Signifor (Pasireotide)
Somatostatin analogue for the treatment of Cushing's disease in adults
Signifor (pasireotide) is a prescription somatostatin analogue used to treat Cushing's disease in adults for whom pituitary surgery is not an option or has been unsuccessful. It works by reducing excess ACTH production from pituitary adenomas, thereby lowering cortisol levels. This guide covers uses, dosage, side effects, drug interactions, storage, and important safety information based on the latest EMA and FDA-approved prescribing information.
Quick Facts
Key Takeaways
- Signifor is a somatostatin analogue indicated for Cushing's disease in adults when surgery is not feasible or has failed.
- The recommended starting dose is 0.6 mg subcutaneously twice daily, with dose adjustments between 0.3 mg and 0.9 mg twice daily based on response.
- Hyperglycaemia is a very common side effect: blood glucose must be monitored before and during treatment, and antidiabetic therapy may be required.
- Gallstones, gastrointestinal symptoms, and QT prolongation are important risks that require regular monitoring.
- Signifor should not be used in patients with severe hepatic impairment or known hypersensitivity to pasireotide.
What Is Signifor and What Is It Used For?
Quick Answer: Signifor (pasireotide) is a somatostatin analogue prescribed for the treatment of Cushing's disease in adults who are not candidates for pituitary surgery or in whom surgery has been unsuccessful. It reduces excessive cortisol production by inhibiting ACTH secretion from pituitary adenomas.
Cushing's disease is a serious endocrine disorder caused by a benign tumour (adenoma) in the pituitary gland, a small gland located at the base of the brain. This tumour overproduces a hormone called adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce excessive amounts of cortisol. Chronically elevated cortisol levels lead to a wide range of debilitating symptoms, including central obesity, muscle weakness, skin thinning, hypertension, diabetes, osteoporosis, and psychiatric disturbances. Left untreated, Cushing's disease is associated with significantly increased morbidity and mortality.
The human body naturally produces a hormone called somatostatin, which regulates the secretion of several other hormones, including growth hormone, thyroid-stimulating hormone, and ACTH. However, natural somatostatin has a very short half-life (approximately 1-3 minutes), making it impractical for therapeutic use. Pasireotide, the active substance in Signifor, is a synthetic somatostatin analogue with a significantly longer duration of action. Unlike older somatostatin analogues such as octreotide and lanreotide, pasireotide has a uniquely high binding affinity for somatostatin receptor subtype 5 (sst5), which is the predominant receptor expressed on corticotroph adenoma cells in Cushing's disease.
By binding to sst5 receptors on the pituitary tumour, pasireotide suppresses the excessive release of ACTH. This in turn reduces cortisol production by the adrenal glands, helping to normalise cortisol levels and alleviate the signs and symptoms of Cushing's disease. Clinical trials have demonstrated that approximately 15-25% of patients treated with Signifor achieve normalisation of urinary free cortisol (UFC) levels within 6 to 12 months of treatment. Many additional patients experience clinically meaningful reductions in UFC even if full normalisation is not achieved.
Signifor was first approved by the European Medicines Agency (EMA) in 2012 and has since been authorised in numerous countries worldwide. It is indicated as a second-line medical therapy for Cushing's disease, typically used when transsphenoidal surgery (the first-line treatment) is contraindicated, has failed, or is declined by the patient. A long-acting formulation, Signifor LAR (pasireotide long-acting release), administered as a monthly intramuscular injection, is also available for patients who have responded to subcutaneous pasireotide.
Somatostatin receptors are classified into five subtypes (sst1-sst5). Corticotroph adenomas predominantly express sst5 receptors. Pasireotide has 40-fold higher affinity for sst5 compared to octreotide, explaining its superior efficacy in suppressing ACTH secretion in Cushing's disease. It also binds to sst1, sst2, and sst3 receptors, contributing to its broad pharmacological profile.
What Should You Know Before Taking Signifor?
Quick Answer: Before starting Signifor, your doctor must evaluate your blood glucose levels, heart rhythm (ECG), liver function, and gallbladder status. Signifor is contraindicated in patients with severe liver disease or hypersensitivity to pasireotide. Close monitoring is essential throughout treatment.
