TIRZEPATIDE PEN INJECTOR
Clinical Criteria Summary
Document 550: MON Tirzepatide ZEPBOUND Monograph Dec 2023
Indication & Patient Selection
- • Indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults.
- • Requires an initial body mass index (BMI) of ≥30 kg/m² (obesity) or ≥27 kg/m² (overweight) with at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).
Dosing & Administration
- • Administered subcutaneously once weekly.
- • Initial dose is 2.5 mg/0.5 mL.
- • Weekly dose should be increased by 2.5 mg at 4-week intervals.
- • Maintenance doses are 5 mg, 10 mg, and 15 mg SC once weekly.
- • Maximum dose is 15 mg SC once weekly.
Contraindications
- • Personal or family history of medullary thyroid carcinoma (MTC).
- • Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
- • Known serious hypersensitivity to tirzepatide or any excipients in ZEPBOUND.
Warnings & Precautions / Monitoring Criteria
- • Pancreatitis: Discontinue promptly if pancreatitis is suspected.
- • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Concomitant use may increase the risk of severe hypoglycemia; reducing dose of insulin secretagogue or insulin may be necessary.
- • Hypersensitivity Reactions: Discontinue tirzepatide if suspected.
- • Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions that could lead to volume depletion.
- • Severe Gastrointestinal Disease: Not recommended in patients with severe gastrointestinal disease.
- • Diabetic Retinopathy Complications: Monitor patients with a history of diabetic retinopathy for progression; not studied in non-proliferative requiring acute therapy, proliferative, or diabetic macular edema.
- • Acute Gallbladder Disease: If cholelithiasis is suspected, perform gallbladder studies and clinical follow-up.
- • Suicide Behavior and Ideation: Avoid use in patients with a history of suicidal attempts or active suicidal ideation. Monitor for emergence or worsening of depression, suicidal thoughts/behaviors, or unusual changes in mood/behavior; discontinue if experienced.
Special Populations
- • Pregnancy/Fetal Harm: Discontinue when pregnancy is recognized. Weight loss offers no benefit to a pregnant patient and may cause fetal harm.
- • Reproductive Potential: Patients using oral contraceptives should switch to a non-oral contraceptive method or add a barrier method for 4 weeks after initiating tirzepatide and for 4 weeks after each dose escalation due to delayed gastric emptying.
Document 551: Tirzepatide ZEPBOUND for weight management CFU
Exclusion Criteria
- Known pregnancy
- Lactating status
- Type 1 diabetes (exception: may be considered under careful supervision if followed by a diabetes/weight management specialist)
- Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2
- Severe gastrointestinal dysmotility, including gastroparesis
- History of pancreatitis (excludes patients with a known cause that no longer presents a risk)
- Known proliferative diabetic retinopathy (PDR), severe non-proliferative diabetic retinopathy (NPDR), clinically significant macular edema (ME), or diabetic macular edema (DME) unless risks/benefits are discussed, documented in the EHR with monitoring plans/follow-up, and an eye specialist is informed at initiation
Inclusion Criteria
- Documented participation in a comprehensive lifestyle intervention (CLI) targeting diet, physical activity, and behavioral changes within the past year
- Body Mass Index (BMI) ≥ 27 kg/m² with at least one weight-related comorbidity
- Weight-related comorbidities include: hypertension, type 2 diabetes, prediabetes, dyslipidemia, metabolic syndrome, obstructive sleep apnea, osteoarthritis, metabolic dysfunction-associated steatotic liver disease, heart failure with preserved ejection fraction, previous myocardial infarction, previous stroke, or symptomatic peripheral arterial disease
- Discontinuation of medications that may precipitate weight gain should be considered if clinically appropriate
Additional Inclusion Criteria (Females Who Can Become Pregnant)
- Pregnancy must be excluded prior to receiving tirzepatide
- Contraceptive counseling regarding potential risks vs. benefits of pregnancy during therapy is required
- Females of childbearing potential using oral contraceptives must be counseled to switch to a non-oral contraceptive method or add a barrier method for 4 weeks after initiation and 4 weeks after each dose escalation
Monitoring & Clinical Management Requirements
- For patients with diabetes, diabetic eye exam results should be available within the past 12 months (or 24 months if no evidence of retinopathy)
- Patients with a history of diabetic retinopathy require planned follow-up with an eye provider to monitor progression; consultation with an eye care specialist is required for any concerns
- Pancreatitis risk factors include triglyceride level > 1000 mg/dL, known gallstones with intact gallbladder, and high alcohol intake
Document 421: Weight Management Medications Clinical Recommendations
Criteria for Phentermine/Topiramate
- Inclusion/Exclusion Criteria: Excluded in pregnancy, hyperthyroidism, and MAOI use during or within 14 days. Requires documented participation in a comprehensive lifestyle intervention targeting diet, physical activity, and behavioral changes within the past year.
