FDA Label for Mounjaro

Warning: Risk Of Thyroid C-Cell Tumors

• In both male and female rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
• MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients regarding the potential risk for MTC with the use of MOUNJARO and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with MOUNJARO [see Contraindications (4) and Warnings and Precautions (5.1)].

1 Indications And Usage

MOUNJARO™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Other

Limitations of Use

• MOUNJARO has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].
• MOUNJARO is not indicated for use in patients with type 1 diabetes mellitus.

Pool of Two Placebo-Controlled Clinical Trials

The data in Table 1 are derived from 2 placebo-controlled trials [1 monotherapy trial (SURPASS-1) and 1 trial in combination with basal insulin with or without metformin (SURPASS-5)] in adult patients with type 2 diabetes mellitus [see Clinical Studies (14.2, 14.4)]. These data reflect exposure of 718 patients to MOUNJARO and a mean duration of exposure to MOUNJARO of 36.6 weeks. The mean age of patients was 58 years, 4% were 75 years or older and 54% were male. The population was 57% White, 27% Asian, 13% American Indian or Alaska Native, and 3% Black or African American; 25% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 9.1 years with a mean HbA1c of 8.1%. As assessed by baseline fundoscopic examination, 13% of the population had retinopathy. At baseline, eGFR was ≥90 mL/min/1.73 m² in 53%, 60 to 90 mL/min/1.73 m² in 39%, 45 to 60 mL/min/1.73 m² in 7%, and 30 to 45 mL/min/1.73 m² in 1% of patients.

Pool of Seven Controlled Clinical Trials

Adverse reactions were also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in seven controlled clinical trials which included two placebo-controlled trials (SURPASS-1 and -5), three trials of MOUNJARO in combination with metformin, sulfonylureas, and/or SGLT2 Inhibitors (SURPASS-2, -3, -4) [see Clinical Studies (14.3)] and two additional trials conducted in Japan. In this pool, a total of 5119 adult patients with type 2 diabetes mellitus were treated with MOUNJARO for a mean duration of 48.1 weeks. The mean age of patients was 58 years, 4% were 75 years or older and 58% were male. The population was 65% White, 24% Asian, 7% American Indian or Alaska Native, and 3% Black or African American; 38% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 9.1 years with a mean HbA1c of 8.3%. As assessed by baseline fundoscopic examination, 15% of the population had retinopathy. At baseline, eGFR was ≥90 mL/min/1.73 m² in 52%, 60 to 90 mL/min/1.73 m² in 40%, 45 to 60 mL/min/1.73 m² in 6%, and 30 to 45 mL/min/1.73 m² in 1% of patients.

Common Adverse Reactions

Table 1 shows common adverse reactions, not including hypoglycemia, associated with the use of MOUNJARO in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on MOUNJARO than on placebo and occurred in at least 5% of patients treated with MOUNJARO.

Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials Reported in ≥5% of MOUNJARO-treated Adult Patients with Type 2 Diabetes Mellitus

Note: Percentages reflect the number of patients who reported at least 1 occurrence of the adverse reaction.
Adverse Reaction	Placebo (N=235) %	MOUNJARO 5 mg (N=237) %	MOUNJARO 10 mg (N=240) %	MOUNJARO 15 mg (N=241) %
Nausea	4	12	15	18
Diarrhea	9	12	13	17
Decreased Appetite	1	5	10	11
Vomiting	2	5	5	9
Constipation	1	6	6	7
Dyspepsia	3	8	8	5
Abdominal Pain	4	6	5	5

In the pool of seven clinical trials, the types and frequency of common adverse reactions, not including hypoglycemia, were similar to those listed in Table 1.

Gastrointestinal Adverse Reactions

In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving MOUNJARO than placebo (placebo 20.4%, MOUNJARO 5 mg 37.1%, MOUNJARO 10 mg 39.6%, MOUNJARO 15 mg 43.6%). More patients receiving MOUNJARO 5 mg (3.0%), MOUNJARO 10 mg (5.4%), and MOUNJARO 15 mg (6.6%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.4%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation and decreased over time.

The following gastrointestinal adverse reactions were reported more frequently in MOUNJARO-treated patients than placebo-treated patients (frequencies listed, respectively, as: placebo; 5 mg; 10 mg; 15 mg): eructation (0.4%, 3.0%, 2.5%, 3.3%), flatulence (0%, 1.3%, 2.5%, 2.9%), gastroesophageal reflux disease (0.4%, 1.7%, 2.5%, 1.7%), abdominal distension (0.4%, 0.4%, 2.9%, 0.8%).

Other Adverse Reactions

Hypoglycemia

Table 2 summarizes the incidence of hypoglycemic events in the placebo-controlled trials.

Table 2: Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Adult Patients with Type 2 Diabetes Mellitus

* Reflects the study treatment period. Data include events occurring during 4 weeks of treatment-free safety follow up. Events after introduction of a new glucose-lowering treatment are excluded.
** Episodes requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
	Placebo %	MOUNJARO 5 mg %	MOUNJARO 10 mg %	MOUNJARO 15 mg %
Monotherapy
(40 weeks)*	N=115	N=121	N=119	N=120
Blood glucose <54 mg/dL	1	0	0	0
Severe hypoglycemia**	0	0	0	0
Add-on to Basal Insulin with or without Metformin
(40 weeks)*	N=120	N=116	N=119	N=120
Blood glucose <54 mg/dL	13	16	19	14
Severe hypoglycemia**	0	0	2	1

Hypoglycemia was more frequent when MOUNJARO was used in combination with a sulfonylurea [see Clinical Studies (14)]. In a clinical trial up to 104 weeks of treatment, when administered with a sulfonylurea, hypoglycemia (glucose level <54 mg/dL) occurred in 13.8%, 9.9%, and 12.8%, and severe hypoglycemia occurred in 0.5%, 0%, and 0.6% of patients treated with MOUNJARO 5 mg, 10 mg, and 15 mg, respectively.

