STEGLATRO SIDE EFFECTS

Last updated on MDtodate: 10/12/2022

SIDE EFFECTS

The following important adverse reactions are described elsewhere in the labeling:

• Hypotension
• Ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function
• Urosepsis and Pyelonephritis
• Lower Limb Amputation
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
• Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)
• Genital Mycotic Infections
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C)

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.

Pool Of Placebo-Controlled Trials Evaluating STEGLATRO 5 And 15 mg

The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. STEGLATRO was used as monotherapy in one trial and as add-on therapy in two trials. These data reflect exposure of 1,029 patients to STEGLATRO with a mean exposure duration of approximately 25 weeks. Patients received STEGLATRO 5 mg (N=519), STEGLATRO 15 mg (N=510), or placebo (N=515) once daily. The mean age of the population was 57 years and 2% were older than 75 years of age. Fifty-three percent (53%) of the population was male and 73% were Caucasian, 15% were Asian, and 7% were Black or African American. At baseline the population had diabetes for an average of 7.5 years, had a mean HbA1c of 8.1%, and 19.4% had established microvascular complications of diabetes. Baseline renal function (mean eGFR 88.9 mL/min/1.73 m²) was normal or mildly impaired in 97% of patients and moderately impaired in 3% of patients.

Table 1 shows common adverse reactions associated with the use of STEGLATRO. These adverse reactions were not present at baseline, occurred more commonly on STEGLATRO than on placebo, and occurred in at least 2% of patients treated with either STEGLATRO 5 mg or STEGLATRO 15 mg.

Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus Treated with STEGLATRO* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of STEGLATRO Monotherapy or Combination Therapy

	Number (%) of Patients
	Placebo N = 515	STEGLATRO 5 mg N = 519	STEGLATRO 15 mg N = 510
Female genital mycotic infections†	3.0%	9.1%	12.2%
Male genital mycotic infections‡	0.4%	3.7%	4.2%
Urinary tract infections§	3.9%	4.0%	4.1%
Headache	2.3%	3.5%	2.9%
Vaginal pruritus¶	0.4%	2.8%	2.4%
Increased urination#	1.0%	2.7%	2.4%
Nasopharyngitis	2.3%	2.5%	2.0%
Back pain	2.3%	1.7%	2.5%
Weight decreased	1.0%	1.2%	2.4%
ThirsÞ	0.6%	2.7%	1.4%
* The three placebo controlled studies included one monotherapy trial and two add-on combination trials with metformin or with metformin and sitagliptin. †Includes: genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis. Percentages calculated with the number of female patients in each group as denominator: placebo (N=235), STEGLATRO 5 mg (N=252), STEGLATRO 15 mg (N=245). ‡ Includes: balanitis candida, balanoposthitis, genital infection, and genital infection fungal. Percentages calculated with the number of male patients in each group as denominator: placebo (N=280), STEGLATRO 5 mg (N=267), STEGLATRO 15 mg (N=265). §Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection. ¶ Includes: vulvovaginal pruritus and pruritus genital. Percentages calculated with the number of female patients in each group as denominator: placebo (N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245). # Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia. Þ Includes: thirst, dry mouth, polydipsia, and dry throat.

 

Volume Depletion

STEGLATRO causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²). In patients with moderate renal impairment, adverse reactions related to volume depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. STEGLATRO may also increase the risk of hypotension in other patients at risk for volume contraction.

Ketoacidosis

Across the clinical program, ketoacidosis was identified in 3 of 3,409 (0.1%) ertugliflozin-treated patients and 0.0% of comparator-treated patients.

Impairment In Renal Function

Treatment with STEGLATRO was associated with increases in serum creatinine and decreases in eGFR (see Table 2). Patients with moderate renal impairment at baseline had larger mean changes. In a study in patients with moderate renal impairment, these abnormal laboratory findings were observed to reverse after treatment discontinuation [see Use In Specific Populations].

Table 2: Changes from Baseline in Serum Creatinine and eGFR in the Pool of Three 26-Week Placebo-Controlled Studies, and a 26-Week Moderate Renal Impairment Study in Patients withType 2 Diabetes Mellitus

		Pool of 26-Week Placebo-Controlled Studies
		Placebo N=515	STEGLATRO 5 mg N=519	STEGLATRO 15 mg N=510
Baseline Mean	Creatinine (mg/dL)	0.83	0.82	0.82
	eGFR (mL/min/1.73 m²)	89.5	88.2	89.0
Week 6 Change	Creatinine (mg/dL)	0.00	0.03	0.03
	eGFR (mL/min/1.73 m²)	-0.3	-2.7	-3.1
Week 26 Change	Creatinine (mg/dL)	-0.01	0.00	0.01
	eGFR (mL/min/1.73 m²)	0.7	0.5	-0.6
		Moderate Renal Impairment Study
		Placebo N=154	STEGLATRO 5 mg N=158	STEGLATRO 15 mg N=155
Baseline	Creatinine (mg/dL)	1.39	1.38	1.37
	eGFR (mL/min/1.73 m²)	46.0	46.8	46.9
Week 6 Change	Creatinine (mg/dL)	-0.02	0.11	0.12
	eGFR (mL/min/1.73 m²)	0.6	-3.2	-4.1
Week 26 Change	Creatinine (mg/dL)	0.02	0.08	0.10
	eGFR (mL/min/1.73 m²)	0.0	-2.7	-2.6

 

Renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with STEGLATRO, particularly in patients with moderate renal impairment where the incidence of renal-related adverse reactions was 0.6%, 2.5%, and 1.3% in patients treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively.

