Levemir (Page 2 of 8)

5.4 Hypoglycemia Due to Medication Errors

Accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting insulins, have been reported. To avoid medication errors between LEVEMIR and other insulins, instruct patients to always check the insulin label before each injection.

5.5 Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR. If hypersensitivity reactions occur, discontinue LEVEMIR; treat per standard of care and monitor until symptoms and signs resolve. LEVEMIR is contraindicated in patients who have had hypersensitivity reactions to insulin detemir or any of the excipients [see Contraindications (4)].

5.6 Hypokalemia

All insulin products, including LEVEMIR, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

5.7 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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere:

Hypoglycemia [see Warnings and Precautions (5.3)]
Medication errors [see Warnings and Precautions (5.4)]
Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)]
Hypokalemia [see Warnings and Precautions (5.6)]

6.1 Clinical Trial Experience

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 frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4 below. See Tables 5 and 6 for the hypoglycemia findings.

In two pooled trials, adults with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=767) or NPH (n=388). The mean duration of exposure to LEVEMIR was 153 days, and the total exposure to LEVEMIR was 321 patient-years. The most common adverse reactions are summarized in Table 1.

Table 1: Adverse Reactions Occurring in ≥5% of LEVEMIR-Treated Adult Patients with Type 1 Diabetes Mellitus in Two Trials of 16 Weeks and 24 Weeks Duration

LEVEMIR, %

(n = 767)

Upper respiratory tract infection

26.1

Headache

22.6

Pharyngitis

9.5

Influenza-like illness

7.8

Abdominal Pain

6.0

Adults with type 1 diabetes were exposed to LEVEMIR (n=161) or insulin glargine (n=159). The mean duration of exposure to LEVEMIR was 176 days, and the total exposure to LEVEMIR was 78 patient-years. The most common adverse reactions are summarized in Table 2.

Table 2: Adverse Reactions Occurring in ≥5% of LEVEMIR-Treated Adult Patients with Type 1 Diabetes Mellitus in a 26-week Trial

LEVEMIR, %

(n = 161)

Upper respiratory tract infection

26.7

Headache

14.3

Back pain

8.1

Influenza-like illness

6.2

Gastroenteritis

5.6

Bronchitis

5.0

In two pooled trials, adults with type 2 diabetes were exposed to LEVEMIR (n=432) or NPH (n=437). The mean duration of exposure to LEVEMIR was 157 days, and the total exposure to LEVEMIR was 186 patient-years. The most common adverse reactions were comparable to that observed in adult patients with type 1 diabetes mellitus; see Table 1.

Pediatric patients with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=232) or NPH (n=115). The mean duration of exposure to LEVEMIR was 180 days, and the total exposure to LEVEMIR was 114 patient-years. The most common adverse reactions are summarized in Table 3.

Table 3: Adverse Reactions Occurring in ≥5% of LEVEMIR-Treated Pediatric Patients with Type 1 Diabetes Mellitus in a 26-week Trial

LEVEMIR, %

(n = 232)

Upper respiratory tract infection

35.8

Headache

31.0

Pharyngitis

17.2

Gastroenteritis

16.8

Influenza-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

Adverse reactions in pregnant patients occurring at an incidence of ≥5% are shown in Table 4. The two most common adverse reactions were nasopharyngitis and headache. These are consistent with findings from other type 1 diabetes trials (see Table 1, Section 6.1.), and are not repeated in Table 4.

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’.

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.

Table 4: 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%)

LEVEMIR, %

(n = 152)

Anemia

13.2

Diarrhea

11.8

Pre-eclampsia

10.5

Urinary tract infection

9.9

Gastroenteritis

8.6

Abdominal pain upper

5.9

Vomiting

5.3

Abortion spontaneous

5.3

Abdominal pain

5.3

Oropharyngeal pain

5.3

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for LEVEMIR with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.

Table 5 (type 1 diabetes) and Table 6 (type 2 diabetes) summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR clinical trials.

