), and thyroid hormones. intervention: dose increases and increased frequency of glucose monitoring may be required when lyumjev is co-administered with these drugs. drugs that may increase or decrease the blood glucose lowering effect of lyumjev 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 lyumjev is co-administered 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 lyumjev is co-administered with these drugs. drugs that increase hypoglycemia risk or increase or decrease blood glucose lowering effect: adjustment of dosage may be needed; closely monitor blood glucose. ( 7 ) drugs that blunt hypoglycemia signs and symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine): increased frequency of glucose monitoring may be required. ( 7 )

ay be life-threatening. monitor potassium levels in patients at risk for hypokalemia and treat if indicated. ( 5.5 ) hypersensitivity reactions: severe, life-threatening, generalized allergy, including anaphylaxis, can occur. discontinue lyumjev, monitor, 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 ) hyperglycemia and ketoacidosis due to insulin pump device malfunction: monitor glucose and administer lyumjev by subcutaneous injection if pump malfunction occurs. ( 5.8 ) 5.1 never share a lyumjev prefilled pen, cartridge, or syringe between patients lyumjev prefilled pens or cartridges should never be shared between patients, even if the needle is changed. patients using lyumjev vials must never 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, 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 an unaffected area) has been reported to result in hypoglycemia [see adverse reactions ( 6.1 )] . 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 anti-diabetic products may be needed. 5.3 hypoglycemia hypoglycemia is the most common adverse reaction associated with insulins, including lyumjev [see adverse reactions ( 6.1 )] . severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life-threatening, or cause death. hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). lyumjev, or any insulin, should not be used during episodes of hypoglycemia [see contraindications ( 4 )] . hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see drug interactions ( 7 )] , or in patients who experience recurrent 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. the timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. as with all insulins, the glucose lowering effect time course of lyumjev may vary in different individuals or at different times in the same individual 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 co-administered medication [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 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 glucose monitoring is recommended. 5.4 hypoglycemia due to medication errors accidental mix-ups between insulin products have been reported. to avoid medication errors between lyumjev and other insulins, instruct patients to always check the insulin label before each injection. do not transfer lyumjev u-200 from the lyumjev kwikpen to a syringe. the markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia [see dosage and administration ( 2.1 ) and warnings and precautions ( 5.3 )] . 5.5 hypokalemia all insulins, including lyumjev, 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). 5.6 hypersensitivity reactions severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including lyumjev [see adverse reactions ( 6.1 )] . if hypersensitivity reactions occur, discontinue lyumjev; treat per standard of care and monitor until symptoms and signs resolve. lyumjev is contraindicated in patients who have had hypersensitivity reactions to insulin lispro-aabc or any of its excipients [see contraindications ( 4 )] . 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, particularly when used in combination with insulin. fluid retention may lead to or exacerbate heart failure. patients treated with insulin, including lyumjev, 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. 5.8 hyperglycemia and ketoacidosis due to insulin pump device malfunction pump or infusion set malfunctions can lead to a rapid onset of hyperglycemia and ketoacidosis. prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. interim therapy with subcutaneous injection of lyumjev may be required. patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see dosage and administration ( 2.2 ), how supplied/storage and handling ( 16.2 ), and patient counseling information ( 17 )] .

yumjev u-200 by continuous subcutaneous infusion. intravenous infusion ( 2.2 ): administer lyumjev u-100 intravenously only under medical supervision. do not administer lyumjev u-200 by intravenous infusion. dilute lyumjev u-100 to a concentration of 1 unit/ml. individualize and adjust the dosage of lyumjev based on the patient's metabolic needs, glucose monitoring results, and glycemic control goal. ( 2.3 ) dose adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., amount and type of food, timing of food intake), changes in renal or hepatic function, or during acute illness. ( 2.3 ) 2.1 important administration instructions always check insulin labels before administration [see warnings and precautions ( 5.4 )] . inspect lyumjev visually before use. it should appear clear and colorless. do not use lyumjev if particulate matter and discoloration is seen. use lyumjev prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. do not perform dose conversion when using any lyumjev u-100 or u-200 prefilled pens. the dose window of lyumjev prefilled pens shows the number of units of lyumjev to be delivered and no conversion is needed . do not transfer lyumjev u-200 from the prefilled pen to a syringe for administration [see warnings and precautions ( 5.4 )] . do not mix lyumjev with any other insulin products. do not administer lyumjev u-200 using continuous subcutaneous infusion insulin pump. do not administer lyumjev u-200 intravenously. 2.2 route of administration instructions subcutaneous injection for lyumjev u-100 or u-200 administer lyumjev at the start of a meal or within 20 minutes after starting a meal subcutaneously into the abdomen, upper arm, thigh, or buttocks. 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 adverse reactions ( 6.1 , 6.2 )]. lyumjev given by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin. the lyumjev u-100 kwikpen, lyumjev u-100 tempo pen, and lyumjev u-200 kwikpen each dial in 1 unit increments and deliver a maximum dose of 60 units per injection. the lyumjev u-100 junior kwikpen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection. continuous subcutaneous insulin infusion (insulin pump) for lyumjev u-100 only do not administer lyumjev u-200 using an insulin pump. refer to the continuous subcutaneous insulin infusion pump user manual to see if lyumjev can be used with the insulin pump. use lyumjev in accordance with the insulin pump system's instructions for use. administer lyumjev u-100 by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. do not infuse into areas of lipodystrophy or localized cutaneous amyloidosis [see warnings and precautions ( 5.2 ) and adverse reactions ( 6.1 )] . train patients using continuous subcutaneous insulin infusion (csii) therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see warnings and precautions ( 5.8 )] . change lyumjev u-100 in the pump reservoir at least every 9 days or according to the pump user manual, whichever is shorter. change the infusion sets and the infusion set insertion site according to the manufacturer's user manual. do not dilute or mix lyumjev u-100 when administering by csii. do not expose lyumjev in the pump reservoir to temperatures greater than 98.6°f (37°c). intravenous administration for lyumjev u-100 only do not administer lyumjev u-200 intravenously. administer lyumjev u-100 intravenously only under medical supervision with close monitoring of glucose and potassium levels to avoid hypoglycemia and hypokalemia [see warnings and precautions ( 5.3 , 5.5 )] . dilute lyumjev u-100 to a concentration of 1 unit/ml using 0.9% sodium chloride injection, usp or 5% dextrose injection, usp infusion solutions. dilutions to concentrations below 1 unit/ml are not recommended. diluted lyumjev may be stored for up to 4 days when refrigerated or up to 12 hours at room temperature [see how supplied/storage and handling ( 16.2 )]. 2.3 general dosage instructions individualize and adjust the dosage of lyumjev based on the patient's metabolic needs, glucose monitoring results, and glycemic control goal. if converting from another mealtime insulin to lyumjev, the change can be done on a unit-to-unit basis. dosage adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see warnings and precautions ( 5.2 , 5.3 ), drug interactions ( 7 ) and use in specific populations ( 8.6 , 8.7 )] . during changes to a patient's insulin regimen, increase the frequency of glucose monitoring [see warnings and precautions ( 5.2 )] . instruct patients who forget a mealtime dose to monitor their glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal.

