pathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. intervention : dosage increases and increased frequency of glucose monitoring may be required when lantus is coadministered with these drugs. drugs that may increase or decrease the blood glucose lowering effect of lantus drugs : alcohol, beta-blockers, clonidine, and lithium salts. pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. intervention : dosage adjustment and increased frequency of glucose monitoring may be required when lantus 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 lantus 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 )

tus. 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 ) 5.1 never share a lantus solostar prefilled pen, insulin syringe, or needle between patients lantus solostar prefilled pens must never be shared between patients, even if the needle is changed. patients using lantus vials must never re-use or share needles or syringes with another person. 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. 5.3 hypoglycemia hypoglycemia is the most common adverse reaction associated with insulins, including lantus. 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 lantus 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 lantus 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. 5.4 hypoglycemia due to medication errors accidental mix-ups among insulin products have been reported. to avoid medication errors between lantus and other insulins, instruct patients to always check the insulin label before each injection [see adverse reactions (6.3) ] . 5.5 hypersensitivity reactions severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including lantus [see adverse reactions (6.1) ] . if hypersensitivity reactions occur, discontinue lantus; treat per standard of care and monitor until symptoms and signs resolve. lantus is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or one of the excipients. 5.6 hypokalemia all insulins, including lantus, 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). 5.7 fluid 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 lantus, 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.

n. only use if the solution is clear and colorless with no visible particles. administer lantus subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see warnings and precautions (5.2) and adverse reactions (6) ] . during changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see warnings and precautions (5.2) ] . do not administer intravenously or via an insulin pump. do not dilute or mix lantus with any other insulin or solution. the lantus solostar prefilled pen dials in 1-unit increments. use lantus solostar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. 2.2 general dosing instructions administer lantus subcutaneously once daily at any time of day but at the same time every day. individualize and adjust the dosage of lantus based on the patient's metabolic needs, blood glucose monitoring results and glycemic control goal. dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see warnings and precautions (5.2) ] . in patients with type 1 diabetes, lantus must be used concomitantly with short-acting insulin. 2.3 initiation of lantus therapy recommended starting dosage in patients with type 1 diabetes the recommended starting dosage of lantus in patients with type 1 diabetes is approximately one-third of the total daily insulin requirements. use short-acting, premeal insulin to satisfy the remainder of the daily insulin requirements. recommended starting dosage in patients with type 2 diabetes the recommended starting dosage of lantus in patients with type 2 diabetes who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily. 2.4 switching to lantus from other insulin therapies dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to lantus from other insulin therapies [see warnings and precautions (5.3) ]. when switching from: once-daily toujeo (insulin glargine 300 units/ml) to once-daily lantus (100 units/ml), the recommended starting lantus dosage is 80% of the toujeo dosage that is being discontinued. once-daily nph insulin to once-daily lantus, the recommended starting lantus dosage is the same as the dosage of nph that is being discontinued. twice-daily nph insulin to once-daily lantus, the recommended starting lantus dosage is 80% of the total nph dosage that is being discontinued.

to lantus 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, 22% were black or african american and 33% were hispanic. the mean bmi was 25.1 kg/m 2 . the data in table 2 reflect the exposure of 1,563 patients with type 2 diabetes to lantus 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 lantus 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 lantus, % (n=1,257) nph, % (n=1,070) 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: adverse reactions occurring ≥5% in pooled clinical studies up to 1 year duration in adults with type 2 diabetes 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: adverse reactions occurring ≥10% in a 5-year study of adults with type 2 diabetes 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: adverse reactions occurring ≥5% in a 28-week clinical study in pediatric patients with type 1 diabetes 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 was the most commonly observed adverse reaction in patients treated with lantus. tables 5, 6, and 7 summarize the incidence of severe hypoglycemia in the lantus 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 lantus-treated adult patients who experienced severe symptomatic hypoglycemia in the lantus 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 lantus n=292 nph n=293 lantus n=264 nph n=270 lantus n=310 nph n=309 lantus 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 lantus n=289 nph n=281 lantus n=259 nph n=259 lantus n=513 nph n=504 percent of patients 1.7 1.1 0.4 2.3 7.8 11.9 table 7 displays the proportion of patients who experienced severe symptomatic hypoglycemia in the lantus 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 lantus n=6231 standard care n=6273 percent of patients 5.6 1.8 peripheral edema some patients taking lantus have experienced sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy. lipodystrophy administration of insulin subcutaneously, including lantus, 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 lantus and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. hypersensitivity reactions local reactions patients taking lantus 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 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. systemic reactions severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including lantus and may be life threatening. 6.2 immunogenicity as with all therapeutic proteins, there is potential for immunogenicity. 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 clinical studies of lantus, increases in titers of antibodies to insulin were observed in nph insulin and lantus treatment groups with similar incidences. 6.3 postmarketing experience the following adverse reactions have been identified during postapproval use of lantus. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. medication errors have been reported in which rapid-acting insulins and other insulins, have been accidentally administered instead of lantus localized cutaneous amyloidosis at the injection site has occurred. hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

pathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. intervention : dosage increases and increased frequency of glucose monitoring may be required when lantus is coadministered with these drugs. drugs that may increase or decrease the blood glucose lowering effect of lantus drugs : alcohol, beta-blockers, clonidine, and lithium salts. pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. intervention : dosage adjustment and increased frequency of glucose monitoring may be required when lantus 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 lantus 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 )

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 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. 8.2 lactation risk summary there are either no or only limited data on the presence of insulin glargine in human milk, the effects on breastfed infant, or the effects on milk production. endogenous insulin is present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for lantus, and any potential adverse effects on the breastfed child from lantus or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of lantus to improve glycemic control in pediatric patients with diabetes mellitus have been established. use of lantus for this indication is supported by evidence from an adequate and well-controlled study (study d) in 174 lantus-treated pediatric patients aged 6 to 15 years with type 1 diabetes mellitus, and from adequate and well-controlled studies of lantus in adults with diabetes mellitus [see clinical pharmacology (12.3) , clinical studies (14.2) ]. in the pediatric clinical study, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in studies with type 1 diabetes [see adverse reactions (6.1) ] . 8.5 geriatric use of the total number of subjects in controlled clinical studies of patients with type 1 and type 2 diabetes who were treated with lantus, 15% (n=316) were ≥65 years of age and 2% (n=42) were ≥75 years of age. no overall differences in safety or effectiveness of lantus have been observed between patients 65 years of age and older and younger adult patients. nevertheless, caution should be exercised when lantus is administered to geriatric patients. in geriatric patients with diabetes, the initial dosing, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. hypoglycemia may be difficult to recognize in geriatric patients. 8.6 renal impairment the effect of kidney impairment on the pharmacokinetics of lantus has not been studied. some studies with human insulin have shown increased circulating levels of insulin in patients with kidney failure. frequent glucose monitoring and dosage adjustment may be necessary for lantus in patients with kidney impairment [see warnings and precautions (5.3) ]. 8.7 hepatic impairment the effect of hepatic impairment on the pharmacokinetics of lantus has not been studied. frequent glucose monitoring and dosage adjustment may be necessary for lantus in patients with hepatic impairment [see warnings and precautions (5.3) ] .

s 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 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.

* determined as amount of glucose infused to maintain constant plasma glucose levels figure 1: glucose-lowering effect over 24 hours in patients with type 1 diabetes the duration of action after abdominal, deltoid, or thigh subcutaneous administration of lantus was similar. the time course of action of insulins, including lantus, may vary between patients and within the same patient. figure 1 12.3 pharmacokinetics absorption after subcutaneous injection of lantus in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to nph insulin. elimination metabolism a metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the b chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, m1 (21 a -gly-insulin) and m2 (21 a -gly-des-30 b -thr-insulin). unchanged drug and these degradation products are also present in the circulation. specific populations age, race, body mass index, and gender effect of age, race, body mass index (bmi), and gender on the pharmacokinetics of insulin glargine has not been evaluated. however, in controlled clinical studies in adults (n=3,890) and a controlled clinical study in pediatric patients (n=349), subgroup analyses based on age, race, bmi, and gender did not show differences in safety and efficacy between lantus and nph insulin [see clinical studies (14) ] .

study in pediatric patients (n=349), subgroup analyses based on age, race, bmi, and gender did not show differences in safety and efficacy between lantus and nph insulin [see clinical studies (14) ] .

rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. consequently, a reduction of the rearing rate occurred in the high-dose group only. similar effects were observed with nph insulin.

s up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. consequently, a reduction of the rearing rate occurred in the high-dose group only. similar effects were observed with nph insulin.

ime when used twice daily. in study a, the average age was 39 years. the majority of patients were white (99%) and 56% were male. the mean bmi was approximately 24.9 kg/m 2 . the mean duration of diabetes was 16 years. in study b, the average age was 39 years. the majority of patients were white (95%) and 51% were male. the mean bmi was approximately 25.8 kg/m 2 . the mean duration of diabetes was 17 years. in another clinical study (study c), patients with type 1 diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with lantus or nph insulin. insulin lispro was used before each meal. lantus was administered once daily at bedtime and nph insulin was administered once or twice daily. the average age was 39 years. the majority of patients were white (97%) and 51% were male. the mean bmi was approximately 25.6 kg/m 2 . the mean duration of diabetes was 19 years. in these 3 adult studies, lantus and nph insulin had similar effects on hba1c (table 9) with a similar overall rate of severe symptomatic hypoglycemia [see adverse reactions (6.1) ] . table 9: type 1 diabetes mellitus – adults study a study b study c treatment duration 28 weeks 28 weeks 16 weeks treatment in combination with regular insulin regular insulin insulin lispro lantus nph lantus nph lantus nph number of subjects treated 292 293 264 270 310 309 hba1c baseline hba1c 8.0 8.0 7.7 7.7 7.6 7.7 adjusted mean change at study end +0.2 +0.1 -0.2 -0.2 -0.1 -0.1 treatment difference (95% ci) +0.1 (0.0; +0.2) +0.1 (-0.1; +0.2) 0.0 (-0.1; +0.1) basal insulin dose baseline mean 21 23 29 29 28 28 mean change from baseline -2 0 -4 +2 -5 +1 total insulin dose baseline mean 48 52 50 51 50 50 mean change from baseline -1 0 0 +4 -3 0 fasting blood glucose (mg/dl) baseline mean 167 166 166 175 175 173 adj. mean change from baseline -21 -16 -20 -17 -29 -12 body weight (kg) baseline mean 73.2 74.8 75.5 75.0 74.8 75.6 mean change from baseline 0.1 -0.0 0.7 1.0 0.1 0.5 pediatric patients with type 1 diabetes in a randomized, controlled clinical study (study d), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. lantus was administered once daily at bedtime and nph insulin was administered once or twice daily. the average age was 11.7 years. the majority of patients were white (97%) and 52% were male. the mean bmi was approximately 18.9 kg/m 2 . the mean duration of diabetes was 5 years. similar effects on hba1c (table 10) were observed in both treatment groups [see adverse reactions (6.1) ] . table 10: type 1 diabetes mellitus – pediatric patients study d treatment duration 28 weeks treatment in combination with regular insulin lantus + regular insulin nph + regular insulin number of subjects treated 174 175 hba1c baseline mean 8.5 8.8 change from baseline (adjusted mean) +0.3 +0.3 difference from nph (adjusted mean) 0.0 (95% ci ) (-0.2; +0.3) basal insulin dose baseline mean 19 19 mean change from baseline -1 +2 total insulin dose baseline mean 43 43 mean change from baseline +2 +3 fasting blood glucose (mg/dl) baseline mean 194 191 mean change from baseline -23 -12 body weight (kg) baseline mean 45.5 44.6 mean change from baseline 2.2 2.5 14.3 clinical studies in adults with type 2 diabetes in a randomized, controlled clinical study (study e) in 570 adults with type 2 diabetes, lantus was evaluated for 52 weeks in combination with oral antidiabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). the average age was 60 years old. the majority of patients were white (93%) and 54% were male. the mean bmi was approximately 29.1 kg/m 2 . the mean duration of diabetes was 10 years. lantus administered once daily at bedtime was as effective as nph insulin administered once daily at bedtime in reducing hba1c and fasting glucose (table 11). the rate of severe symptomatic hypoglycemia was similar in lantus and nph insulin treated patients [see adverse reactions (6.1) ] . in a randomized, controlled clinical study (study f), in adult patients with type 2 diabetes not using oral antidiabetic medications (n=518), a basal-bolus regimen of lantus once daily at bedtime or nph insulin administered once or twice daily was evaluated for 28 weeks. regular