- Efficacy & Maintenance Goals: Initial: If 3% weight loss not achieved at 12 weeks on 7.5 mg/46 mg, increase dose per prescribing information. If 5% loss of baseline body weight not achieved at 12 weeks on 15 mg/92 mg, taper to discontinue. Maintenance: Maintain ≥67% initial weight loss or >5% loss from baseline weight or continued weight loss; ongoing participation in comprehensive lifestyle intervention required.
- Comorbidity Considerations:
- Hypertension: ↓ BP in HTN; Warning/Precaution for risk of hypotension with antihypertensive medications.
- Cardiac/Cerebrovascular Disease: Warning/Precaution for ↑ HR, monitor (especially in cardiac or cerebrovascular disease); ↓ or DC if sustained. Not recommended or studied in recent or unstable disease.
- Diabetes Mellitus: Improved glycemic parameters in DM.
- Mental Health Conditions/Suicidality: Dose-related ↑ depression, anxiety, adverse events; Warning/Precaution for mood and sleep disorders, cognitive impairment.
- Seizure Disorder: Warning/Precaution; Abrupt DC may cause seizures (regardless of history); ↑ risk for seizures; taper if DC.
- Nephrolithiasis: Warning/Precaution; Risk may be ↑ with ketogenic diet or ↑ urinary oxalate and concomitant carbonic anhydrase inhibitors; may ↓ risk with ↑ fluid intake.
- Glaucoma: Contraindication; Warning/Precaution for acute myopia and secondary angle closure glaucoma; DC if acute onset ↓ visual acuity or ocular pain.
- Contraindications & Warnings/Precautions: Fetal toxicity (REMS), ↑ HR, suicidal behavior and ideation, acute myopia and secondary angle closure glaucoma, metabolic acidosis, hypokalemia, adjust dose per CrCl (avoid in ESRD), nephrolithiasis, adjust dose in moderate hepatic impairment, hypoglycemia with antidiabetic medications, oligohidrosis and hyperthermia, serious skin reactions, avoid abrupt withdrawal due to potential for seizures, contains phentermine (potential for abuse), interference with absorption of fat-soluble vitamins, cyclosporine, warfarin, amiodarone, thyroid hormone, antiepileptic drugs, and antiretroviral drugs.
Criteria for Orlistat
- Inclusion/Exclusion Criteria: Excluded in pregnancy, chronic malabsorption syndrome, and cholestasis. Requires documented participation in a comprehensive lifestyle intervention targeting diet, physical activity, and behavioral changes within the past year.
- Efficacy & Maintenance Goals: Initial: 3% weight loss at 12 weeks. Maintenance: Maintain ≥67% initial weight loss or >5% loss from baseline weight or continued weight loss; ongoing participation in comprehensive lifestyle intervention required.
- Comorbidity Considerations:
- Hypertension: ↓ BP in HTN.
- Cardiac/Cerebrovascular Disease: Unknown impact on listed comorbidity as several conditions excluded from clinical trials.
- Diabetes Mellitus: Improved glycemic parameters in DM; ↓ risk of DM.
- Mental Health Conditions/Suicidality: Boxed Warning for suicidal behavior or ideation; Warning/Precaution for neuropsychiatric adverse events and suicide risk (in smoking cessation).
- Nephrolithiasis: Warning/Precaution; ↑ urinary oxalate and risk of oxalate nephrolithiasis and oxalate nephropathy; caution in renal impairment, history hyperoxaluria or calcium oxalate stones. DC if oxalate nephropathy develops.
- Contraindications & Warnings/Precautions: Hepatotoxicity, cholelithiasis, oxalate nephrolithiasis and oxalate nephropathy with renal failure, gastrointestinal events if taken with a diet high in fat.
Criteria for Naltrexone/Bupropion
- Inclusion/Exclusion Criteria: Excluded in pregnancy, seizure disorder, bulimia or anorexia nervosa, chronic opioid use or acute opioid withdrawal, MAOI use during or within 14 days, and abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiepileptic drugs. Requires documented participation in a comprehensive lifestyle intervention targeting diet, physical activity, and behavioral changes within the past year.
- Efficacy & Maintenance Goals: Initial: 5% weight loss by 12 weeks; per prescribing information, discontinue if not achieved. Maintenance: Maintain ≥67% initial weight loss or >5% loss from baseline weight or continued weight loss; ongoing participation in comprehensive lifestyle intervention required.
- Comorbidity Considerations:
- Hypertension: Contraindication in Uncontrolled HTN; Warning/Precaution May ↑ BP/cause HTN.
- Cardiac/Cerebrovascular Disease: Warning/Precaution ↑ HR or BP, monitor per usual practice; DC if sustained.
- Diabetes Mellitus: Improved glycemic parameters in DM.
- Mental Health Conditions/Suicidality: Boxed Warning for suicidal behavior or ideation; Warning/Precaution for mood and sleep disorders, cognitive impairment; Monitor patients especially during initial months, dose changes post-marketing; multiple post-marketing meta-analyses support no increased risk in suicidal ideation and/or behavior and FDA has issued a letter for this to be removed from prescribing information.
