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Victoza

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Victoza

Side Effects
Interactions

SIDE EFFECTS

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 Victoza® has been evaluated in 8 clinical trials [see Clinical Studies]:

  • A double-blind 52-week monotherapy trial compared Victoza® 1.2 mg daily, Victoza® 1.8 mg daily, and glimepiride 8 mg daily.
  • A double-blind 26 week add-on to metformin trial compared Victoza® 0.6 mg once-daily, Victoza® 1.2 mg once-daily, Victoza® 1.8 mg once-daily, placebo, and glimepiride 4 mg once-daily.
  • A double-blind 26 week add-on to glimepiride trial compared Victoza® 0.6 mg daily, Victoza® 1.2 mg once-daily, Victoza® 1.8 mg once-daily, placebo, and rosiglitazone 4 mg once-daily.
  • A 26 week add-on to metformin + glimepiride trial, compared double-blind Victoza® 1.8 mg once-daily, double-blind placebo, and open-label insulin glargine once-daily.
  • A double-blind 26-week add-on to metformin + rosiglitazone trial compared Victoza® 1.2 mg once-daily, Victoza® 1.8 mg once-daily and placebo.
  • An open-label 26-week add-on to metformin and/or sulfonylurea trial compared Victoza® 1.8 mg once-daily and exenatide 10 mcg twice-daily.
  • An open-label 26-week add-on to metformin trial compared Victoza® 1.2 mg once-daily, Victoza® 1.8 mg once-daily, and sitagliptin 100 mg once-daily.
  • An open-label 26-week trial compared insulin detemir as add-on to Victoza® 1.8 mg + metformin to continued treatment with Victoza® + metformin alone.
Withdrawals

The incidence of withdrawal due to adverse events was 7.8% for Victoza®-treated patients and 3.4% for comparator-treated patients in the five double-blind controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients. In these five trials, the most common adverse reactions leading to withdrawal for Victoza®-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials.

Common Adverse Reactions

Tables 1, 2, 3 and 4 summarize common adverse reactions (hypoglycemia is discussed separately) reported in seven of the eight controlled trials of 26 weeks duration or longer. Most of these adverse reactions were gastrointestinal in nature.

In the five double-blind clinical trials of 26 weeks duration or longer, gastrointestinal adverse reactions were reported in 41% of Victoza®-treated patients and were dose-related. Gastrointestinal adverse reactions occurred in 17% of comparator-treated patients. Common adverse reactions that occurred at a higher incidence among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation.

In the five double-blind and three open-label clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. In the five double-blind trials approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment.

In the 26-week open-label trial comparing Victoza® to exenatide, both in combination with metformin and/or sulfonylurea, gastrointestinal adverse reactions were reported at a similar incidence in the Victoza® and exenatide treatment groups (Table 3).

In the 26-week open-label trial comparing Victoza® 1.2 mg, Victoza® 1.8 mg and sitagliptin 100 mg, all in combination with metformin, gastrointestinal adverse reactions were reported at a higher incidence with Victoza® than sitagliptin (Table 4).

In the remaining 26-week trial, all patients received Victoza® 1.8 mg + metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only those patients who completed the run-in period with inadequate glycemic control were randomized to 26 weeks of add-on therapy with insulin detemir or continued, unchanged treatment with Victoza® 1.8 mg + metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in ≥ 5% of patients treated with Victoza® 1.8 mg + metformin + insulin detemir (11.7%) and greater than in patients treated with Victoza® 1.8 mg and metformin alone (6.9%).

Table 1: Adverse reactions reported in ≥ 5% of Victoza®-treated patients in a 52-week monotherapy trial

  All Victoza®
N = 497
Glimepiride
N = 248
Adverse Reaction (%) (%)
Nausea 28.4 8.5
Diarrhea 17.1 8.9
Vomiting 10.9 3.6
Constipation 9.9 4.8
Headache 9.1 9.3

Table 2: Adverse reactions reported in ≥ 5% of Victoza®-treated patients and occurring more frequently with Victoza® compared to placebo: 26-week combination therapy trials

  Add-on to Metformin Trial
All Victoza® + Metformin
N = 724
Placebo + Metformin
N = 121
Glimepiride + Metformin
N = 242
Adverse Reaction (%) (%) (%)
Nausea 15.2 4.1 3.3
Diarrhea 10.9 4.1 3.7
Headache 9 6.6 9.5
Vomiting 6.5 0.8 0.4
  Add-on to Glimepiride Trial
  All Victoza® + Glimepiride
N = 695
Placebo + Glimepiride
N = 114
Rosiglitazone + Glimepiride
N = 231
Adverse Reaction (%) (%) (%)
Nausea 7.5 1.8 2.6
Diarrhea 7.2 1.8 2.2
Constipation 5.3 0.9 1.7
Dyspepsia 5.2 0.9 2.6
  Add-on to Metformin + Glimepiride
  Victoza® 1.8 + Metformin + Glimepiride
N = 230
Placebo + Metformin + Glimepiride
N = 114
Glargine + Metformin + Glimepiride
N = 232
Adverse Reaction (%) (%) (%)
Nausea 13.9 3.5 1.3
Diarrhea 10.0 5.3 1.3
Headache 9.6 7.9 5.6
Dyspepsia 6.5 0.9 1.7
Vomiting 6.5 3.5 0.4
  Add-on to Metformin + Rosiglitazone
  All Victoza® + Metformin + Rosiglitazone
N = 355
Placebo + Metformin + Rosiglitazone
N = 175
 
