Levemir PI Flashcards
Levemir is indicated to improve glycemic control in adults and ____________ with diabetes mellitus.
children
How can Levemir be dosed?
Either once daily or in divided daily doses.
When should Levemir be dosed when dosing once daily?
Either with the evening meal or at bedtime.
Why should injection sites be rotated within an injection area when taking Levemir?
to reduce the risk of lipodystrophy
May converting from other insulin therapies require adjustment of timing and dose of Levemir?
Yes. Blood glucoses should be monitored closely upon converting to Levemir.
How is Levemir supplied?
in either a 3mL Levemir FlexPen or a 10mL vial
Is it ok to administer Levemir via an insulin pump?
No, Levemir should not be administered via an insulin pump.
Is it ok to mix or dilute Levemir with other insulins or solutions?
No.
What are the adverse reactions associated with Levemir?
- hypoglycemia
- allergic reactions
- injection site reactions
- lipodystrophy
- rash
- pruritus
The signs of hypoglycemia may be reduced or absent in patients taking ___________ drugs with Levemir.
anti-andrenergic drugs.
What are examples of anti-adrenergic drugs?
- beta blockers
- clonidine
- guanethidine
- reserpine
Has Levemir been studied in children with type 2 diabetes?
No, Levemir has not been studied in children with type 2 diabetes. It has also not been studied in children with type 1 diabetes less than 2 years of age.
What specific populations is Levemir indicated to treat?
- adults with type 1 or type 2 diabetes
- children with type 1 diabetes who are 2 years of age or older
What 3 ways may Levemir be dosed when doing twice daily injections?
- with the evening meal
- at bedtime
- 12 hours after the morning dose
What is the recommended starting dose of Levemir in patients with Type 1 diabetes?
approximately 1/3 of their total daily insulin requirements
What is the recommended starting dose of Levemir in patients with type 2 diabetes who are inadequately controlled on oral antidiabetic medications?
10 units (or 0.1-0.2 units/kg) given once daily in the evening or divided into a twice daily regimen
When changing from Lantus to Levemir, can the change be done on a unit-to-unit basis?
Yes.
If converting from NPH to Levemir, can the change be done on a unit-for-unit basis?
Yes, but some patients may require more Levemir than NPH.
Can Levemir be administered intravenously or intramuscularly?
No, the intended duration of activity of Levemir is dependent on SC injection. Severe hypoglycemia could be caused by IM or IV injection.
What is the most common adverse reaction associated with insulin therapy, Levemir included?
Hypoglycemia
If a GLP-1 agonist is used in combination with Levemir what considerations should be made?
the Levemir dose may need to be lowered or more conservatively titrated to guard against hypoglycemia
Was any difference observed in the pharmacokinetics of Levemir between non-diabetic individuals with renal impairment and healthy volunteers?
No, difference was observed. However, some studies have shown increased circulating insulin concentrations in patients with renal impairment.
True/False: Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers.
True. Although some studies have shown increased circulating insulin concentrations in patients with liver impairment.
In the Levemir add-on to liraglutide+met trial, what dose of liraglutide did all patients receive during the 12-week run-in period?
1.8 mg
During the run-in period of the Levemir add-on to liraglutide+met trial, what percentage of patients withdrew from the trial?
17% (or 167 patients)
Why did most patients in the run-in period of the Levemir add-on to liraglutide+met withdraw from the trial?
GI adverse events
True/False: only patients who completed the 12-week run-in period of the Levemir add-on to lira+met trial with inadequate control were randomized to 26 weeks of add-on therapy with Levemir, or continued unchanged on lira 1.8 mg+met.
True
During the 26 week trial looking at Levemir as add-on to lira+met, what was the only adverse reaction reported in >5% of patients and greater than in patients treated with lira 1.8 mg+met alone?
Diarrhea
In 2 pooled trials, 1155 adults with type ___ diabetes were exposed to individualized doses of Levemir (n=767) or NPH (n=388).
type 1 diabetes
The mean duration of exposure to Levemir during the Levemir/NPH pooled trial was ___ days, and the total exposure to Levemir was ___ patient years.