human insulin was used before meals, as needed. the average age was 59 years. the majority of patients were white (81%) and 60% were male. the mean bmi was approximately 30.5 kg/m 2 . the mean duration of diabetes was 14 years. lantus had similar effectiveness as either once- or twice-daily nph insulin in reducing hba1c and fasting glucose (table 11) with a similar incidence of hypoglycemia [see adverse reactions (6.1) ] . in a randomized, controlled clinical study (study g), adult patients with type 2 diabetes were randomized to 5 years of treatment with once-daily lantus or twice-daily nph insulin. for patients not previously treated with insulin, the starting dosage of lantus or nph insulin was 10 units daily. patients who were already treated with nph insulin either continued on the same total daily nph insulin dose or started lantus at a dosage that was 80% of the total previous nph insulin dosage. the primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the early treatment diabetic retinopathy study (etdrs) scale. hba1c change from baseline was a secondary endpoint. similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. patients or study personnel used an algorithm to adjust the lantus and nph insulin dosages to a target fasting plasma glucose ≤100 mg/dl. after the lantus or nph insulin dosage was adjusted, other antidiabetic agents, including premeal insulin were to be adjusted or added. the average age was 55 years. the majority of patients were white (85%) and 54% were male. the mean bmi was approximately 34.3 kg/m 2 . the mean duration of diabetes was 11 years. the lantus group had a smaller mean reduction from baseline in hba1c compared to the nph insulin group, which may be explained by the lower daily basal insulin doses in the lantus group (table 11). the incidences of severe symptomatic hypoglycemia were similar between groups [see adverse reactions (6.1) ] . table 11: type 2 diabetes mellitus – adults study e study f study g treatment duration 52 weeks 28 weeks 5 years treatment in combination with oral agents regular insulin regular insulin lantus nph lantus nph lantus nph number of subjects treated 289 281 259 259 513 504 hba1c baseline mean 9.0 8.9 8.6 8.5 8.4 8.3 adjusted mean change from baseline -0.5 -0.4 -0.4 -0.6 -0.6 -0.8 lantus – nph -0.1 +0.2 +0.2 95% ci for treatment difference (-0.3; +0.1) (0.0; +0.4) (+0.1; +0.4) basal insulin dose in study g, the baseline dose of basal or total insulin was the first available on-treatment dose prescribed during the study (on visit month 1.5). baseline mean 14 15 44.1 45.5 39 44 mean change from baseline +12 +9 -1 +7 +23 +30 total insulin dose baseline mean 14 15 64 67 48 53 mean change from baseline +12 +9 +10 +13 +41 +40 fasting blood glucose (mg/dl) baseline mean 179 180 164 166 190 180 adj. mean change from baseline -49 -46 -24 -22 -45 -44 body weight (kg) baseline mean 83.5 82.1 89.6 90.7 100 99 adj. mean change from baseline 2.0 1.9 0.4 1.4 3.7 4.8 14.4 additional clinical studies in adults with diabetes type 1 and type 2 different timing of lantus administration in diabetes type 1 and diabetes type 2 the safety and efficacy of once daily lantus administered either at pre-breakfast, pre-dinner, or at bedtime were evaluated in a randomized, controlled clinical study in adult patients with type 1 diabetes (study h, n=378). patients were also treated with insulin lispro at mealtime. the average age was 41 years. all patients were white (100%) and 54% were male. the mean bmi was approximately 25.3 kg/m 2 . the mean duration of diabetes was 17 years. lantus administered at pre-breakfast or at pre-dinner (both once daily) resulted in similar reductions in hba1c compared to that with bedtime administration (see table 12 ). in these patients, data are available from 8-point home glucose monitoring. the maximum mean blood glucose was observed just prior to lantus injection regardless of time of administration. in this study, 5% of patients in the lantus-breakfast group discontinued treatment because of lack of efficacy. no patients in the other two groups (pre-dinner, bedtime) discontinued for this reason. the safety and efficacy of once daily lantus administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (study i, n=697) in patients with type 2 diabetes not adequately controlled on oral antidiabetic therapy. all patients in this study also received glimepiride 3 mg daily. the average age was 61 years. the majority of patients were white (97%) and 54% were male. the mean bmi was approximately 