Dulaglutide

Registered South African indications:

• Type 2 diabetes mellitus (as an adjunct to diet and exercise), as monotherapy or in combination with other glucose-lowering medicines 
• Risk reduction of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors

Contraindications

International manufacturer recommendations

• Hypersensitivity to dulaglutide or to any of it’s excipients

South African manufacturer recommendations

• Hypersensitivity to dulaglutide or to any of it’s excipients
• A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Pancreatitis
• Type 1 diabetes mellitus
• Diabetic ketoacidosis
• Severe gastrointestinal disease, including severe gastroparesis

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• End-stage renal disease (eGFR <15ml/min/1.73m²)
• Porphyria
• Type 1 diabetes mellitus
• Diabetic ketoacidosis
• Severe gastrointestinal disease, including severe gastroparesis
• May impair the ability to drive and operate heavy machinery (especially in combination with sulphonylurea or insulin)

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• End-stage renal disease (eGFR <15ml/min/1.73m²)
• Patients at risk of thyroid C-cell tumours
  (See Additional Prescribing Points)
• May impair the ability to drive and operate heavy machinery (especially in combination with sulphonylurea or insulin)

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

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

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

• SC: 0.75mg, weekly

- As add-on therapy (in addition to other medicinal products for the treatment of diabetes)  

• SC: 1.5mg, weekly

---

Potentially vulnerable populations: 0.75mg, weekly can be considered as a starting dose

---

For additional glycaemic control:
- The 1.5mg dose may be increased after ≥4 weeks to 3mg, weekly
- The 3mg dose may be increased after ≥4 weeks to 4.5mg, weekly; Max: 4.5mg/week

---

The dose can be administered at any time of the day, with or without meals, and is to be injected subcutaneously (SC) in the abdomen, thigh or upper arm

---

 Dulaglutide should not be administered intravenously (IV) or intramuscularly (IM)

---

See Additional Prescribing Points 

---

South African manufacturer recommendations

Type 2 diabetes mellitus (as an adjunct to diet and exercise) 
- As monotherapy
- In combination with other glucose-lowering medicines
Risk reduction of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus
- In patients who have established cardiovascular disease or multiple cardiovascular risk factors

• SC: 1.5mg, weekly

---

The dose can be administered at any time of the day, with or without meals, and can be injected subcutaneously (SC) in the abdomen, thigh or upper arm

---

Dulaglutide should not be administered intravenously (IV) or intramuscularly (IM)

---

See Additional Prescribing Points 

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• There are no or limited amount of data from the use of dulaglutide in pregnant women
• Studies in animals have shown reproductive toxicity. Therefore, the use of dulaglutide is not recommended during pregnancy

Breastfeeding

• Caution; not recommended
• It is unknown whether dulaglutide is excreted in human milk
• A risk to newborns/ infants cannot be excluded. Dulaglutide should not be used during breastfeeding

Fertility

• The effect of dulaglutide on fertility in humans is unknown. In the rat, there was no direct effect on mating or fertility following treatment with dulaglutide

Renal Impairment

• Mild to severe, not requiring dialysis (eGFR ≥15-<90ml/min/1.73m2): No dose adjustment recommended
• End-stage renal disease (eGFR <15ml/min/1.73m²): Caution; no information available
  There is very limited experience in patients with end-stage renal disease, therefore dulaglutide cannot be recommended in this population

Hepatic Impairment

• No dose adjustment recommended

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Nausea and vomiting are reported as very common side effects of dulaglutide that may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Fatigue

Cardiovascular Disorders

• Sinus tachycardia
• First degree atrioventricular block (AVB)/PR interval prolongation
• Increased heart rate
• Decreased systolic blood pressure

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal pain
• Decreased appetite
• Decreased weight
• Dyspepsia
• Constipation
• Flatulence
• Abdominal distention
• Gastroesophageal reflux disease
• Eructation
• Acute pancreatitis
• Increase in pancreatic enzymes (lipase and/or pancreatic amylase)
• Delayed gastric emptying
• Non-mechanical intestinal obstruction

Hepatobiliary Disorders

• Cholelithiasis
• Cholecystitis

Endocrine and Metabolic Disorders

• Hypoglycaemia (in combination with insulin, glimepiride, metformin or metformin plus glimepiride)
• Hypoglycaemia (as monotherapy or in combination with metformin plus pioglitazone)
• Dehydration

Skin and Subcutaneous Tissue Disorders

• Angioedema
• Injection site reactions
  - Rash
  - Erythema

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Anaphylactic reaction
• Immunogenicity

• Sitagliptin
• Metformin
• Insulin
• Sulphonylurea 
• Oral medicinal products requiring rapid gastrointestinal absorption
• Prolonged release formulations

• Blood glucose
• HbA1C
• Serum calcitonin
• Thyroid ultrasound

None routine. Specific cases may require

• Serum calcitonin
• Thyroid ultrasound
• Physical neck examination or neck imaging
• Pancreatic enzymes (lipase and/or pancreatic amylase)
• Renal function

Risk of thyroid C-cell tumours

• In males and female rats, dulaglutide causes a dose-related and treatment duration-dependent increase in the incidence of thyroid C-cell tumours (adenomas and carcinomas) after lifetime exposure
• It is unknown whether dulaglutide causes thyroid C-cell tumours, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumours has not been determined
• One case of MTC was reported in a patient treated with dulaglutide in thephase 3 clinical studies. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the long-term cardiovascular outcomes study (REWIND)
• Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the post-marketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans
• Dulaglutide is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Counsel patients regarding the potential risk of MTC with use of dulaglutide and inform them of symptoms of thyroid tumours (e.g. mass in the neck, dysphagia, dyspnoea, persistent hoarseness)
• Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value of early detection of MTC in patients treated with dulaglutide
• 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 >50ng/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

Coadministration of dulaglutide with other hypoglycaemic agents

• When dulaglutide is added to existing metformin and/or pioglitazone therapy, the current dose of metformin and/or pioglitazone can be continued. When dulaglutide 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 it is added to existing therapy of a sulphonylurea or insulin, a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia
• The use of dulaglutide does not require blood glucose self-monitoring. Blood glucose self-monitoring is necessary to adjust the dose of sulphonylurea or insulin, particularly when dulaglutide therapy is started and insulin is reduced. A stepwise approach to insulin dose reduction is recommended

Missed dose

• If a dose is missed, it should be administered as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. If less than 3 days remain before the next scheduled dose, the missed dose should be skipped and the next dose should be administered 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 last dose was administered 3 or more days (72 hours or more) before

Directions for use

• The pre-filled pen is for single-use only and should not be used if particles appear or if the solution is cloudy and/or discoloured
• Dulaglutide that has been frozen must not be used
• Dulaglutide is photosensitive and must be protected from light until administration. Store in original package in order to protect from light

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded

Dulaglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist that exhibits several antihyperglycaemic actions of GLP-1. The molecule consists of 2 identical disulfide-linked chains, each containing a modified human GLP-1 analogue sequence covalently linked to a modified human immunoglobulin G4 (IgG4) heavy chain fragment (Fc) by a small peptide linker.  In the presence of elevated glucose concentrations, dulaglutide increases intracellular cyclic AMP (cAMP) in pancreatic beta cells leading to insulin release. Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. Dulaglutide also slows gastric emptying.

In contrast to regular GLP-1 analogues, dulaglutide is resistant to degradation by DPP-4, and has a large size that slows absorption and reduces renal clearance, resulting in a soluble formulation and a prolonged half-life of 4.7 days.

Injection 1.5mg/0.5ml

• Trulicity (Eli Lilly)