Adverse Reaction (%) (%)  
Nausea 34.6 8.6  
Diarrhea 14.1 6.3  
Vomiting 12.4 2.9  
Headache 8.2 4.6  
Constipation 5.1 1.1  

Table 3: Adverse Reactions reported in ≥ 5% of Victoza®-treated patients in a 26-Week Open-Label Trial versus Exenatide

  Victoza® 1.8 mg once daily + metformin and/or sulfonylurea
N = 235
Exenatide 10 mcg twice daily + metformin and/or sulfonylurea
N = 232
Adverse Reaction (%) (%)
Nausea 25.5 28.0
Diarrhea 12.3 12.1
Headache 8.9 10.3
Dyspepsia 8.9 4.7
Vomiting 6.0 9.9
Constipation 5.1 2.6

Table 4: Adverse Reactions in ≥ 5% of Victoza®-treated patients in a 26-Week Open-Label Trial versus Sitagliptin

  All Victoza® + metformin
N = 439
Sitagliptin 100 mg/day + metformin
N = 219
Adverse Reaction (%) (%)
Nausea 23.9 4.6
Headache 10.3 10.0
Diarrhea 9.3 4.6
Vomiting 8.7 4.1

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five double-blind clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®- treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the double-blind 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the double-blind 26-week add-on combination therapy trials. These crossreacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the double-blind 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the doubleblind 26-week add-on combination therapy trials.

Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®- treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®- treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment.

In the five double-blind clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies.

Injection Site Reactions

Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five double-blind clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions.

Papillary Thyroid Carcinoma

In clinical trials of Victoza®, there were 7 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1000 patientyears). Most of these papillary thyroid carcinomas were < 1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound.

Hypoglycemia

In the eight clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 11 Victoza®-treated patients (2.3 cases per 1000 patient-years) and in two exenatide-treated patients. Of these 11 Victoza®-treated patients, six patients were concomitantly using metformin and a sulfonylurea, one was concomitantly using a sulfonylurea, two were concomitantly using metformin (blood glucose values were 65 and 94 mg/dL) and two were using Victoza® as monotherapy (one of these patients was undergoing an intravenous glucose tolerance test and the other was receiving insulin as treatment during a hospital stay). For these two patients on Victoza® monotherapy, the insulin treatment was the likely explanation for the hypoglycemia.

In the 26-week open-label trial comparing Victoza® to sitagliptin, the incidence of hypoglycemic events defined as symptoms accompanied by a fingerstick glucose < 56 mg/dL was comparable among the treatment groups (approximately 5%).

Table 5: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials

  Victoza® Treatment Active Comparator Placebo Comparator
Monotherapy Victoza®
(N = 497)
Glimepiride
(N = 248)
None
Patient not able to self-treat 0 0
Patient able to self-treat 9.7 (0.24) 25.0 (1.66)
Not classified 1.2 (0.03) 2.4 (0.04)
Add-on to Metformin Victoza® + Metformin
(N = 724)
Glimepiride + Metformin
(N = 242)
Placebo + Metformin
(N = 121)
Patient not able to self-treat 0.1 (0.001) 0 0
Patient able to self-treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06)
Add-on to Victoza® + Metformin Insulin detemir + Victoza® + Metformin
(N = 163)
Continued Victoza® + Metformin alone
(N = 158*)
None
Patient not able to self-treat 0 0
Patient able to self-treat 9.2 (0.29) 1.3 (0.03)
Add-on to Glimepiride Victoza® + Glimepiride
(N = 695)
Rosiglitazone + Glimepiride
(N = 231)
Placebo + Glimepiride
(N = 114)
Patient not able to self-treat 0.1 (0.003) 0 0
Patient able to self-treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17)
Not classified 0.9 (0.05) 0.9 (0.02) 0
Add-on to Metformin + Rosiglitazone Victoza® + Metformin + Rosiglitazone
(N = 355)
None Placebo + Metformin + Rosiglitazone
(N = 175)
Patient not able to self-treat 0 0
Patient able to self-treat 7.9 (0.49) 4.6 (0.15)
Not classified 0.6 (0.01) 1.1 (0.03)
Add-on to Metformin + Glimepiride Victoza® + Metformin + Glimepiride
(N = 230)
Insulin glargine + Metformin + Glimepiride
(N = 232)
Placebo + Metformin + Glimepiride
(N = 114)
Patient not able to self-treat 2.2 (0.06) 0 0
Patient able to self-treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95)
Not classified 0 1.7 (0.04) 0
*One patient is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a history of frequent hypoglycemia prior to the study.

In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events, no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established.

Laboratory Tests

In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®- treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown.

Vital Signs

Victoza® did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed with Victoza® compared to placebo. The long-term clinical effects of the increase in pulse rate have not been established [see WARNINGS AND PRECAUTIONS].

Post-Marketing Experience

The following additional adverse reactions have been reported during post-approval use of Victoza®. Because these events 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.

Read the Victoza (liraglutide [rdna] injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Oral Medications

Victoza® causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, Victoza® did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, caution should be exercised when oral medications are concomitantly administered with Victoza®.

Last reviewed on RxList: 5/9/2013
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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