Drug Information for Lantus (Physicians Total Care, Inc.): 6. ADVERSE REACTIONS

  • The following adverse reactions are discussed elsewhere:

    • Hypoglycemia [See Warnings and Precautions (5.3)]
    • Hypersensitivity and allergic reactions [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 to 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 LANTUS 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 pooled clinical trials up to 28 weeks duration in adults with type 1 diabetes (adverse events with frequency greater than or equal to 5%)
    LANTUS, %(n=1257)NPH, %(n=1070)
    Upper respiratory tract infection22.423.1
    Infection (*)9.410.3
    Accidental injury5.76.4
    (*) Body System not Specified
    Table 2: Treatment –emergent adverse events in pooled clinical trials up to 1 year duration in adults with type 2 diabetes (adverse events with frequency greater than or equal to 5%)
    LANTUS, %(n=849)NPH, %(n=714)
    Upper respiratory tract infection11.413.3
    Infection (*)10.411.6
    Retinal vascular disorder5.87.4
    (*) Body System not Specified
    Table 3: Treatment –emergent adverse events in a 5-year trial of adults with type 2 diabetes (adverse events with frequency greater than or equal to 10%)
    LANTUS, %(n=514)NPH, %(n=503)
    Upper respiratory tract infection29.033.6
    Edema peripheral20.022.7
    Pain in extremity13.013.1
    Back pain12.812.3
    Urinary tract infection10.710.1
    Table 4: Treatment –emergent adverse events in a 28-week clinical trial of children and adolescents with type 1 diabetes (adverse events with frequency greater than or equal to 5%)
    LANTUS, %(n=174)NPH, %(n=175)
    Infection (*)13.817.7
    Upper respiratory tract infection13.816.0
    (*) Body System no Specified
    • Severe Hypoglycemia

    Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LANTUS [See Warnings and Precautions (5.3)]. Tables 5 and 6 summarize the incidence of severe hypoglycemia in the LANTUS individual clinical trials. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (=56 mg/dL in the 5-year trial) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration.

    The rates of severe symptomatic hypoglycemia in the LANTUS clinical trials (see Section 14 for a description of the study designs) were comparable for all treatment regimens (see Tables 5 and 6). In the pediatric phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type 1 diabetes. (see Table 5) [See Clinical Studies (14)].

    Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes
    Study A Diabetes Adults In combination regular Type 1 28 weeks with insulinStudy B Diabetes Adults In combinationregularType 128 weeks with insulin Study C Diabetes AdultsIn combination insulinType 116 weeks withlisproStudy D Diabetes PediatricsIn combinationregular Type 126 weeks with insulin
    Percent ofpatients (n/totalN)10.6(31/292)15.0(44/293)8.7(23/264)10.4(28/270)6.5(20/310)5.2(16/309)23.0(40/174)28.6(50/175)
    Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes
    Study E Diabetes Adults In combination oralType 2 52 weekswith agentsStudy F Diabetes Adults In combination regular Type 228 weekswith insulinStudy G Diabetes Adults In combination regularType 2 5 yearswithinsulin
    Percent ofpatients (n/totalN)1.7(5/289)1.1(3/281)0.4(1/259)2.3(6/259)7.8(40/513)11.9(60.504)
    • Retinopathy

    Retinopathy was evaluated in the LANTUS clinical studies by analysis of reported retinal adverse events and fundus photography. The numbers of retinal adverse events reported for LANTUS and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes.

    LANTUS was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 diabetes (mean age 55 yrs) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. Patients with pre-specified post-baseline eye procedures (pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 7 for both the per-protocol and Intent-to-Treat populations, and indicate similarity of Lantus to NPH in the progression of diabetic retinopathy as assessed by this outcome.

    Table 7. Number (%) of patients with 3 or more step progression on ETDRS scale at endpoint
    Lantus (%)NPH (%)Difference (*,**) (SE)95% CI for difference
    Per-protocol 53/374 (14.2%)57/363 (15.7%)-2.0% (2.6%)-7.0% to +3.1%
    Intent-to-Treat63/502 (12.5%)71/487 (14.6%)-2.1% (2.1%)-6.3% to +2.1%
    (*) Difference = Lantus - NPH(**) using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function
    • 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 LANTUS, 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 or infusion sites within the same region to reduce the risk of lipodystrophy. [See Dosage and Administration (2.1)].

    • Weight gain

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

    • Peripheral Edema

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

    • Allergic Reactions

    Local Allergy

    As with any insulin therapy, patients taking LANTUS may experience injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of treatment-emergent injection site pain in LANTUS-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). 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.

    Systemic Allergy

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

    • Antibody production

    All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of LANTUS, increases in titers of antibodies to insulin were observed in NPH insulin and insulin glargine treatment groups with similar incidences.

    6.2 Postmarketing experience

    The following adverse reactions have been identified during post-approval use of LANTUS.

    Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

    Medication errors have been reported in which other insulins, particularly short-acting insulins, have been accidentally administered instead of LANTUS [See Patient Counseling Information (17)]. To avoid medication errors between LANTUS and other insulins, patients should be instructed to always verify the insulin label before each injection.

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