Victoza Information
Victoza (Liraglutide recombinant) Warning: Risk Of Thyroid C-cell Tumors
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza (Liraglutide recombinant) causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza (Liraglutide recombinant) is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors
Victoza (Liraglutide recombinant) Indications And Usage
Victoza (Liraglutide recombinant) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Victoza (Liraglutide recombinant) Dosage And Administration
Victoza (Liraglutide recombinant) can be administered once daily at any time of day, independently of meals, and can be injected subcutaneously in the abdomen, thigh or upper arm. The injection site and timing can be changed without dose adjustment.
For all patients, Victoza (Liraglutide recombinant) should be initiated with a dose of 0.6 mg per day for one week. The 0.6 mg dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg.
When initiating Victoza (Liraglutide recombinant) , consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycemia
Victoza (Liraglutide recombinant) solution should be inspected prior to each injection, and the solution should be used only if it is clear, colorless, and contains no particles.
Victoza (Liraglutide recombinant) Dosage Forms And Strengths
Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL).
Victoza (Liraglutide recombinant) Contraindications
Victoza (Liraglutide recombinant) is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
Victoza (Liraglutide recombinant) Warnings And Precautions
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice . Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza (Liraglutide recombinant) will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies .
In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza (Liraglutide recombinant) -treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza (Liraglutide recombinant) -treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non-liraglutide-treated patient developed elevated calcitonin concentrations while on treatment.
Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza (Liraglutide recombinant) clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza (Liraglutide recombinant) -treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza (Liraglutide recombinant) 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza (Liraglutide recombinant) 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza (Liraglutide recombinant) . In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza (Liraglutide recombinant) 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza (Liraglutide recombinant) 1.2 mg, placebo and active control, respectively. Otherwise, Victoza (Liraglutide recombinant) did not produce consistent dose-dependent or time-dependent increases in serum calcitonin.
Patients with MTC usually have calcitonin values >50 ng/L. In Victoza (Liraglutide recombinant) clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza (Liraglutide recombinant) -treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza (Liraglutide recombinant) -treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza (Liraglutide recombinant) . The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza (Liraglutide recombinant) -treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza (Liraglutide recombinant) . The clinical significance of these findings is unknown.
Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza (Liraglutide recombinant) , if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.
Victoza (Liraglutide recombinant) has not been found to be directly nephrotoxic in animal studies or clinical trials. There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in Victoza (Liraglutide recombinant) -treated patients . Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration . Some of the reported events occurred in patients receiving one or more medications known to affect renal function or hydration status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including Victoza (Liraglutide recombinant) . Use caution when initiating or escalating doses of Victoza (Liraglutide recombinant) in patients with renal impairment .
Victoza (Liraglutide recombinant) Adverse Reactions
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 (Liraglutide recombinant) was evaluated in a 52-week monotherapy trial and in five 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza (Liraglutide recombinant) 1.2 mg daily, Victoza (Liraglutide recombinant) 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza (Liraglutide recombinant) 0.6 mg, Victoza (Liraglutide recombinant) 1.2 mg, Victoza (Liraglutide recombinant) 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza (Liraglutide recombinant) 0.6 mg, Victoza (Liraglutide recombinant) 1.2 mg, Victoza (Liraglutide recombinant) 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza (Liraglutide recombinant) 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza (Liraglutide recombinant) 1.2 mg, Victoza (Liraglutide recombinant) 1.8 mg or placebo .
Withdrawals
The incidence of withdrawal due to adverse events was 7.8% for Victoza (Liraglutide recombinant) -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 (Liraglutide recombinant) -treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza (Liraglutide recombinant) -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, 2 and 3 summarize the adverse events reported in ≥5% of Victoza (Liraglutide recombinant) -treated patients in the six controlled trials of 26 weeks duration or longer.