28.7 kg/m 2 . the mean duration of diabetes was 10 years. lantus given before breakfast was at least as effective in lowering hba1c as lantus given at bedtime or nph insulin given at bedtime (see table 12 ). table 12: study of different times of once daily lantus dosing in type 1 (study h) and type 2 (study i) diabetes mellitus treatment duration treatment in combination with study h 24 weeks insulin lispro study i 24 weeks glimepiride lantus before breakfast lantus before dinner lantus bedtime lantus before breakfast lantus bedtime nph bedtime number of subjects treated intent-to-treat 112 124 128 234 226 227 hba1c baseline mean 7.6 7.5 7.6 9.1 9.1 9.1 mean change from baseline -0.2 -0.1 0.0 -1.3 -1.0 -0.8 basal insulin dose (units) baseline mean 22 23 21 19 20 19 mean change from baseline 5 2 2 11 18 18 total insulin dose (units) – – – na not applicable na na baseline mean 52 52 49 – – – mean change from baseline 2 3 2 – – – body weight (kg) baseline mean 77.1 77.8 74.5 80.7 82 81 mean change from baseline 0.7 0.1 0.4 3.9 3.7 2.9 progression of retinopathy evaluation in adults with diabetes type 1 and diabetes type 2 lantus was compared to nph insulin in a 5-year randomized clinical study 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 years) 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 prespecified postbaseline 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 13 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. in this study, the numbers of retinal adverse events reported for lantus and nph insulin treatment groups were similar for adult patients with type 1 and type 2 diabetes. table 13: number (%) of patients with 3 or more step progression on etdrs scale at endpoint lantus (%) nph (%) difference 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 (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-treat 63/502 (12.5%) 71/487 (14.6%) -2.1% (2.1%) -6.3% to +2.1% the origin study of major cardiovascular outcomes in patients with established cv disease or cv risk factors the outcome reduction with initial glargine intervention study (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 (cv) outcomes in 12,537 adults ≥ 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 cv disease or cv risk factors at baseline. the objective of the study was to demonstrate that lantus use could significantly lower the risk of major cv outcomes compared to standard care. there were two coprimary composite cv endpoints: the first coprimary endpoint was the time to first occurrence of a major adverse cv event defined as the composite of cv death, nonfatal myocardial infarction, and nonfatal stroke. the second coprimary 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. patients were randomized to either lantus (n=6,264) titrated to a goal fasting plasma glucose of ≤95 mg/dl or to standard care (n=6,273). anthropometric and disease characteristics were balanced at baseline. the mean age was 64 years and 8% of patients were 75 years of age or older. the majority of patients 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 2 . approximately 12% of patients 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 the patients had had a prior cv event and 39% had documented coronary artery disease or other cv risk factors. vital status was available for 99.9% and 99.8% of patients randomized to lantus and standard care respectively at end of study. 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 study 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 study 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 cv outcomes was similar between groups (see table 14 ). all-cause mortality was also similar between groups. table 14: cardiovascular outcomes in origin in patients with established cv disease or cv risk factors – time to first event analyses lantus n=6,264 standard care n=6,273 lantus vs standard care n (events per 100 py) n (events per 100 py) hazard ratio (95% ci) coprimary 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 coprimary endpoints cv death 580 576 1.00 (0.89, 1.13) myocardial infarction (fatal or nonfatal) 336 326 1.03 (0.88, 1.19) stroke (fatal or nonfatal) 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) in the origin study, the overall incidence of cancer (all types combined) or death from cancer (table 15) was similar between treatment groups. table 15: cancer outcomes in origin – time to first event analyses lantus n=6,264 standard care n=6.273 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)