Heart Rate Increase

In the pool of placebo-controlled trials, treatment with MOUNJARO resulted in a mean increase in heart rate of 2 to 4 beats per minute compared to a mean increase of 1 beat per minute in placebo-treated patients. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, also were reported in 4.3%, 4.6%, 5.9% and 10% of subjects treated with placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. For patients enrolled in Japan, these episodes were reported in 7% (3/43), 7.1% (3/42), 9.3% (4/43), and 23% (10/43) of patients treated with placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. The clinical relevance of heart rate increases is uncertain.

Hypersensitivity Reactions

Hypersensitivity reactions have been reported with MOUNJARO in the pool of placebo-controlled trials, sometimes severe (e.g., urticaria and eczema); hypersensitivity reactions were reported in 3.2% of MOUNJARO-treated patients compared to 1.7% of placebo-treated patients.

In the pool of seven clinical trials, hypersensitivity reactions occurred in 106/2,570 (4.1%) of MOUNJARO-treated patients with anti-tirzepatide antibodies and in 73/2,455 (3.0%) of MOUNJARO-treated patients who did not develop anti-tirzepatide antibodies [see Clinical Pharmacology (12.6)].

Injection Site Reactions

In the pool of placebo-controlled trials, injection site reactions were reported in 3.2% of MOUNJARO-treated patients compared to 0.4% of placebo-treated patients.

In the pool of seven clinical trials, injection site reactions occurred in 119/2,570 (4.6%) of MOUNJARO-treated patients with anti-tirzepatide antibodies and in 18/2,455 (0.7%) of MOUNJARO-treated patients who did not develop anti-tirzepatide antibodies [see Clinical Pharmacology (12.6)].

Acute Gallbladder Disease

In the pool of placebo-controlled clinical trials, acute gallbladder disease (cholelithiasis, biliary colic and cholecystectomy) was reported by 0.6% of MOUNJARO-treated patients and 0% of placebo-treated patients.

Laboratory Abnormalities

Amylase and Lipase Increase

In the pool of placebo-controlled clinical trials, treatment with MOUNJARO resulted in mean increases from baseline in serum pancreatic amylase concentrations of 33% to 38% and serum lipase concentrations of 31% to 42%. Placebo-treated patients had a mean increase from baseline in pancreatic amylase of 4% and no changes were observed in lipase. The clinical significance of elevations in lipase or amylase with MOUNJARO is unknown in the absence of other signs and symptoms of pancreatitis.

Risk Summary

Available data with MOUNJARO use in pregnant women are insufficient to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide during pregnancy. MOUNJARO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities occurred at clinical exposure in maternal rats based on AUC. In rabbits administered tirzepatide during organogenesis, fetal growth reductions were observed at clinically relevant exposures based on AUC. These adverse embryo/fetal effects in animals coincided with pharmacological effects on maternal weight and food consumption (see Data).

The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7% and has been reported to be as high as 20–25% in women with an HbA1c >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 2–4% and 15–20%, 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

Animal Data

In pregnant rats given twice weekly subcutaneous doses of 0.02, 0.1, and 0.5 mg/kg tirzepatide (0.03-, 0.07-, and 0.5-fold the MRHD of 15 mg once weekly based on AUC) during organogenesis, increased incidences of external, visceral, and skeletal malformations, increased incidences of visceral and skeletal developmental variations, and decreased fetal weights coincided with pharmacologically-mediated reductions in maternal body weights and food consumption at 0.5 mg/kg. In pregnant rabbits given once weekly subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg tirzepatide (0.01-, 0.06-, and 0.2-fold the MRHD) during organogenesis, pharmacologically-mediated effects on the gastrointestinal system resulting in maternal mortality or abortion in a few rabbits occurred at all dose levels. Reduced fetal weights associated with decreased maternal food consumption and body weights were observed at 0.1 mg/kg. In a pre- and post-natal study in rats administered subcutaneous doses of 0.02, 0.10, or 0.25 mg/kg tirzepatide twice weekly from implantation through lactation, F₁ pups from F₀ maternal rats given 0.25 mg/kg tirzepatide had statistically significant lower mean body weight when compared to controls from post-natal day 7 through post-natal day 126 for males and post-natal day 56 for females.

Risk Summary

There are no data on the presence of tirzepatide in animal or human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MOUNJARO and any potential adverse effects on the breastfed infant from MOUNJARO or from the underlying maternal condition.

Contraception

Use of MOUNJARO may reduce the efficacy of oral hormonal contraceptives due to delayed gastric emptying. This delay is largest after the first dose and diminishes over time. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO [see Drug Interactions (7.2) and Clinical Pharmacology (12.2, 12.3)].

First and Second-Phase Insulin Secretion

Tirzepatide enhances the first- and second-phase insulin secretion. (Figure 1)



Figure 1: Mean insulin concentration at 0-120 minutes during hyperglycemic clamp at baseline and Week 28

Figure 1 - moun uspi f1 v1

Insulin Sensitivity

Tirzepatide increases insulin sensitivity, as demonstrated in a hyperinsulinemic euglycemic clamp study after 28 weeks of treatment.

Glucagon Secretion

Tirzepatide reduces fasting and postprandial glucagon concentrations. Tirzepatide 15 mg reduced fasting glucagon concentration by 28% and glucagon AUC after a mixed meal by 43%, compared with no change for placebo after 28 weeks of treatment.

