Levemir

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity and allergic reactions [see WARNINGS AND PRECAUTIONS]

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 the LEVEMIR® add-on to liraglutide+metformin trial, all patients received liraglutide 1.8 mg + metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only those patients who completed the run-in period with inadequate glycemic control were randomized to 26 weeks of add-on therapy with LEVEMIR® or continued, unchanged treatment with liraglutide 1.8 mg + metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in ≥ 5% of patients treated with liraglutide 1.8 mg + metformin (11.7%) and greater than in patients treated with liraglutide 1.8 mg and metformin alone (6.9%).

In two pooled trials, a total of 1155 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 (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

A total of 320 adults with type 1 diabetes were exposed to individualized doses of 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 (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR® to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

In two pooled trials, a total of 869 adults with type 2 diabetes were exposed to individualized doses of 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 are summarized in Table 3.

Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)

A total of 347 children and adolescents (6-17 years) 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 4.

Table 4: Adverse reactions (excluding hypoglycemia) in one 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Pregnancy

A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1 diabetes. [see Use in Specific Populations]

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR® [see WARNINGS AND PRECAUTIONS].

Tables 5 and 6 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 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.

The rates of hypoglycemia in the LEVEMIR® clinical trials (see Clinical Studies) were comparable between LEVEMIR®-treated patients and non-LEVEMIR®-treated patients (see Tables 5 and 6).

Table 5: Hypoglycemia in Patients with Type 1 Diabetes

Table 6: Hypoglycemia in Patients with Type 2 Diabetes

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. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy [see DOSAGE AND ADMINISTRATION].

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].

Peripheral Edema

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

Allergic Reactions

As with any insulin therapy, 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%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy.

Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks.

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 [see WARNINGS AND PRECAUTIONS].

Antibody Production

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 phase 3 clinical trials of LEVEMIR®, antibody development has been observed with no apparent impact on glycemic control.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of LEVEMIR®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported during post-approval use of LEVEMIR® in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR® [see PATIENT INFORMATION]. To avoid medication errors between LEVEMIR® and other insulins, patients should be instructed always to verify the insulin label before each injection.

Levemir is a prescription medication used to treat type 1 and type 2 diabetes. Levemir, a long-acting form of insulin, works by replacing the insulin that is normally produced by the body and by helping the body to use sugar for energy. It also stops the liver from producing more sugar.

This medication comes in an injectable form and is typically injected under the skin once or twice daily.

Common side effects include redness and skin thickening at the injection site, weight gain, and constipation.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik)
• beta blockers such as atenolol (Tenormin), labetalol (Normodyne), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), and propranolol (Inderal)
• certain cholesterol-lowering medications such as fenofibrate (Antara, Lofibra, TriCor, Triglide) and gemfibrozil (Lopid)
• clonidine (Catapres, Catapres-TTS, in Clorpres)
• danazol
• disopyramide (Norpace, Norpace CR)
• diuretics ('water pills')
• fluoxetine (Prozac, Sarafem, in Symbyax)
• hormone replacement therapy
• isoniazid (INH, Nydrazid)
• lithium (Eskalith, Lithobid)
• medications for asthma and colds
• medications for mental illness and nausea
• monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl), and tranylcypromine (Parnate)
• octreotide (Sandostatin)
• oral contraceptives (birth control pills)
• oral medications for diabetes
• oral steroids such as dexamethasone (Decadron, Dexone)
• methylprednisolone (Medrol), and prednisone (Deltasone)
• pentamidine (NebuPent, Pentam)
• reserpine
• salicylate pain relievers such as aspirin, choline magnesium trisalicylate (Tricosal, Trilisate), choline salicylate (Arthropan), diflunisal (Dolobid), magnesium salicylate (Doan's, others), and salsalate (Argesic, Disalcid, Salgesic)
• somatropin (Nutropin, Serostim, others)
• sulfa antibiotics
• thyroid medications

This is not a complete list of Levemir drug interactions. Ask your doctor or pharmacist for more information.

Levemir can cause serious side effects, including:

• Low blood sugar (hypoglycemia). Symptoms of low blood sugar may include:
  • dizziness or lightheadedness
  • shakiness
  • hunger
  • fast heart beat
  • tingling in your hands, feet, lips or tongue
  • trouble concentrating or confusion
  • blurred vision
  • slurred speech
  • anxiety or mood changes
  • headache
  • sweating

Very low blood sugar (hypoglycemia) can cause loss of consciousness (passing out), seizures, and death. Talk to your doctor about how to tell if you have low blood sugar and what to do if this happens while taking Levemir. Know your symptoms of low blood sugar. Follow your doctor’s instructions for treating low blood sugar.