Gastrointestinal adverse events
In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza (Liraglutide recombinant) -treated patients and were dose-related. Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza (Liraglutide recombinant) -treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In a 26-week study of Victoza (Liraglutide recombinant) versus exenatide, both in combination with metformin and/or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza (Liraglutide recombinant) and exenatide.
In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza (Liraglutide recombinant) -treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment.
In a 26 week study of Victoza (Liraglutide recombinant) versus exenatide, both in combination with metformin and/or sulfonylurea , the proportion of patients with nausea also declined over time.
Immunogenicity
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza (Liraglutide recombinant) may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza (Liraglutide recombinant) -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 (Liraglutide recombinant) -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 (Liraglutide recombinant) -treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza (Liraglutide recombinant) -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 assay occurred in 2.3% of the Victoza (Liraglutide recombinant) -treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza (Liraglutide recombinant) -treated patients in the 26-week add-on combination therapy trials.
Among Victoza (Liraglutide recombinant) -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 (Liraglutide recombinant) -treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza (Liraglutide recombinant) -treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza (Liraglutide recombinant) -treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza (Liraglutide recombinant) -treated, placebo-treated and active-control-treated patients, respectively. Among Victoza (Liraglutide recombinant) -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 (Liraglutide recombinant) -treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza (Liraglutide recombinant) when comparing mean HbA 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 HbA with Victoza (Liraglutide recombinant) treatment.
In clinical trials of Victoza (Liraglutide recombinant) , events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza (Liraglutide recombinant) -treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza (Liraglutide recombinant) -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 (Liraglutide recombinant) -treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza (Liraglutide recombinant) -treated patients discontinued due to injection site reactions.
Papillary thyroid carcinoma
In clinical trials of Victoza (Liraglutide recombinant) , there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza (Liraglutide recombinant) 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 (Liraglutide recombinant) -treated patients (2.6 cases per 1000 patient-years) and in two comparator-treated patients. Six of these 7 patients treated with Victoza (Liraglutide recombinant) were also taking a sulfonylurea. One other patient was taking Victoza (Liraglutide recombinant) in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 4). 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 (Liraglutide recombinant) , 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).
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 (Liraglutide recombinant) , 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 (Liraglutide recombinant) -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 (Liraglutide recombinant) -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.
The following additional adverse reactions have been reported during post-approval use of Victoza (Liraglutide recombinant) . 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.
Gastrointestinal: nausea, vomiting and diarrhea sometimes resulting in dehydration.
Renal and Urinary Disorders: increased serum creatinine, acute renal failure or worsening of chronic renal failure, which may sometimes require hemodialysis.
Victoza (Liraglutide recombinant) Use In Specific Populations
Pregnancy Category C.
There are no adequate and well-controlled studies of Victoza (Liraglutide recombinant) in pregnant women. Victoza (Liraglutide recombinant) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Liraglutide has been shown to be teratogenic in rats at or above 0.8 times the human systemic exposures resulting from the maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma area under the time-concentration curve (AUC). Liraglutide has been shown to cause reduced growth and increased total major abnormalities in rabbits at systemic exposures below human exposure at the MRHD based on plasma AUC.
Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day.
Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥ 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥ 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group.
In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times human exposure at the MRHD of 1.8 mg/day, based on plasma AUC. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F generation rats descended from liraglutide-treated rats compared to F generation rats descended from controls, but differences did not reach statistical significance for any group.
Victoza (Liraglutide recombinant) Overdosage
In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza (Liraglutide recombinant) 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.
Victoza (Liraglutide recombinant) Description
Victoza (Liraglutide recombinant) contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in has been engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor. The molecular formula of liraglutide is CHNO and the molecular weight is 3751.2 Daltons. The structural formula (Figure 1) is:
Victoza (Liraglutide recombinant) is a clear, colorless solution. Each 1 mL of Victoza (Liraglutide recombinant) solution contains 6 mg of liraglutide. Each pre-filled pen contains a 3 mL solution of Victoza (Liraglutide recombinant) equivalent to 18 mg liraglutide (free-base, anhydrous) and the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14 mg; phenol, 5.5 mg; and water for injection.