Gastric Emptying

Tirzepatide delays gastric emptying. The delay is largest after the first dose and this effect diminishes over time. Tirzepatide slows post-meal glucose absorption, reducing postprandial glucose.

Absorption

Following subcutaneous administration, the time to maximum plasma concentration of tirzepatide ranges from 8 to 72 hours. The mean absolute bioavailability of tirzepatide following subcutaneous administration is 80%. Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm.

Distribution

The mean apparent steady-state volume of distribution of tirzepatide following subcutaneous administration in patients with type 2 diabetes mellitus is approximately 10.3 L. Tirzepatide is highly bound to plasma albumin (99%).

Elimination

The apparent population mean clearance of tirzepatide is 0.061 L/h with an elimination half-life of approximately 5 days, enabling once-weekly dosing.

Metabolism

Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety and amide hydrolysis.

Excretion

The primary excretion routes of tirzepatide metabolites are via urine and feces. Intact tirzepatide is not observed in urine or feces.

Specific Populations

The intrinsic factors of age, gender, race, ethnicity, or body weight do not have a clinically relevant effect on the PK of tirzepatide.

Patients with Renal Impairment

Renal impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function. This was also shown for patients with both type 2 diabetes mellitus and renal impairment based on data from clinical studies [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Hepatic impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function [see Use in Specific Populations (8.7)].

Drug Interactions Studies

Potential for Tirzepatide to Influence the Pharmacokinetics of Other Drugs

In vitro studies have shown low potential for tirzepatide to inhibit or induce CYP enzymes, and to inhibit drug transporters.

MOUNJARO delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications [see Drug Interactions (7.2)].

The impact of tirzepatide on gastric emptying was greatest after a single dose of 5 mg and diminished after subsequent doses.

Following a first dose of tirzepatide 5 mg, acetaminophen maximum concentration (C_max) was reduced by 50%, and the median peak plasma concentration (t_max) occurred 1 hour later. After coadministration at week 4, there was no meaningful impact on acetaminophen C_max and t_max. Overall acetaminophen exposure (AUC_0-24hr) was not influenced.

Following administration of a combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) in the presence of a single dose of tirzepatide 5 mg, mean C_max of ethinyl estradiol, norgestimate, and norelgestromin was reduced by 59%,66%, and 55%, while mean AUC was reduced by 20%, 21%, and 23%, respectively. A delay in t_max of 2.5 to 4.5 hours was observed.

Add-on to metformin

SURPASS-2 (NCT03987919) was a 40-week open-label trial (double-blind with respect to MOUNJARO dose assignment) that randomized 1879 adult patients with type 2 diabetes mellitus with inadequate glycemic control on stable doses of metformin alone to the addition of MOUNJARO 5 mg, MOUNJARO 10 mg, or MOUNJARO 15 mg once weekly or subcutaneous semaglutide 1 mg once weekly.

Patients had a mean age of 57 years and 47% were men. The mean duration of type 2 diabetes mellitus was 8.6 years, and the mean BMI was 34 kg/m². Overall, 83% were White, 4% were Black or African American, and 1% were Asian; 70% identified as Hispanic or Latino ethnicity.

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with semaglutide 1 mg once weekly (see Table 4 and Figure 2).

Table 4: Results at Week 40 in a Trial of MOUNJARO versus Semaglutide 1 mg in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin

a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 3%, 2%, 1%, and 1% of patients randomized to semaglutide 1 mg, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 40 the HbA1c endpoint was missing for 5%, 4%, 5%, and 5% of patients randomized to semaglutide 1 mg, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 40 data were imputed using multiple imputation with retrieved dropout.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c p<0.05 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity.
d p<0.001 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity.
e Analyzed using logistic regression adjusted for baseline value and other stratification factors.
f p<0.01 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity.
	Semaglutide 1 mg	MOUNJARO 5 mg	MOUNJARO 10 mg	MOUNJARO 15 mg
Modified Intent-to-Treat (mITT) Population (N)a	468	470	469	469
HbA1c (%)
Baseline (mean)	8.3	8.3	8.3	8.3
Change at Week 40b	-1.9	-2.0	-2.2	-2.3
Difference from semaglutideb (95% CI)	--	-0.2c (-0.3, -0.0)	-0.4d (-0.5, -0.3)	-0.5d (-0.6, -0.3)
Patients (%) achieving HbA1c <7%e	79	82	86f	86f
Fasting Serum Glucose (mg/dL)
Baseline (mean)	171	174	174	172
Change at Week 40b	-49	-55	-59	-60
Body Weight (kg)
Baseline (mean)	93.7	92.5	94.8	93.8
Change at Week 40b	-5.7	-7.6	-9.3	-11.2
Difference from semaglutideb (95% CI)	--	-1.9c (-2.8, -1.0)	-3.6d (-4.5, -2.7)	-5.5d (-6.4, -4.6)

Figure 2. Mean HbA1c (%) Over Time - Baseline to Week 40

Number of patients
MOUNJARO 5mg	470									451	470
MOUNJARO 10mg	469									445	469
MOUNJARO 15mg	469									447	469
Semaglutide 1mg	468									443	468

Note: Displayed results are from modified Intent-to-Treat Full Analysis Set. (1) Observed mean value from Week 0 to Week 40, and (2) least-squares mean ± standard error at Week 40 multiple imputation (MI).

