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Product Modules > Victoza PI > Flashcards

Victoza PI Flashcards

1
Q

Victoza carries a boxed warning for what?

A

risk of thyroid c-cell tumors

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2
Q

What is Victoza’s official indication?

A

Victoza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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3
Q

Does Victoza have any contraindications?

A

Yes, Victoza is contraindicated in: - patients with a personal or family history of MTC (medullary thyroid carcinoma) - patients with Multiple Endocrine Neoplasia syndrome 2 (MEN 2)

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4
Q

What does MTC in the Victoza PI stand for?

A

Medullary Thyroid Carcinoma

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5
Q

What does MEN 2 stand for in the Victoza PI?

A

Multiple Endocrine Neoplasia syndrome type 2

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6
Q

Victoza has 4 important limitations of use. What are they?

A
  1. Not recommended as first-line therapy for patients inadequately controlled on diet and exercise
  2. Limited data in patients with a history of pancreatitis
  3. Not for treatment of type 1 DM or DKA
  4. Has not been studied with prandial insulin.
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7
Q

When is Victoza dosed?

A

once a day, any time of day, independent of meals

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8
Q

Where can Victoza be injected?

A

subcutaneously in the abdomen, thigh, or upper arm

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9
Q

What dosage should therapy be initiated with Victoza?

A

Initiate at 0.6mg per day for one week. After one week, increase dose to 1.2 mg. If 1.2 is inadequate, increase to 1.8 mg.

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10
Q

Name the 6 Warnings & Precautions in the Victoza PI

A
  1. Thyroid C-cell rumors in animals
  2. Pancreatitis
  3. Serious hypoglycemia (when used with SFU or insulin)
  4. Renal impairment
  5. Hypersensitivity
  6. Macrovascular outcomes: no studies
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11
Q

What were the 4 common adverse reactions that were reported in >5% of treatment patients and more common than placebo?

A
  1. Headache
  2. Nausea
  3. Diarrhea
  4. Anti-liraglutide antibody formation
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12
Q

What were the rates of immunogenicity-related events, including urticaria, in Victoza-treated patients versus comparator patients?

A

0.8% (Victoza) versus 0.4% (comparator)

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13
Q

What is the exact wording of the boxed warning regarding thyroid c-cell rumors?

A

Liraglutide causes dose-dependent and treatment-duration dependent thyroid c-cell rumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza causes c-cell tumors, including MTC in humans, as human relevance could not be rules out by clinic or non clinical studies.

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14
Q

What is the function of the thyroid?

A

to regulate the body’s metabolism.

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15
Q

What percentage of new cases of cancers in the US are thyroid cancers?

A

2.5%

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16
Q

What percentage of cancer deaths in the US in 2009 was due to thyroid cancer?

A

0.3%

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17
Q

According to data from Surveillance Epidemiology and End Results (SEER), how many estimated cases of medullary thyroid cancer are represented per year?

A

600 cases per year

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18
Q

What are the 3 types of thyroid cancer?

A
  1. Differentiated (94%)
  2. Medullary (4%)
  3. Anaplastic (2%)
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19
Q

What is the 10-year survival rate of patients treated for MTC?

A

70-90%

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20
Q

According to Victoza’s indication, can it be used as monotherapy?

A

Yes, Victoza can be used as monotherapy. Although, a limitation of use is in the PI that says that it should not be used as first-line therapy.

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21
Q

Victoza has been studied with other diabetes medications in 5 different combinations. What are they?

A
  1. Victoza + metformin
  2. Victoza + SFU
  3. Victoza + met + SFU
  4. Victoza + met + insulin
  5. Victoza + met + TZD
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22
Q

Has Victoza been studied in combination with prandial insulin?

A

No

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23
Q

Should Victoza be used in patients with type 1 diabetes? Why or Why not?

A

No, because Victoza requires functioning beta cells to be effective.

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24
Q

Based on elimination half-life, patients should be advised to reinitiate Victoza at 0.6 mg if more than ________ days have elapsed since the last Victoza dose.

A

3 days. Upon reinitiation, Victoza should be titrated at the discretion of the prescribing HCP.