153 days, 321 patient years.
In 2 pooled clinical trials of 16 weeks and 24 weeks comparing Levemir to NPH in adults with type 1, excluding hypoglycemia, what was the most common adverse reactions (incidence over 5%) in the Levemir arm?
- Upper respiratory infection - 26.1%
- Headache - 22.6%
- Pharyngitis - 9.5%
- Flu-like illness - 7.8%
- Abdominal pain - 6.0%
In a 26-week trial comparing Levemir +aspart to Lantus+aspart in adults with Type 1, what were the most common adverse events (over 5%) in the Levemir arm?
- Upper respiratory infection - 26.7%
- Headache - 14.3%
- Back pain - 8.1%
- Flu-like illness - 6.2%
- Gastroenteritis - 5.6%
- Bronchitis - 5.0%
In 2 pooled clinical trials of 22 weeks and 24 weeks in adults with Type 2 diabetes comparing Levemir+aspart to NPH+aspart, what were the most common adverse events (excluding hypoglycemia)?
- Upper respiratory infection - 12.5%
- Headache - 6.5%
Trial Info:
Levemir+aspart vs. NPH+aspart
26 weeks
Children and Adolescents
Type 1 diabetes
List the adverse events.
- Upper respiratory infection - 35.8%
- Headache - 31.0%
- Pharyngitis - 17.2%
- Gastroenteritis - 16.8%
- Flu-like illness - 13.8%
- Abdominal pain - 13.4%
- Pyrexia - 10.3%
- Cough - 8.2%
- Viral infection - 7.3%
- Nausea - 6.5%
- Rhinitis - 6.5%
- Vomiting - 6.5%
True/False: Intensification or rapid improvement in glucose control has been associated with a transitory, reversible opthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.
True.
Can weight gain occur with Levemir use?
Yes.
In phase 3 clinical trials of Levemir, antibody development was observed with _______ impact on glycemic control.
no apparent
True/False: the adverse events associated with Levemir were less than those observed with other insulin therapies.
False. The adverse events observed with Levemir were comparable to those observed with other insulin therapies.
Was the incidence of severe hypoglycemia similar for both Levemir and NPH patients with type 1 or type 2 diabetes?
Yes, although the incidence was higher overall in patients with type 1 diabetes.
List some of the drugs that may increase the blood-glucose-lowering effect of insulins including Levemir.
- OAD meds
- pramlintide acetate
- angiotensin converting enzyme (ACE) inhibitors
- disopyramide
- fibrates
- fluoxetine
- monoamine oxidase (MAO) inhibitors
- propoxyphene
- pentoxifylline
- salicylates
- somatostatin analogs
- sulfonamide antibiotics
List some of the drugs that may reduce the blood-glucose-lowering effect insulins including Levemir.
- corticosteroids
- niacin
- danazol
- diuretics
- sympathomimetic agents (epiniphrine, albuterol, terbutaline)
- glucagon
- isoniazid
- phenothiazine derivatives
- somatropin
- thyroid hormones
- estrogens
- progestogens (in oral contraceptives)
- protease inhibitors
- atypical antipsychotic medications
Name some medications that may either increase or decrease the blood-gucose lowering effect of insulin including Levemir.
- beta blockers
- clonidine
- lithium salts
- alcohol
- Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia
Anti-adrenergic drugs like beta blockers, clonidine, guanethidine, and reserpine may do what in patients taking insulin?
may reduce or hide the signs of hypoglycemia
What pregnancy category is Levemir?
Pregnancy Category B
True/False: A randomized controlled clinical trial of pregnant women with type 1 diabetes using Levemir during pregnancy did not show an increase in the risk of fetal abnormalities.
True.
What were the 2 most common adverse reactions in pregnant patients with type 1 diabetes?
- Nasopharyngitis
- Headache
True or False: the rates of pre-eclampsia observed in the Levemir study with pregnant patients were within expected rates for pregnancy complicated by diabetes.
True.
What was the proportion of patients experiencing severe hypoglycemia in Levemir and NPH treated patients?