Add-on to metformin with or without SGLT2 inhibitor

SURPASS-3 (NCT03882970) was a 52-week open-label trial that randomized 1444 adult patients with type 2 diabetes mellitus with inadequate glycemic control on stable doses of metformin with or without SGLT2 inhibitor to the addition of MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or insulin degludec 100 units/mL once daily. In this trial, 32% of patients were on SGLT2 inhibitor. Insulin degludec was initiated at 10 units once daily and adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values. At Week 52, 26% of patients randomized to insulin degludec achieved the fasting serum glucose target of <90 mg/dL, and the mean daily insulin degludec dose was 49 U (0.5 U per kilogram).

Patients had a mean age of 57 years, and 56% were men. The mean duration of type 2 diabetes mellitus was 8.4 years, and the mean baseline BMI was 34 kg/m². Overall, 91% were White, 3% were Black or African American, and 5% were Asian; 29% identified as Hispanic or Latino ethnicity.

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 52 weeks resulted in a statistically significant reduction in HbA1c compared with daily insulin degludec (see Table 5).

Table 5: Results at Week 52 in a Trial of MOUNJARO versus Insulin Degludec in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin with or without SGLT2 Inhibitor

a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 1%,1%, 1%, and 2% of patients randomized to insulin degludec, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 52 the HbA1c endpoint was missing for 9%, 6%, 10%, and 5% of patients randomized to insulin degludec, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 52 data were imputed using multiple imputation with retrieved dropout.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c p<0.001 (two-sided) for superiority vs. insulin degludec, adjusted for multiplicity.
d Analyzed using logistic regression adjusted for baseline value and other stratification factors.
	Insulin Degludec	MOUNJARO 5 mg	MOUNJARO 10 mg	MOUNJARO 15 mg
Modified Intent-to-Treat (mITT)a Population (N)	359	358	360	358
HbA1c (%)
Baseline (mean)	8.1	8.2	8.2	8.2
Change at Week 52b	-1.3	-1.9	-2.0	-2.1
Difference from insulin degludecb (95% CI)	--	-0.6c (-0.7, -0.5)	-0.8c (-0.9, -0.6)	-0.9c (-1.0, -0.7)
Patients (%) achieving HbA1c <7%d	58	79c	82c	83c
Fasting Serum Glucose (mg/dL)
Baseline (mean)	167	172	170	168
Change at Week 52b	-51	-47	-50	-54
Body Weight (kg)
Baseline (mean)	94.0	94.4	93.8	94.9
Change at Week 52b	1.9	-7.0	-9.6	-11.3
Difference from insulin degludecb (95% CI)	--	-8.9c (-10.0, -7.8)	-11.5c (-12.6, -10.4)	-13.2c (-14.3, -12.1)

Add-on to 1-3 oral anti-hyperglycemic agents (metformin, sulfonylurea or SGLT-2 inhibitor)

SURPASS-4 (NCT03730662) was a 104-week open-label trial (52-week primary endpoint) that randomized 2002 adult patients with type 2 diabetes mellitus with increased cardiovascular risk to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or insulin glargine 100 units/mL once daily (1:1:1:3 ratio) on a background of metformin (95%) and/or sulfonylureas (54%) and/or SGLT2 inhibitors (25%).

Patients had a mean age of 64 years, and 63% were men. The mean duration of type 2 diabetes mellitus was 11.8 years, and the mean baseline BMI was 33 kg/m². Overall, 82% were White, 4% were Black or African American, and 4% were Asian; 48% identified as Hispanic or Latino ethnicity. Across all treatment groups, 87% had a history of cardiovascular disease. At baseline, eGFR was ≥90 mL/min/1.73 m² in 43%, 60 to 90 mL/min/1.73 m² in 40%, 45 to 60 mL/min/1.73 m² in 10%, and 30 to 45 mL/min/1.73 m² in 6% of patients.

Insulin glargine was initiated at 10 U once daily and adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values. At Week 52, 30% of patients randomized to insulin glargine achieved the fasting serum glucose target of <100 mg/dL, and the mean daily insulin glargine dose was 44 U (0.5 U per kilogram).

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 52 weeks resulted in a statistically significant reduction in HbA1c compared with insulin glargine once daily (see Table 6).

Table 6: Results at Week 52 in a Trial of MOUNJARO versus Insulin Glargine in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin and/or Sulfonylurea and/or SGLT2 Inhibitor

a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 1%, 0%, 0%, and 1% of patients randomized to insulin glargine, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 52 the HbA1c endpoint was missing for 9%, 9%, 6%, and 4% of patients randomized to insulin glargine, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 52 data were imputed using multiple imputation with retrieved dropout.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c p<0.001 (two-sided) for superiority vs. insulin glargine, adjusted for multiplicity.
d Analyzed using logistic regression adjusted for baseline value and other stratification factors.
	Insulin Glargine	MOUNJARO 5 mg	MOUNJARO 10 mg	MOUNJARO 15 mg
Modified Intent-to-Treat (mITT) Population (N)a	998	328	326	337
HbA1c (%)
Baseline (mean)	8.5	8.5	8.6	8.5
Change at Week 52b	-1.4	-2.1	-2.3	-2.4
Difference from insulin glargineb (95% CI)	--	-0.7c (-0.9, -0.6)	-0.9c (-1.1, -0.8)	-1.0c (-1.2, -0.9)
Patients (%) achieving HbA1c <7%d	49	75c	83c	85c
Fasting Serum Glucose (mg/dL)
Baseline (mean)	168	172	176	174
Change at Week 52b	-49	-44	-50	-55
Body Weight (kg)
Baseline (mean)	90.2	90.3	90.6	90.0
Change at Week 52b	1.7	-6.4	-8.9	-10.6
Difference from insulin glargineb (95% CI)	--	-8.1c (-8.9, -7.3)	-10.6c (-11.4, -9.8)	-12.2c (-13.0, -11.5)

Risk of Thyroid C-Cell Tumors

Inform patients that MOUNJARO causes thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

Pancreatitis

Inform patients of the potential risk for pancreatitis. Instruct patients to discontinue MOUNJARO promptly and contact their healthcare provider if pancreatitis is suspected (severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting) [see Warnings and Precautions (5.2)].