Contraindications
Signifor must not be used if you are allergic to pasireotide or any of the other ingredients in this medicine (mannitol, tartaric acid, sodium hydroxide, and water for injections). It is also contraindicated in patients with severe hepatic impairment (Child-Pugh C), as drug clearance is significantly reduced in these patients, leading to increased plasma concentrations and higher risk of adverse effects.
Warnings and Precautions
Talk to your doctor before using Signifor if you have or have ever had any of the following conditions:
- Blood glucose abnormalities: Signifor frequently causes hyperglycaemia. If you have pre-existing diabetes mellitus, impaired glucose tolerance, or risk factors for diabetes (such as obesity or a family history), you are at higher risk. Your doctor should check fasting plasma glucose and HbA1c before starting treatment and monitor these regularly (weekly during the first 2-3 months, then periodically). Antidiabetic medication (metformin, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin) may need to be started or adjusted.
- Heart problems: Including recent heart attack, heart failure (inability of the heart to pump sufficient blood), or unstable angina (sudden chest pain). Signifor can cause bradycardia (slow heart rate) and QT prolongation, a heart rhythm disturbance that can be detected on an electrocardiogram (ECG).
- Heart rhythm disorders: Such as irregular heartbeat or a prolonged QT interval. Your doctor should perform an ECG before starting treatment and monitor your heart rhythm periodically, especially if you take other QT-prolonging medications.
- Low potassium or magnesium levels: Electrolyte imbalances increase the risk of cardiac arrhythmias and must be corrected before initiating Signifor therapy.
- Gallstones (cholelithiasis): Somatostatin analogues, including pasireotide, are known to cause gallstones. Your doctor should perform an ultrasound examination of the gallbladder before starting treatment and at regular intervals during therapy (e.g., every 6-12 months).
- Liver disease: Patients with mild to moderate hepatic impairment may require dose adjustments. Liver function tests should be monitored periodically during treatment.
Signifor regulates the overproduction of cortisol, but this regulation can sometimes be too strong, leading to cortisol deficiency (hypocortisolism). Symptoms include extreme weakness, fatigue, weight loss, nausea, vomiting, and low blood pressure. If you experience these symptoms, contact your doctor immediately, as cortisol deficiency can be life-threatening if untreated. Your doctor may need to prescribe temporary glucocorticoid replacement therapy.
Monitoring During Treatment
During treatment with Signifor, your doctor will regularly monitor the following:
- Blood glucose: Fasting glucose and HbA1c should be checked frequently, particularly in the first months of treatment. Patients who develop significant hyperglycaemia may require initiation or adjustment of antidiabetic therapy.
- Heart rate and rhythm: ECG monitoring is recommended, especially in patients with cardiac risk factors or those taking concomitant QT-prolonging drugs. Signifor can cause sinus bradycardia.
- Gallbladder: Periodic ultrasound examinations to detect gallstone formation. If symptomatic gallstones develop, standard medical or surgical management should be considered.
- Liver function: Liver enzymes (ALT, AST, bilirubin) should be tested before treatment and periodically thereafter.
- Pituitary hormones: Monitoring of pituitary function, including thyroid hormones and growth hormone, as somatostatin analogues can suppress multiple pituitary axes.
Children and Adolescents
Signifor is not recommended for use in children and adolescents under 18 years of age due to the absence of clinical data in this population. The safety and efficacy of pasireotide have not been established in paediatric patients.
Pregnancy and Breastfeeding
Signifor should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus. Animal studies have shown reproductive toxicity, but there are no adequate and well-controlled studies in pregnant women. If you are pregnant or think you may be pregnant, inform your doctor immediately so that the risks and benefits of continued treatment can be discussed.
It is not known whether pasireotide is excreted in human breast milk. Breastfeeding is not recommended during treatment with Signifor. Women of childbearing potential should use effective contraception during treatment. Discuss the need for contraception with your doctor before starting this medicine.
Driving and Using Machines
Signifor may have a minor effect on the ability to drive and use machines. Some side effects, such as dizziness, headache, and fatigue, may impair your ability to drive or operate machinery safely. If you experience these symptoms, avoid driving or using machines until you know how Signifor affects you.
