Zepbound Kwikpen (tirzepatide)

No dosing information is available for this tab.

Tirzepatide is administered via subcutaneous injection once weekly with or without meals. Tirzepatide for the treatment of type 2 diabetes (Mounjaro(R)) is available in pre-filled single-dose pens or single-dose vials in the following strengths per 0.5 mL: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg. Tirzepatide for weight management (Zepbound(R)) is available in pre-filled single-dose pens in the following strengths per 0.5 mL: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg. Tirzepatide is a clear, colorless to slightly yellow solution; do not use if particulate matter or discoloration is seen.

Train patients and/or caregivers on proper injection technique. Inject subcutaneously into the abdomen, thigh, or upper arm. Rotate injection sites with each dose.

Instruct patients using the single-dose vial to use an appropriate syringe for administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose). When using tirzepatide with insulin, administer as separate injections and do not mix in the same syringe. Injections of tirzepatide and insulin can be given in the same body region but the injections should not be adjacent to one other.

If a dose is missed, administer as soon as possible within 4 days (96 hours) after the missed dose; then, resume the regular once weekly dosing schedule. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. The day of weekly administration can be changed, if necessary, as long as the time between the 2 doses is at least 3 days (72 hours).

Store tirzepatide vials and prefilled injection pens in a refrigerator at 2-8degreesC. If necessary, the drug can be stored out of the refrigerator at temperatures not to exceed 30degreesC for up to 21 days. Do not freeze or use if frozen. Store in the original carton to protect the drug from light.

No dosing information is available for this tab.

In vitro studies have shown low potential for tirzepatide to inhibit or induce cytochrome P-450 (CYP) enzymes, and to inhibit drug transporters.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Antidiabetic Agents/Gatifloxacin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of gatifloxacin may result in hypoglycemia and/or hyperglycemia.(1-4) Hypoglycemia is more common during the first three days of concurrent therapy. Hyperglycemia is more common after the first three days of concurrent therapy.(2)

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(2)

PATIENT MANAGEMENT: Patients receiving concurrent gatifloxacin should be closely monitored for hypoglycemia during the first three days of concurrent therapy and for hyperglycemia after the first three days of concurrent therapy. Patients should be instructed to discontinue gatifloxacin if hypoglycemia or hyperglycemia occur.(2)

DISCUSSION: Hypoglycemia has been reported with gatifloxacin and glyburide(1,5,6) or glimepiride.(7) In a study in patients with type 2 diabetes mellitus, concurrent gatifloxacin (400 mg daily for 10 days) had no effect on the pharmacokinetics of glyburide (steady state daily regimen); however, pharmacodynamic interactions have been reported.(2) Health Canada has received 19 reports of hypoglycemia in patients taking gatifloxacin. Seventeen of these involved concurrent hypoglycemic agents. Health Canada has received 2 reports of hyperglycemia in patients taking gatifloxacin and hypoglycemic agents. Health Canada has received 2 reports of patients experiencing hypoglycemia and hyperglycemia during concurrent gatifloxacin and hypoglycemic agents.(3) In a study, 13 reports of dysglycemia were reported in patients taking gatifloxacin. Ten of these patients had diabetes mellitus and were on concurrent hypoglycemic agents. Of these ten patients, nine patients experienced hypoglycemia, while one patient experienced hyperglycemia.(8)

Selected Glp-1 Receptor Agonists/Oral Contraceptives

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: GLP-1 receptor agonists delay gastric emptying, which may result in decreased oral contraceptive absorption.(1-3)

CLINICAL EFFECTS: GLP-1 receptor agonists may result in decreased levels and effectiveness of oral contraceptives.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of orforglipron and tirzepatide state patients should be advised to switch from oral hormonal contraceptives to a non-oral contraceptive method or to add a barrier method of contraception. Patients should use a non-oral contraceptive or barrier method of contraception for 4 weeks after starting a GLP-1 receptor agonist and for 4 weeks after each dose escalation of the GLP-1 receptor agonist.(1-3) Hormonal contraceptives that are not administered orally are not expected to be affected by GLP-1 receptor agonists.(1-3)