– adult patients with type 1 and type 2 diabetes the data in table 1 reflect the exposure of 780 adult patients with type 1 diabetes to lyumjev with a mean exposure duration of 26 weeks [see clinical studies ( 14.2 )] . the mean age was 44 years, the mean duration of diabetes was 19 years, 55% were male, 77% were white, 2% were black or african american, and 9% were hispanic. the mean bmi was 26.6 kg/m 2 and the mean hba 1c at baseline was 7.3%. the data in table 2 reflect the exposure of 336 adult patients with type 2 diabetes to lyumjev with a mean exposure duration of 26 weeks [see clinical studies ( 14.3 )] . the mean age was 60 years, the mean duration of diabetes was 16 years, 55% were male, 69% were white, 4% were black or african american, and 24% were hispanic. the mean bmi was 32.1 kg/m 2 and the mean hba 1c at baseline was 7.3%. the data in table 3 reflect the exposure of 215 adult patients with type 1 diabetes to lyumjev via csii administration with a mean exposure duration of 16 weeks [see clinical studies ( 14.4 )] . the mean age was 48 years, the mean duration of diabetes was 26 years, 44% were male, 94% were white, 3% were black or african american, and 8% were hispanic. the mean bmi was 27.0 kg/m 2 and the mean hba 1c at baseline was 7.6%. common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% and at the same rate or greater for lyumjev-treated patients than humalog-treated patients. table 1. adverse reactions that occurred in ≥5% of lyumjev-treated adult patients with type 1 diabetes mealtime lyumjev + basal insulin (n=451) % postmeal lyumjev + basal insulin (n=329) % nasopharyngitis 14.2 14.6 table 2. adverse reactions that occurred in ≥5% of lyumjev-treated adult patients with type 2 diabetes mealtime lyumjev + basal insulin (n=336) % nasopharyngitis 12.5 upper respiratory tract infection 7.4 table 3. adverse reactions that occurred in ≥5% of lyumjev-treated adult patients with type 1 diabetes using continuous subcutaneous insulin infusion csii lyumjev administration (n=215) % infusion site reaction 19.1 infusion site pain 15.8 nasopharyngitis 6.0 adverse reaction database – pediatric patients with type 1 diabetes the data in table 4 reflect the exposure of 418 pediatric patients with type 1 diabetes to lyumjev with a mean exposure duration of 26 weeks [see clinical studies ( 14.5 )] . the mean age was 12 years; 50% were male, 91% were white, 1% were black or african american; and 24% of the us subpopulation in this trial were hispanic. the mean bmi was 20.5 kg/m 2 , the mean duration of diabetes was 5 years, and the mean hba 1c at baseline was 7.8%. common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% and at the same rate or greater for lyumjev-treated patients than humalog-treated patients. table 4. adverse reactions that occurred in ≥5% of lyumjev-treated pediatric patients with type 1 diabetes mealtime lyumjev + basal insulin (n=280) % postmeal lyumjev + basal insulin (n=138) % nasopharyngitis 8.2 5.1 upper respiratory tract infection 5.4 1.4 hypoglycemia hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including lyumjev. the rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. for these reasons, comparing rates of hypoglycemia in clinical trials for lyumjev with the incidence of hypoglycemia for other products may be misleading and also may not be representative of hypoglycemia rates that occur in clinical practice. incidence rates for severe hypoglycemia in adults with type 1 and type 2 diabetes mellitus and pediatric patients with type 1 diabetes mellitus treated with lyumjev in clinical trials are shown in table 5 [see clinical studies ( 14 )] . table 5. proportion of patients with type 1 diabetes and type 2 diabetes who experienced at least one episode of severe hypoglycemia in adult and pediatric clinical trials a severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions pronto-t1d (adult type 1) pronto-t2d (adult type 2) pronto-pump-2 (adult type 1 csii) pronto-peds (pediatric type 1) mealtime lyumjev + basal insulin (n=451) % postmeal lyumjev + basal insulin (n=329) % mealtime lyumjev + basal insulin (n=336) % lyumjev (n=215) % mealtime lyumjev + basal insulin (n=280) % postmeal lyumjev + basal insulin (n=298) % severe hypoglycemia a 5.5 4.6 0.9 1.4 1.1 0 allergic reactions severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including lyumjev, and may be life threatening. generalized hypersensitivity reactions such as skin rashes and hypersensitivity were reported in adult patients treated with lyumjev: eczema (0.4%), rash (0.4%), dermatitis (0.3%), hypersensitivity (0.2%), and pruritus (0.2%). generalized hypersensitivity reactions reported in more than 1 pediatric patient treated with lyumjev included: rhinitis (0.7%), dermatitis (0.7%), rash (0.5%), and hypersensitivity (0.5%). lipodystrophy administration of insulin, including lyumjev, has resulted in lipohypertrophy (enlargement or thickening of tissue) and lipoatrophy (depression in the skin). lipodystrophy was reported in 0.2% of adult and pediatric patients treated with lyumjev [see dosage and administration ( 2.2 )] . injection/infusion site reactions injection or infusion site reactions can occur with insulin therapy. with lyumjev, adult and pediatric patients have experienced rash, redness, inflammation, pain, bruising, or itching at the site of lyumjev injection or infusion. lyumjev contains treprostinil sodium and sodium citrate dihydrate as inactive ingredients [see description ( 11 )] which have been associated with infusion and injection site reactions with other non-insulin products. subcutaneous injection site-related reactions : in studies pronto-t1d and pronto-t2d, injection site-related reactions occurred in 2.7% of adult patients treated with lyumjev (mild in 2.2% and moderate in 0.5%). with <0.1% of patients discontinuing from treatment due to injection site-related reactions. in study pronto-peds, injection site-related reactions occurred in 6.2% of pediatric patients treated with lyumjev (mild in 5.7% and moderate in 0.5%), with <0.5% of patients discontinuing from treatment due to injection site-related reactions. continuous subcutaneous insulin infusion (csii) site-related reactions: in study pronto-pump-2, infusion site-related reactions were reported in 37.7% of adult patients treated with lyumjev (mild in 27.9%, moderate in 7.9%, and severe in 1.9%), with 3.3% of patients discontinuing from treatment due to infusion site-related reactions. see table 4 . weight gain weight gain can occur with insulin therapy, including lyumjev, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. adult patients with type 1 diabetes treated with lyumjev gained an average of 0.6 kg and patients with type 2 diabetes treated with lyumjev gained an average of 1.5 kg. peripheral edema insulin, including lyumjev, may cause sodium retention and edema, particularly if previous poor metabolic control is improved by intensified insulin therapy. peripheral edema occurred in 0.2% of adult patients treated with lyumjev. 6.2 postmarketing experience the following additional adverse reactions have been identified during post-approval use of insulin lispro. 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. localized cutaneous amyloidosis at the injection site has occurred with insulin use. 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.