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25
Q

What should a patient do if they miss their scheduled Victoza dose?

A

a patient should just wait until their next schedule dose and take it as scheduled.

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26
Q

Each Victoza pen comes in a pre-filled pen that contains a total of ________ of liraglutide in solution.

A

18 mg

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27
Q

How many days worth of medicine is in one Victoza pen if the patient is on 1.2 mg daily?

A

15 days

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28
Q

How many days worth of medicine is in a Victoza pen if the patient is on 1.8 mg daily?

A

10 days

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29
Q

In clinical trials of Victoza, malignant C-cell carcinomas were detected in rats and mice. How much greater was the clinical exposure to these rats compared to controls?

A

A statistically significant increase in cancer was observed in rats receiving Victoza at 8-TIMES clinical exposure compared to controls.

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30
Q

In clinical trials of Victoza, how many reported cases of thyroid C-cell hyperplasia were there in the Victoza arm compared to the comparator-treated patients?

A

6 cases in Victoza patients compared to 2 in the comparator-treated arm (equals 1.3 vs. 1.0 cases per 1000 patient-years)

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31
Q

Of the 6 Victoza-treated patients who developed thyroid C-cell hyperplasia, how many had elevated calcitonin levels at baseline and throughout the trial?

A

5 out of 6

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32
Q

What is considered to be a biological marker for MTC?

A

calcitonin

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33
Q

True or False: At Weeks 26 and 52 in the Victoza clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator.

A

True

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34
Q

True or False: No cases of MTC have been reported in patients taking Victoza in the clinical trial, although 1 case was reported in a comparator group.

A

True.

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35
Q

What are the symptoms associated with thyroid tumors?

A
  1. mass in the neck
  2. trouble swallowing (dysphagia)
  3. shortness of breath (dyspnea)
  4. persistent hoarseness
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36
Q

In clinical trials of Victoza, how many cases of pancreatitis were reported in the Victoza-treated arm?

A

13 cases of pancreatitis were reported in Victoza-treated patients (compared to 1 in comparator-treated patients)

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37
Q

Of the 13 reported cases of pancreatitis in Victoza-treated patients, how many were acute pancreatitis versus chronic pancreatitis?

A

9 acute pancreatitis, 4 chronic pancreatitis

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38
Q

How many Victoza-treated patients had pancreatitis with necrosis, resulting in death, in the clinical trials?

A

1 patient, although clinical causality could not be established

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39
Q

What is the definition of pancreatitis?

A

inflammation of the pancreas

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40
Q

What is acute pancreatitis?

A

Acute pancreatitis is an inflammation of the pancreas that occurs suddenly. It usually resolves in a few days with treatment. It can be life-threatening illness with severe complications.

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41
Q

What are some of the causes of pancreatitis?

A
  1. Gallstones, which obstruct the ducts that carry bile or pancreatic secretions
  2. Chronic, heavy alcohol use
  3. Abdominal trauma
  4. Medications
  5. Infections
  6. Tumors
  7. Severe elevations of triglycerides
  8. Hyperglycemia
  9. Genetic abnormalities of the pancreas
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42
Q

What is chronic pancreatitis and what are its characteristics?

A

Chronic pancreatitis is inflammation of the pancreas that does not heal or improve. - it worsens over time and leads to permanent damage

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43
Q

What are some of the causes of chronic pancreatitis?

A
  1. heavy alcohol use (most common cause)
  2. hereditary disorders of the pancreas
  3. cystic fibrosis
  4. hyperglycemia
  5. hyperlipidemia
  6. hypertriglyceridemia
  7. Some medications
  8. Certain autoimmune conditions
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44
Q

True or False: the rate of pancreatitis in Victoza-treated patients is lower than in the general population of patients with type 2 diabetes.

A

True

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45
Q

Has Victoza been found to be directly nephrotoxic in either animal studies or clinical trials?

A

No, but there have been postmarketing reports of acute renal failure and worsening of chronic renal failure.

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46
Q

Is dose adjustment required in patients with renal impairment?

A

No, but initiation and dose escalation should be done with caution in these patients.