Signifor contains less than 1 mmol sodium (23 mg) per dose and is essentially sodium-free. This information is relevant for patients on a controlled sodium diet.
How Does Signifor Interact with Other Drugs?
Quick Answer: Signifor can interact with QT-prolonging medications, heart rate-lowering drugs, antidiabetic medicines, and immunosuppressants like cyclosporine. Always inform your doctor about all medications you are taking, including over-the-counter products.
Signifor may affect how other medicines work, and other medicines may affect how Signifor works. Your doctor may need to monitor your heart more closely or adjust the dose of Signifor or your other medicines. It is essential to tell your doctor, pharmacist, or nurse about all medicines you are using, have recently used, or might use.
Major Interactions
The following medicines require particular caution when used concomitantly with Signifor due to the risk of additive QT prolongation or other significant pharmacological interactions:
| Drug / Class | Used For | Interaction Risk |
|---|---|---|
| Disopyramide, Procainamide, Quinidine, Sotalol, Dofetilide, Ibutilide, Amiodarone, Dronedarone | Irregular heartbeat (antiarrhythmics) | Additive QT prolongation; increased risk of life-threatening cardiac arrhythmias |
| Clarithromycin, Moxifloxacin (oral); Erythromycin, Pentamidine (IV) | Bacterial infections (antibiotics) | Additive QT prolongation; ECG monitoring recommended |
| Ketoconazole (except shampoo) | Fungal infections (antifungal) | QT prolongation risk; also inhibits CYP3A4 metabolism |
| Chlorpromazine, Thioridazine, Fluphenazine, Pimozide, Haloperidol, Tiapride, Amisulpride, Sertindole, Methadone | Psychiatric disorders (antipsychotics, opioids) | Additive QT prolongation; cardiac monitoring essential |
| Terfenadine, Astemizole, Mizolastine | Allergies (antihistamines) | QT prolongation risk; most are withdrawn from market |
| Chloroquine, Halofantrine, Lumefantrine | Malaria (antimalarials) | Additive QT prolongation |
| Cyclosporine | Organ transplant (immunosuppressant) | Pasireotide may reduce bioavailability of cyclosporine; dose adjustment may be needed |
Other Important Interactions
The following medicines should also be discussed with your doctor, as dose adjustments or additional monitoring may be required:
| Drug / Class | Used For | Interaction Risk |
|---|---|---|
| Metoprolol, Carteolol, Propranolol, Sotalol (beta-blockers) | Blood pressure regulation | Additive bradycardia; heart rate monitoring recommended |
| Bepridil, Verapamil, Diltiazem (calcium channel blockers) | Blood pressure regulation | Additive bradycardia and potential QT effects |
| Rivastigmine, Physostigmine (cholinesterase inhibitors) | Dementia, myasthenia gravis | Additive bradycardia |
| Insulin, Metformin, Liraglutide, Vildagliptin, Nateglinide | Diabetes management | Blood glucose effects; antidiabetic dose adjustment may be needed |
| Potassium and magnesium supplements | Electrolyte balance | Electrolyte imbalance affects cardiac rhythm; monitoring recommended |
What Is the Correct Dosage of Signifor?
Quick Answer: The recommended starting dose is 0.6 mg injected subcutaneously twice daily. Your doctor may adjust the dose to 0.3 mg or 0.9 mg twice daily based on your clinical response and tolerability. Inject at the same times each day for consistency.
Always use this medicine exactly as your doctor has told you. Check with your doctor, pharmacist, or nurse if you are not sure. Signifor comes in ampoules (small glass containers) containing a clear, colourless solution for injection. Each ampoule contains 1 ml of solution.
Adults
Standard Dosing Regimen
Starting dose: 0.6 mg subcutaneously twice daily.
Dose escalation: Your doctor may increase the dose to 0.9 mg twice daily based on clinical response (typically assessed after 2 months by measuring urinary free cortisol levels).
Dose reduction: If side effects occur, the dose may be temporarily reduced by 0.3 mg per injection.