Victoza (Liraglutide recombinant) Clinical Pharmacology
Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying.
GLP-1(7-37) has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP.
Victoza (Liraglutide recombinant) ’s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as Victoza (Liraglutide recombinant) lowered fasting, premeal and postprandial glucose throughout the day .
Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after treatment to steady state with 0.6, 1.2 and 1.8 mg Victoza (Liraglutide recombinant) or placebo. Compared to placebo, the postprandial plasma glucose AUC was 35% lower after Victoza (Liraglutide recombinant) 1.2 mg and 38% lower after Victoza (Liraglutide recombinant) 1.8 mg.
Glucose-dependent insulin secretion
The effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) Victoza (Liraglutide recombinant) on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes during graded glucose infusion. In these patients, on average, the ISR response was increased in a glucose-dependent manner (Figure 2).
Glucagon secretion
Victoza (Liraglutide recombinant) lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of Victoza (Liraglutide recombinant) 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations.
Gastric emptying
Victoza (Liraglutide recombinant) causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.
Cardiac Electrophysiology (QTc)
The effect of Victoza (Liraglutide recombinant) on cardiac repolarization was tested in a QTc study. Victoza (Liraglutide recombinant) at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation.
Absorption
Distribution
Metabolism
3
Elimination
3
Specific Populations
Gender
Race and Ethnicity
Body Weight
Drug Interactions
In vitro assessment of drug-drug interactions
Victoza (Liraglutide recombinant) has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP) and plasma protein binding.
In vivo assessment of drug-drug interactions
The drug-drug interaction studies were performed at steady state with Victoza (Liraglutide recombinant) 1.8 mg/day. Before administration of concomitant treatment, subjects underwent a 0.6 mg weekly dose increase to reach the maximum dose of 1.8 mg/day. Administration of the interacting drugs was timed so that C of Victoza (Liraglutide recombinant) (8-12 h) would coincide with the absorption peak of the co-administered drugs.
Digoxin
A single dose of digoxin 1 mg was administered 7 hours after the dose of Victoza (Liraglutide recombinant) at steady state. The concomitant administration with Victoza (Liraglutide recombinant) resulted in a reduction of digoxin AUC by 16%; C decreased by 31%. Digoxin median time to maximal concentration (T) was delayed from 1 h to 1.5 h.
Lisinopril
A single dose of lisinopril 20 mg was administered 5 minutes after the dose of Victoza (Liraglutide recombinant) at steady state. The co-administration with Victoza (Liraglutide recombinant) resulted in a reduction of lisinopril AUC by 15%; C decreased by 27%. Lisinopril median T was delayed from 6 h to 8 h with Victoza (Liraglutide recombinant) .
Atorvastatin
Victoza (Liraglutide recombinant) did not change the overall exposure (AUC) of atorvastatin following a single dose of atorvastatin 40 mg, administered 5 hours after the dose of Victoza (Liraglutide recombinant) at steady state. Atorvastatin C was decreased by 38% and median T was delayed from 1 h to 3 h with Victoza (Liraglutide recombinant) .
Acetaminophen
Victoza (Liraglutide recombinant) did not change the overall exposure (AUC) of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after the dose of Victoza (Liraglutide recombinant) at steady state. Acetaminophen C was decreased by 31% and median T was delayed up to 15 minutes.
Griseofulvin
Victoza (Liraglutide recombinant) did not change the overall exposure (AUC) of griseofulvin following co-administration of a single dose of griseofulvin 500 mg with Victoza (Liraglutide recombinant) at steady state. Griseofulvin C increased by 37% while median T did not change.