), and thyroid hormones. intervention: dose increases and increased frequency of glucose monitoring may be required when lyumjev is co-administered with these drugs. drugs that may increase or decrease the blood glucose lowering effect of lyumjev 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 lyumjev is co-administered 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 lyumjev is co-administered with these drugs. drugs that increase hypoglycemia risk or increase or decrease blood glucose lowering effect: adjustment of dosage may be needed; closely monitor blood glucose. ( 7 ) drugs that blunt hypoglycemia signs and symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine): increased frequency of glucose monitoring may be required. ( 7 )

0% in women with pre-gestational diabetes with a hba 1c >7 and has been reported to be as high as 20% to 25% in women with a hba 1c >10. the estimated background risk of miscarriage for the indicated population is unknown. 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. clinical considerations disease-associated maternal and/or embryo-fetal risk poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, 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 from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. however, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups. animal data animal reproduction studies have not been performed with lyumjev. however, subcutaneous reproduction and teratology studies have been conducted with insulin lispro. in a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through gestation day 19. there were no adverse effects on female fertility, implantation, or fetal viability and morphology. however, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter. in an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on gestation days 7 through 19. there were no adverse effects on fetal viability, weight, and morphology at any dose. 8.2 lactation risk summary available data from published literature suggests that exogenous human insulin products, including insulin lispro, are transferred into human milk. there are no adverse reactions reported in breastfed infants in the literature. there are no data on the effects of exogenous human insulin products, including insulin lispro, on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for insulin, any potential adverse effects on the breastfed child from lyumjev or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of lyumjev to improve glycemic control in pediatric patients with diabetes mellitus have been established. use of lyumjev for this indication is supported by evidence from an adequate and well-controlled study in 716 pediatric patients with type 1 diabetes mellitus aged 1 year and older, and from studies in adult and pediatric patients with diabetes mellitus [see clinical pharmacology ( 12.3 ) and clinical studies ( 14.5 )] . lyumjev-treated pediatric patients reported a higher incidence of subcutaneous injection site-related reactions compared to lyumjev-treated adults [see adverse reactions ( 6.1 )] . it is expected that lyumjev-treated pediatric patients who receive continuous subcutaneous insulin infusion (csii) are more likely to have infusion site-related adverse reactions than those who receive subcutaneous injections [see adverse reactions ( 6.1 )] . monitor injection and infusion sites closely when initiating therapy with lyumjev in pediatric patients. if persistent injection or infusion site reactions occur, discontinue lyumjev and initiate therapy with an alternative insulin. 8.5 geriatric use of the total number of lyumjev-treated patients in clinical studies for type 1 or type 2 diabetes (pronto-t1d and pronto-t2d, respectively), 17% (187/1,116) were 65 years of age and older, while 2% (18/1,116) were 75 years of age and older [see clinical studies ( 14.2 , 14.3 )] . no overall differences in safety or effectiveness of lyumjev have been observed between patients 65 years of age and older and younger adult patients. 8.6 renal impairment patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent lyumjev dose adjustment and more frequent glucose monitoring [see warnings and precautions ( 5.3 ) and clinical pharmacology ( 12.3 )] . 8.7 hepatic impairment patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent lyumjev dose adjustment and more frequent glucose monitoring [see warnings and precautions ( 5.3 ) and clinical pharmacology ( 12.3 )] .

al diabetes with a hba 1c >7 and has been reported to be as high as 20% to 25% in women with a hba 1c >10. the estimated background risk of miscarriage for the indicated population is unknown. 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. clinical considerations disease-associated maternal and/or embryo-fetal risk poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, 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 from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. however, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups. animal data animal reproduction studies have not been performed with lyumjev. however, subcutaneous reproduction and teratology studies have been conducted with insulin lispro. in a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through gestation day 19. there were no adverse effects on female fertility, implantation, or fetal viability and morphology. however, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter. in an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on gestation days 7 through 19. there were no adverse effects on fetal viability, weight, and morphology at any dose.

in pediatric patients. if persistent injection or infusion site reactions occur, discontinue lyumjev and initiate therapy with an alternative insulin.

