Tirzepatide

Registered South African indications:

• Treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
  - As monotherapy when metformin is considered inappropriate due to intolerance or contraindications
  - In addition to other medicinal products for the treatment of diabetes
• Weight management as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of
  - ≥ 30kg/m² (obesity) or
  - ≥ 27kg/m² to < 30kg/m² (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidaemia, obstructive sleep apnoea, cardiovascular disease, prediabetes, or type 2 diabetes mellitus)

Warning: Risk of thyroid C-cell tumours Tirzepatide causes thyroid C-cell tumours in rats. It is unknown whether tirzepatide causes thyroid C-cell tumours, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumours has not been determined. Tirzepatide 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 tumours.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment and end stage renal disease (ESRD)
• Severe hepatic impairment

Risk of thyroid C-cell tumours

• In both sexes of rats, tirzepatide caused a dose-dependent and treatment-duration dependent increase in the incidence of thyroid C-cell tumours (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures
• It is unknown whether tirzepatide causes thyroid C-cell tumours, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumours has not been determined
• Tirzepatide 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 tirzepatide and inform them of symptoms of thyroid tumours (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 tirzepatide
• 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

Acute pancreatitis

• Tirzepatide has not been studied in patients with a history of pancreatitis and should be used with caution in these patients
• Acute pancreatitis has been reported in patients treated with tirzepatide
• Patients should be informed of the symptoms of acute pancreatitis
• If pancreatitis is suspected, tirzepatide should be discontinued
• If the diagnosis of pancreatitis is confirmed, tirzepatide should not be restarted
• In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis

Hypoglycaemia

• Patients receiving tirzepatide in combination with an insulin secretagogue (for example, a sulphonylurea) or insulin may have an increased risk of hypoglycaemia
• The risk of hypoglycaemia may be lowered by a reduction in the dose of the insulin secretagogue or insulin

Gastrointestinal effects

• Tirzepatide has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhoea
• These adverse reactions may lead to dehydration, which could lead to a deterioration in renal function including acute renal failure
• Patients treated with tirzepatide should be advised of the potential risk of dehydration, due to the gastrointestinal adverse reactions and take precautions to avoid fluid depletion and electrolyte disturbances
• This should particularly be considered in the elderly, who may be more susceptible to such complications

Severe gastrointestinal disease

• Tirzepatide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and should be used with caution in these patients

Diabetic retinopathy

• Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy or diabetic macular oedema, and should be used with caution in these patients with appropriate monitoring

Elderly

• Only very limited data are available from patients aged ≥ 85 years

Sodium content

• This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’

Effects on ability to drive and use machines

• Tirzepatide has no or negligible influence on the ability to drive or use machines
• When tirzepatide is used in combination with a sulphonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment and end stage renal disease (ESRD)
• Severe hepatic impairment

Acute pancreatitis

• Tirzepatide has not been studied in patients with a history of pancreatitis, and should be used with caution in these patients
• Acute pancreatitis has been reported in patients treated with tirzepatide
• Patients should be informed of the symptoms of acute pancreatitis. If pancreatitis is suspected, tirzepatide should be discontinued. If the diagnosis of pancreatitis is confirmed, tirzepatide should not be restarted. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis

Hypoglycaemia in patients with type 2 diabetes mellitus

• Patients receiving tirzepatide in combination with an insulin secretagogue (for example, a sulphonylurea) or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of the insulin secretagogue or insulin

Gastrointestinal effects

• Tirzepatide has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhoea
• These adverse reactions may lead to dehydration, which could lead to a deterioration in renal function including acute renal failure. Patients treated with tirzepatide should be advised of the potential risk of dehydration, due to the gastrointestinal adverse reactions and take precautions to avoid fluid depletion and electrolyte disturbances. This should particularly be considered in the elderly, who may be more susceptible to such complications

Severe gastrointestinal disease

• Tirzepatide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and should be used with caution in these patients

Diabetic retinopathy

• Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy or diabetic macular oedema, and should be used with caution in these patients with appropriate monitoring

Aspiration in association with general anaesthesia or deep sedation

• Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonists undergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastric content due to delayed gastric emptying should be considered prior to performing procedures with general anaesthesia or deep sedation