Oral Contraceptives
A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of Victoza (Liraglutide recombinant) at steady state. Victoza (Liraglutide recombinant) lowered ethinylestradiol and levonorgestrel C by 12% and 13%, respectively. There was no effect of Victoza (Liraglutide recombinant) on the overall exposure (AUC) of ethinylestradiol. Victoza (Liraglutide recombinant) increased the levonorgestrel AUC by 18%. Victoza (Liraglutide recombinant) delayed T for both ethinylestradiol and levonorgestrel by 1.5 h.
Victoza (Liraglutide recombinant) Clinical Studies
A total of 4445 patients with type 2 diabetes participated in 6 phase 3 trials. There were 5 double-blind (one of these trials had an open-label active control insulin glargine arm), randomized, controlled clinical trials, one of 52 weeks duration and four of 26 weeks duration. There was also a 26 week open-label trial comparing Victoza (Liraglutide recombinant) to twice-daily exenatide. These multinational trials were conducted to evaluate the glycemic efficacy and safety of Victoza (Liraglutide recombinant) in type 2 diabetes as monotherapy and in combination with one or two oral anti-diabetic medications. The 5 add-on combination therapy trials enrolled patients who were previously treated with anti-diabetic therapy, and approximately two-thirds of patients in the monotherapy trial also were previously treated with anti-diabetic therapy. In total, 272 (6%) of the 4445 patients in these 6 trials were new to anti-diabetic therapy. In these 6 clinical trials, patients ranged in age from 19-80 years old and 54% were men. Approximately 79% of patients were Caucasian, and 6% were Black. In the 3 trials where ethnicity was captured, 23% of patients were Hispanic/Latino (n=399). In each of these trials, treatment with Victoza (Liraglutide recombinant) produced clinically and statistically significant improvements in hemoglobin A and fasting plasma glucose (FPG) compared to placebo. Victoza (Liraglutide recombinant) did not have adverse effects on blood pressure.
All Victoza (Liraglutide recombinant) -treated patients started at 0.6 mg/day. The dose was increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg for patients randomized to these higher doses. Victoza (Liraglutide recombinant) 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance .
Victoza (Liraglutide recombinant) How Supplied/storage And Handling
Victoza (Liraglutide recombinant) is available in the following package sizes containing disposable, pre-filled, multi-dose pens. Each individual pen delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL).
Each Victoza (Liraglutide recombinant) pen is for use by a single patient. A Victoza (Liraglutide recombinant) pen should never be shared between patients, even if the needle is changed.
Prior to first use, Victoza (Liraglutide recombinant) should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC) (Table 11). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze Victoza (Liraglutide recombinant) and do not use Victoza (Liraglutide recombinant) if it has been frozen.
After initial use of the Victoza (Liraglutide recombinant) pen, the pen can be stored for 30 days at controlled room temperature (59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Keep the pen cap on when not in use. Victoza (Liraglutide recombinant) should be protected from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the Victoza (Liraglutide recombinant) pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy.
Victoza (Liraglutide recombinant) Patient Counseling Information
Patients should be informed of the potential risks and benefits of Victoza (Liraglutide recombinant) and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.
Patients should be advised that the most common side effects of Victoza (Liraglutide recombinant) are headache, nausea and diarrhea. Nausea is most common when first starting Victoza (Liraglutide recombinant) , but decreases over time in the majority of patients and does not typically require discontinuation of Victoza (Liraglutide recombinant) .
Physicians should instruct their patients to read the before starting Victoza (Liraglutide recombinant) therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
See separate leaflet
Date of Issue: May 18, 2011
Version: 3
Victoza (Liraglutide recombinant) is a registered trademark of Novo Nordisk A/S.
Victoza (Liraglutide recombinant) is covered by US Patent Nos. 6,268,343, 6,458,924 and 7,235,627 and other patents pending.
Victoza (Liraglutide recombinant) Pen is covered by US Patent Nos. 6,004,297, 6,235,004, 6,582,404 and other patents pending.