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Inform patients that the risk of hypoglycemia is increased when MOUNJARO is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions have been reported with use of MOUNJARO. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking MOUNJARO and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.4)].

Acute Kidney Injury

Advise patients treated with MOUNJARO of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see Warnings and Precautions (5.5].

Severe Gastrointestinal Adverse Reactions

Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.6)].

Diabetic Retinopathy Complications

Inform patients to contact their healthcare provider if changes in vision are experienced during treatment with MOUNJARO [see Warnings and Precautions (5.7].

Acute Gallbladder Disease

Inform patients of the risk of acute gallbladder disease. Instruct patients to contact their healthcare provider for appropriate clinical follow-up if gallbladder disease is suspected [see Warnings and Precautions (5.8)].

Pregnancy

Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific Populations (8.1)].

Contraception

Use of MOUNJARO may reduce the efficacy of oral hormonal contraceptives. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO [see Drug Interactions (7.2), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)].

Missed Doses

Inform patients if a dose is missed, it should be administered as soon as possible within 4 days after the missed dose. If more than 4 days have passed, the missed dose should be skipped and the next dose should be administered on the regularly scheduled day. In each case, inform patients to resume their regular once weekly dosing schedule [see Dosage and Administration (2.1)].

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 2022, Eli Lilly and Company. All rights reserved.

MOU-0001-USPI-20220513

2.1 Dosage

• The recommended starting dosage of MOUNJARO is 2.5 mg injected subcutaneously once weekly. The 2.5 mg dosage is for treatment initiation and is not intended for glycemic control.
• After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.
• If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose.
• The maximum dosage of MOUNJARO is 15 mg injected subcutaneously once weekly.
• If a dose is missed, instruct patients to administer MOUNJARO as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
• The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours).

2.2 Important Administration Instructions

• Administer MOUNJARO once weekly, any time of day, with or without meals.
• Inject MOUNJARO subcutaneously in the abdomen, thigh, or upper arm.
• Rotate injection sites with each dose.
• Inspect MOUNJARO visually before use. It should appear clear and colorless to slightly yellow. Do not use MOUNJARO if particulate matter or discoloration is seen.
• When using MOUNJARO with insulin, administer as separate injections and never mix. It is acceptable to inject MOUNJARO and insulin in the same body region, but the injections should not be adjacent to each other.

3 Dosage Forms And Strengths

Injection: Clear, colorless to slightly yellow solution available in pre-filled single-dose pens of the following strengths:

• 2.5 mg/0.5 mL
• 5 mg/0.5 mL
• 7.5 mg/0.5 mL
• 10 mg/0.5 mL
• 12.5 mg/0.5 mL
• 15 mg/0.5 mL

4 Contraindications

MOUNJARO is contraindicated in patients with:

• A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].
• Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO [see Warnings and Precautions (5.4)].

5.1 Risk Of Thyroid C-Cell Tumors

In both sexes of rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.

MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of MOUNJARO and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with MOUNJARO. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

5.2 Pancreatitis

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists.

In clinical studies, 14 events of acute pancreatitis were confirmed by adjudication in 13 MOUNJARO-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure). MOUNJARO has not been studied in patients with a prior history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on MOUNJARO.

After initiation of MOUNJARO, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue MOUNJARO and initiate appropriate management.

5.3 Hypoglycemia With Concomitant Use Of Insulin Secretagogues Or Insulin

Patients receiving MOUNJARO in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1), Drug Interactions (7.1)].

The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.4 Hypersensitivity Reactions

Hypersensitivity reactions have been reported with MOUNJARO in clinical trials (e.g., urticaria and eczema) and were sometimes severe. If hypersensitivity reactions occur, discontinue use of MOUNJARO; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous serious hypersensitivity reaction to tirzepatide or any of the excipients in MOUNJARO [see Contraindications (4)].

Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use caution in patients with a history of angioedema or anaphylaxis with a GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with MOUNJARO.

5.5 Acute Kidney Injury

MOUNJARO has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhea [see Adverse Reactions (6.1)]. These events may lead to dehydration, which if severe could cause acute kidney injury.

In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of MOUNJARO in patients with renal impairment reporting severe gastrointestinal adverse reactions.

5.6 Severe Gastrointestinal Disease

Use of MOUNJARO has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions 6.1]. MOUNJARO has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

5.7 Diabetic Retinopathy Complications In Patients With A History Of Diabetic Retinopathy

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. MOUNJARO has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.

5.8 Acute Gallbladder Disease

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing.

In MOUNJARO placebo-controlled clinical trials, acute gallbladder disease (cholelithiasis, biliary colic, and cholecystectomy) was reported by 0.6% of MOUNJARO-treated patients and 0% of placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

6 Adverse Reactions

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
• Pancreatitis [see Warnings and Precautions (5.2)]
• Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)]
• Hypersensitivity [see Warnings and Precautions (5.4)]
• Acute Kidney Injury [see Warnings and Precautions (5.5)]
• Severe Gastrointestinal Disease [see Warnings and Precautions (5.6)]
• Diabetic Retinopathy Complications [see Warnings and Precautions (5.7)]
• Acute Gallbladder Disease [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

7.1 Concomitant Use With An Insulin Secretagogue (E.G., Sulfonylurea) Or With Insulin

When initiating MOUNJARO, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)].

