ADVERSE REACTIONS
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 was evaluated in a 52-week monotherapy trial and in four 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza 1.2 mg daily, Victoza 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza 1.2 mg, Victoza 1.8 mg or placebo [see Clinical Studies].
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 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. 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.
Tables 1 and 2 summarize the adverse events reported in ≥5% of Victoza-treated patients in the five controlled trials of 26 weeks duration or longer.
Table 1 Adverse events reported in ≥5% of Victoza-treated patients or ≥5% of glimepiride-treated patients: 52-week monotherapy trial
|
|
All Victoza
N = 497
|
Glimepiride
N = 248
|
|
Adverse Event Term
|
(%) |
(%) |
| Nausea |
28.4 |
8.5 |
| Diarrhea |
17.1 |
8.9 |
| Vomiting |
10.9 |
3.6 |
| Constipation |
9.9 |
4.8 |
| Upper Respiratory Tract Infection |
9.5 |
5.6 |
| Headache |
9.1 |
9.3 |
| Influenza |
7.4 |
3.6 |
| Urinary Tract Infection |
6.0 |
4.0 |
| Dizziness |
5.8 |
5.2 |
| Sinusitis |
5.6 |
6.0 |
| Nasopharyngitis |
5.2 |
5.2 |
| Back Pain |
5.0 |
4.4 |
| Hypertension |
3.0 |
6.0 |
Table 2 Adverse events 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 Event Term
|
(%) |
(%) |
(%) |
| Nausea |
15.2 |
4.1 |
3.3 |
| Diarrhea |
10.9 |
4.1 |
3.7 |
| Headache |
9.0 |
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 Event Term
|
(%) |
(%) |
(%) |
| 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 Event Term
|
(%) |
(%) |
(%) |
| 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 Event Term
|
(%) |
(%) |
| Nausea |
34.6 |
8.6 |
| Diarrhea |
14.1 |
6.3 |
| Vomiting |
12.4 |
2.9 |
| Decreased Appetite |
9.3 |
1.1 |
| Anorexia |
9.0 |
0.0 |
| Headache |
8.2 |
4.6 |
| Constipation |
5.1 |
1.1 |
| Fatigue |
5.1 |
1.7 |
Gastrointestinal adverse events
In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza-treated patients and were dose-related. Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment.
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 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 52-week monotherapy trial and in 4.8% of the Victoza-treated patients in the 26-week add-on combination therapy trials. These cross-reacting 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 52-week monotherapy trial and in 1.0% of the Victoza-treated patients in the 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 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 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 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). 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 clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza-treated patients (2.6 cases per 1000 patient-years) and in no comparator-treated patients. Six of these 7 patients treated with Victoza were also taking a sulfonylurea. One other patient was taking Victoza in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 3). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake).
Table 3 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 |
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 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 |
|
|
|
|
|
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 [ see Adverse Reactions], 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.
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REPORTS OF SUSPECTED VICTOZA SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Victoza. The information is not vetted and should not be considered as verified clinical evidence.
Possible Victoza side effects / adverse reactions in 64 year old male
Reported by a physician from United States on 2011-10-05
Patient: 64 year old male weighing 136.5 kg (300.3 pounds)
Reactions: Weight Decreased, Pancreatitis
Adverse event resulted in: hospitalization
Suspect drug(s):
Victoza
Dosage: 1.2 mg, qd
Indication: Weight Decreased
Start date: 2011-06-01
End date: 2011-06-18
Victoza
Dosage: 0.6 mg, qd
Indication: Type 2 Diabetes Mellitus
Start date: 2011-05-17
Other drugs received by patient: Levemir
Possible Victoza side effects / adverse reactions in 71 year old female
Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-05
Patient: 71 year old female weighing 78.6 kg (173.0 pounds)
Reactions: Pancreatitis
Adverse event resulted in: hospitalization
Suspect drug(s):
Victoza
Other drugs received by patient: Metformin HCL
Possible Victoza side effects / adverse reactions in 38 year old female
Reported by a physician from United States on 2011-10-05
Patient: 38 year old female weighing 121.9 kg (268.2 pounds)
Reactions: Cerebrovascular Accident
Adverse event resulted in: hospitalization
Suspect drug(s):
Victoza
Other drugs received by patient: Xanax; Opana; Lantus; Twynsta /06289301/
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