© 2010-2011 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Victoza (Liraglutide recombinant) contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
1-877-484-2869
Victoza (Liraglutide recombinant) Medication Guide
Read this Medication Guide and Patient Instructions for Use that come with Victoza (Liraglutide recombinant) before you start using Victoza (Liraglutide recombinant) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have questions about Victoza (Liraglutide recombinant) after reading this information, ask your healthcare provider or pharmacist.
Serious side effects may happen in people who take Victoza (Liraglutide recombinant) , including:
These medical conditions can make you more likely to get pancreatitis in general. It is not known if having these conditions will lead to a higher chance of getting pancreatitis while taking Victoza (Liraglutide recombinant) .
Stop taking Victoza (Liraglutide recombinant) and call your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may happen with or without vomiting. The pain may be felt going from your abdomen through to your back. This type of pain may be a symptom of pancreatitis.
Do not use Victoza (Liraglutide recombinant) if:
Talk with your healthcare provider if you are not sure if you have any of these conditions.
Before taking Victoza (Liraglutide recombinant) , tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Victoza (Liraglutide recombinant) slows stomach emptying and can affect medicines that need to pass through the stomach quickly. Victoza (Liraglutide recombinant) may affect the way some medicines work and some other medicines may affect the way Victoza (Liraglutide recombinant) works. Tell your healthcare provider if you take other diabetes medicines, especially sulfonylurea medicines or insulin.
Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine.
Talk to your healthcare provider about how to recognize and treat low blood sugar. Make sure that your family and other people who are around you a lot know how to recognize and treat low blood sugar.
Call your healthcare provider right away if you have nausea, vomiting, or diarrhea that does not go away, or if you cannot drink liquids by mouth.
Common side effects of Victoza (Liraglutide recombinant) include:
Nausea is most common when first starting Victoza (Liraglutide recombinant) , but decreases over time in most people as their body gets used to the medicine. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the side effects with Victoza (Liraglutide recombinant) . For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Victoza (Liraglutide recombinant) for a condition for which it was not prescribed. Do not give Victoza (Liraglutide recombinant) to other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information you should know about using Victoza (Liraglutide recombinant) . If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Victoza (Liraglutide recombinant) that is written for health professionals.
For more information, go to Victoza (Liraglutide recombinant) .com or call 1-877-484-2869.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Victoza (Liraglutide recombinant) contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
1-877-484-2869
Issued: May 18, 2011
Version: 2
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Victoza (Liraglutide recombinant) is a registered trademark of Novo Nordisk A/S.
Victoza (Liraglutide recombinant) is covered by US Patent Nos. 6,268,343, 6,458,924 and 7,235,627 and other patents pending.
Victoza (Liraglutide recombinant) pen is covered by US Patent Nos. 6,004,297, 6,235,004, 6,582,404 and other patents pending.
© 2010-2011 Novo Nordisk
First read the Medication Guide that comes with your Victoza (Liraglutide recombinant) pen and then read these Patient Instructions for Use for information about how to use your Victoza (Liraglutide recombinant) pen the right way.
These instructions do not take the place of talking with your healthcare provider about your medical condition or your treatment.
Your Victoza (Liraglutide recombinant) pen contains 3 mL of Victoza (Liraglutide recombinant) and will deliver doses of 0.6 mg, 1.2 mg or 1.8 mg. The number of doses that you can take with a Victoza (Liraglutide recombinant) pen depends on the dose of medicine that is prescribed for you. Your healthcare provider will tell you how much Victoza (Liraglutide recombinant) to take.
Victoza (Liraglutide recombinant) pen should be used with Novo Nordisk disposable needles. Talk to your healthcare provider or pharmacist for more information about needles for your Victoza (Liraglutide recombinant) pen.
If you still see no drop of Victoza (Liraglutide recombinant) , use a new pen and contact Novo Nordisk at 1-877-484-2869.
Victoza (Liraglutide recombinant)
Victoza (Liraglutide recombinant)