For the adult trials and one of the pediatric trials (Study D), severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a plasma glucose value below 56 mg/dL (blood glucose below 50 mg/dL) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. For the other pediatric trial (Study I), severe hypoglycemia was defined as an event with semi-consciousness, unconsciousness, coma and/or convulsions in a patient who could not assist in the treatment and who may have required glucagon or intravenous glucose.

For the adult trials, including the trial in pregnant women (study G), and pediatric Study D, non-severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose <56 mg/dL (or equivalently blood glucose <50 mg/dL as used in Study A and C) that was self-treated by the patient. For pediatric Study I, non-severe hypoglycemia included asymptomatic events with plasma glucose <65 mg/dL as well as symptomatic events that the patient could self-treat or treat by taking oral therapy provided by the caregiver.

Table 5: Hypoglycemia in Patients with Type 1 Diabetes

Severe Hypoglycemia

Non-Severe Hypoglycemia

Percent of patients with at least 1 event

(n/total N)

Event/patient/

year

Percent of patients

(n/total N)

Event/patient/

year

Study A

Type 1 Diabetes

Adults

16 weeks

In combination with

insulin aspart

Twice-Daily

LEVEMIR

8.7

(24/276)

0.52

88.0

(243/276)

26.4

Study B

Type 1 Diabetes

Adults

26 weeks

In combination with

insulin aspart

Twice-Daily

LEVEMIR

5.0

(8/161)

0.13

82.0

(132/161)

20.2

Study C

Type 1 Diabetes

Adults

24 weeks

In combination with

regular insulin

Once-Daily LEVEMIR

7.5

(37/491)

0.35

88.4

(434/491)

31.1

Study D

Type 1 Diabetes

Pediatrics

26 weeks

In combination with

insulin aspart

Once- or Twice Daily LEVEMIR

15.9

(37/232)

0.91

93.1

(216/232)

31.6

Study I

Type 1 Diabetes

Pediatrics

52 weeks

In combination with insulin aspart

Once- or Twice Daily LEVEMIR

1.7

(3/177)

0.02

94.9

(168/177)

56.1

Study G

Type 1 Diabetes Pregnancy

In combination with insulin aspart

Once- or Twice Daily LEVEMIR

16.4

(25/152)

1.1

94.7

(144/152)

114.2

Table 6: Hypoglycemia in Patients with Type 2 Diabetes

Study E

Type 2 Diabetes

Adults

24 weeks

In combination with

oral agents

Study F

Type 2 Diabetes

Adults

22 weeks

In combination with

insulin aspart

Study H

Type 2 Diabetes

Adults

26 weeks in combination with Liraglutide and Metformin

Twice-Daily LEVEMIR

Once- or Twice Daily LEVEMIR

Once Daily LEVEMIR + Liraglutide +

Metformin

Severe hypoglycemia

Percent of patients with at least 1 event (n/total N)

0.4

(1/237)

1.5

(3/195)

0

Event/patient/year

0.01

0.04

0

Non-severe hypoglycemia

Percent of patients (n/total N)

40.5

(96/237)

32.3

(63/195)

9.2

(15/163)

Event/patient/year

3.5

1.6

0.29

Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR, and may be life-threatening.

Insulin Initiation and Intensification of Glucose Control

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy

Long-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration (2.1)].

Weight Gain

Weight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria [see Clinical Studies (14)]. In the clinical program, the mean change in body weight from baseline in adult patients with type 1 diabetes (Study A, B, and C) treated with LEVEMIR ranged from -0.3 kg to 0.5 kg. The mean change in body weight from baseline in adult patients with type 2 diabetes (Study E, F, and H) treated with LEVEMIR ranged from 0.5 kg to 1.2 kg.

Peripheral Edema

Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Injection Site Reactions

Patients taking LEVEMIR may experience injection site reactions, including localized erythema, pain, pruritus, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR reported injection site pain (0.25%).

Immunogenicity

All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In clinical trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic control.

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