DRUG INTERACTIONS-( summary)

 MOUNJARO delays gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications. 

BRIEF SUMMARY

TIRZEPATIDE-(May 2022)

Indn- To Inprove Blood sugar Control in Diabetes, in                                                                    addition to Diet and Excercise   

Comp-  Injection: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg per 0.5 mL in single-dose pen . indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

ADR- common adverse reactions, reported in =5% of patients treated are: nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain.

CI- Known serious hypersensitivity to tirzepatide or any of the excipients

WARNINGS -

  Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected.

  Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary.

Pat inform-

Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their healthcare provider

 Pancreatitis- Inform patients of the potential risk for pancreatitis.

Instruct patients to discontinue 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)].

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin-       Inform patients that the risk of hypoglycemia is increased whens used with an insulin secretagogue (such as a sulfonylurea) or insulin.

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U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 14

Name of the Drug-   MUNJACO

Active Ingredient -   Tirzepatide

Pharmacological Classification- To Inprove Blood sugar Control in Diabetes, in                                                                    addition to Diet and Excercise                                                                                                                                               

Date of Approval-         5/13/22

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                      MOUNJARO safely and effectively. See full prescribing information for MOUNJARO. MOUNJAROTM (tirzepatide) Injection, for subcutaneous use

Initial U.S. Approval: 2022

WARNING: RISK OF THYROID C-CELL TUMORS

See full prescribing information for complete boxed warning.                                           

 • Tirzepatide causes thyroid C-cell tumors in rats. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the 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 Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).                         Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors

 INDICATIONS AND USAGE-

 MOUNJARO™ is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

 Limitations of Use: • Has not been studied in patients with a history of pancreatitis     * it  Is not indicated for use in patients with type 1 diabetes mellitus

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ADVERSE REACTIONS-

 The most common adverse reactions, reported in =5% of patients treated with MOUNJARO are: nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain.

 CONTRAINDICATIONS

 • Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2

 • Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO

WARNINGS AND PRECAUTIONS-

 • Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected.

 • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary.

 • Hypersensitivity Reactions: Hypersensitivity reactions have been reported. Discontinue MOUNJARO if suspected.

 • Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.

 • Severe Gastrointestinal Disease: Use may be associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in patients with severe gastrointestinal disease and is not recommended in these patients.

 • Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy: Has not been studied in patients with nonproliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Monitor patients with a history of diabetic retinopathy for progression.

 • Acute Gallbladder Disease: Has occurred in clinical trials. If cholelithiasis is suspected, gallbladder studies and clinical followup are indicated.

DOSAGE AND ADMINISTRATION-

 • The recommended starting dosage is 2.5 mg injected subcutaneously once weekly

 • After 4 weeks, increase 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 is 15 mg subcutaneously once weekly

. • Administer once weekly at any time of day, with or without meals.

 • Inject subcutaneously in the abdomen, thigh, or upper arm.

 • Rotate injection sites with each dose.

DOSAGE FORMS AND STRENGTHS-

 Injection: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg per 0.5 mL in single-dose pen 

PATIENT COUNSELING INFORMATION-

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

 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)].

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.

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 [

. 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.

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 

Diabetic Retinopathy Complications-                                                                          Inform patients to contact their healthcare provider if changes in vision are experienced during treatment with MOUNJARO

 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 

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 

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),

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

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © YYYY, Eli Lilly and Company. All rights reserved. A6.0-MOU-0001-USPI-YYYYMMD

CLINICAL PHARMACOLOGY

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 glucosedependent manner

2. Pharmacodynamics-                                                                                      Tirzepatide lowers fasting and postprandial glucose concentration, decreases food intake, and reduces body weight in patients with type 2 diabetes mellitus. First and Second-Phase Insulin Secretion Tirzepatide enhances the first- and second-phase insulin secretion.

3. Pharmacokinetics-                                                                                                   The pharmacokinetics of tirzepatide is similar between healthy subjects and patients with type 2 diabetes mellitus. Steadystate plasma tirzepatide concentrations were achieved following 4 weeks of once weekly administration.

Tirzepatide exposure increases in a dose-proportional manner.

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.                                                                                               Patients with Hepatic Impairment-  Hepatic impairment does not impact the pharmacokinetics of tirzepatide.

Patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function

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

 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 (Cmax) was reduced by 50%, and the median peak plasma concentration (tmax) occurred 1 hour later.

After coadministration at week 4, there was no meaningful impact on acetaminophen Cmax and tmax. Overall acetaminophen exposure (AUC0-24hr) was not influenced.

USE IN SPECIFIC POPULATIONS

1. Pregnancy 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 (

 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.

2. Lactation 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.

3. Females and Males of Reproductive Potential-                                              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.

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

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.

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.

 Monitor renal function when initiating or escalating doses of MOUNJARO in patients with renal impairment reporting severe adverse gastrointestinal reactions                       

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 

 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.