"Miriam E. Tucker
Medscape Medical News
The U.S. Food and Drug Administration (FDA) will now require a "for single patient use only" warning on all multidose pen devices used for injectable diabetes medications.
Dosage Adjustment And Monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.
As with all insulin preparations, the time course of action for LEVEMIR may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity.
LEVEMIR should only be administered subcutaneously.
Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular administration of the usual subcutaneous dose could result in severe hypoglycemia.
Do not use LEVEMIR in insulin infusion pumps.
Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR and the mixed insulin may be altered in an unpredictable manner.
Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk of hypoglycemia increases with intensive glycemic control.
When a GLP-1 receptor agonist is used in combination with LEVEMIR, the LEVEMIR dose may need to be lowered or more conservatively titrated to minimize the risk of hypoglycemia [see ADVERSE REACTIONS].
All patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion, or glucagon administration has been observed in clinical trials with insulin, including trials with LEVEMIR.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia [see DRUG INTERACTIONS].
The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia.
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control [see DRUG INTERACTIONS]. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient's awareness of hypoglycemia.
Hypersensitivity And Allergic Reactions
No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with renal impairment [see CLINICAL PHARMACOLOGY].
Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].
Fluid Retention And Heart Failure With Concomitant Use of PPAR-Gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including LEVEMIR, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
Patient Counseling Information
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
Instructions for Patients
Patients should be informed that changes to insulin regimens must be made cautiously and only under medical supervision. Patients should be informed about the potential side effects of insulin therapy, including hypoglycemia, weight gain, lipodystrophy (and the need to rotate injection sites within the same body region), and allergic reactions. Patients should be informed that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use caution when driving or operating machinery.
Accidental mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to always check the insulin label before each injection.
LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution.
Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals.
Patients should receive proper training on how to use Levemir. Instruct patients that when injecting Levemir, they must press and hold down the dose button until the dose counter shows 0 and then keep the needle in the skin and count slowly to 6. When the dose counter returns to 0, the prescribed dose is not completely delivered until 6 seconds later. If the needle is removed earlier, they may see a stream of insulin coming from the needle tip. If so, the full dose will not be delivered (a possible under-dose may occur by as much as 20%), and they should increase the frequency of checking their blood glucose levels and possible additional insulin administration may be necessary.
- If 0 does not appear in the dose counter after continuously pressing the dose button, the patient may have used a blocked needle. In this case they would not have received any insulin – even though the dose counter has moved from the original dose that was set.
- If the patient did have a blocked needle, instruct them to change the needle as described in Section 5 of the Instructions for Use and repeat all steps in the IFU starting with Section 1: Prepare your pen with a new needle. Make sure the patient selects the full dose needed.
Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or are contemplating pregnancy. Refer patients to the LEVEMIR “Patient Information” for additional information.
Never Share a LEVEMIR FlexPen or LEVEMIR FlexTouch Between Patients
Counsel patients that they should never share a LEVEMIR FlexPen or LEVEMIR FlexTouch with another person, even if the needle is changed. Sharing of the FlexPen or FlexTouch between patients may pose a risk of transmission of infection.
Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test. In a fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.
Use In Specific Populations
Pregnancy Category B
The background risk of birth defects, pregnancy loss, or other adverse events that exists for all pregnancies is increased in pregnancies complicated by hyperglycemia. Female patients should be advised to tell their physician if they intend to become, or if they become pregnant while taking LEVEMIR. A randomized controlled clinical trial of pregnant women with type I diabetes using LEVEMIR during pregnancy did not show an increase in the risk of fetal abnormalities. Reproductive toxicology studies in non-diabetic rats and rabbits that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and teratogenicity that were attributed to maternal hypoglycemia.
The increased risk of adverse events in pregnancies complicated by hyperglycemia may be decreased with good glucose control before conception and throughout pregnancy. Because insulin requirements vary throughout pregnancy and in the post-partum period, careful monitoring of glucose control is essential in pregnant women.
In an, open-label, clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of 152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the study (Total pregnant women = 310). Approximately one half of the study participants in each arm were randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first 8 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was < 7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient (n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically significant.