neous administration of 7, 15, and 30 units of lyumjev in healthy subjects. table 7. timing of insulin effect (i.e., mean pharmacodynamic effect) after subcutaneous administration of 7, 15, and 30 units of lyumjev in healthy subjects (n=42) and corresponding to the data shown in figure 1 parameter for insulin effect lyumjev 7 units lyumjev 15 units lyumjev 30 units time to first measurable effect ~17 minutes ~17 minutes ~15 minutes time to peak effect ~120 minutes ~138 minutes ~174 minutes time for effect to return to baseline ~4.6 hours ~6.2 hours ~7.3 hours on average, the pharmacodynamic effects of lyumjev, measured as area under the glucose infusion rate-time curve (auc gir ), was 1080 mg/kg, 1860 mg/kg, and 3030 mg/kg following administration of 7, 15, and 30 units of lyumjev in healthy subjects. similar pharmacodynamic profiles were observed in separate studies conducted in 40 patients with type 1 diabetes and 38 patients with type 2 diabetes given lyumjev subcutaneously as a single 15 unit dose. the onset and total glucose lowering were similar when lyumjev was administered in the abdomen, deltoid, or thigh. the day-to-day variability [percent coefficient of variation (cv%)] within subjects in the glucose-lowering-effect of lyumjev was 24% for the early glucose lowering (auc gir , 0-1h), 27% for the total glucose lowering (auc gir , 0-10h), and 19% for maximum glucose lowering effect (gir max ). figure 1 postprandial glucose lowering when given at the start of a meal or 20 minutes after the start of the meal, lyumjev reduced postprandial glucose during a standardized test meal over the complete 5-hour period [change from premeal auc(0-5h)] in patients with type 1 or type 2 diabetes. the maximum and total glucose lowering were comparable for a single 15 unit dose of lyumjev 200 units/ml or lyumjev 100 units/ml when administered subcutaneously to healthy subjects. the insulin time action profile with lyumjev 200 units/ml was the same as observed with lyumjev 100 units/ml. 12.3 pharmacokinetics absorption absorption of insulin lispro-aabc was evaluated in healthy subjects (see figure 2 ) and patients with diabetes following subcutaneous injection of lyumjev. insulin lispro-aabc appeared in circulation approximately 1 minute after injection of lyumjev. time to 50% maximum insulin lispro-aabc concentration was 13 minutes. time to maximum insulin lispro-aabc concentration was achieved at 57 minutes. in healthy subjects, the day-to-day variability [cv%] within subjects of lyumjev was 10% for total exposure (auc, 0-10h) and 16% for maximum insulin lispro-aabc concentration (c max ). figure 2. mean serum insulin lispro-aabc after subcutaneous injection of lyumjev (15 unit dose) in healthy subjects the absolute bioavailability of insulin lispro-aabc after subcutaneous administration of lyumjev in the abdomen, deltoid, and thigh was approximately 65%. the rate of absorption of insulin lispro-aabc is maintained regardless of injection site. maximum concentration and time to maximum concentration were comparable for the abdomen and upper arm regions; time to maximum concentration was longer and maximum concentration was lower for the thigh. total insulin lispro-aabc exposure and maximum insulin lispro-aabc concentration increased proportionally with increasing subcutaneous doses of lyumjev within the therapeutic dose range. the results of a study in healthy subjects demonstrated that lyumjev 200 units/ml is bioequivalent to lyumjev 100 units/ml following administration of a single 15 unit dose for the area under the serum insulin lispro-aabc concentration-time curve from time zero to infinity and maximum insulin lispro-aabc concentration. the rate of insulin lispro-aabc absorption after administration of lyumjev 200 units/ml was similar as observed with lyumjev 100 units/ml. figure 2 distribution following a 15 unit intravenous bolus injection of lyumjev in healthy subjects, the geometric mean (cv%) volume of distribution of insulin lispro-aabc (vd) was 34 l (30%). elimination following a 15 unit intravenous bolus injection of lyumjev in healthy subjects, the geometric mean (cv%) clearance of insulin lispro-aabc was 32 l/hour (22%) and the median half-life of insulin lispro-aabc was 44 minutes. specific populations age, biological sex, and race did not affect the pharmacokinetics and pharmacodynamics of lyumjev. patients with renal and hepatic impairment renal and hepatic impairment is not known to impact the pharmacokinetics of insulin lispro-aabc. insulin requirements may be reduced in the presence of renal or hepatic impairment. 12.6 immunogenicity the observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of insulin lispro-aabc or of other insulin lispro products. in a 26-week trial in adult patients with type 1 diabetes (study pronto-t1d) [see clinical studies ( 14.2 )] , 49% of lyumjev-treated patients were anti-drug (insulin lispro-aabc) antibody (ada)-positive at baseline, 91% of whom had cross-reactive antibodies with native insulin. during this 26-week period in this trial, 33% of lyumjev-treated patients had treatment-emergent ada post-baseline (i.e., either new ada or a 57% increase in assay signal over baseline), 75% of whom had cross-reactive antibodies with native insulin. in a 26-week trial in adult patients with type 2 diabetes (study proto-t2d) [see clinical studies ( 14.3 )] , 35% of lyumjev-treated patients were ada-positive at baseline, 81% of whom had cross-reactive antibodies with native insulin. during this 26-week period in this trial, 31% of lyumjev-treated patients had treatment-emergent ada post-baseline (i.e., either new ada or a 57% increase in assay signal over baseline), 68% of whom had cross-reactive antibodies with native insulin. in a 26-week trial in pediatric patients with type 1 diabetes (study-pronto-peds) [see clinical studies ( 14.5 )] , 73% of lyumjev-treated patients were ada-positive at baseline. of these ada-positive patients, 97% had cross-reactive antibodies with native insulin. during this 26-week period in this trial, 31% of lyumjev-treated patients had treatment-emergent ada post-baseline (i.e., either new ada or a 57% increase in assay signal over baseline). of these treatment-emergent ada-positive patients, 84% had cross-reactive antibodies with native insulin. in these clinical trials, there were no identified clinically significant effects of ada on safety or effectiveness (measured by hba1c) of lyumjev over the treatment duration of 26-weeks.