DISCUSSION: In a pharmacokinetic study, a single dose of tirzepatide 5 mg with combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) decreased the mean concentration maximum (Cmax) of ethinyl estradiol, norgestimate, and norelgestromin by 59%, 66%, and 55%, respectively, while mean area-under-curve (AUC) was reduced by 20%, 21%, and 23%, respectively.(1,2) A study in pregnant rats, tirzepatide caused fetal growth restrictions and fetal abnormalities at clinical exposure. A study in pregnant rabbits, tirzepatide caused fetal growth restrictions at clinically relevant exposures.(1) In a pharmacokinetic study, acetaminophen Cmax was decreased by 28% after the first dose of orforglipron 0.8 mg. This effect diminished after repeated dosing of orforglipron 17.2 mg.(3) A study in pregnant rabbits, orforglipron resulted in decreased fetal and placental weights and external malformations at a dose 14 times the clinical exposure from the maximum recommended human dose.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Glp-1 Receptor Agonists/Anesthesia Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: GLP-1 receptor agonists can cause delayed gastric emptying.(1,2)

CLINICAL EFFECTS: Gastric contents may remain in the stomach after preoperative fasting, which could increase the risk of regurgitation and aspiration.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The American Society of Anesthesiologists (ASA) recommends the following for patients receiving elective procedures: - For patients on daily dosing, consider holding GLP-1 agonists on the day of the procedure. For patients on weekly dosing, consider holding GLP-1 agonists a week prior to the procedure. - Consult an endocrinologist for patients taking GLP-1 agonists for diabetes management if the GLP-1 agonist is held longer than the dosing schedule to avoid hyperglycemia. - For patients requiring urgent or emergent procedures, proceed and treat the patient as 'full stomach.'(3)

DISCUSSION: In one case report, a 31-year-old patient taking semaglutide followed preoperative fasting guidelines but food residue was discovered upon endoscopy, leading to cancellation of the surgical procedure.(4) In a case report, a semaglutide-treated patient experienced regurgitation upon induction of general anesthesia despite a 20 hour preoperative fasting period. The patient received semaglutide two days before the scheduled procedure.(5) A case report of a 42-year-old patient after fasting for 18 hours showed substantial gastric content upon endoscopy. The patient experienced intraoperative pulmonary aspiration of gastric contents which were suctioned from the trachea and bronchi using bronchoscopy.(6)

Glp-1 Receptor Agonists/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown but may be related to nausea, vomiting, and/or diarrhea caused by volume depletion resulting in the decreased renal clearance of lithium. Weight loss may also cause stable doses of lithium to be too high for weight-based dosing.(1-6)