- Levemir - 16.4%
- NPH - 20.4%
- But the rate was 1.1 and 1.2 events per patient year, respectively.
In about _____% of infants, Levemir was detected in the infant cord blood at levels above the lower level of quantification (<25pmol/L).
25%
True or False: No differences in pregnancy outcomes or the health of the fetus and newborn were seen with Levemir use.
True.
Is it known whether Levemir is excreted in human milk?
No, it is not known whether Levemir is excreted in human milk. Therefore, caution should be used when adminstering Levemir to a nursing woman.
What population of pediatric patients is acceptable to use Levemir.
- Type 1 patients who are 2 years of age or older
Has Levemir been studied in type 2 pediatric patients?
No, it has not.
Has Levemir been studied in the geriatric population?
Yes (3.9% of type 1 patients were over 65 and 28.6% in type 2 study were over 65; a total of 1.9% of patients were over 75 years).
What percentage of patients in the type 1 study were over the age of 65?
3.9% (64 patients)
What percentage of patients in the type 2 Levemir study were over 65?
28.6% (309 patients)
Was there any overall difference observed in safety or effectiveness between younger and geriatric patients in Levemir trials?
No.
True or False: Levemir and NPH had similar effects on A1c levels and hypoglycemia in pediatric patients.
True.
How is insulin detemir (Levemir) different from human insulin?
- amino acid threonine in position B30 has been omitted
- a C14 fatty acid chain has been atached to the amino acid B29
Describe how Levemir’s duration of action is generated?
- Self-associates to dimers and hexamers to delay absorption
- slowed by binding to albumin
A pharmacodynamic study of Levemir in type 1 patients showed a range of mean time between injection and the end of pharmacodynamic event to be from _____ to _________.
7.6 hours, >24 hours (24 hours was the end of the monitoring period).
True or False: In general, Levemir has a gradual GIR (glucose infusion rate) increase and sustained activity for many hours.
True.
After SC injection of Levemir, serum concentrations had a relatively constant concentration/time profile over _____ hours with the maximum serum concentration reached between ______ hours post-dose.
24 hours, 6-8 hours
Cmax of Levemir is achieved when?
between 6-8 hours post-dose
Levemir was more slowly absorbed when injected into the thigh. How much lower was its AUC compared to the upper arm and abdomen?
30-40% lower
What is the absolute bioavailability of Levemir?
approximately 60%
More than ____% of insulin detemir in the bloodstream is bound to albumin.
98%
Levemir has a very small volume of distribution. What is it?
0.1 L/kg
What is the terminal half-life of Levemir?
5-7 hours depending on the dose
Injection of Levemir resulted in higher AUC levels in what special populations?
children (6-12 years) 10% and elderly patients (>68 years) 35% due to reduced clearance
Was there any difference in pharmacokinetics of Levemir in healthy patients and patients with renal impairment?
No, the pharmacokinetics were not changed (although some studies of insulin have suggested that renal impairment may increase circulating levels of insulin).
True or False: Liver dysfunction was observed to change the pharmacokinetic parameters of Levemir.
True.
What was the change in pharmacokinetics of Levemir in patients with hepatic (liver) impairment?
Levemir exposure DECREASED with increasing degrees of hepatic impairment with a corresponding INCREASE in apparent clearance.
Describe the various clinical trials of Levemir.
- Levemir compared to NPH (either once or twice daily) in adult type 1 patients
- Levemir compared to NPH (either once or twice daily) in pediatric type 1 patients
- Levemir compared to NPH (either once or twice daily) in adults with type 2
- Levemir twice daily compared to Lantus once daily in patients with type 1 diabetes
In the Levemir clinical trials, what was used to determine the morning Levemir dosing titration?
the pre-dinner blood glucose from the evening before
In the Levemir clinical trials, was the reduction in HbA1c similar between Levemir, Lantus, and NPH groups>
Yes. There were no clinically relevant differences.
Describe Study A (Home study) of the Levemir clinical trials.