ed) in-use (opened) refrigerated room temperature (36°f–46°f [2°c–8°c]) (up to 86°f [30°c]) (see temperature below) 10 ml multiple-dose vial until expiration date 28 days 28 days refrigerated or room temperature 3 ml single-patient-use solostar prefilled pen until expiration date 28 days 28 days room temperature only (do not refrigerate)

frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see warnings and precautions (5.3) ]. advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see warnings and precautions (5.2) ] . hypoglycemia due to medications errors instruct patients to always check the insulin label before each injection to reduce the risk of a medication error [see warnings and precautions (5.4) ] . hypersensitivity reactions advise patients that hypersensitivity reactions have occurred with lantus. inform patients about the symptoms of hypersensitivity reactions [see warnings and precautions (5.5) ].

s (thiazolidinediones). have heart failure or other heart problems. if you have heart failure, it may get worse while you take tzds with lantus. are pregnant, planning to become pregnant, or are breastfeeding. it is not known if lantus may harm your unborn baby or breastfeeding baby. tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. before you start using lantus, talk to your healthcare provider about low blood sugar and how to manage it. how should i use lantus? read the detailed instructions for use that come with your lantus insulin. use lantus exactly as your healthcare provider tells you to. your healthcare provider should tell you how much lantus to use and when to use it. know the amount of lantus you use. do not change the amount of lantus you use unless your healthcare provider tells you to. check your insulin label each time you give your injection to make sure you are using the correct insulin. do not re-use needles. always use a new needle for each injection. re-use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose of lantus. using a new needle for each injection lowers your risk of getting an infection. you may take lantus at any time during the day but you must take it at the same time every day. only use lantus that is clear and colorless. if your lantus is cloudy or slightly colored, return it to your pharmacy for a replacement. lantus is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). do not use lantus in an insulin pump or inject lantus into your vein (intravenously). change (rotate) injection sites within the area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. do not use the exact same spot for each injection. do not inject where the skin has pits, is thickened, or has lumps. do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. do not mix lantus with any other type of insulin or liquid medicine. check your blood sugar levels. ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. keep lantus and all medicines out of the reach of children. your dose of lantus may need to change because of: a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of the medicines you take. what should i avoid while using lantus? while using lantus do not: drive or operate heavy machinery, until you know how lantus affects you. drink alcohol or use over-the-counter medicines that contain alcohol. what are the possible side effects of lantus and other insulins? lantus may cause serious side effects that can lead to death, including: low blood sugar (hypoglycemia). signs and symptoms that may indicate low blood sugar include: dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. severe allergic reaction (whole body reaction). get medical help right away if you have any of these signs or symptoms of a severe allergic reaction: a rash over your whole body, trouble breathing, a fast heartbeat, or sweating. low potassium in your blood (hypokalemia). heart failure. taking certain diabetes pills called tzds (thiazolidinediones) with lantus may cause heart failure in some people. this can happen even if you have never had heart failure or heart problems before. if you already have heart failure it may get worse while you take tzds with lantus. your healthcare provider should monitor you closely while you are taking tzds with lantus. tell your healthcare provider if you have any new or worse symptoms of heart failure including: shortness of breath, swelling of your ankles or feet, sudden weight gain. treatment with tzds and lantus may need to be changed or stopped by your healthcare provider if you have new or worse heart failure. get emergency medical help if you have: trouble breathing; shortness of breath; fast heartbeat; swelling of your face, tongue, or throat; sweating; extreme drowsiness; dizziness; confusion. the most common side effects of lantus include: low blood sugar (hypoglycemia); weight gain; allergic reactions, including reactions at your injection site; skin thickening or pits at the injection site (lipodystrophy). these are not all the possible side effects of lantus. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. general information about the safe and effective use of lantus. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use lantus for a condition for which it was not prescribed. do not give lantus to other people, even if they have the same symptoms that you have. it may harm them. this patient information leaflet summarizes the most important information about lantus. if you would like more information, talk with your healthcare provider. you can ask your pharmacist or healthcare provider for information about lantus that is written for healthcare provider. for more information, go to www.lantus.com or call 1-800-633-1610. what are the ingredients in lantus? active ingredient: insulin glargine 10 ml vial inactive ingredients: glycerol 85%, m-cresol, polysorbate 20, zinc, and water for injection, usp. hydrochloric acid and sodium hydroxide may be added to adjust the ph. manufactured by: sanofi-aventis u.s. llc, bridgewater, nj 08807, a sanofi company. u.s. license no. 1752 this patient information has been approved by the u.s. food and drug administration. revised: june 2022