7.2 Oral Medications

MOUNJARO delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with MOUNJARO.

Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with MOUNJARO.

Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO. Hormonal contraceptives that are not administered orally should not be affected [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.2, 12.3)].

8.4 Pediatric Use

Safety and effectiveness of MOUNJARO have not been established in pediatric patients (younger than 18 years of age).

8.5 Geriatric Use

In the pool of seven clinical trials, 1539 (30.1%) MOUNJARO-treated patients were 65 years of age or older, and 212 (4.1%) MOUNJARO-treated patients were 75 years of age or older at baseline.

No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

No dosage adjustment of MOUNJARO is recommended for patients with renal impairment. In subjects with renal impairment including end-stage renal disease (ESRD), no change in tirzepatide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. Monitor renal function when initiating or escalating doses of MOUNJARO in patients with renal impairment reporting severe adverse gastrointestinal reactions [see Warnings and Precautions (5.5)].

8.7 Hepatic Impairment

No dosage adjustment of MOUNJARO is recommended for patients with hepatic impairment. In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no change in tirzepatide PK was observed [see Clinical Pharmacology (12.3)].

10 Overdosage

In the event of an overdosage, contact Poison Control for latest recommendations. Appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. A period of observation and treatment for these symptoms may be necessary, taking into account the half-life of tirzepatide of approximately 5 days.

11 Description

MOUNJARO (tirzepatide) injection, for subcutaneous use, contains tirzepatide, a once weekly GIP receptor and GLP-1 receptor agonist. It is a 39-amino-acid modified peptide based on the GIP sequence. Tirzepatide contains 2 non-coded amino acids (aminoisobutyric acid, Aib) in positions 2 and 13, a C-terminal amide, and Lys residue at position 20 that is attached to 1,20-eicosanedioic acid via a linker. The molecular weight is 4813.53 Da and the empirical formula is C₂₂₅H₃₄₈N₄₈O₆₈.

Structural formula:

Structural Formula - moun uspi chem struc

MOUNJARO is a clear, colorless to slightly yellow, sterile, preservative-free solution for subcutaneous use. Each single-dose pen contains a 0.5 mL solution of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg of tirzepatide and the following excipients: sodium chloride (4.1 mg), sodium phosphate dibasic heptahydrate (0.7 mg), and water for injection. Hydrochloric acid solution and/or sodium hydroxide solution may have been added to adjust the pH. MOUNJARO has a pH of 6.5 – 7.5.

12.1 Mechanism Of Action

Tirzepatide is a GIP receptor and GLP-1 receptor agonist. It is a 39-amino-acid modified peptide with a C20 fatty diacid moiety that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1.

Tirzepatide enhances first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner.

12.2 Pharmacodynamics

Tirzepatide lowers fasting and postprandial glucose concentration, decreases food intake, and reduces body weight in patients with type 2 diabetes mellitus.

12.3 Pharmacokinetics

The pharmacokinetics of tirzepatide is similar between healthy subjects and patients with type 2 diabetes mellitus. Steady-state plasma tirzepatide concentrations were achieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a dose-proportional manner.

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 trials described below with the incidence of anti-drug antibodies in other trials, including those of tirzepatide or of GLP-1 receptor agonist products.

During the 40- to 104-week treatment periods with ADA sampling conducted up to 44 to 108 weeks in seven clinical trials in adults with type 2 diabetes mellitus [see Clinical Studies (14)], 51% (2,570/5,025) of MOUNJARO-treated patients developed anti-tirzepatide antibodies. In these trials, anti-tirzepatide antibody formation in 34% and 14% of MOUNJARO-treated patients showed cross-reactivity to native GIP or native GLP-1, respectively.

Of the 2,570 MOUNJARO-treated patients who developed anti-tirzepatide antibodies during the treatment periods in these seven trials, 2% and 2% developed neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors, respectively, and 0.9% and 0.4% developed neutralizing antibodies against native GIP or GLP-1, respectively.

There was no identified clinically significant effect of anti-tirzepatide antibodies on pharmacokinetics or effectiveness of MOUNJARO. More MOUNJARO-treated patients who developed anti-tirzepatide antibodies experienced hypersensitivity reactions or injection site reactions than those who did not develop these antibodies [see Adverse Reactions (6.1)].

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.1-, 0.4-, and 1-fold the MRHD of 15 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. A statistically significant increase in thyroid C-cell adenomas was observed in males (≥0.5 mg/kg) and females (≥0.15 mg/kg), and a statistically significant increase in thyroid C-cell adenomas and carcinomas combined was observed in males and females at all doses examined. In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered by subcutaneous injection twice weekly was not tumorigenic.

Tirzepatide was not genotoxic in a rat bone marrow micronucleus assay.

In fertility and early embryonic development studies, male and female rats were administered twice weekly subcutaneous doses of 0.5, 1.5, or 3 mg/kg (0.3-, 1-, and 2-fold and 0.3-, 0.9-, and 2-fold, respectively, the MRHD of 15 mg once weekly based on AUC). No effects of tirzepatide were observed on sperm morphology, mating, fertility, and conception. In female rats, an increase in the number of females with prolonged diestrus and a decrease in the mean number of corpora lutea resulting in a decrease in the mean number of implantation sites and viable embryos was observed at all dose levels. These effects were considered secondary to the pharmacological effects of tirzepatide on food consumption and body weight.