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47
Q

True or False: Patients have reported anaphylactic reactions and angioedema in postmarketing use of Victoza.

A

True.

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48
Q

The safety of Victoza has been evaluated in ____ clinical trials.

A

8

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49
Q

Of the 8 Victoza clinical trials, what was the length of each trial?

A

There was one 52-week monotherapy trial, and seven 26-week add-on therapy trials.

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50
Q

The incidence of withdrawals due to adverse events was _____ % for Victoza-treated patients and _____% for comparator-treated patients in the 5 double-blind trials of 26 weeks or longer.

A

7.8% (Victoza), 3.4% (comparator)

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51
Q

Of the 8 clinical trials evaluating Victoza, how many double-blind and how many were open-label?

A

5 double-blind, 3 open-label

52
Q

In the five double-blind clinical trial studies, what was the most common adverse reaction that led to withdrawal for Victoza-treated patients? What was the rate of incidence in these adverse reactions?

A
  1. Nausea (2.8% versus 0%)
  2. Vomiting (1.5% versus 0.1%)
53
Q

What was the incidence of nausea that lead to withdrawal in Victoza clinical trials?

A

2.8%

54
Q

What was the incidence of vomiting that led to withdrawal for Victoza-treated patients in the clinical trials?

A

1.5%

55
Q

When did withdrawal due to GI adverse events usually occur in Victoza clinical trials?

A

the first 2-3 months

56
Q

In the 5 double-blind clinical trials of 26 weeks or longer, GI adverse reactions were reported in ______% of Victoza-treated patients. Were these adverse events dose related?

A

41%. Yes.

57
Q

GI adverse events were reported in _____% of comparator-treated patients in Victoza clinical trials.

A

17%

58
Q

What were the common adverse reactions that occurred at a higher incidence among Victoza-treated patients?

A
  1. Nausea
  2. Vomiting
  3. Diarrhea
  4. Dyspepsia
  5. Constipation Acronym help: NVDDC
59
Q

In the 5 double-blind Victoza trials, approximately ______% of Victoza-treated patients reported nausea during the first 2 weeks of treatment compared to _____% of comparator-treated patients.

A

13%, 2%

60
Q

Were the incidence of GI side effect similar between Victoza and Byetta in the trial comparing two when used in combination with met and SFU?

A

Yes, the incidences were similar.

61
Q

In the 52-week Victoza monotherapy trial, the incidence of nausea in the Victoza arm was _____% compared to _____% in the glimepiride arm.

A

28.4%, 8.5%

62
Q

Approximately __________% of Victoza-treated patients in the 5 double-blind studies were tested for anti-liraglutide antibodies at the end of treatment. Low titers of anti-liraglutide antibodies were detected in ____% of these Victoza-treated patients.

A

50-70%, 8.6%

63
Q

Victoza is _______% homologous to endogenous GLP-1.

A

97%

64
Q

Among patients treated with Victoza in clinical studies, what percentage developed antibodies to the drug?

A

8.6%

65
Q

Test-tube studies in the Victoza clinical trial showed that there were enough antibodies present to neutralize the drug in _____% of samples from the monotherapy trial and ______% from the add-on studies.

A

2.3%, 1.0%

66
Q

Was there any difference in mean A1c reduction between patients with Victoza antibodies and those without?

A

No, there was no difference in mean A1c reduction (although the 3 patients with the highest level of antibodies showed no A1c reduction).

67
Q

In Victoza clinical trials, it was found that ___% of patients in the monotherapy trial and ____% in the add-on studies developed anti-liraglutide antibodies that reacted to the patients’ endogenous GLP-1 because it was so similar to liraglutide.

A

6.9%, 4.8%

68
Q

What was the most important consequence of antibody formation in the Victoza clinical trials?

A

There was an increase in the percentage of patients developing infections during Victoza treatment

69
Q

What percentage of patients who developed Victoza antibodies also had infections compared to those who did not develop antibodies?

A

40% versus 36%

70
Q

What was the most common type of infection seen in the Victoza patients who developed antibodies?

A

Nonserious upper respiratory infections

71
Q

What percentage of Victoza-treated patients reported injection site reactions?