and time to maximum concentration were comparable for the abdomen and upper arm regions; time to maximum concentration was longer and maximum concentration was lower for the thigh. total insulin lispro-aabc exposure and maximum insulin lispro-aabc concentration increased proportionally with increasing subcutaneous doses of lyumjev within the therapeutic dose range. the results of a study in healthy subjects demonstrated that lyumjev 200 units/ml is bioequivalent to lyumjev 100 units/ml following administration of a single 15 unit dose for the area under the serum insulin lispro-aabc concentration-time curve from time zero to infinity and maximum insulin lispro-aabc concentration. the rate of insulin lispro-aabc absorption after administration of lyumjev 200 units/ml was similar as observed with lyumjev 100 units/ml. figure 2 distribution following a 15 unit intravenous bolus injection of lyumjev in healthy subjects, the geometric mean (cv%) volume of distribution of insulin lispro-aabc (vd) was 34 l (30%). elimination following a 15 unit intravenous bolus injection of lyumjev in healthy subjects, the geometric mean (cv%) clearance of insulin lispro-aabc was 32 l/hour (22%) and the median half-life of insulin lispro-aabc was 44 minutes. specific populations age, biological sex, and race did not affect the pharmacokinetics and pharmacodynamics of lyumjev. patients with renal and hepatic impairment renal and hepatic impairment is not known to impact the pharmacokinetics of insulin lispro-aabc. insulin requirements may be reduced in the presence of renal or hepatic impairment.