Adverse reactions in pregnant patients occurring at an incidence of ≥ 5% are shown in Table 7. The two most common adverse reactions were nasopharyngitis and headache. These are consistent with findings from other type 1 diabetes trials (see Table 1), and are not repeated in Table 7.
The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the LEVEMIR and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia, eight (8) cases in the LEVEMIR group and 1 case in the NPH insulin group required hospitalization. The rates of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by diabetes. Pre-eclampsia is a syndrome defined by symptoms, hypertension and proteinuria; the definition of pre-eclampsia was not standardized in the trial making it difficult to establish a link between a given treatment and an increased risk of pre-eclampsia. All events were considered unlikely related to trial treatment. In all nine (9) cases requiring hospitalization the women had healthy infants. Events of hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group than in the NPH insulin group as a whole. There was no difference between the treatment groups in mean blood pressure during pregnancy and there was no indication of a general increase in blood pressure.
In the NPH insulin group there were 6 serious adverse reactions in four mothers of the following placental disorders, 'Placenta previa', 'Placenta previa hemorrhage', and 'Premature separation of placenta' and 1 serious adverse reaction of 'Antepartum haemorrhage'. There were none reported in the LEVEMIR group.
The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6% and 5.1%, respectively. The abortions were reported under the following terms: 'Abortion spontaneous', 'Abortion missed', 'Blighted ovum', 'Cervical incompetence' and 'Abortion incomplete'.
Table 7: Adverse reactions during pregnancy in a trial
comparing insulin aspart + LEVEMIR to insulin aspart + NPH insulin in pregnant
women with type 1 diabetes (adverse reactions with incidence ≥ 5%)
|Urinary tract infection||9.9||5.7|
|Abdominal pain upper||5.9||3.8|
|*Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.|
The proportion of subjects experiencing severe hypoglycemia was 16.4% and 20.9% in LEVEMIR and NPH treated patients respectively. The rate of severe hypoglycemia was 1.1 and 1.2 events per patientyear in LEVEMIR and NPH treated patients respectively. Proportion and incidence rates for non-severe episodes of hypoglycemia were similar in both treatment groups (Table 8).
Table 8: Hypoglycemia in Pregnant Women with Type 1
|Study G Type 1 Diabetes Pregnancy In combination with insulin aspart|
|Severe hypoglycemia*||Percent of patients with at least 1 event (n/total N)||16.4 (25/152)||20.9 (33/158)|
|Non-severe hypoglycemia*||Percent of patients with at least 1 event (n/total N)||94.7 (144/152)||92.4 (146/158)|
|* For definition regarding severe and non-severe hypoglycemia see ADVERSE REACTIONS, Hypoglycemia. In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower level of quantification ( < 25 pmol/L).|
No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR use.
In a fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day (approximately 135 times a human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of 900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia resulting from insulin exposure in normal animals.
It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, use caution when administering LEVEMIR to a nursing woman. Women with diabetes who are lactating may require adjustments of their insulin doses.
The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been established in pediatric patients (age 2 to 17 years) with type 1 diabetes [see CLINICAL PHARMACOLOGY and Clinical Studies]. LEVEMIR has not been studied in pediatric patients younger than 2 years of age with type 1 diabetes. LEVEMIR has not been studied in pediatric patients with type 2 diabetes.
The dose recommendation when converting to LEVEMIR is the same as that described for adults [see DOSAGE AND ADMINISTRATION and Clinical Studies]. As in adults, the dosage of LEVEMIR must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose.
In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients (3.9%) in the type 1 diabetes trials and 309 of 1082 patients (28.6%) in the type 2 diabetes trials were ≥ 65 years of age. A total of 52 (7 type 1 and 45 type 2) patients (1.9%) were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but small sample sizes, particularly for patients ≥ 65 years of age in the type 1 diabetes trials and for patients ≥ 75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly.
Last reviewed on RxList: 12/2/2013
This monograph has been modified to include the generic and brand name in many instances.
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