Elderly

• Only very limited data are available from patients aged ≥ 85 years

Sodium content

• This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'

Benzyl alcohol [E1519]

• This medicine contains 5.4 mg Benzyl Alcohol [E1519] in each 0.6 ml dose
• Benzyl alcohol may cause allergic reactions
• Patients with hepatic or renal impairment should be informed of the potential risk of metabolic acidosis due to accumulation of benzyl alcohol over time

Effects on ability to drive and use machines

• Tirzepatide has no or negligible influence on the ability to drive or use machines. When tirzepatide is used in combination with a sulphonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
- As monotherapy when metformin is considered inappropriate due to intolerance or contraindications
- In addition to other medicinal products for the treatment of diabetes
Weight management as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of
- ≥ 30kg/m² (obesity) or
- ≥ 27kg/m² to < 30kg/m² (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidaemia, obstructive sleep apnoea, cardiovascular disease, prediabetes, or type 2 diabetes mellitus)

• SC: Initial: 2.5mg, once weekly; Increase to: 5mg, once weekly after 4 weeks; Subsequent increases can be made in 2.5mg increments after a min. of 4 weeks on the current dose; Maintenance: 5mg, 10mg and 15mg, once weekly; Max: 15mg/week

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Changing the dosing schedule: The day of weekly administration can be changed, if necessary, as long as the time between two doses is at least 3 days

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When tirzepatide is added to existing metformin and/or sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy, the current dose of metformin and/or SGLT2i can be continued. When tirzepatide is added to existing therapy of a sulphonylurea and/or insulin, a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of sulphonylurea and insulin. A stepwise approach to insulin reduction is recommended

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Missed doses
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, 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

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Method of administration
Tirzepatide is to be injected subcutaneously in the abdomen, thigh or upper arm. The dose can be administered at any time of day, with or without meals. Injection sites should be rotated with each dose. If a patient also injects insulin, they should inject tirzepatide into a different injection site. Patients should be advised to read the instructions for use included with the package leaflet carefully before administering the medicinal product

Not established for use in children below 18 years

Pregnancy 

South African recommendations

• Caution; not recommended
• There are no or a limited amount of data from the use of tirzepatide in pregnant women. Studies in animals have shown reproductive toxicity
• Tirzepatide is not recommended during pregnancy and in women of childbearing potential not using contraception

Recommendations in other jurisdictions

• Caution; not recommended
• There are no or a limited amount of data from the use of tirzepatide in pregnant women. Studies in animals have shown reproductive toxicity
• Tirzepatide is not recommended during pregnancy and in women of childbearing potential not using contraception
• If a patient wishes to become pregnant, tirzepatide should be discontinued at least 1 month before a planned pregnancy due to the long half-life of tirzepatide. Tirzepatide should not be used during pregnancy

Breastfeeding

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; not recommended
• It is unknown whether tirzepatide is excreted in human milk. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• The effect of tirzepatide on fertility in humans is unknown. Animal studies with tirzepatide did not indicate direct harmful effects with respect to fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate: No dose adjustment recommended
• Severe and end stage renal disease (ESRD): Caution; no dose adjustment recommended

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Immune System Disorders

Common

• Hypersensitivity reactions

Rare

• Anaphylactic reaction (post-marketing reports)
• Angioedema (post-marketing reports)

Metabolism and Nutrition Disorders

Very common (frequency reported in clinical trials supporting the type 2 diabetes indication)

• Hypoglycaemia (when used with sulphonylurea or insulin)

Common (frequency reported in clinical trials supporting the type 2 diabetes indication)

• Hypoglycaemia (when used with metformin and SGLT2i)
• Decreased appetite

Uncommon (frequency reported in clinical trials supporting the type 2 diabetes indication)

• Hypoglycaemia (when used with metformin)
• Decreased weight

Nervous System Disorders

Common (frequency reported in clinical trials supporting the weight management indication)

• Dizziness

Uncommon

• Dysgeusia

Vascular Disorders

Common (frequency reported in clinical trials supporting the weight management indication)

• Hypotension-related events
  • Decreased blood pressure
  • Hypotension
  • Orthostatic hypotension

Gastrointestinal Disorders

Very common

• Nausea
• Diarrhoea
• Vomiting (frequency reported in clinical trials supporting the weight management indication)
• Constipation (frequency reported in clinical trials supporting the weight management indication)