g/day subcutaneously (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

), all in combination with either insulin glargine or insulin degludec. mealtime lyumjev or humalog was injected 0 to 2 minutes before the meal and postmeal lyumjev was injected 20 minutes after the start of the meal. patients had a mean age of 44 years; mean duration of diabetes of 19 years; 56% were male; race: 77% white, 19% asian, and 2% black or african american. eight percent of the randomized patients were hispanic. the mean bmi was 26.6 kg/m 2 . at week 26, treatment with mealtime lyumjev provided a mean reduction in hba 1c that met the pre-specified non-inferiority margin (0.4%) (see table 8 ). in addition, postmeal lyumjev met the prespecified non-inferiority margin (0.4%) compared to mealtime humalog. insulin doses were similar in all treatment groups at baseline and at 26 weeks. table 8. results from study pronto-t1d: 26 week trial of mealtime lyumjev and postmeal lyumjev compared with mealtime humalog, all in combination with basal insulin in adults with type 1 diabetes a analysis population: all randomized subjects regardless of adherence to treatment or availability of post-baseline assessment. missing data at week 26 were imputed by return to baseline approach. at week 26, primary efficacy assessment was missing for 3.8%, 4.8%, and 5.2% of subjects, for mealtime lyumjev, mealtime humalog, and postmeal lyumjev, respectively. b least-squares (ls) mean from ancova adjusted for baseline value and other stratification factors. c tested for non-inferiority. mealtime lyumjev + basal insulin mealtime humalog + basal insulin postmeal lyumjev + basal insulin number of randomized subjects (n) 451 442 329 hba 1c (%) (mean) a baseline 7.3 7.3 7.4 adjusted mean change from baseline b -0.12 -0.04 0.1 estimated treatment difference versus humalog [95% ci] -0.08 [-0.16, 0.00] c 0.14 [0.05, 0.22] 14.3 adults with type 2 diabetes pronto-t2d (nct03214380) was a 26-week, randomized (1:1), active controlled, treat-to-target, multinational trial that evaluated the efficacy of lyumjev in 673 adult patients with type 2 diabetes who at study entry were on multiple daily injections with either basal insulin and at least one prandial insulin injection or premixed insulin with at least two injections daily. patients may also have been treated with up to three oral anti-diabetic medications (oams) in addition to insulin. patients were allowed to continue on metformin and/or a sglt2 inhibitor and were randomized to either mealtime lyumjev (n=336) or to mealtime humalog (n=337), both in combination with insulin glargine or insulin degludec in a basal-bolus regimen. mealtime lyumjev or mealtime humalog was injected 0-2 minutes before the meal. patients had a mean age of 61 years; mean duration of diabetes of 17 years; 53% were male; race: 69% white, 24% asian, and 5% black or african american. twenty-three percent of the randomized patients were hispanic. the mean bmi was 32.3 kg/m 2 . at week 26, treatment with mealtime lyumjev provided a mean reduction of hba 1c from baseline that met the pre-specified non-inferiority margin (0.4%) compared to mealtime humalog (see table 9 ). insulin doses were similar in both treatment groups at baseline and at 26 weeks. table 9. results from study pronto-t2d: 26 week trial of mealtime lyumjev compared with mealtime humalog, both in combination with basal insulin in adults with type 2 diabetes a analysis population: all randomized subjects regardless of adherence to treatment or availability of post-baseline assessment. missing data at week 26 were imputed by return to baseline approach. at week 26, primary efficacy assessment was missing for 4.8% of subjects for mealtime lyumjev and for 4.5% mealtime humalog. b least-squares (ls) mean from ancova adjusted for baseline value and other stratification factors. c tested for non-inferiority. mealtime lyumjev + basal insulin mealtime humalog + basal insulin number of randomized subjects (n) 336 337 hba 1c (%) a baseline mean 7.3 7.3 adjusted mean change from baseline b -0.36 -0.38 estimated treatment difference versus humalog [95% ci] c 0.03 [-0.08, 0.13] 14.4 adults with type 1 diabetes – continuous subcutaneous insulin infusion (csii) pronto-pump-2 (nct03830281) was a 16 week randomized (1:1), active controlled, treat-to-target, multinational trial that evaluated the efficacy of lyumjev in 432 adult patients with type 1 diabetes currently using continuous subcutaneous insulin infusion. patients were randomized to either blinded lyumjev (n=215) or blinded humalog (n= 217). mealtime lyumjev or humalog boluses were initiated 0 to 2 minutes before the meal. patients had a mean age of 46 years; mean duration of diabetes of 26 years; 45% were male; race: 95% white, 3% black or african american, and 0.5% asian. eight percent of the randomized patients were hispanic. the mean bmi was 27.1 kg/m 2 . at week 16, treatment with lyumjev provided a mean reduction in hba 1c that met the pre-specified non-inferiority margin (0.4%) compared to mealtime humalog (see table 10 ). total daily insulin doses were similar for both treatment groups at baseline and at 16 weeks. table 10. results from study pronto-pump-2: 16 week trial of lyumjev compared with humalog in adults with type 1 diabetes a analysis population: all randomized subjects regardless of adherence to treatment or availability of post-baseline assessment. missing data at week 16 were imputed by return to baseline approach. at week 16, primary efficacy assessment was missing for 7% and 4.6% of subjects, for lyumjev and humalog, respectively. b least-squares (ls) mean from ancova adjusted for baseline value and other stratification factors. c tested for non-inferiority. lyumjev humalog number of randomized subjects (n) 215 217 hba 1c (%) a baseline mean 7.6 7.5 adjusted mean change from baseline b -0.06 -0.09 estimated treatment difference versus humalog [95% ci] c 0.03 [-0.05, 0.11] 14.5 pediatric patients with type 1 diabetes pronto-peds (nct03740919) was a 26-week, randomized (2:2:1), active controlled, treat-to-target, multinational trial that evaluated the efficacy of lyumjev in 716 pediatric patients with type 1 diabetes. patients were randomized to either blinded mealtime lyumjev (n=280), blinded mealtime humalog (n=298), or open-label postmeal lyumjev (n=138), all in combination with basal insulin (insulin glargine, insulin degludec or insulin detemir). mealtime lyumjev or humalog was injected 0 to 2 minutes before the meal and postmeal lyumjev was injected within 20 minutes after the start of the meal. patients had a mean age of 12 years (3-17 years); 51% were male; race: 89% white, 6% asian, and 2% black or african american. in the u.s. subpopulation in this trial, 24% of the randomized patients were hispanic. the mean bmi was 20.4 kg/m 2 and the mean duration of diabetes was 5 years. at week 26, treatment with mealtime lyumjev provided a mean change in hba1c that met the pre-specified non-inferiority margin (0.4%) (see table 11). in addition, postmeal lyumjev met the prespecified non-inferiority margin (0.4%) compared to mealtime humalog. insulin doses were similar in all treatment groups at baseline and at 26 weeks. table 11. results from study pronto-peds: 26 week trial of mealtime lyumjev and postmeal lyumjev compared with mealtime humalog, all in combination with basal insulin in pediatric patients with type 1 diabetes a analysis population: all randomized subjects regardless of adherence to treatment or availability of post-baseline assessment. missing data at week 26 were imputed by return to baseline approach. at week 26, primary efficacy assessment was missing for 5.4%, 7.1%, and 5.1% of subjects, for mealtime lyumjev, mealtime humalog, and postmeal lyumjev, respectively. b least-squares (ls) mean from ancova adjusted for baseline value and other stratification factors. c tested for non-inferiority. mealtime lyumjev + basal insulin mealtime humalog + basal insulin postmeal lyumjev + basal insulin number of randomized subjects (n) 280 298 138 hba 1c (%) (mean) a baseline 7.8 7.8 7.8 adjusted mean change from baseline b 0.06 0.06 0.06 estimated treatment difference versus humalog [95% ci] c -0.01 [-0.15, 0.14] -0.00 [-0.18, 0.18]