CLINICAL EFFECTS: Lithium has a narrow therapeutic range; even modest, unintended increases in lithium concentration may result in lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: The manufacturer of semaglutide states consider increased clinical or laboratory monitoring for medications that have a narrow therapeutic index or that require clinical monitoring.(1) An expert review article on the interaction between GLP-1 agonists and lithium states that clinicians may need to monitor lithium more closely when a GLP-1 agonist is initiated, whether clinically or through therapeutic drug monitoring. A cautious approach might be to consider monitoring at the following time points when there is a plan to introduce a GLP-1 agonist with lithium: 1. Before GLP-1 agonist initiation, 2. Near 1 week after starting a GLP-1 agonist, 3. Near 1 weak after each dose increases (i.e., several monthly intervals for weekly subcutaneous semaglutide and tirzepatide), and 4. Longitudinally, at more frequent intervals than guidelines recommend during the first year after GLP-1 agonist initiation, when weight loss begins to plateau. Increased monitoring may also be considered when switching between GLP-1 agonists.(7) Monitor closely to decrease the risk for lithium toxicity. Evaluate renal function and most recent lithium levels. If renal function is not stable, it would be prudent to withhold combination therapy until renal function is stable. Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: The impact of GLP-1 agonists on the pharmacokinetics of lithium has not been investigated in clinical studies. Literature is limited to a small number of case reports. In a case report, a 23-year-old male established on semaglutide was started on lithium and titrated to 1800 mg daily, corresponding to a lithium level of 0.9mEq/L. The patient was then switched from semaglutide to tirzepatide 5 mg weekly. Four days after his first dose of tirzepatide, he reported early symptoms of potential lithium toxicity, which progressed significantly after his second dose. Symptoms corresponded to a 15-hour post-dose level of 1.7 mEq/L, despite no changes in renal function, hydration status, or other concurrent medications. Management with intravenous fluids was sufficient, and close monitoring of lithium levels and tapering of the lithium dose prevented future toxicity. The patient remained on tirzepatide and a maintenance dose of lithium extended-release 1200 mg daily, with a lithium level measured 15-hour post-dose of 0.6mEq/L. The patient's weight remained the same from the start of tirzepatide therapy.(8) In a case report, a 62-year-old male stable on lithium for 6 years (lithium ER 600 mg daily) started semaglutide 0.25 mg twice weekly 2 to 3 weeks prior to visiting the emergency department. Patient had multiple comorbidities and medications were unchanged except for semaglutide. 6 weeks prior to visiting the ED, the patient was instructed to decrease his fluid intake due to urinary proteinuria symptoms. Lithium level was 1.8mmol/L in ED. Both lithium and semaglutide were discontinued. Lithium was restarted at 300 mg, increased to lithium ER 450 mg 10 days later and lithium levels increased to 0.8 and 0.9mmol/L. Further dose adjustment back to 300 mg resulted in a steady lithium serum level of 0.6mmol/L. No significant changes to kidney function were observed. Semaglutide was not reintroduced.(9) In another case report, a 23-year-old female was admitted to hospital for lithium toxicity. Medication list included lithium carbonate ER 900 mg and she was reported as restarting semaglutide recently. Further questioning revealed inconsistent semaglutide use over the previous 2 years, with unclear timing of a recent restart. Her lithium level on admission was found to be 2.1mmol/L. Both lithium and semaglutide were discontinued. Lithium ER had been a long-standing medication at 900 mg dose since she was 9 years old with no previous incidents of clinical lithium toxicity. She was recorded as having significant side effects to semaglutide, including nausea and vomiting. At the time of discharge, 4 days after admission, the lithium level was 0.5mmol/L and it was recommended to avoid combining lithium and semaglutide in the future. No significant changes to kidney function were observed.(9) In a case report, a 22-year-old-male stable on 2100 mg lithium carbonate ER daily was initiated on semaglutide for weight management. Patient had regular monitoring of his lithium level prior to and during dose escalation with semaglutide. During the semaglutide increase and tapering of his lithium dose, there were no report of nausea, vomiting, diarrhea, decreased oral/fluid intake, and no medication changes were made. There were no changes in mental status, symptoms concerning psychiatric decompensation, or symptoms of lithium toxicity.(9) In a 40-week study of patients with stable bipolar disorder, liraglutide resulted in a significantly greater weight loss as compared with placebo. 7 of the 60 participants were on lithium, no instances of lithium toxicity was reported and liraglutide was well tolerated.(10)

Glp-1 Receptor Agonists/Thyroid Preparations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown but may be related to decreased GI motility resulting in increased absorption of levothyroxine. Weight loss may also cause stable doses of levothyroxine to be too high for weight-based dosing.(1)

CLINICAL EFFECTS: Concurrent administration of GLP-1 receptor agonists and thyroid preparations may increase the clinical effects of the thyroid agent, resulting in symptoms of hyperthyroidism.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking thyroid preparations and GLP-1 receptor agonists should be monitored for changes in thyroid function. Symptoms of hyperthyroidism include weight loss, rapid heartbeat, nervousness, sweating, tremor, fatigue, and difficulty sleeping. The dosage of levothyroxine may need to be adjusted accordingly.

