REZVOGLAR™ is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. Limitations of Use REZVOGLAR is not recommended for the treatment of diabetic ketoacidosis. REZVOGLAR™ is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. ( 1 ) Limitations of Use : Not recommended for the treatment of diabetic ketoacidosis.
( 1 )
Contraindications
REZVOGLAR is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . in patients with hypersensitivity to insulin glargine products or any of the excipients in REZVOGLAR [see Warnings and Precautions ( 5.5 )] . During episodes of hypoglycemia. ( 4 ) Hypersensitivity to insulin glargine products or any of the excipients in REZVOGLAR. ( 4 )
Warnings and precautions
Never share a REZVOGLAR KwikPen prefilled pen between patients, even if the needle is changed. ( 5.1 ) Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ( 5.2 ) Hypoglycemia: May be life-threatening.
Increase frequency of glucose monitoring with changes to: insulin dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. ( 5.3 , 6.1 ) Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. ( 5.4 , 6.3 ) Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur.
Discontinue REZVOGLAR. Monitor and treat if indicated. ( 5.5 , 6.1 ) Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. ( 5.6 ) Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. ( 5.7 )
REZVOGLAR KwikPen Prefilled Pen Between Patients REZVOGLAR KwikPen prefilled pens must never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.
5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6 )] .
Make any changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant oral and antidiabetic products may be needed.
5.3Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including insulin glargine products. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient.
Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )] , or who experience recurrent hypoglycemia. The long-acting effect of insulin glargine products may delay recovery from hypoglycemia. Risk Factors for Hypoglycemia 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 insulins, the glucose lowering effect time course of insulin glargine products may vary in different patients or at different times in the same patient and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology ( 12.2 )] . 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 concomitant drugs [see Drug Interactions ( 7 )] .
Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )] . Risk Mitigation Strategies for Hypoglycemia 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.
5.4Hypoglycemia Due to Medication Errors
Accidental mix-ups among insulin products have been reported. To avoid medication errors between REZVOGLAR and other insulins, instruct patients to always check the insulin label before each injection [see Adverse Reactions ( 6.3 )] .
5.5Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including insulin glargine products [see Adverse Reactions ( 6.1 )] . If hypersensitivity reactions occur, discontinue REZVOGLAR; treat per standard of care and monitor until symptoms and signs resolve. REZVOGLAR is contraindicated in patients who have had hypersensitivity reactions to insulin glargine products or one of the excipients in REZVOGLAR.
5.6Hypokalemia
All insulins, including insulin glargine products, 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).
5.7Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Thiazolidinediones
(TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including REZVOGLAR, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If 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.
Interactions
Table 8 includes clinically significant drug interactions with REZVOGLAR. Table 8: Clinically Significant Drug Interactions with REZVOGLAR Drugs that May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), sulfonamide antibiotics.
GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when REZVOGLAR is coadministered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of REZVOGLAR Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Intervention: Dosage increases and increased frequency of glucose monitoring may be required when REZVOGLAR is coadministered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of REZVOGLAR Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when REZVOGLAR is coadministered with these drugs.
Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine. Intervention: Increased frequency of glucose monitoring may be required when REZVOGLAR is coadministered with these drugs. Drugs that affect glucose metabolism: Adjustment of insulin dosage may be needed. ( 7 ) Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent.
( 5.3 , 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Published studies with use of insulin glargine products during pregnancy have not reported a clear association with insulin glargine products and adverse developmental outcomes (see Data). 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 glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dosage of 0.2 units/kg/day.
Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >10.
The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo-fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human Data Published data do not report a clear association with insulin glargine products and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups.
Animal Data Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day), on a mg/kg basis.
In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day on a mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles.
Fertility and early embryonic development appeared normal.
Adverse reactions
The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.3 )] . Hypoglycemia Due to Medication Errors [see Warnings and Precautions ( 5.4 )] . Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] . Hypokalemia [see Warnings and Precautions ( 5.6 )] . Adverse reactions commonly associated with insulin glargine products include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The data in Table 1 reflect the exposure of 2327 patients with type 1 diabetes to insulin glargine or NPH in Studies A, B, C, and D [see Clinical Studies ( 14.2 )] .