ally ones called tzds (thiazolidinediones). have heart failure or other heart problems. if you have heart failure, it may get worse while you take tzds with lantus. are pregnant, planning to become pregnant, or are breastfeeding. it is not known if lantus may harm your unborn baby or breastfeeding baby. tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. before you start using lantus, talk to your healthcare provider about low blood sugar and how to manage it. how should i use lantus solostar? read the detailed instructions for use that come with your lantus solostar single-patient-use prefilled pen. use lantus exactly as your healthcare provider tells you to. your healthcare provider should tell you how much lantus to use and when to use it. know the amount of lantus you use. do not change the amount of lantus you use unless your healthcare provider tells you to. check your insulin label each time you give your injection to make sure you are using the correct insulin. the dose counter on your solostar pen shows your dose of lantus. do not make any dose changes unless your healthcare provider tells you to. do not use a syringe to remove lantus from your solostar disposable prefilled pen. do not re-use needles. always use a new needle for each injection. re-use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose of lantus. using a new needle for each injection lowers your risk of getting an infection. if your needle is blocked, follow the instructions in step 3 of the instructions for use . you may take lantus at any time during the day but you must take it at the same time every day. lantus is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). do not use lantus in an insulin pump or inject lantus into your vein (intravenously). change (rotate) your injection sites within area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. do not use the exact same spot for each injection. do not inject where the skin has pits, is thickened, or has lumps. do not inject where skin is tender, bruised, scaly or hard, or into scars or damaged skin. do not mix lantus with any other type of insulin or liquid medicine. check your blood sugar levels. ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. keep lantus and all medicines out of the reach of children. your dose of lantus may need to change because of: a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of the medicines you take. what should i avoid while using lantus? while using lantus do not: drive or operate heavy machinery, until you know how lantus affects you. drink alcohol or use over-the-counter medicines that contain alcohol. what are the possible side effects of lantus and other insulins? lantus may cause serious side effects that can lead to death, including: low blood sugar (hypoglycemia). signs and symptoms that may indicate low blood sugar include: dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. severe allergic reaction (whole body reaction). get medical help right away if you have any of these signs or symptoms of a severe allergic reaction: a rash over your whole body, trouble breathing, a fast heartbeat, or sweating. low potassium in your blood (hypokalemia). heart failure. taking certain diabetes pills called tzds (thiazolidinediones) with lantus may cause heart failure in some people. this can happen even if you have never had heart failure or heart problems before. if you already have heart failure it may get worse while you take tzds with lantus. your healthcare provider should monitor you closely while you are taking tzds with lantus. tell your healthcare provider if you have any new or worse symptoms of heart failure including: shortness of breath, swelling of your ankles or feet, sudden weight gain. treatment with tzds and lantus may need to be changed or stopped by your healthcare provider if you have new or worse heart failure. get emergency medical help if you have: trouble breathing; shortness of breath; fast heartbeat; swelling of your face, tongue, or throat; sweating; extreme drowsiness; dizziness; confusion. the most common side effects of lantus include: low blood sugar (hypoglycemia); weight gain; allergic reactions, including reactions at your injection site; skin thickening or pits at the injection site (lipodystrophy). these are not all the possible side effects of lantus. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. general information about the safe and effective use of lantus. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use lantus for a condition for which it was not prescribed. do not give lantus to other people, even if they have the same symptoms that you have. it may harm them. this patient information leaflet summarizes the most important information about lantus. if you would like more information, talk with your healthcare provider. you can ask your healthcare provider or pharmacist for information about lantus that is written for healthcare professionals. for more information about lantus call 1-800-633-1610 or go to the website www.lantus.com. what are the ingredients in lantus? active ingredient: insulin glargine 3 ml solostar prefilled pen inactive ingredients: glycerol 85%, m-cresol, zinc, and water for injection, usp. hydrochloric acid and sodium hydroxide may be added to adjust the ph. manufactured by: sanofi-aventis u.s. llc, bridgewater, nj 08807, a sanofi company. u.s. license no. 1752 this patient information has been approved by the u.s. food and drug administration. revised: june 2022