SOLIQUA SIDE EFFECTS

Last updated on MDtodate: 10/11/2022

SIDE EFFECTS

The following adverse reactions are discussed elsewhere:

• Anaphylaxis and Serious Hypersensitivity Reactions
• Pancreatitis
• Hypoglycemia
• Acute Kidney Injury
• Hypokalemia
• Acute Gallbladder Disease

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

The safety of SOLIQUA 100/33 (n=834, with a mean treatment duration of 203 days) has been evaluated in two clinical studies (30 weeks duration) in type 2 diabetes patients. The studies, Study A and B, had the following characteristics: mean age was approximately 59 years; approximately 50% were male, 90% were Caucasian, 6% were Black or African American, and 18% were Hispanic. The mean duration of diabetes was 10.3 years, mean HbA1c at screening for Study A was 8.2 and Study B was 8.5. The mean BMI at baseline was 32 kg/m². Baseline eGFR was ≥60 mL/min in 87.2% of the pooled study population and mean baseline eGFR was 83.0 mL/min/1.73 m².

Table 1: Adverse Reactions Occurring in ≥5% of SOLIQUA 100/33-Treated Patients with Type 2 Diabetes Mellitus from Two Pooled Clinical Trials

	SOLIQUA 100/33, % (n=834)
Nausea	10.0
Nasopharyngitis	7.0
Diarrhea	7.0
Upper respiratory tract infection	5.5
Headache	5.4

 

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, and insulin-containing products including SOLIQUA 100/33. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for SOLIQUA 100/33 with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.

In the SOLIQUA 100/33 program, severe hypoglycemia was defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions and documented symptomatic hypoglycemia was defined as an event with typical symptoms of hypoglycemia accompanied by a self-monitored plasma glucose value equal to or less than 70 mg/dL (see Table 4).

No clinically important differences in risk of severe hypoglycemia between SOLIQUA 100/33 and comparators were observed in clinical trials.

Table 2: Hypoglycemic Episodes in SOLIQUA-Treated Patients with T2DM

	SOLIQUA 100/33 Study A N=469	SOLIQUA 100/33 Study B N=365
Severe symptomatic hypoglycemia* (%)	0	1.1
Hypoglycemia (self-monitored plasma glucose <54 mg/dL) (%)	8.1	17.8
* Defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

 

Gastrointestinal Adverse Reactions

Gastrointestinal adverse reactions are the most commonly observed adverse reaction in patients using lixisenatide. Gastrointestinal adverse reactions occur more frequently at the beginning of SOLIQUA 100/33 therapy. Gastrointestinal adverse reactions including nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesophageal reflux disease, abdominal distension, and decreased appetite have been reported in patients treated with SOLIQUA 100/33.

In Study A, vomiting was 6.4% in the lixisenatide-treated patients versus 3.2% in the SOLIQUA 100/33–treated patients and 1.5% in the insulin glargine–treated patients; nausea was 24% in the lixisenatide-treated patients versus 9.6% in the SOLIQUA 100/33–treated patients, and 3.6% in the insulin glargine–treated patients.

Lipodystrophy

Administration of insulin subcutaneously, including SOLIQUA 100/33, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients.

Anaphylaxis And Hypersensitivity

Lixisenatide

In the lixisenatide development program anaphylaxis cases were adjudicated. Anaphylaxis was defined as a skin or mucosal lesion of acute onset associated with at least 1 other organ system involvement. Symptoms such as hypotension, laryngeal edema or severe bronchospasm could be present but were not required for the case definition. More cases adjudicated as meeting the definition for anaphylaxis occurred in lixisenatide-treated patients (incidence rate of 0.2% or 16 cases per 10,000 patient years) than placebo-treated patient (incidence rate of 0.1% or 7 cases per 10,000 patient years).

Allergic reactions (such as anaphylactic reaction, angioedema, and urticaria) adjudicated as possibly related to the study medication were observed more frequently in lixisenatide-treated patients (0.4%) than placebo-treated patients (0.2%).

Insulin Glargine

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including SOLIQUA 100/33, and may be life-threatening.

Acute Gallbladder Disease

In a cardiovascular outcomes trial, cholelithiasis occurred in 0.4% of lixisenatide-treated patients versus 0.2% in placebo-treated patients and acute cholecystitis in 0.3% of lixisenatide-treated patients versus 0.2% in placebo-treated patients.

Injection-Site Reactions

As with any insulin or GLP-1 receptor agonist–containing product, patients taking SOLIQUA 100/33 may experience injection-site reactions, including injection-site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection-site mass. In the clinical program the proportion of injection-site reactions occurring in patients treated with SOLIQUA 100/33 was 1.7%.

Insulin Initiation And Intensification Of Glucose Control

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Peripheral Edema

Some patients taking insulin glargine, a component of SOLIQUA 100/33 have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Weight Gain

Weight gain can occur with insulin-containing products, including SOLIQUA 100/33, and has been attributed to the anabolic effects of insulin.

Immunogenicity

SOLIQUA 100/33

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SOLIQUA 100/33 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

After 30 weeks of treatment with SOLIQUA 100/33 in two phase 3 trials, the incidence of formation of anti-insulin glargine antibodies was 21.0% and 26.2%. In approximately 93% of the patients, anti-insulin glargine antibodies showed cross-reactivity to human insulin. The incidence of formation of anti-lixisenatide antibodies was approximately 43%.

Lixisenatide

In the pool of 9 placebo-controlled studies, 70% of patients exposed to lixisenatide tested positive for anti-lixisenatide antibodies during the trials. In the subset of patients (2.4%) with the highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed. A higher incidence of allergic reactions and injection-site reactions occurred in antibody positive patients.

Anti-lixisenatide antibody characterization studies have demonstrated the potential for development of antibodies cross-reactive with endogenous GLP-1 and glucagon, but their incidence has not been fully determined and the clinical significance of these antibodies is not currently known.

No information regarding the presence of neutralizing antibodies is currently available.

Postmarketing Experience

The following additional adverse reactions have been identified during post approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Renal: Acute kidney injury

Skin: Localized cutaneous amyloidosis at the injection site has occurred with insulins. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

Hepatobiliary: Cholecystitis, cholelithiasis requiring cholecystectomy