A

2%

72
Q

What was the discontinuation rate in Victoza patients due to injection site reactions?

A

0.2%

73
Q

How many cases of papillary thyroid carcinoma were reported in the Victoza clinical trials?

A

7 cases in patients treated with Victoza, 1 case in comparator-treated patient

74
Q

In the 8 clinical trials of Victoza, how many Victoza-treated patients experienced hypoglycemia that required the assistance of another person compared to Byetta?

A

11 for Victoza versus 2 with Byetta

75
Q

In the open-label trial comparing Victoza to sitagliptin (Januvia), was the incidence of hypoglycemia comparable between treatment groups?

A

Yes

76
Q

In pooled analysis of Victoza clinical trials, what was the incidence rate (per 1,000 patient years) for malignant neoplasms for Victoza? Placebo? Comparator-treated?

A

10.9 - Victoza

6.3 - Placebo

7.2 - Comparator

77
Q

What is serum blilrubin a measure of?

A

Liver function

78
Q

Elevated serum bilirubin may reflect decreased ______________________.

A

liver function.

79
Q

Mildly elevated serum bilirubin concentrations occurred in _______% of Victoza-treated patients, _____% of placebo treated patients, and ______% of comparator-treated patients.

A

4.0%, 2.1%, 3.5%

80
Q

Did Victoza have any adverse effects on blood pressure in the clinical trials?

A

No.

81
Q

Mean increases from baseline in heart rate of ______ beats per minute have been observed with Victoza compared to placebo. The long term effects of this have not been established.

A

2 to 3

82
Q

What other adverse reactions have been reported in postmarketing use of Victoza?

A
  1. Dehydration from nausea, vomiting, and diarrhea
  2. Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring dialysis
  3. Angioedema and anaphylactic reactions
83
Q

What pregnancy category is Victoza?

A

C.

84
Q

Is it known whether Victoza is excreted in human milk?

A

It is not known. In lactating rats, Victoza was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations.

85
Q

Is Victoza indicated for pediatric use?

A

No.

86
Q

In the Victoza clinical trials, what percentage of the patients were 65 years or older? 75 years and older?

A

20%, 2.8%

87
Q

Was there any differences in safety or effectiveness between geriatric patients and younger patients in the Victoza clinical trials?

A

No.

88
Q

Is a dose adjustment recommended for patients with renal or hepatic impairment.

A

No, dose adjustment is not recommended, but there has been limited experience in patients with mild, moderate, or severe renal or hepatic impairment.

89
Q

Victoza is ___% homologous to endogenous GLP-1 by substituting _________ for _________ at position ___.

A

97%, arginine, lysine, 34.

90
Q

What 2 changes have been made that make liraglutide 97% homologous to native GLP-1?

A

The lysine at position 34 of the protein has been replaced with arginine, and a fatty acid chain (called palmitic acid) has been attached to the other lysine at position 26.

91
Q

Name the 3 ways that palmitic acid helps lengthen the lifetime of liraglutide in the body.

A
  1. promotes self-association of liraglutide in the subcutaneous space, slowing uptake into the blood
  2. binds liraglutide to plasma proteins, because bound liraglutide does not leave the bloodstream or get degraded
  3. helps to block degradation by DPP-4 and neutral endopeptidases
92
Q

True or False: the body contains several types of endogenous GLP-1.

A

True.

93
Q

What version of endogenous GLP-1 is modified to form liraglutide?

A

GLP-1 (7-37)

94
Q

What does GLP-1 (7-37) mean?

A

it means that it contains amino acids 7 through 37 from a longer precursor chain.

95
Q

GLP-1 (7-37) is less than _____% of the circulating GLP-1 in the blood, but it is an _______ form.

A

20%, active

96
Q

What is the half-life of endogenous GLP-1 (7-37)?

A

1 1/2 - 2 minutes

97
Q

What is the plasma half-life of liraglutide?

A

13 hours

98
Q

Why is the half-life of liraglutide 13 hours and the half-life of GLP-1 (7-37) is 2 minutes?