The type 1 diabetes population had the following characteristics: Mean age was 39 years. Fifty-four percent were male, 97% were Caucasian, 2% were Black or African American and 3% were Hispanic. The mean BMI was 25.1 kg/m 2 . The data in Table 2 reflect the exposure of 1563 patients with type 2 diabetes to insulin glargine or NPH in Studies E, F, and G [see Clinical Studies ( 14.3 )] . The type 2 diabetes population had the following characteristics: Mean age was 59 years.
Fifty-eight percent were male, 87% were Caucasian, 8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m 2 . The frequencies of adverse reactions during insulin glargine clinical studies in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below (Tables 1 , 2 , 3 , and 4 ). Table 1: Adverse Reactions Occurring ≥5% in Pooled Clinical Studies up to 28 Weeks Duration in Adults with Type 1 Diabetes * Body system not specified Insulin Glargine, % (n=1257) NPH, % (n=1070) Upper respiratory tract infection 22.4
23.1 Infection* 9.4
10.3 Accidental injury 5.7
6.4 Headache 5.5
4.7Table 2: Adverse Reactions
Occurring ≥5% in Pooled Clinical Studies up to 1 Year Duration in Adults with Type 2 Diabetes * Body system not specified Insulin Glargine, % (n=849) NPH, % (n=714) Upper respiratory tract infection 11.4
13.3 Infection* 10.4
11.6 Retinal vascular disorder 5.8
7.4Table 3: Adverse Reactions
Occurring ≥10% in a 5-Year Study of Adults with Type 2 Diabetes Insulin Glargine, % (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
16.1Pain
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
9.3Table 4: Adverse Reactions
Occurring ≥5% in a 28-Week Clinical Study in Pediatric Patients with Type 1 Diabetes * Body system not specified Insulin Glargine,% (n=174) NPH, % (n=175) Infection* 13.8
17.7 Upper respiratory tract infection 13.8
16.0 Pharyngitis 7.5
8.6 Rhinitis 5.2
5.1Severe Hypoglycemia
Hypoglycemia was the most commonly observed adverse reaction in patients treated with insulin glargine. Tables 5 , 6 , and 7 summarize the incidence of severe hypoglycemia in insulin glargine clinical studies. 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 study and ≤36 mg/dL in the ORIGIN study) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration.
Percentages of insulin glargine-treated adult patients who experienced severe symptomatic hypoglycemia in the insulin glargine clinical studies [see Clinical Studies ( 14 )] were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables 5 and 6 ). In the pediatric clinical study, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult studies with type 1 diabetes.
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 Insulin Glargine N=292 NPH N=293 Insulin Glargine N=264 NPH N=270 Insulin Glargine N=310 NPH N=309 Insulin Glargine N=174 NPH N=175 Percent of patients 10.6 15.0 8.7 10.4 6.5 5.2 23.0
28.6 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 Insulin Glargine N=289 NPH N=281 Insulin Glargine N=259 NPH N=259 Insulin Glargine N=513 NPH N=504 Percent of patients 1.7 1.1 0.4 2.3 7.8
11.9Table
7 displays the proportion of patients who experienced severe symptomatic hypoglycemia in the insulin glargine and Standard Care groups in the ORIGIN study [see Clinical Studies ( 14 )] . Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN Study ORIGIN Study Median duration of follow-up: 6.2 years Insulin Glargine (N=6231) Standard Care (N=6273) Percent of patients 5.6
1.8Peripheral Edema
Some patients taking insulin glargine products have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy Administration of insulin subcutaneously, including insulin glargine products, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration ( 2.2 )] .
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. Weight Gain Weight gain has occurred with insulin including insulin glargine products and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.
Hypersensitivity Reactions Local Reactions Patients taking insulin glargine experienced injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of injection site pain in insulin glargine-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.
Systemic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including insulin glargine products and may be life threatening.
6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
For the
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
INSULIN GLARGINE-AGLR 3ML(100UNITS/ML)
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA761215.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
