Humalog

HUMALOG- insulin lispro injection, solution
Dispensing Solutions, Inc.

1 INDICATIONS AND USAGE

HUMALOG is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage Considerations

When given subcutaneously, HUMALOG has a more rapid onset of action and a shorter duration of action than regular human insulin.

The dosage of HUMALOG must be individualized. Blood glucose monitoring is essential in all patients receiving insulin therapy.

The total daily insulin requirement may vary and is usually between 0.5 to 1 unit/kg/day. Insulin requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or coadministered drugs.

2.2 Subcutaneous Administration

HUMALOG should be given within 15 minutes before a meal or immediately after a meal.

HUMALOG given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin.

HUMALOG administered by subcutaneous injection should be given in the abdominal wall, thigh, upper arm, or buttocks. Injection sites should be rotated within the same region (abdomen, thigh, upper arm, or buttocks) from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].

2.3 Continuous Subcutaneous Infusion (Insulin Pump)

HUMALOG may be administered by continuous subcutaneous infusion by an external insulin pump. Do not use diluted or mixed insulins in external insulin pumps. Infusion sites should be rotated within the same region to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)]. Change the HUMALOG in the reservoir at least every 7 days, change the infusion sets and the infusion set insertion site at least every 3 days.

The initial programming of the external insulin infusion pump should be based on the total daily insulin dose of the previous regimen. Although there is significant variability among patients, approximately 50% of the total dose is usually given as meal-related boluses of HUMALOG and the remainder is given as a basal infusion. HUMALOG is recommended for use in pump systems suitable for insulin infusion such as MiniMed, Disetronic, and other equivalent pumps [see For Patients Using Continuous Subcutaneous Insulin Pumps (17.2)].

3 DOSAGE FORMS AND STRENGTHS

HUMALOG 100 units per mL (U-100) is available as:

  • 10 mL vials
  • 3 mL vials
  • 3 mL prefilled pens
  • 3 mL Humalog KwikPen (prefilled)
  • 3 mL cartridges

4 CONTRAINDICATIONS

HUMALOG is contraindicated:

  • during episodes of hypoglycemia
  • in patients who are hypersensitive to HUMALOG or to any of its excipients.

5 WARNINGS AND PRECAUTIONS

5.1 Dose Adjustment and Monitoring

Glucose monitoring is essential for 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 insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted.

As with all insulin preparations, the time course of action for HUMALOG may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the site of injection, local blood supply, or local temperature. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages.

5.2 Hypoglycemia

Hypoglycemia is the most common adverse effect associated with insulins, including HUMALOG. The risk of hypoglycemia increases with tighter glycemic control. Patients must be educated to recognize and manage hypoglycemia. Hypoglycemia can happen suddenly and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening or cause death.

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), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions (7)].

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.

Rapid changes in serum glucose levels may induce symptoms similar to hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers [see Drug Interactions (7)] , or intensified diabetes control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.

5.3 Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMALOG [see Adverse Reactions (6.1)].

5.4 Hypokalemia

All insulin products, including HUMALOG, 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. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

5.5 Renal or Hepatic Impairment

Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment [see Clinical Pharmacology (12.3)].

5.6 Mixing of Insulins

HUMALOG for subcutaneous injection should not be mixed with insulin preparations other than NPH insulin. If HUMALOG is mixed with NPH insulin, HUMALOG should be drawn into the syringe first. Injection should occur immediately after mixing.

Do not mix HUMALOG with other insulins for use in an external subcutaneous infusion pump.

5.7 Subcutaneous Insulin Infusion Pumps

When used in an external insulin pump for subcutaneous infusion, HUMALOG should not be diluted or mixed with any other insulin. Change the HUMALOG in the reservoir at least every 7 days, change the infusion sets and the infusion set insertion site at least every 3 days. HUMALOG should not be exposed to temperatures greater than 98.6°F (37°C).

Malfunction of the insulin pump or infusion set or insulin degradation can rapidly lead to hyperglycemia and ketosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with HUMALOG may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see Dosage and Administration (2.3), How Supplied/Storage and Handling (16), and Patient Counseling Information (17.2)].

