B levels was observed in approximately 7% of patients.
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use. Because these 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.
Empagliflozin
Gastrointestinal Disorders: Constipation
Infections: Necrotizing fasciitis of the perineum (Fournier’s gangrene), urosepsis and pyelonephritis
Metabolism and Nutrition Disorders: Ketoacidosis
Renal and Urinary Disorders: Acute kidney injury
Skin and Subcutaneous Tissue Disorders: Angioedema, skin reactions (e.g., rash, urticaria)
Metformin Hydrochloride
Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury.
SRC: NLM .