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adverse reactions
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) Adverse reactions commonly associated with LANTUS include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain. ( ) 6.1 To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 ≥ 5%) LANTUS, % (n=1257) NPH, % (n=1070) Upper respiratory tract infection 22.4 23.1 Infection Body System not Specified 9.4 10.3 Accidental injury 5.7 6.4 Headache 5.5 4.7 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 ≥ 5%) LANTUS, % (n=849) NPH, % (n=714) Upper respiratory tract infection 11.4 13.3 Infection Body System not Specified 10.4 11.6 Retinal vascular disorder 5.8 7.4 Table 3: Treatment –emergent adverse events in a 5-year trial of adults with type 2 diabetes (adverse events with frequency ≥ 10%) LANTUS, % (n=514) NPH, % (n=503) Upper respiratory tract infection 29.0 33.6 Edema peripheral 20.0 22.7 Hypertension 19.6 18.9 Influenza 18.7 19.5 Sinusitis 18.5 17.9 Cataract 18.1 15.9 Bronchitis 15.2 14.1 Arthralgia 14.2 16.1 Pain in extremity 13.0 13.1 Back pain 12.8 12.3 Cough 12.1 7.4 Urinary tract infection 10.7 10.1 Diarrhea 10.7 10.3 Depression 10.5 9.7 Headache 10.3 9.3 Table 4: Treatment –emergent adverse events in a 28-week clinical trial of children and adolescents with type 1 diabetes (adverse events with frequency ≥ 5%) LANTUS, % (n=174) NPH, % (n=175) Infection Body System not Specified 13.8 17.7 Upper respiratory tract infection 13.8 16.0 Pharyngitis 7.5 8.6 Rhinitis 5.2 5.1 Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LANTUS . Tables 5, and 6 and 7 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 and ≤36 mg/dL in the ORIGIN trial) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. [See ] Warnings and Precautions (5.3) The proportion of patients experiencing severe symptomatic hypoglycemia in the LANTUS clinical trials [ ] in adults with type 1 diabetes and type 2 diabetes were comparable for all treatment regimens (see and ). 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 Clinical Studies (14) Tables 5 6 Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study B Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study C Type 1 Diabetes Adults 16 weeks In combination with insulin lispro Study D Type 1 Diabetes Pediatrics 26 weeks In combination with regular insulin LANTUS NPH LANTUS NPH LANTUS NPH LANTUS NPH Percent of patients (n/total N) 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 Type 2 Diabetes Adults 52 weeks In combination with oral agents Study F Type 2 Diabetes Adults 28 weeks In combination with regular insulin Study G Type 2 Diabetes Adults 5 years In combination with regular insulin LANTUS NPH LANTUS NPH LANTUS NPH Percent of patients (n/total N) 1.7 (5/289) 1.1 (3/281) 0.4 (1/259) 2.3 (6/259) 7.8 (40/513) 11.9 (60/504) Table 7 displays the proportion of patients experiencing severe symptomatic hypoglycemia in the Lantus and Standard Care groups in the ORIGIN Trial [ ]. see Adverse Reactions (cardiovascular safety) Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN trial Median duration of follow-up: 6.2 years ORIGIN Trial LANTUS Standard Care Percent of patients (n/total N) 5.6 (352/6231) 1.8 (113/6273) 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 8 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 8: Number (%) of patients with 3 or more step progression on ETDRS scale at endpoint Lantus (%) NPH (%) Difference (SE) 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 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-Treat 63/502 (12.5%) 71/487 (14.6%) - 2.1% (2.1%) -6.3% to +2.1% 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 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. Cardiovascular Safety The Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an open-label, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of LANTUS to standard care on major adverse cardiovascular outcomes in 12,537 participants ≥ 50 years of age with abnormal glucose levels [i.e., impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)] or early type 2 diabetes mellitus and established cardiovascular (i.e., CV) disease or CV risk factors at baseline. The objective of the trial was to demonstrate that LANTUS use could significantly lower the risk of major cardiovascular outcomes compared to standard care. Two co-primary composite cardiovascular endpoints were used in ORIGIN. The first co-primary endpoint was the time to first occurrence of a major adverse cardiovascular event defined as the composite of CV death, nonfatal myocardial infarction and nonfatal stroke. The second co-primary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure. Participants were randomized to either LANTUS (N=6264) titrated to a goal fasting plasma glucose of ≤ 95 mg/dL or to standard care (N=6273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of participants were 75 years of age or older. The majority of participants were male (65%). Fifty nine percent were Caucasian, 25% were Latin, 10% were Asian and 3% were Black. The median baseline BMI was 29 kg/m . Approximately 12% of participants had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes. For patients with type 2 diabetes, 59% were treated with a single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure. The mean HbA1c (SD) at baseline was 6.5% (1.0). Fifty nine percent of participants had had a prior cardiovascular event and 39% had documented coronary artery disease or other cardiovascular risk factors. 2 Vital status was available for 99.9% and 99.8% of participants randomized to LANTUS and standard care respectively at end of trial. The median duration of follow-up was 6.2 years [range: 8 days to 7.9 years]. The mean HbA1c (SD) at the end of the trial was 6.5% (1.1) and 6.8% (1.2) in the LANTUS and standard care group respectively. The median dose of LANTUS at end of trial was 0.45 U/kg. Eighty-one percent of patients randomized to LANTUS were using LANTUS at end of the study. The mean change in body weight from baseline to the last treatment visit was 2.2 kg greater in the LANTUS group than in the standard care group. Overall, the incidence of major adverse cardiovascular outcomes was similar between groups (see ). All-cause mortality was also similar between groups. Table 9 Table 9: Cardiovascular Outcomes in ORIGIN - Time to First Event Analyses LANTUS N=6264 Standard Care N=6273 LANTUS vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Co-primary endpoints CV death, nonfatal myocardial infarction, or nonfatal stroke 1041 (2.9) 1013 (2.9) 1.02 (0.94, 1.11) CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure or revascularization procedure 1792 (5.5) 1727 (5.3) 1.04 (0.97, 1.11) Components of co-primary endpoints CV death 580 576 1.00 (0.89, 1.13) Myocardial Infarction (fatal or non-fatal) 336 326 1.03 (0.88, 1.19) Stroke (fatal or non-fatal) 331 319 1.03 (0.89, 1.21) Revascularizations 908 860 1.06 (0.96, 1.16) Hospitalization for heart failure 310 343 0.90 (0.77, 1.05) Cancer In the ORIGIN trial, the overall incidence of cancer (all types combined) or death from cancer (Table 10) was similar between treatment groups. Table 10: Cancer Outcomes in ORIGIN - Time to First Event Analyses LANTUS N=6264 Standard Care N=6273 LANTUS vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Cancer endpoints Any cancer event (new or recurrent) 559 (1.56) 561 (1.56) 0.99 (0.88, 1.11) New cancer events 524 (1.46) 535 (1.49) 0.96 (0.85, 1.09) Death due to Cancer 189 (0.51) 201 (0.54) 0.94 (0.77, 1.15) 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 ]. To avoid medication errors between LANTUS and other insulins, patients should be instructed to always verify the insulin label before each injection. [See Patient Counseling Information (17)