Lower Limb Amputation

Across seven Phase 3 clinical trials in which STEGLATRO was studied as monotherapy and in combination with other antihyperglycemic agents, non-traumatic lower limb amputations occurred in 1 of 1,450 (0.1%) in the non-STEGLATRO group, 3 of 1,716 (0.2%) in the STEGLATRO 5 mg group, and 8 of 1,693 (0.5%) in the STEGLATRO 15 mg group.

Hypoglycemia

The incidence of hypoglycemia by study is shown in Table 3.

Table 3: Incidence of Overall* and Severe†Hypoglycemia in Placebo-Controlled Clinical Studies inPatients with Type 2 Diabetes Mellitus

Monotherapy (26 weeks)	Placebo (N = 153)	STEGLATRO 5 mg (N =156)	STEGLATRO 15 mg (N = 152)
Overall [N (%)]	1 (0.7)	4 (2.6)	4 (2.6)
Severe [N (%)]	0 (0.0)	0 (0.0)	2 (1.3)
Add-on Combination Therapy with Metformin (26 weeks)	Placebo (N = 209)	STEGLATRO 5 mg (N = 207)	STEGLATRO 15 mg (N = 205)
Overall [N (%)]	9 (4.3)	15 (7.2)	16 (7.8)
Severe [N (%)]	1 (0.5)	1 (0.5)	0 (0.0)
Add-on Combination Therapy with Metformin and Sitagliptin (26 weeks)	Placebo (N = 153)	STEGLATRO 5 mg (N = 156)	STEGLATRO 15 mg (N = 153)
Overall [N (%)]	5 (3.3)	7 (4.5)	3 (2.0)
Severe [N (%)]	1 (0.7)	1 (0.6)	0 (0.0)
In Combination with Insulin and/or an Insulin Secretagogue in Patients with Moderate Renal Impairment	Placebo (N = 133)	STEGLATRO 5 mg (N = 148)	STEGLATRO 15 mg (N = 143)
Overall [N (%)]	48 (36.1)	53 (35.8)	39 (27.3)
Severe [N (%)]	3 (2.3)	5 (3.4)	3 (2.1)
* Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL. †Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose.

 

Genital Mycotic Infections

In the pool of three placebo-controlled clinical trials, the incidence of female genital mycotic infections (e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 3%, 9.1%, and 12.2% of females treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively (see Table 1). In females, discontinuation due to genital mycotic infections occurred in 0% and 0.6% of patients treated with placebo and STEGLATRO, respectively.

In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital infection, genital infection fungal) occurred in 0.4%, 3.7%, and 4.2% of males treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively (see Table 1). Male genital mycotic infections occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.2% of patients treated with placebo and STEGLATRO, respectively. Phimosis was reported in 8 of 1729 (0.5%) male ertugliflozin-treated patients, of which four required circumcision.

Laboratory Tests

Increases In Low-Density Lipoprotein Cholesterol (LDL-C)

In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in patients treated with STEGLATRO. Mean percent changes from baseline to Week 26 in LDL-C relative to placebo were 2.6% and 5.4% with STEGLATRO 5 mg and STEGLATRO 15 mg, respectively. The range of mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups.

Increases In Hemoglobin

In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to Week 26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with STEGLATRO 5 mg, and 0.48 g/dL (3.5%) with STEGLATRO 15 mg. The range of mean baseline hemoglobin was 13.90 to 14.00 g/dL across treatment groups. At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively, had a hemoglobin increase greater than 2 g/dL and above the upper limit of normal.

Increases In Serum Phosphate

In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with STEGLATRO 5 mg, and 0.26 mg/dL (8.5%) with STEGLATRO 15 mg. The range of mean baseline serum phosphate was 3.53 to 3.54 mg/dL across treatment groups. In a clinical trial of patients with moderate renal impairment, mean changes (percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%) with placebo, 0.29 mg/dL (9.7%) with STEGLATRO 5 mg, and 0.24 mg/dL (7.8%) with STEGLATRO 15 mg.

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.

• Cases of necrotizing fasciitis of the perineum (Fournier’s gangrene) have been seen with SGLT2 inhibitors