Common

• Abdominal pain
• Vomiting (frequency reported in clinical trials supporting the type 2 diabetes indication)
• Constipation (frequency reported in clinical trials supporting the type 2 diabetes indication)
• Dyspepsia
• Abdominal distention
• Eructation
• Flatulence
• Gastroesophageal reflux disease

Uncommon

• Cholelithiasis
• Acute pancreatitis
• Cholecystitis (frequency reported in clinical trials supporting the weight management indication)

Skin and Subcutaneous Tissue Disorders

Common (frequency reported in clinical trials supporting the weight management indication)

• Hair loss

General Disorders and Administration Site Conditions

Common

• Fatigue
• Injection site reactions

Uncommon

• Injection site pain

Investigations

Common

• Increased heart rate (frequency reported in clinical trials supporting the type 2 diabetes indication)
• Increased lipase
• Increased amylase (frequency reported in clinical trials supporting the type 2 diabetes indication)

Uncommon

• Increased blood calcitonin
• Increased amylase (frequency reported in clinical trials supporting the weight management indication)
• Increased heart rate (frequency reported in clinical trials supporting the weight management indication)

• Oral contraceptives
• Oral medicinal products with a narrow therapeutic index
• Warfarin
• Digoxin
• Ethinyl estradiol
• Norelgestromin
• Norgestimate

• Blood glucose
• Heart rate
• HbA_1c
  • Monitored at least twice yearly in those who have stable glycaemic control and meeting treatment goals
  • Monitored quarterly in those whom treatment goals have not been met, or with change of therapy
  • Note: In those prone to glycaemic variability (eg, insulin deficiency), or in those whose HbA_1c is discordant with serum glucose levels or symptoms, HbA_1c evaluation in combination with blood glucose levels and/or a glucose management indicator should be considered

Specific cases may require

• Renal function tests (at baseline and following dose increments particularly in those with renal impairment reporting severe gastrointestinal adverse reactions)
• Body weight (when used for chronic weight management)

Additional observations

• GI adverse reactions (e.g., nausea, vomiting, diarrhoea)
• Worsening diabetic retinopathy (in those with a prior history of the disease)
• Emergence of worsening depression, suicidal thoughts/behaviour, behaviour changes
• Signs/symptoms of:
  • Pancreatitis (e.g., persistent severe abdominal pain, possibly radiating to the back which may or may not be accompanied by vomiting)
  • Gallbladder disease

Tirzepatide is a long acting dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Both receptors are present on the pancreatic α and β endocrine cells, heart, vasculature, immune cells (leukocytes), gut and kidney. GIP receptors are also present on adipocytes. In addition, both GIP and GLP-1 receptors are expressed in the areas of the brain important to appetite regulation. Tirzepatide is highly selective to human GIP and GLP-1 receptors. Tirzepatide has high affinity to both the GIP and GLP-1 receptors. The activity of tirzepatide on the GIP receptor is similar to native GIP hormone. The activity of tirzepatide on the GLP-1 receptor is lower compared to native GLP-1 hormone.

Appetite regulation and energy metabolism

Tirzepatide lowers body weight and body fat mass. The mechanisms associated with body weight and body fat mass reduction involve decreased food intake through the regulation of appetite and modulation of fat utilization. Clinical studies show that tirzepatide reduces energy intake and appetite by increasing feelings of satiety (fullness), decreasing feelings of hunger, and decreasing food cravings. Tirzepatide significantly decreased the amount of food consumed and calorie intake during ad libitum lunch, dinner and combined compared to placebo in people with obesity. Tirzepatide significantly lowered overall appetite as measured by retrospective visual analogue scale (VAS) throughout an 18-week period compared to placebo. Tirzepatide decreased hunger and prospective food consumption starting at week 1 of the treatment and increased satiety starting at week 3. Tirzepatide significantly decreased craving for fast-food fats, and sweets, carbohydrates and starches, except craving for vegetables and fruit, compared to placebo in people with obesity.

Glycaemic control

Tirzepatide improves glycaemic control by lowering fasting and postprandial glucose concentrations in patients with type 2 diabetes through several mechanisms.