DISCUSSION: In an open-label, one-sequence, crossover, 2-part trial examining the effect of administering 14 mg oral semaglutide and levothyroxine together, a 33% increase in levothyroxine AUC was identified. The trial also examined the impact of SNAC , the absorption enhancer in oral GLP-1 receptor agonists, and found that SNAC alone did not impact absorption of levothyroxine.(2) In a single-center, prospective trial, participants with diabetes without thyroid disease were given exenatide and TSH levels were measured. After 6 months of treatment, mean TSH concentration decreased from 2.3 to 1.8 without impact to T4 and T3. The mechanism that was proposed was that exenatide can increase the sensitivity of the hypothalamus or pituitary gland to the thyroid hormone negative feedback or increase the number of receptors on the hypothalamus or pituitary gland. No relationship was found between weight change and TSH level.(3) In a case report, a post-thyroidectomy patient on a stable dose of levothyroxine (125 mcg daily) started concurrent subcutaneous semaglutide therapy. Five months after starting treatments together, she started experiencing palpitations, perspiration, and heat intolerance. The levothyroxine dose was decreased to 88 mcg daily resulting in a resolution of symptoms.(4) In another case report, a 43-year-old female patient was on a stable dose of levothyroxine (200 mcg) and started on subcutaneous semaglutide. After 5 months, her TSH level dropped to 0.01 ng/dL and levothyroxine was reduced to 150 mcg daily.(5)

Selected Antidiabetic Agents/Chloroquine; Hydroxychloroquine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Chloroquine and hydroxychloroquine may increase insulin sensitivity by inhibiting insulin metabolism and inflammation and increasing cellular uptake of glucose and glycogen synthesis.(1,2) These effects may result in additive hypoglycemia with anti-diabetic agents.

CLINICAL EFFECTS: Concurrent use of chloroquine or hydroxychloroquine and antidiabetic agents may result in severe hypoglycemia.(3) Hypoglycemia can lead to coma.

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.

PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with chloroquine or hydroxychloroquine should be closely monitored for hypoglycemia. A decrease in the dose of insulin or other anti-diabetic medications may be required. Patients should be advised of the risk and symptoms of hypoglycemia and to contact their doctor if hypoglycemia occurs.(3) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety.

DISCUSSION: Hydroxychloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening.(3) Concomitant hypoglycemic agents may increase the risk and/or severity of this effect. A 77 year old man who was stable on twice daily insulin suffered two episodes of hypoglycemic coma 2 weeks after starting prednisone 5 mg daily and hydroxychloroquine 400 mg daily for rheumatoid arthritis. His insulin dosage required a decrease of 37%.(4) Many studies have investigated the glucose-lowering effect of hydroxychloroquine. In a clinical trial of type II diabetics on maximal doses of sulfonylureas, addition of hydroxychloroquine lowered hemoglobin A1C (HbA1C) up to 1% more than placebo.(5) Another clinical trial of type II diabetics on metformin and glimepiride or gliclazide found that hydroxychloroquine 400 mg daily reduced fasting blood glucose (FBG), post-prandial glucose (PPG), and HbA1C to a similar degree as pioglitazone 15 mg daily at 24 weeks.(6) In a prospective observational study, 250 uncontrolled type II diabetics on metformin, glimepiride, pioglitazone, sitagliptin, and a SGLT-2 inhibitor received hydroxychloroquine 400 mg daily for 48 weeks. HbA1C decreased from 8.83% to 6.44%, FBG decreased by 40.78%, and PPG decreased by 58.95%. The doses of metformin were reduced by 50%, glimepiride and sitagliptin by 75%, and SGLT-2 inhibitors were discontinued in most patients.(7)

Selected Antidiabetic Agents/Selected Quinolones

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of quinolones and antidiabetic agents may result in severe hypoglycemia.(1-7) Hypoglycemia can lead to coma.