Talk to your doctor if low blood sugar is a problem for you. Your dose of Levemir may need to be changed.

• Skin thickening or pits at the injection site (lipodystrophy). Change (rotate) the area where you inject your insulin to help prevent these skin changes from happening. Do not inject insulin into areas of skin that have thickening or pits.
• Serious allergic reactions. Levemir can cause life-threatening symptoms. Get medical help right away if you have any of these symptoms of an allergic reaction:
  • a rash all over your body
  • itching
  • shortness of breath
  • trouble breathing (wheezing)
  • fast heartbeat
  • sweating
  • feel faint

Do not use Levemir if:

• Your blood sugar is too low (hypoglycemia).
• You are allergic to anything in Levemir.

While using Levemir you should avoid alcohol. Alcohol, including beer and wine, may affect your blood sugar when you take Levemir.

You may have difficulty concentrating or reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a car or operate machinery. Ask your doctor if it is alright to drive if you often have:

• low blood sugar
• decreased or no warning signs of low blood sugar

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Levemir falls into category B. In animal studies, pregnant animals were given Levemir, and some babies had problems.

It is very important to maintain control of your blood sugar levels during pregnancy. Your doctor will decide which insulin is best for you during your pregnancy.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Insulin overdose can cause life-threatening hypoglycemia. Symptoms include drowsiness, confusion, blurred vision, numbness or tingling in your mouth, trouble speaking, muscle weakness, clumsy or jerky movements, seizure (convulsions), or loss of consciousness.

Get emergency medical help if you have signs of insulin allergy: redness or swelling where an injection was given, itchy skin rash over the entire body, trouble breathing, fast heartbeats, feeling like you might pass out, or swelling in your tongue or throat.

Call your doctor at once if you have:

• fluid retention--weight gain, swelling in your hands or feet, feeling short of breath; or

• low potassium--leg cramps, constipation, irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling, muscle weakness or limp feeling.

Common side effects may include:

• low blood sugar;

• itching, mild skin rash; or

• thickening or hollowing of the skin where you injected the medicine.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Diabetes Mellitus

Treatment of type 1 diabetes mellitus in adults and children ≥6 years of age or type 2 diabetes mellitus in adults who require long-acting (basal) insulin for control of hyperglycemia.1 2 3 4 5

Not indicated for the treatment of diabetic ketoacidosis; short-acting IV insulins (e.g., regular insulin) are preferred.17 18 20

At least as effective for glycemic control in adults as isophane insulin human or insulin glargine.1 2 3 7 16 18

May be associated with less interindividual variability in fasting blood glucose concentration,2 7 10 16 17 22 23 lower risk for hypoglycemia,2 7 16 17 22 23 and a lower risk of weight gain1 2 7 16 17 22 than isophane insulin human.17 18 May provide advantages over isophane insulin human in patients who have had difficulty achieving adequate glycemic control without frequent hypoglycemic episodes and/or those at high risk of hypoglycemia, particularly nocturnal hypoglycemia.16 17 23 Additional study needed, especially in pediatric and geriatric patients.16 18 23

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Levemir is indicated to improve glycemic control in adults and children with diabetes mellitus.

Important Limitations of Use:

How Supplied

Levemir is available in the following package sizes: each presentation containing 100 Units of insulin detemir per mL (U-100).

FlexTouch can be used with NovoFine® or NovoTwist® disposable needles. Each FlexTouch is for use by a single patient. Levemir FlexTouch must never be shared between patients, even if the needle is changed.

Storage

Unused (unopened) Levemir should be stored in the refrigerator between 2° and 8°C (36° to 46°F). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not use Levemir if it has been frozen.

Unused (unopened) Levemir can be kept until the expiration date printed on the label if it is stored in a refrigerator. Keep unused Levemir in the carton so that it stays clean and protected from light.

If refrigeration is not possible, unused (unopened) Levemir can be kept unrefrigerated at room temperature, below 30°C (86°F) as long as it is kept as cool as possible and away from direct heat and light. Unrefrigerated Levemir should be discarded 42 days after it is first kept out of the refrigerator, even if the FlexTouch or vial still contains insulin.

Vials:

After initial use, vials should be stored in a refrigerator, never in a freezer. If refrigeration is not possible, the in-use vial can be kept unrefrigerated at room temperature, below 30°C (86°F) as long as it is kept as cool as possible and away from direct heat and light. Refrigerated Levemir vials should be discarded 42 days after initial use. Unrefrigerated Levemir vials should be discarded 42 days after they are first kept out of the refrigerator.

