Tresiba

Insulin degludec (rDNA origin) is a biosynthetic, long-acting human insulin analog.

Contraindications

• During episodes of hypoglycemia.1

• Hypersensitivity to insulin degludec or one of its excipients.1

Warnings/Precautions

Never Share an Insulin Degludec FlexTouch Pen Between Patients

Insulin degludec FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.1

Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

Changes in insulin, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously and only under medical supervision and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, adjustments in concomitant oral anti-diabetic treatment may be needed. When converting from other insulin therapies to insulin degludec follow dosing recommendations. 1

Hypoglycemia

Hypoglycemia is the most common adverse reaction of insulin, including insulin degludec. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Insulin degludec, or any insulin, should not be used during episodes of hypoglycemia.1

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers), or in patients who experience recurrent hypoglycemia.1

The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of insulin degludec may vary among different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature.1

Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.1

Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.1

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 insulin degludec and other insulins, instruct patients to always check the insulin label before each injection.1

Do not transfer insulin degludec from the insulin degludec pen to a syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia.1

Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including insulin degludec. If hypersensitivity reactions occur, discontinue insulin degludec; treat per standard of care and monitor until symptoms and signs resolve. Insulin degludec is contraindicated in patients who have had hypersensitivity reactions to insulin degludec or one of the excipients.1

Hypokalemia

All insulin products, including insulin degludec, 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).1

Fluid Retention and Congestive Heart Failure with Concomitant Use of a Peroxisome Proliferator-activated Receptor (PPAR)-Gamma Agonist

Thiazolidinediones (TZDs), which are PPAR-gamma agonists, can cause dose related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin, including insulin degludec and a PPAR-gamma agonist, should be observed for signs and symptoms of congestive heart failure. If congestive 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.1

Specific Populations

Pregnancy Category C.1

There are no well-controlled clinical studies of the use of insulin degludec in pregnant women. Patients should be advised to discuss with their health care provider if they intend to or if they become pregnant. Because animal reproduction studies are not always predictive of human response, insulin degludec should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients.1

Subcutaneous reproduction and teratology studies have been performed with insulin degludec and human insulin (NPH) as a comparator in rats and rabbits. In these studies, insulin was given to female rats before mating throughout pregnancy until weaning, and to rabbits during organogenesis. The effect of insulin degludec was consistent with those observed with human insulin as both caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at an insulin degludec dose of 21 units/kg/day (approximately 5 times the human exposure (AUC) at a human subcutaneous dose of 0.75 units/kg/day) and in rabbits at a dose of 3.3 units/kg/day (approximately 10 times the human exposure (AUC) at a human subcutaneous dose of 0.75 units/kg/day). The effects are probably secondary to maternal hypoglycemia.1

It is unknown whether insulin degludec is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, caution should be exercised when insulin degludec is administered to a nursing mother. Women with diabetes who are lactating may require adjustments in insulin dose, meal plan, or both.1

In rats, insulin degludec was secreted in milk and the concentration in milk was lower than in plasma.1

The safety and efficacy of insulin degludec in children and adolescents under the age of 18 have not been established.1

In controlled clinical studies a total of 77 (7%) of the 1102 insulin degludec-treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 insulin degludec-treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years or older. Differences in safety or effectiveness were not suggested in subgroup analyses comparing subjects older than 65 years to younger subjects.1

Nevertheless, greater caution should be exercised when insulin degludec is administered to geriatric patients since greater sensitivity of some older individuals to the effects of insulin degludec cannot be ruled out. The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the elderly.1

In clinical studies, a total of 75 (7%) of the 1102 insulin degludec-treated patients with type 1 diabetes had an estimated GFR less than 60 mL/min/1.73 m2 and 1 (0.1%) had an estimated GFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 insulin degludec-treated patients with type 2 diabetes had an estimated GFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR less than 30 mL/min/1.73 m2. 1