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(5)

PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with a quinolone should be closely monitored for hypoglycemia.(1-4) Patients should be instructed to discontinue quinolone use and contact their doctor if hypoglycemia occurs.(2,4) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety.

DISCUSSION: Hypoglycemia has been reported with concurrent ciprofloxacin and glyburide,(1,8,9) levofloxacin and glyburide,(2,10,11) norfloxacin and glyburide,(3) levofloxacin and glipizide (12) as well as levofloxacin and metformin-glibenclamide.(14) There has been one report of fatal hypoglycemia with concurrent levofloxacin and glyburide(9) and one of the above reports of hypoglycemia with concurrent levofloxacin and glyburide resulted in hypoxic brain injury.(11) A review of postmarketing adverse event data for the fluoroquinolones and hypoglycemic coma identified 56 reports in FAERS search from October 1987- April 2017 and 11 additional cases in the medical literature. Most patients had risk factors for hypoglycemia. 41 patients were taking one or more hypoglycemic drugs. 13 deaths occurred (some of these patients had renal insufficiency). 9 patients did not fully recover and had resultant disability.(13)

*Personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).

*Known serious hypersensitivity to tirzepatide or any excipients.

• Pregnancy

• Family history of medullary thyroid carcinoma
• Gastroparesis
• Medullary thyroid carcinoma
• Multiple endocrine neoplasia type 2
• Pancreatitis

• Dehydration
• Diabetic retinopathy
• Hypoglycemic disorder
• Kidney disease with reduction in glomerular filtration rate (GFr)

Adverse reactions reported in >=5% of patients receiving tirzepatide for type 2 diabetes mellitus include nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain.

Adverse reactions reported in >=5% of patients receiving tirzepatide for chronic weight management include nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, and gastroesophageal reflux disease.

Rare or Very Rare

• Acute kidney injury
• Acute pancreatitis
• Anaphylaxis
• Angioedema
• Biliary calculus
• Dehydration
• Gallbladder disease
• Hypersensitivity drug reaction
• Ileus
• Intestinal obstruction

More Frequent

• Acute abdominal pain
• Anorexia
• Constipation
• Diarrhea
• Dyspepsia
• Nausea
• Vomiting

Less Frequent

• Abdominal distension
• Alopecia
• Dizziness
• Elevated serum amylase
• Elevated serum lipase
• Eructation
• Fatigue
• Flatulence
• Gastroesophageal reflux disease
• Injection site sequelae
• Xerostomia

Rare or Very Rare

• Dysesthesia
• Dysgeusia
• Eczema
• Hypoglycemic disorder
• Hypotension
• Tachycardia
• Urticaria
• Weight loss

No enhanced messaging available.

Safety and effectiveness of tirzepatide have not been established in pediatric patients (<18 years of age).

Available data with tirzepatide use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide during pregnancy. In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities (including external, visceral, and skeletal malformations) occurred at clinically relevant exposures based on AUC. In rabbits administered tirzepatide during organogenesis, fetal growth reductions were observed at clinically relevant exposures based on AUC. Tirzepatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are no data on the presence of tirzepatide in animal or human milk, the effects on the breast-fed 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 tirzepatide and any potential adverse effects on the breast-fed infant from tirzepatide or from the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In clinical trials of tirzepatide for diabetes mellitus, 30.1% of tirzepatide-treated patients were >=65 years of age and 4.1% were >=75 years of age. In clinical trials of tirzepatide for chronic weight management, 9% of tirzepatide-treated patients were >=65 years of age and 0.5% were >=75 years of age. No overall differences in safety or efficacy have been observed between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.