Hepatic impairment: If you have mild to moderate liver disease, your doctor may start you on a lower dose of 0.3 mg twice daily.
Signifor is available in three ampoule strengths (0.3 mg, 0.6 mg, and 0.9 mg) to accommodate the dose prescribed by your doctor. Try to inject at the same times each day to help you remember. Recommended injection sites are the thigh and abdomen. Rotate the injection site with each dose to minimise local irritation and discomfort. Avoid injecting into areas that are sore, bruised, or irritated.
| Patient Group | Starting Dose | Dose Range | Frequency |
|---|---|---|---|
| Adults (normal liver function) | 0.6 mg | 0.3 - 0.9 mg | Twice daily (SC) |
| Mild-moderate hepatic impairment | 0.3 mg | 0.3 - 0.6 mg | Twice daily (SC) |
| Severe hepatic impairment | Contraindicated | ||
| Children (<18 years) | Not recommended (no data) | ||
How to Self-Inject
Your doctor or nurse will demonstrate the correct injection technique before you begin self-administering Signifor. Signifor is intended for subcutaneous use, meaning it is injected with a short needle into the fatty tissue just beneath the skin. Follow these steps carefully:
- Prepare: Wash your hands thoroughly. Gather a Signifor ampoule, alcohol swabs, a sterile syringe, and a short fine sterile needle. Allow the solution to reach room temperature before injecting to reduce local discomfort.
- Open the ampoule: Tap the top of the ampoule to ensure no liquid is trapped above the neck. Hold the ampoule upright and break off the top at the score mark (coloured dot indicates break point).
- Draw up the solution: Attach the needle to the syringe, insert into the ampoule, and withdraw the entire contents. Remove air bubbles by tapping the syringe and pressing the plunger until a drop appears at the needle tip.
- Clean the injection site: Use an alcohol swab to clean the chosen injection area (thigh or abdomen).
- Inject: Gently pinch the skin at the injection site. Insert the needle at approximately a 45-degree angle. Pull back the plunger slightly to check for blood (if blood appears, withdraw and use a new site). Slowly push the plunger all the way in, hold for 5 seconds, then release the skin and gently withdraw the needle.
- Dispose safely: Place the used syringe and needle immediately in a sharps container. Never reuse needles or syringes.
Do not use Signifor if the solution is not clear, is discoloured, or contains particles. The solution should be clear, colourless, and free from visible particles.
Missed Dose
If you forget to inject a dose of Signifor, do not inject a double dose to make up for the missed one. Simply inject the next dose at the scheduled time according to your regular dosing schedule. Setting a daily alarm can help you remember to take your injections consistently.
Overdose
If you accidentally use more Signifor than your doctor has prescribed, contact your doctor, pharmacist, or hospital emergency department immediately. Symptoms of overdose may include severe gastrointestinal symptoms (diarrhoea, nausea, vomiting), marked hypoglycaemia or hyperglycaemia, and cardiac rhythm disturbances. There is no specific antidote; treatment is supportive and symptomatic.
Stopping Treatment
Do not stop using Signifor unless your doctor tells you to. If you stop treatment, cortisol levels may rise again and your symptoms may return. Your doctor will assess your response regularly (typically every 2-3 months) and will advise you on how long to continue treatment. If Signifor is not adequately controlling your cortisol levels after a reasonable treatment period, your doctor may consider alternative therapies.
What Are the Side Effects of Signifor?
Quick Answer: The most common side effects include hyperglycaemia (changes in blood sugar), gallstones, diarrhoea, nausea, abdominal pain, fatigue, and injection site reactions. Some side effects, particularly hyperglycaemia and gallstones, can be serious and require regular monitoring.