No clinically relevant difference in the pharmacokinetics of insulin degludec was identified in a study comparing healthy subjects and subjects with renal impairment including subjects with end stage renal disease. However, as with all insulin products, glucose monitoring should be intensified and the insulin degludec dosage adjusted on an individual basis in patients with renal impairment.1

No difference in the pharmacokinetics of insulin degludec was identified in a study comparing healthy subjects and subjects with hepatic impairment (mild, moderate, and severe hepatic impairment). However, as with all insulin products, glucose monitoring should be intensified and the insulin degludec dosage adjusted on an individual basis in patients with hepatic impairment.1

Common Adverse Effects

Adverse reactions commonly associated with insulin degludec are:

• Hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain.1

Specific Drugs

It is essential that the manufacturer’s labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Drugs that affect glucose metabolism: Adjustment of insulin dosage may be needed; closely monitor blood glucose.1

• Anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent.1

Insulin degludec is a long-acting type of insulin that works slowly, over about 24 hours. Insulin is one of many hormones that help the body turn the food we eat into energy. This is done by using the glucose (sugar) in the blood as quick energy. Also, insulin helps us store energy that we can use later. When you have diabetes mellitus, your body cannot make enough insulin or does not use insulin properly. This causes you to have too much sugar in your blood. Like other types of insulin, insulin degludec is used to keep your blood sugar level close to normal.

This medicine is available only with your doctor's prescription.

Never share insulin pens with others under any circumstances. It is not safe for one pen to be used for more than one person. Sharing needles or pens can result in transmission of hepatitis viruses, HIV, or other bloodborne illnesses.

Your doctor will want to check your or your child's progress at regular visits, especially during the first few weeks you take this medicine. Blood tests may be needed to check for unwanted effects.

It is very important to follow carefully any instructions from your health care team about:

• Alcohol—Drinking alcohol may cause severe low blood sugar. Discuss this with your health care team.
• Other medicines—Do not take other medicines during the time you or your child is taking insulin degludec unless they have been discussed with your doctor. This especially includes nonprescription medicines such as aspirin, and medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems.
• Counseling—Other family members need to learn how to prevent side effects or help with side effects if they occur. Also, patients with diabetes may need special counseling about diabetes medicine dosing changes that might occur because of lifestyle changes, such as changes in exercise and diet. Furthermore, counseling on contraception and pregnancy may be needed because of the problems that can occur in patients with diabetes during pregnancy.
• Travel—Keep a recent prescription and your medical history with you. Be prepared for an emergency as you would normally. Make allowances for changing time zones and keep your meal times as close as possible to your usual meal times.

In case of emergency—There may be a time when you need emergency help for a problem caused by your diabetes. You need to be prepared for these emergencies. It is a good idea to:

• Wear a medical identification (ID) bracelet or neck chain at all times. Also, carry an ID card in your wallet or purse that says that you have diabetes and a list of all of your medicines.
• Keep an extra supply of insulin degludec and syringes with needles or injection devices on hand in case high blood sugar occurs.
• Keep some kind of quick-acting sugar handy to treat low blood sugar.
• Have a glucagon kit and a syringe and needle available in case severe low blood sugar occurs. Check and replace any expired kits regularly.

Too much insulin degludec can cause hypoglycemia (low blood sugar). Low blood sugar also can occur if you use insulin degludec with another antidiabetic medicine, delay or miss a meal or snack, exercise more than usual, or drink alcohol. Symptoms of low blood sugar must be treated before they lead to unconsciousness (passing out). Different people may feel different symptoms of low blood sugar. It is important that you learn which symptoms of low blood sugar you usually have so that you can treat it quickly.

Symptoms of low blood sugar include anxiety, behavior change similar to being drunk, blurred vision, cold sweats, confusion, difficulty in thinking, dizziness or lightheadedness, drowsiness, excessive hunger, fast heartbeat, headache, irritability or abnormal behavior, nervousness, nightmares, restless sleep, shakiness, slurred speech, and tingling in the hands, feet, lips, or tongue.