5.8 Drug Interactions

Some medications may alter insulin requirements and the risk for hypoglycemia or hyperglycemia [see Drug Interactions (7)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere:

  • Hypoglycemia [see Warnings and Precautions (5.2)].
  • Hypokalemia [see Warnings and Precautions (5.4)].

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 with those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

The frequencies of Treatment-Emergent Adverse Events during HUMALOG clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.

Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus (adverse events with frequency ≥5%)
Events, n (%) Lispro(n=81) Regular human insulin(n=86) Total(n=167)
Flu syndrome 28 (34.6) 28 (32.6) 56 (33.5)
Pharyngitis 27 (33.3) 29 (33.7) 56 (33.5)
Rhinitis 20 (24.7) 25 (29.1) 45 (26.9)
Headache 24 (29.6) 19 (22.1) 43 (25.7)
Pain 16 (19.8) 14 (16.3) 30 (18.0)
Cough increased 14 (17.3) 15 (17.4) 29 (17.4)
Infection 11 (13.6) 18 (20.9) 29 (17.4)
Nausea 5 (6.2) 13 (15.1) 18 (10.8)
Accidental injury 7 (8.6) 10 (11.6) 17 (10.2)
Surgical procedure 5 (6.2) 12 (14.0) 17 (10.2)
Fever 5 (6.2) 10 (11.6) 15 (9.0)
Abdominal pain 6 (7.4) 7 (8.1) 13 (7.8)
Asthenia 6 (7.4) 7 (8.1) 13 (7.8)
Bronchitis 6 (7.4) 6 (7.0) 12 (7.2)
Diarrhea 7 (8.6) 5 (5.8) 12 (7.2)
Dysmenorrhea 5 (6.2) 6 (7.0) 11 (6.6)
Myalgia 6 (7.4) 5 (5.8) 11 (6.6)
Urinary tract infection 5 (6.2) 4 (4.7) 9 (5.4)
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus (adverse events with frequency ≥5%)
Events, n (%) Lispro(n=714) Regular human insulin(n=709) Total(n=1423)
Headache 63 (11.6) 66 (9.3) 149 (10.5)
Pain 77 (10.8) 71 (10.0) 148 (10.4)
Infection 72 (10.1) 54 (7.6) 126 (8.9)
Pharyngitis 47 (6.6) 58 (8.2) 105 (7.4)
Rhinitis 58 (8.1) 47 (6.6) 105 (7.4)
Flu syndrome 44 (6.2) 58 (8.2) 102 (7.2)
Surgical procedure 53 (7.4) 48 (6.8) 101 (7.1)

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 HUMALOG, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.2, 2.3)].

Weight gain

Weight gain can occur with insulin therapy, including HUMALOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

Peripheral Edema

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

Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)

In a 12-week, randomized, crossover study in adult patients with type 1 diabetes (n=39), the rates of catheter occlusions and infusion site reactions were similar for HUMALOG and regular human insulin treated patients (see Table 3).

Table 3: Catheter Occlusions and Infusion Site Reactions
HUMALOG(n=38) Regular human insulin(n=39)
Catheter occlusions/month 0.09 0.10
Infusion site reactions 2.6% (1/38) 2.6% (1/39)

In a randomized, 16-week, open-label, parallel design study of children and adolescents with type 1 diabetes, adverse event reports related to infusion-site reactions were similar for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site adverse events were infusion site erythema and infusion site reaction.

Allergic Reactions

Local Allergy — As with any insulin therapy, patients taking HUMALOG may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of HUMALOG. 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.

Systemic Allergy — Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including HUMALOG. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.

In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving HUMALOG (n=2944).

Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in HUMALOG [see Contraindications (4)].

Antibody Production

In large clinical trials with patients with type 1 (n=509) and type 2 (n=262) diabetes mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both regular human insulin and HUMALOG (including patients previously treated with human insulin and naive patients). As expected, the largest increase in the antibody levels occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and declined over the remaining years of the study These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types.

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