- Nephrolithiasis: May ↑ urinary oxalate and risk of oxalate nephropathy; caution in renal impairment.
- Contraindications & Warnings/Precautions: Suicidal behavior and ideation [Boxed Warning], neuropsychiatric adverse events and suicide risk, seizures (increased risk with factors that decrease seizure threshold), vulnerability to opioid overdose, precipitated opioid withdrawal, hepatotoxicity (adjust dose in hepatic impairment, not recommended in severe hepatic impairment), activation of mania, increased blood pressure and heart rate, hypoglycemia with use of antidiabetic medications, adjust dose in moderate to severe renal impairment (avoid in ESRD).
Criteria for Liraglutide, Semaglutide, and Tirzepatide
- Inclusion/Exclusion Criteria: Excluded in pregnancy (liraglutide only per table note), personal or family history of medullary thyroid carcinoma, or multiple endocrine neoplasia type 2 (MEN2). Requires documented participation in a comprehensive lifestyle intervention targeting diet, physical activity, and behavioral changes within the past year.
- Efficacy & Maintenance Goals:
- Liraglutide: Initial: 4% weight loss at week 16; per prescribing information, discontinue if not achieved. Maintenance: Maintain ≥67% initial weight loss or >5% loss from baseline weight or continued weight loss; ongoing participation in comprehensive lifestyle intervention required.
- Semaglutide: Initial: 5% weight loss after achieving dose titration to a maintenance dose of 2.4 mg (recommended) (approximately 20 weeks) or 1.7 mg once weekly for injection or 25 mg daily for oral tablet. Per prescribing information, if a dose is not tolerated during titration, the dose increase can be delayed for 4 weeks. Maintenance: Maintain ≥67% initial weight loss or >5% loss from baseline weight or continued weight loss; ongoing participation in comprehensive lifestyle intervention required.
- Tirzepatide: Initial: 5% weight loss after achieving dose titration to a maintenance dose of 5 mg, 10 mg, or 15 mg once weekly (titration duration ranges 4-16 weeks depending on maintenance dose). Per prescribing information, if a maintenance dose is not tolerated, a lower maintenance dose should be considered. Maintenance: Maintain ≥67% initial weight loss or >5% loss from baseline weight or continued weight loss; ongoing participation in comprehensive lifestyle intervention required.
- Comorbidity Considerations:
- Hypertension: ↓ BP in HTN reported in ADRs of semaglutide and tirzepatide.
- Cardiac/Cerebrovascular Disease: Warning/Precaution ↑ HR, monitor. Semaglutide: ↓ risk of death from CV cause, nonfatal MI, or nonfatal stroke in preexisting CV disease without diabetes. No specific precaution for listed comorbidity otherwise.
- Diabetes Mellitus: Improved glycemic parameters in DM. Avoid use of a concurrent DPP-4 inhibitor due to lack of additive efficacy. Liraglutide: ↓ risk of DM. Semaglutide and Tirzepatide: Improved glycemic parameters in preDM.
- Mental Health Conditions/Suicidality: Monitor for emergence or ↑ depressive symptoms, suicidal thoughts or behavior; recommend avoiding if history of suicide attempts or active suicidal ideation.
- Contraindications & Warnings/Precautions: Thyroid C-cell tumors (medullary carcinoma) [Boxed Warning], acute pancreatitis, acute cholelithiasis or cholecystitis, severe gastrointestinal adverse reactions (intestinal obstruction, severe constipation including fecal impaction), hypoglycemia (may need to adjust concomitant DM agents), ↑ HR, renal impairment (use with caution in existing CKD for liraglutide; acute kidney injury for semaglutide and tirzepatide), diabetic retinopathy complications (semaglutide and tirzepatide).
Shared Criteria for All Weight Management Medications
- Efficacy/Discontinuation Rule: If sufficient weight loss is not achieved within the first 3 months of a maximally tolerated dose or significant weight gain/regain after initial loss occurs, discontinue medication. A trial of a different weight management medication may be warranted provided the patient continues to adhere to comprehensive lifestyle intervention.
- Refill Requirements: Initial refill after 12 to 24 weeks requires continued participation in a comprehensive lifestyle intervention (or previously completed one within the past year with at least one follow-up visit). Refills every 6 months require no specific documentation for continued lifestyle intervention, but maintenance of ≥67% initial weight loss or >5% loss from baseline weight or continued weight loss is a reasonable goal; continued participation may be necessary to meet these goals.
- General Prescribing Considerations: Pharmacotherapy must be in conjunction with a comprehensive lifestyle intervention (diet, physical activity, behavioral changes). Weight management medications should be viewed as long-term therapy. Selection requires shared decision-making considering efficacy, side effects, cautions, warnings, and patient comorbidities. Review current treatment regimen for medications with potential for weight gain and consider alternate therapy.