If symptoms of low blood sugar occur, eat glucose tablets or gel, corn syrup, honey, or sugar cubes, or drink fruit juice, non diet soft drink, or sugar dissolved in water to relieve the symptoms. Also, check your blood for low blood sugar. Get to a doctor or a hospital right away if the symptoms do not improve. Someone should call for emergency help immediately if severe symptoms such as convulsions (seizures) or unconsciousness occur. Have a glucagon kit available, along with a syringe and needle, and know how to use it. Members of your household also should know how to use it.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your antidiabetic medicine or insulin, you overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual.

Symptoms of high blood sugar include blurred vision, drowsiness, dry mouth, flushed, dry skin, fruit-like breath odor, increased urination, ketones in the urine, loss of appetite, stomachache, nausea or vomiting, tiredness, troubled breathing (rapid and deep), unconsciousness, and unusual thirst.

If symptoms of high blood sugar occur, check your blood sugar level and then call your doctor for instructions.

This medicine can cause low blood sugar. Do not drive or do anything else that could be dangerous until you know how this medicine affects you.

This medicine may cause serious allergic reactions, including anaphylaxis, which can be life-threatening and require immediate medical attention. Tell your doctor right away if you or your child have a rash, itching, swelling of the face, tongue, and throat, trouble breathing, or chest pain after you receive the medicine.

This medicine may cause low levels of potassium in your blood. Do not use medicines, supplements, or salt substitutes that contain potassium unless you have discussed this with your doctor.

Using this medicine together with other diabetes medicine (eg, pioglitazone, rosiglitazone, Actos®, Actoplus Met®, Avandia®) may cause serious heart problem or edema (fluid retention). Check with your doctor immediately if you are rapidly gaining weight, having shortness of breath, chest pain or discomfort, extreme tiredness or weakness, trouble breathing, uneven heartbeat, or excessive swelling of the hands, wrist, ankles, or feet.

Tresiba is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus.

Limitations of Use

Tresiba is available as a clear, and colorless solution for injection in:

Pregnancy

Risk Summary

There are no available data with Tresiba or insulin degludec in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organogenesis. Pre-and post-implantation losses and visceral/skeletal abnormalities were observed in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day. These effects were similar to those observed in rats administered human insulin (NPH) [see Data].

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data

Animal Data

Insulin degludec was investigated in studies covering fertility, embryo-fetal development and pre- and post-natal development in rats and during the period of embryofetal development in rabbits. Human insulin (NPH insulin) was included as comparator. In these studies insulin degludec caused pre- and post-implantation losses and visceral/skeletal abnormalities when given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. Overall, the effects of insulin degludec were similar to those observed with human insulin, which were probably secondary to maternal hypoglycemia.

Lactation

Risk Summary

There are no data on the presence of insulin degludec in human milk, the effects on the breastfed infant, or the effects on milk production. Insulin degludec is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tresiba and any potential adverse effects on the breastfed infant from Tresiba or from the underlying maternal condition.

Data

In lactating rats, insulin degludec was present in milk at a concentration lower than that in plasma.

Pediatric Use

The safety and effectiveness of Tresiba to improve glycemic control in type 1 and type 2 diabetes mellitus have been established in pediatric patients 1 year of age and older. The safety and effectiveness of Tresiba have not been established in pediatric patients less than 1 year old.

The use of Tresiba in pediatric patients 1 year of age and older with type 1 and type 2 diabetes mellitus is supported by evidence from an adequate and well-controlled study and a pharmacokinetic study (studies included pediatric patients 1 year of age and older with type 1 diabetes mellitus) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The use of Tresiba in pediatric patients 1 year of age and older with type 2 diabetes mellitus is also supported by evidence from adequate and well-controlled studies in adults with type 2 diabetes mellitus [see Clinical Studies (14.3)].

In pediatric patients 1 year of age and older already on insulin therapy, start Tresiba at a reduced dose to minimize the risk of hypoglycemia [see Dosage and Administration (2.4)].

Geriatric Use

In controlled clinical studies [see Clinical Studies (14)] a total of 77 (7%) of the 1102 Tresiba -treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 Tresiba-treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years or older. Differences in safety or effectiveness were not suggested in subgroup analyses comparing subjects older than 65 years to younger subjects.