Levemir FlexTouch:

After initial use, the Levemir FlexTouch must NOT be stored in a refrigerator and must NOT be stored with the needle in place. Keep the opened (in use) Levemir FlexTouch away from direct heat and light at room temperature, below 30°C (86°F). Unrefrigerated Levemir FlexTouch should be discarded 42 days after they are first kept out of the refrigerator.

Always remove the needle after each injection and store the Levemir FlexTouchwithout a needle attached. This prevents contamination and/or infection, or leakage of insulin, and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination.

The storage conditions are summarized in Table 13:

Preparation and Handling

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Levemir should be inspected visually prior to administration and should only be used if the solution appears clear and colorless.

Mixing and diluting: Levemir must NOT be mixed or diluted with any other insulin or solution [See Warnings and Precautions (5.3)].

Common side effects of Levemir include: severe hypoglycemia. See below for a comprehensive list of adverse effects.

Applies to insulin detemir: subcutaneous solution

Along with its needed effects, insulin detemir (the active ingredient contained in Levemir) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking insulin detemir:

• Anxiety
• blurred vision
• chills
• cold sweats
• confusion
• cool, pale skin
• cough
• depression
• difficulty swallowing
• dizziness
• fast heartbeat
• fever
• headache
• hives
• hoarseness
• increased hunger
• irritation
• itching
• joint pain
• nausea
• nightmares
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness of the skin
• seizures
• shakiness
• skin rash
• slurred speech
• stiffness or swelling
• swelling of the eyelids, face, lips, hands, or feet
• tightness in the chest
• trouble breathing
• unusual tiredness or weakness

Some side effects of insulin detemir may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• decrease in the amount of urine
• noisy, rattling breathing
• redistribution or accumulation of body fat
• swelling of the fingers, hands, feet, or lower legs
• trouble breathing at rest
• weight gain

Applies to insulin detemir: subcutaneous solution

General

Adverse reactions associated with insulin detemir (the active ingredient contained in Levemir) include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash, and pruritus.[Ref]

Metabolic

Severe hypoglycemia defined as third party intervention, occurred in approximately 6% of patients receiving insulin detemir (the active ingredient contained in Levemir) in clinical trials. Weight gain has been reported with insulin therapy and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.[Ref]

Very common (10% or more): Hypoglycemia
Frequency not reported: Weight gain[Ref]

Local

Injection site reactions seem to occur more frequently with insulin detemir (the active ingredient contained in Levemir) than with human insulin products. Reactions have included pain, redness, hives, inflammation, bruising, swelling, and itching at the injection site. Most injection site reactions have been minor and transitory, disappearing in a few days to a few weeks, even with continued treatment.[Ref]

Common (1% to 10%): Injection site reactions
Uncommon (0.1% to 1%): Injection site pain[Ref]

Hypersensitivity

Hypersensitivity side effects have included both local and systemic reactions. Anaphylaxis has been reported. Local reactions have presented as erythema, local edema, and pruritus at the injection site. Most minor reactions to insulin at the injection site resolve in a few days to a few weeks.

Allergic reactions and potentially allergic reactions were reported more frequently in 3 clinical studies with subjects receiving combination oral antidiabetic agents compared with the frequency across all studies (2.2% versus 0.1% to 1%).[Ref]

Uncommon (0.1% to 1%): Allergic reactions[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Peripheral edema[Ref]

Insulin may cause sodium retention and edema, especially as metabolic control is improving.[Ref]

Ocular

Frequency not reported: Refraction disorder, worsening of diabetic retinopathy[Ref]

Rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder and worsening of diabetic retinopathy. However, long-term glycemic control decreases the risk of diabetic retinopathy.[Ref]

Dermatologic

Common (1% to 10%): Lipohypertrophy
Uncommon (0.1% to 1%): Lipoatrophy
Postmarketing reports: Rash urticaria[Ref]

Immunologic

In phase 3 trials, antibody development with no apparent impact on glycemic control was observed.[Ref]

Very common (10% or more): Influenza-like illness (up to 13%)
Common (1% to 10%): Viral infection
Frequency not reported: Antibody development[Ref]

Other

Common (1% to 10%): Pyrexia, fatigue[Ref]

Gastrointestinal

Very common (10% or more): Gastroenteritis (up to 16%), abdominal pain (up to 13%)
Common (1% to 10%): Nausea, vomiting, toothache[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection[Ref]

Nervous system

Rapid improvement in glucose control has been associated with a transitory, reversible acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk.[Ref]

Very common (10% or more): Headache (up to 31%)
Common (1% to 10%): Migraine, dizziness
Rare (less than 0.1%): Painful peripheral neuropathy[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 35%), pharyngitis (up to 17%)
Common (1% to 10%): Bronchitis, cough, rhinitis, sinusitis[Ref]

Some side effects of Levemir may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.