tempo pen b 0002-8235-05 100 units/ml 300 units 1 unit 5 pens u-200 single-patient-use 3 ml kwikpen 0002-8228-27 200 units/ml 600 units 1 unit 2 pens 16.2 storage and handling dispense in the original sealed carton with the enclosed instructions for use. refrigerate unopened lyumjev vials, pens, and cartridges between 36°f to 46°f (2°c to 8°c) until time of use and keep in the original carton to protect from light. do not freeze or use lyumjev if it has been frozen. do not expose to direct heat. discard opened or unopened lyumjev vials, pens, and cartridges stored at room temperature below 86°f (30°c) after 28 days. the storage conditions for vials, pens, and cartridges are summarized in table 13 . table 13. storage conditions for vials, pens, and cartridges a in-use (opened) vials, whether or not refrigerated, must be used within 28 days. b when stored at room temperature, lyumjev can only be used for a total of 28 days including both not in-use (unopened) and in-use (opened) storage time. lyumjev presentation not in-use (unopened) in-use (opened) room temperature (below 86°f [30°c]) refrigerated (36°f to 46°f [2°c to 8°c]) room temperature (below 86°f [30°c]) refrigerated (36°f to 46°f [2°c to 8°c]) 10 ml vial a,b 28 days until expiration date 28 days 28 days 3 ml cartridge b 28 days until expiration date 28 days do not refrigerate 3 ml lyumjev kwikpen (u-100 and u-200) b 28 days until expiration date 28 days do not refrigerate 3 ml lyumjev junior kwikpen b 28 days until expiration date 28 days do not refrigerate 3 ml lyumjev tempo pen b 28 days until expiration date 28 days do not refrigerate storage of lyumjev in insulin pump change the lyumjev u-100 in the pump reservoir at least every 9 days, or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 98.6°f (37°c). storage of lyumjev in intravenous infusion fluids diluted lyumjev may be stored for up to 4 days when refrigerated at 36°f to 46°f (2°c to 8°c) until time of use. the same solution may be stored up to 12 hours at room temperature at 68°f to 77°f (20°c to 25°c) [see dosage and administration ( 2.2 )].

l 300 units 1 unit 5 pens u-200 single-patient-use 3 ml kwikpen 0002-8228-27 200 units/ml 600 units 1 unit 2 pens

ate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. instruct patients on the management of hypoglycemia. inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. advise patients who have 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 medication errors instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products. inform patients that lyumjev u-200 contains 2 times as much insulin per ml as lyumjev u-100. the lyumjev u-200 kwikpen dose window shows the number of units of lyumjev u-200 to be injected so no dose conversion is required [see dosage and administration ( 2.1 )] . instruct patients to not transfer lyumjev u-200 from the lyumjev u-200 kwikpen to a syringe [see warnings and precautions ( 5.4 )] . hypersensitivity reactions advise patients that hypersensitivity reactions have occurred with lyumjev. inform patients on the symptoms of hypersensitivity reactions [see warnings and precautions ( 5.6 )] . instructions for patients using continuous subcutaneous infusion (insulin pump) do not use lyumjev u-200 in an insulin pump. train patients in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories. instruct patients to follow healthcare provider recommendations when setting pump basal rates and bolus settings. refer to the continuous subcutaneous infusion pump user manual to see if lyumjev can be used with the pump. see recommended reservoir and infusion sets in the insulin pump user manual. instruct patients to replace insulin in the reservoir at least every 9 days, or according to the pump user manual whichever is shorter. by following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative. instruct patients to discard insulin exposed to temperatures higher than 98.6°f (37°c). instruct patients to inform healthcare provider and select a new site for infusion if infusion site becomes erythematous, pruritic, or thickened. instruct patients on the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. instruct patients on the risk of hypoglycemia from pump malfunction. if these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their healthcare provider [see warnings and precautions ( 5 ) and how supplied/storage and handling ( 16.2 )] . eli lilly and company, indianapolis, in 46285, usa us license no. 1891 copyright © 2020, 2022, eli lilly and company. all rights reserved. lum-0003-uspi-20221014