A

is a result of self-association that delays absorption, plasma protein binding and stability agsinst metabolic degradation by DPP-4 and NEP (neutral endopeptidases).

99
Q

Compared to placebo, the postprandial plasma glucose AUC (area under curve) was ____% lower after Victoza 1.2 mg and ____% lower after Victoza 1.8 mg.

A

35%, 38%

100
Q

Over 5 hours, the AUC of the graph of blood glucose vs time was ________% lower with approved doses of Victoza than with placebo.

A

35-38%

101
Q

Did Victoza produce QTc prolongation?

A

No

102
Q

Following subcutaneous injection of Victoza, when are maximum concentrations of liraglutide achieved?

A

8-12 hour post-dosing

103
Q

Overall, approximately ____% of injected liraglutide reached the bloodstream intact (its bioavailability).

A

55%

104
Q

Total exposure (AUC of the blood concentration vs. time graph) was ___% lower when the injection was made in the ______ compared with the abdomen.

A

22%, thigh

105
Q

The mean apparent clearance following SQ dosing of liraglutide is approximately _____L/h with an elimination half-life of approximately _____.

A

1.2 L/h, 13 hours.

106
Q

Did age have any effect on the pharmacokinetics of Victoza in clinical trials?

A

No.

107
Q

Based on pharmacokinetics analyses, females have ___% lower weight-adjusted clearance of Victoza compared to males.

A

34%

108
Q

What impact does patient body weight have Victoza pharmacokinetics?

A

With an increase in baseline body weight there is a decrease in the exposure of liraglutide.

109
Q

Compared to healthy subjects, how much lower was liraglutide AUC in mild, moderate, severe, and ESRD renal impairment?

A
  • Mild = 35%
  • Moderate = 19%
  • Severe = 29%
  • ESRD = 30%
110
Q

Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate, and severe hepatic impairment was how much lower?

A
  • Mild = 11%
  • Moderate = 14%
  • Severe = 42%
111
Q

True or False: Victoza has a high potential for pharmacokinetic drug-drug interactions related to CYP450 and plasma protein binding.

A

False: Victoza has a LOW potential for pharmacokinetic drug-drug interactions related to CYP450 and plasma protein binding.

112
Q

Name 7 drugs that were tested concomitantly with Victoza for drug-drug interactions.

A
  1. Digoxin
  2. Lisinopril
  3. Atorvastatin
  4. Acetaminophen
  5. Griseofulvin
  6. Oral contraceptives
  7. Insulin detemir
113
Q

There are 2 ways that drug-drug interactions can occur. What are they?

A
  1. When drugs are metabolized by the same system
  2. When drugs are excreted by the same organ
114
Q

Why is it unlikely for either metabolic interactions or elimination interactions to apply to liraglutide?

A

Because there is no dominant organ that metabolizes or excretes liraglutide.

115
Q

What is the most likely source for interactions between Victoza and other drugs?

A

The effect of delayed gastric emptying caused by Victoza.

116
Q

How many total patients participated in the Victoza phase 3 trials?

A

6,090 patients

117
Q

What did the 3 open-label Victoza trials study?

A
  1. Victoza compared to Byetta
  2. Victoza compared to Januvia
  3. Victoza + met + Levemir compared to Victoza + met alone
118
Q

How long was the Victoza monotherapy trial and what was it called?

A

52 weeks. LEAD-3

119
Q

What does LEAD stand for in the liraglutide clinical trials?

A

Liraglutide Effect and Action in Diabetes

120
Q

What percentage of the 6,090 patients enrolled in the Victoza clinical trials were new to anti-diabetic therapy?

A

4% (or 272 patients)

121
Q

What did LEAD-2 study in Victoza clinical trials?

A

Victoza as add-on to metformin

122
Q

What did LEAD-1 study?

A

Victoza as add-on to SFU

123
Q

Which Victoza clinical trial looked at Victoza as add-on to metformin and SFU?

A

LEAD-5

124
Q

What treatment combination did LEAD-4 study?

A

Victoza as add-on to metformin and TZD

125
Q

Which LEAD study compared Victoza and Byetta + metformin and/or SFU?

A

LEAD-6

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