- 16 weeks
- Open label
- Adults with type 1 diabetes
- Patients were randomized to either:
- Levemir at 12 hour intervals
- Levemir in the morning at bedtime
- NPH in the morning and bedtime
- Insulin aspart (Novolog) was given before each meal
- Results: A1c reductions and FPG were similar in both arms
Describe Study B (Pieber study) of the Levemir clinical trials.
- 26 weeks
- Open label
- N = 320
- Adults with type 1 diabetes
- Randomized to either:
- twice daily Levemir (AM and bedtime)
- once daily Lantus (bedtime)
- patients received Novolog pre-meals
- A1c reductions were similar between the 2 arms
Describe Study C (Russell-Jones study) of the Levemir clinical trials.
- 24 weeks
- Open label
- N = 749
- Adults with type 1 diabetes
- Randomized to either:
- once daily Levemir (at bedtime) with regular human insulin at meals
- once daily NPH (at bedtime) with regular human insulin at meals
- Levemir and NPH had similar effects on A1c reduction
Studies A, B, and C in the Levemir clinical trials all studied what specific patient?
Type 1 adult patients
What was the duration of Study A comparing twice daily Levemir to twice daily NPH?
16 weeks
What was the duration of Study B comparing twice daily Levemir to once daily Lantus?
26 weeks
What was the duration of Study C comparing once daily Levemir to once daily NPH?
24 weeks
Describe the pediatric clinical trials for Levemir.
Study D - Type 1 (Robertson study)
- 26 weeks
- ages 6-17
- once or twice daily Levemir compared to once or twice daily NPH
- Novolog before meals
Study I - Type 1 (Thalange study)
- 52 weeks
- Ages 2-16
- once or twice daily Levemir compared to once or twice daily NPH
- Novolog before meals
Describe the Levemir clinical trials for adults with type 2 diabetes.
Study E (Hermansen study)
- 24 weeks
- open label
- Levemir twice daily vs. NPH twice daily
- in combination with 1 or 2 of these orals:
- metformin
- SFU
- AGI
- all patients were new to insulin
- A1c reductions were similar in both arms
Study F (Raslova study)
- 22 weeks
- open label
- Levemir vs.NPH both either once or twice daily with Novolog at meals
- Similar efficacy in both arms
What percentage of patients achieved an A1c goal of <7% in the adult type 2 Levemir studies who were not adequately controlled on OADs alone?
70% of Levemir patients and 74% of NPH patients
Describe the design of the Levemir combination trial with liraglutide.
- 26 week
- open label
- 988 patients inadequately controlled on metformin alone or inadequately controlled on metformin + SFU
- If pt was already on met+SFU, pt discontinued SFU for 12-week run-in period
- during the run-in period, pts received titrated 1.8mg Victoza
- 50% of pts after run-in period achieved <7%; these pts continued treatment in nonrandomized, observational arm
- 17% of pts withdrew due to GI events
- Remaining pts were randomized to 26 weeks of once daily Levemir (w/ met) or continued unchanged on Lira+met.
- Starting dose of Levemir was 10u
- Mean dose at study end was 39 u/day.
What percentage of patients discontinued the Levemir-liraglutide+met trial due to ineffective therapy in the lira arm vs the Levemir arm?
- 2% in the Victoza arm
- 2% in the Levemir arm
What was the percentage of patients achieving <7% in the Levemir+Lira+Met arm compared to the Lira+Met arm?
- 43% (Levemir+lira+met)
- 17% (lira+met arm)
How should unused Levemir be stored?
in the refrigerator between 2-8 degrees C (36-46 degrees F)
How long is unopened Levemir good without refrigeration?
Unfrigerated Levemir should be discarded 42 days after it is first kept out of the refrigerator.
After initial use, where should Levemir vials be kept?
in a refrigerator
Can an in-use vial of Levemir be stored outside of a refrigerator?
The in-use Levemir vial may be kept at room temperature, but it should be discarded 42 days after first being unrefrigerated.
After first use, how should a Levemir FlexPen be stored?
- it must NOT be stored in a refrigerator
- it must NOT be stored with a needle in place
- it must be kept in a cool place, away from direct sunlight and heat
- Unrefrigerated Levemir FlexPens should be discarded 42 days after first kept out of refrigerator.