14.1 Overview Of Clinical Studies

The effectiveness of MOUNJARO as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus was established in five trials. In these trials, MOUNJARO was studied as monotherapy (SURPASS-1); as an add-on to metformin, sulfonylureas, and/or sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) (SURPASS-2, -3, and -4); and in combination with basal insulin with or without metformin (SURPASS-5). In these trials, MOUNJARO (5 mg, 10 mg, and 15 mg given subcutaneously once weekly) was compared with placebo, semaglutide 1 mg, insulin degludec, and/or insulin glargine.

In adult patients with type 2 diabetes mellitus, treatment with MOUNJARO produced a statistically significant reduction from baseline in HbA1c compared to placebo. The effectiveness of MOUNJARO was not impacted by age, gender, race, ethnicity, region, or by baseline BMI, HbA1c, diabetes duration, or renal function.

14.2 Monotherapy Use Of Mounjaro In Adult Patients With Type 2 Diabetes Mellitus

SURPASS-1 (NCT03954834) was a 40-week double-blind trial that randomized 478 adult patients with type 2 diabetes mellitus with inadequate glycemic control with diet and exercise to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg, or placebo once weekly.

Patients had a mean age of 54 years, and 52% were men. The mean duration of type 2 diabetes mellitus was 4.7 years, and the mean BMI was 32 kg/m². Overall, 36% were White, 35% were Asian, 25% were American Indians/Alaska Natives, and 5% were Black or African American; 43% identified as Hispanic or Latino ethnicity.

Monotherapy with MOUNJARO 5 mg, 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 3).

14.4 Mounjaro Use In Combination With Basal Insulin With Or Without Metformin In Adult Patients With Type 2 Diabetes Mellitus

SURPASS-5 (NCT04039503) was a 40-week double-blind trial that randomized 475 patients with type 2 diabetes mellitus with inadequate glycemic control on insulin glargine 100 units/mL, with or without metformin, to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or placebo. The dose of background insulin glargine was adjusted using a treat-to-target algorithm based on self-measured fasting blood glucose values, targeting <100 mg/dL.

Patients had a mean age of 61 years, and 56% were men. The mean duration of type 2 diabetes mellitus was 13.3 years, and the mean baseline BMI was 33 kg/m². Overall, 80% were White, 1% were Black or African American, and 18% were Asian; 5% identified as Hispanic or Latino ethnicity.

The mean dose of insulin glargine at baseline was 34, 32, 35, and 33 units/day for patients receiving MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. At randomization, the initial insulin glargine dose in patients with HbA1c ≤8.0% was reduced by 20%. At week 40, mean dose of insulin glargine was 38, 36, 29, and 59 units/day for patients receiving MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively.

Treatment with MOUNJARO 5 mg once weekly, 10 mg once weekly and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 7).

16.1 How Supplied

MOUNJARO is a clear, colorless to slightly yellow solution available in pre-filled single-dose pens as follows:

16.2 Storage And Handling

• Store MOUNJARO in a refrigerator at 2°C to 8°C (36°F to 46°F).
• If needed, each single-dose pen can be stored unrefrigerated at temperatures not to exceed 30°C (86°F) for up to 21 days.
• Do not freeze MOUNJARO. Do not use MOUNJARO if frozen.
• Store MOUNJARO in the original carton to protect from light.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Spl Medguide

MOU-0001-MG-20220513

Instructions For Use

INSTRUCTIONS FOR USE MOUNJARO™ (mown-JAHR-OH) (tirzepatide) injection, for subcutaneous use 2.5 mg/0.5 mL single-dose pen 5 mg/0.5 mL single-dose pen 7.5 mg/0.5 mL single-dose pen 10 mg/0.5 mL single-dose pen 12.5 mg/0.5 mL single-dose pen 15 mg/0.5 mL single-dose pen use 1 time each week

Figure - moun ifu 1 v1

Important information you need to know before injecting MOUNJARO

Read this Instructions for Use and the Medication Guide before using your MOUNJARO Pen and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Talk to your healthcare provider about how to inject MOUNJARO the right way.

• MOUNJARO is a single-dose prefilled pen.
• MOUNJARO is used 1 time each week.
• Inject under the skin (subcutaneously) only.
• You or another person can inject into your stomach (abdomen) or thigh.
• Another person can inject into the back of your upper arm.

Storage and handling

• Store your Pen in the refrigerator between 36°F to 46°F (2°C to 8°C).
• You may store your Pen at room temperature up to 86°F (30°C) for up to 21 days.
• Do not freeze your Pen. If the Pen has been frozen, throw the Pen away and use a new Pen.
• Store your Pen in the original carton to protect your Pen from light.
• The Pen has glass parts. Handle it carefully. If you drop the Pen on a hard surface, do not use it. Use a new Pen for your injection.
• Keep your MOUNJARO Pen and all medicines out of the reach of children.

Guide to parts

Preparing to inject MOUNJARO

Remove the Pen from the refrigerator. Leave the gray base cap on until you are ready to inject.
Check the Pen label to make sure you have the right medicine and dose, and that it has not expired. Inspect the Pen to make sure that it is not damaged.
Make sure the medicine:
is not frozen is not cloudy	is colorless to slightly yellow does not have particles
Wash your hands.

Step 1	Choose your injection site
	Your healthcare provider can help you choose the injection site that is best for you. You or another person can inject the medicine in your stomach (abdomen) or thigh.
	Another person should give you the injection in the back of your upper arm. Change (rotate) your injection site each week. You may use the same area of your body but be sure to choose a different injection site in that area.

Step 2	Pull off the gray base cap
		Make sure the Pen is locked. Do not unlock the Pen until you place the clear base on your skin and are ready to inject.
		Pull the gray base cap straight off and throw it away in your household trash. Do not put the gray base cap back on – this could damage the needle. Do not touch the needle.