ave heart failure or other heart problems. if you have heart failure, it may get worse while you take tzds with lyumjev. are pregnant or plan to become pregnant. talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant. are breastfeeding or plan to breastfeed. it is not known if lyumjev passes into your breast milk. you and your healthcare provider should decide if you will take lyumjev while you breastfeed. tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. before you start taking lyumjev, talk to your healthcare provider about low blood sugar and how to manage it. how should i take lyumjev? read the instructions for use that come with your lyumjev. take lyumjev exactly as your healthcare provider tells you to. your healthcare provider will tell you how much lyumjev to take and when to take it. lyumjev starts acting fast. inject lyumjev at the beginning of a meal or within 20 minutes after you start eating a meal. know the type and strength of insulin you take. do not change the type or amount of insulin you take unless your healthcare provider tells you to. the amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin. check your insulin label each time you give your injection to make sure you are using the correct insulin. check your blood sugar levels. ask your healthcare provider what your blood sugars should be and when you should check your blood sugar level. lyumjev comes in u-100 (100 units/ml) and u-200 (200 units/ml) insulin strengths. lyumjev u-200 contains 2 times as much insulin (200 units/ml) in 1 ml as lyumjev u-100 (100 units/ml). lyumjev u-100 and lyumjev u-200 can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms. lyumjev u-100 can be given by continuous infusion under the skin (subcutaneously) through an insulin pump into an area of your body recommended in the instructions that come with your insulin pump. lyumjev u-200 cannot be given through an insulin pump. lyumjev u-100 can also be given in your vein (intravenously) by your healthcare provider. lyumjev u-200 cannot be given in your vein. change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting pits in skin or thickened skin (lipodystrophy) and skin with lumps (localized cutaneous amyloidosis) 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. if you miss a dose of lyumjev, monitor your blood sugar levels to decide if an insulin dose is needed. continue with your regular dosing schedule at the next meal. lyumjev comes in a vial, single-patient-use prefilled pen, or in a cartridge. do not use a syringe to remove lyumjev from your single-patient-use prefilled pen or cartridge. keep lyumjev and all medicines out of the reach of children . your dose of lyumjev 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 other medicines you take. what should i avoid while taking lyumjev? while taking lyumjev do not: drive or operate heavy machinery, until you know how lyumjev affects you. drink alcohol or take other medicines that contain alcohol. what are the possible side effects of lyumjev? lyumjev 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, hunger, anxiety, irritability, or mood changes. low potassium in your blood (hypokalemia). serious allergic reactions (whole body allergic reaction). get emergency medical help right away, if you have any of these symptoms of a severe allergic reaction: a rash over your whole body, trouble breathing, a fast heartbeat, swelling of your face, tongue, or throat, sweating, or feeling faint. heart failure. taking certain diabetes pills called thiazolidinediones (tzds) with lyumjev may cause heart failure in some people. this can happen even if you have never had heart failure or heart failure problems before. if you already have heart failure it may get worse while you take tzds with lyumjev. your healthcare provider should monitor you closely while you are taking tzds with lyumjev. 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, or sudden weight gain. treatment with tzds and lyumjev may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure. sudden onset of high blood sugar (hyperglycemia) and high amounts of ketones in the blood or urine (ketoacidosis) due to insulin pump problems. if lyumev is given through an insulin pump and the pump is not working the right way or in case of handling errors, you may not get the right amount of insulin, which can cause a sudden onset of high blood sugar and high amounts of ketones in the blood or urine. 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, or confusion. the most common side effects of lyumjev include: low blood sugar (hypoglycemia) allergic reactions rash itching (pruritus) thickening or pits at the injection or infusion site (lipodystrophy) weight gain reactions or pain at the site of injection or at the site of infusion with insulin pump use (treprostinil sodium and sodium citrate dihydrate are inactive ingredients in lyumjev that have been known to cause reactions and pain at the infusion and injection sites in other non-insulin medicines) these are not all the possible side effects of lyumjev . 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 lyumjev. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not take lyumjev for a condition for which it was not prescribed. do not give lyumjev to other people, even if they have the same symptoms that you have. it may harm them. you can ask your pharmacist or healthcare provider for information about lyumjev that is written for health professionals. what are the ingredients in lyumjev? active ingredient: insulin lispro-aabc inactive ingredients: glycerol, magnesium chloride hexahydrate, metacresol, sodium citrate dihydrate, treprostinil sodium, zinc oxide (zinc ion), and water for injection, usp lyumjev ® is a registered trademark of eli lilly and company. eli lilly and company indianapolis, in 46285, usa us license number 1891 copyright © 2020, 2022, eli lilly and company. all rights reserved. for more information, go to www.lilly.com or call 1-800-545-5979. lum-0003-ppi-20221014