Nevertheless, greater caution should be exercised when Tresiba is administered to geriatric patients since greater sensitivity of some older individuals to the effects of Tresiba cannot be ruled out. The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the elderly.

Renal Impairment

In clinical studies [see Clinical Studies (14)] a total of 75 (7%) of the 1102 Tresiba-treated patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1 (0.1%) had an eGFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 Tresiba-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR less than 30 mL/min/1.73 m2.

No clinically relevant difference in the pharmacokinetics of Tresiba was identified in a study comparing healthy subjects and subjects with renal impairment including subjects with end stage renal disease [see Clinical Pharmacology (12.3)]. However, as with all insulin products, glucose monitoring should be intensified and the Tresiba dosage adjusted on an individual basis in patients with renal impairment.

Hepatic Impairment

No difference in the pharmacokinetics of Tresiba was identified in a study comparing healthy subjects and subjects with hepatic impairment (mild, moderate, and severe hepatic impairment) [see Clinical Pharmacology (12.3)]. However, as with all insulin products, glucose monitoring should be intensified and the Tresiba dosage adjusted on an individual basis in patients with hepatic impairment.

How Supplied

Tresiba is available as a clear and colorless solution in the following package sizes (see Table 15).

Table 15 Presentations of Tresiba

Recommended Storage

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

Unopened FlexTouch disposable prefilled pen:

Not in-use (unopened) Tresiba disposable prefilled pen should be stored in a refrigerator (36°F to 46°F [2°C to 8°C]). Discard after expiration date.

Open (In-Use) FlexTouch disposable prefilled pen:

The in-use Tresiba FlexTouch pen should be refrigerated (36°F to 46°F [2°C to 8°C]) or be kept at room temperature (below 86°F [30°C]) away from direct heat and light. The opened (in-use) Tresiba FlexTouch pen may be used for up to 56 days (8 weeks) after being opened, if it is refrigerated or kept at room temperature.

The storage conditions are summarized in Table 16:

Table 16: Storage Conditions for Tresiba FlexTouch

You should not use Tresiba if you are allergic to insulin degludec, or if you are having an episode of hypoglycemia (low blood sugar).

To make sure Tresiba is safe for you, tell your doctor if you have:

• liver or kidney disease;

• low levels of potassium in your blood (hypokalemia); or

• diabetic ketoacidosis (call your doctor for treatment).

Tell your doctor if you also take pioglitazone or rosiglitazone (sometimes contained in combinations with glimepiride or metformin). Taking certain oral diabetes medicines while you are using insulin may increase your risk of serious heart problems.

Follow your doctor's instructions about using insulin if you are pregnant or breast-feeding a baby. Blood sugar control is very important during pregnancy, and your dose needs may be different during each trimester of pregnancy. Your dose needs may also be different while you are breast-feeding.

Applies to insulin degludec: subcutaneous solution

Along with its needed effects, insulin degludec (the active ingredient contained in Tresiba) 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 degludec:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• rapid weight gain
• tingling of the hands or feet
• unusual weight gain or loss

• Anxiety
• blurred vision
• chills
• cold sweats
• confusion
• convulsions
• cool, pale skin
• cough
• decreased urine
• depression
• difficulty with swallowing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• fast heartbeat
• headache
• hives, itching, or skin rash
• increased hunger
• increased thirst
• irregular heartbeat
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• muscle pain or cramps
• nausea or vomiting
• nightmares
• numbness or tingling in the hands, feet, or lips puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• shakiness
• slurred speech
• sweating
• tightness in the chest
• unusual tiredness or weakness

Some side effects of insulin degludec 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:

• Abdominal or stomach pain
• body aches or pain
• diarrhea
• dry mouth
• ear congestion
• fever
• headache
• loss of voice
• nasal congestion
• nausea or vomiting
• runny nose
• sneezing
• sore throat

• 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
• redistribution or accumulation of body fat