Step 3	Place clear base on skin, then unlock
		Place the clear base flat against your skin at the injection site.
		Unlock by turning the lock ring.

Step 4	Press and hold up to 10 seconds
		Press and hold the purple injection button for up to 10 seconds. Listen for: • First click = injection started • Second click = injection completed
		You will know your injection is complete when the gray plunger is visible.

After your injection, place the used Pen in a sharps container.

See Disposing of your used Pen.

made of a heavy-duty plastic,
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
upright and stable during use,
leak-resistant, and
properly labeled to warn of hazardous waste inside the container.

-

-

-

-

-

Disposing of your used Pen Put your used Pen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) Pens in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:

• When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
• Do not recycle your used sharps disposal container.

Commonly asked questions

What if I see air bubbles in my Pen?

Air bubbles are normal.

What if my Pen is not at room temperature?

It is not necessary to warm the Pen to room temperature.

What if I unlock the Pen and press the purple injection button before pulling off the gray base cap?

Do not remove the gray base cap. Throw away the Pen and get a new Pen.

What if there is a drop of liquid on the tip of the needle when I remove the gray base cap?

A drop of liquid on the tip of the needle is normal. Do not touch the needle.

Do I need to hold the injection button down until the injection is complete?

This is not necessary, but it may help you keep the Pen steady against your skin.

I heard more than 2 clicks during my injection—2 loud clicks and 1 soft one. Did I get my complete injection?

Some people may hear a soft click right before the second loud click. That is the normal operation of the Pen. Do not remove the Pen from your skin until you hear the second loud click.

I am not sure if my Pen worked the right way.

Check to see if you have received your dose. Your dose was delivered the right way if the gray plunger is visible. Also, see Step 4 of the instructions. If you do not see the gray plunger, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) for further instructions. Until then, store your Pen safely to avoid an accidental needle stick.

What if there is a drop of liquid or blood on my skin after my injection?

This is normal. Press a cotton ball or gauze over the injection site. Do not rub the injection site.

Other information

• If you have vision problems, do not use your Pen without help from a person trained to use the MOUNJARO Pen.

Where to learn more

• If you have questions or problems with your MOUNJARO Pen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider.

• For more information about the MOUNJARO Pen, visit our website at www.mounjaro.com.

Scan this code to launch www.mounjaro.com

Marketed by:

Lilly USA, LLC

Indianapolis, IN 46285, USA

MOUNJARO is a trademark of Eli Lilly and Company.

Copyright © 2022, Eli Lilly and Company. All rights reserved.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: May 2022

MOU-0001-IFU-20220513

Package Label.Principal Display Panel

PACKAGE LABEL - Mounjaro™, 2.5 mg/0.5 mL, Carton, 4 Single-Dose Pens

NDC 0002-1506-80

Mounjaro™

(tirzepatide) injection

2.5 mg / 0.5 mL

Use one pen every week.

4 Single-dose prefilled pens

4 x 2.5 mg/0.5 mL prefilled pens

Rx Only

For Subcutaneous Use

Dispense enclosed Medication Guide to each patient.

Lilly

PACKAGE LABEL - Mounjaro™, 2.5 mg/0.5 mL, Carton, 4 Single-Dose Pens - moun cart 2point5mg 066 00

PACKAGE LABEL - Mounjaro™, 5 mg/0.5 mL, Carton, 4 Single-Dose Pens

NDC 0002-1495-80

Mounjaro™

(tirzepatide) injection

5 mg / 0.5 mL

Use one pen every week.

4 Single-dose prefilled pens

4 x 5 mg/0.5 mL prefilled pens

Rx Only

For Subcutaneous Use

Dispense enclosed Medication Guide to each patient.

Lilly

PACKAGE LABEL - Mounjaro™, 7.5 mg/0.5 mL, Carton, 4 Single-Dose Pens

NDC 0002-1484-80

Mounjaro™

(tirzepatide) injection

7.5 mg / 0.5 mL

Use one pen every week.

4 Single-dose prefilled pens

4 x 7.5 mg/0.5 mL prefilled pens

Rx Only

For Subcutaneous Use

Dispense enclosed Medication Guide to each patient.

Lilly

PACKAGE LABEL - Mounjaro™, 10 mg/0.5 mL, Carton, 4 Single-Dose Pens

NDC 0002-1471-80

Mounjaro™

(tirzepatide) injection

10 mg / 0.5 mL

Use one pen every week.

4 Single-dose prefilled pens

4 x 10 mg/0.5 mL prefilled pens

Rx Only

For Subcutaneous Use

Dispense enclosed Medication Guide to each patient.

Lilly

PACKAGE LABEL - Mounjaro™, 12.5 mg/0.5 mL, Carton, 4 Single-Dose Pens

NDC 0002-1460-80

Mounjaro™

(tirzepatide) injection

12.5 mg / 0.5 mL

Use one pen every week.

4 Single-dose prefilled pens

4 x 12.5 mg/0.5 mL prefilled pens

Rx Only

For Subcutaneous Use

Dispense enclosed Medication Guide to each patient.

Lilly

PACKAGE LABEL - Mounjaro™, 15 mg/0.5 mL, Carton, 4 Single-Dose Pens

NDC 0002-1457-80

Mounjaro™

(tirzepatide) injection

15 mg / 0.5 mL

Use one pen every week.

4 Single-dose prefilled pens

4 x 15 mg/0.5 mL prefilled pens

Rx Only

For Subcutaneous Use

Dispense enclosed Medication Guide to each patient.

Lilly