Like all medicines, Signifor can cause side effects, although not everybody gets them. Some side effects can be serious. Tell your doctor if you experience any of the following:
Very Common
May affect more than 1 in 10 people
- Changes in blood sugar levels (hyperglycaemia): excessive thirst, increased urination, increased appetite with weight loss, fatigue, nausea, vomiting, abdominal pain
- Gallstones (cholelithiasis): fever, chills, yellowing of skin or eyes, sudden back pain or pain in the right side of the abdomen
- Extreme fatigue
- Diarrhoea
- Nausea
- Abdominal pain (stomach pain)
- Injection site pain or reactions
Common
May affect up to 1 in 10 people
- Low cortisol levels (hypocortisolism): extreme weakness, fatigue, weight loss, nausea, vomiting, low blood pressure
- Slow heart rate (bradycardia)
- Low blood pressure (hypotension): dizziness, faintness, lightheadedness on standing
- Bile flow problems (cholestasis): yellow skin, dark urine, pale stools, itching
- Gallbladder inflammation (cholecystitis)
- Prolonged QT interval (abnormal heart electrical signal)
- Loss of appetite
- Vomiting
- Headache
- Dizziness
- Hair loss (alopecia)
- Itching (pruritus)
- Muscle pain (myalgia)
- Joint pain (arthralgia)
- Abnormal liver function test results
- Abnormal pancreatic function test results
- Abnormal blood clotting
Uncommon
May affect up to 1 in 100 people
- Low red blood cell count (anaemia)
Not Known
Frequency cannot be estimated from available data
- Diabetic ketoacidosis (DKA): increased ketone levels in urine or blood due to high blood sugar; symptoms include fruity-smelling breath, difficulty breathing, and confusion. This is a medical emergency.
- Oily or fatty stools (steatorrhoea)
- Discoloured stools
Contact your doctor or seek emergency medical care immediately if you experience: signs of diabetic ketoacidosis (fruity breath, rapid breathing, confusion), severe abdominal pain with fever and jaundice (possible gallbladder emergency), symptoms of severe hypocortisolism (collapse, severe weakness, very low blood pressure), or any signs of an allergic reaction (rash, swelling of the face or throat, difficulty breathing).
The hyperglycaemic effect of pasireotide is thought to be related to its suppression of insulin and incretin hormone secretion, while having a relatively lesser effect on glucagon secretion. This mechanism differs from type 2 diabetes and may explain why some patients require specific antidiabetic strategies. Clinical studies have shown that DPP-4 inhibitors and GLP-1 receptor agonists may be particularly effective in managing pasireotide-induced hyperglycaemia, as they address the underlying incretin deficiency.
If you experience any side effects, including any not listed above, talk to your doctor, pharmacist, or nurse. Reporting side effects helps regulatory authorities continuously monitor the benefit-risk balance of medicines.
How Should You Store Signifor?
Quick Answer: Store Signifor in the original packaging to protect from light, out of the reach of children. Do not use after the expiry date printed on the ampoule and carton. No special temperature storage requirements.
Keep this medicine out of the sight and reach of children. Store the ampoules in the original carton to protect from light. Do not use this medicine after the expiry date stated on the ampoule and carton after "EXP". The expiry date refers to the last day of that month.
Ampoules should be opened immediately before administration. Any unused solution must be discarded. Do not save any remaining solution for later use. Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures help to protect the environment.
For patient comfort, allow the ampoule to reach room temperature before injection, as this can reduce injection site discomfort. Always check the expiry date and the prescribed dose before each injection. Inspect the solution visually before use: do not inject if it is cloudy, discoloured, or contains particles.
What Does Signifor Contain?
Quick Answer: Signifor contains pasireotide (as pasireotide diaspartate) as the active ingredient, along with mannitol, tartaric acid, sodium hydroxide, and water for injections as inactive ingredients. Available in 0.3 mg, 0.6 mg, and 0.9 mg ampoules.
The active substance in Signifor is pasireotide, present as pasireotide diaspartate. Each 1 ml ampoule contains either 0.3 mg, 0.6 mg, or 0.9 mg of pasireotide. The other ingredients (excipients) are:
- Mannitol – a sugar alcohol used as a tonicity agent to ensure the solution is isotonic with body fluids
- Tartaric acid – a pH adjusting agent to maintain the stability of the solution
- Sodium hydroxide – used for pH adjustment
- Water for injections – the solvent
Signifor solution for injection is a clear, colourless liquid in a glass ampoule. Each ampoule contains 1 ml of solution. Signifor is available in packs containing 6 ampoules, or in multipacks containing 18 (3 packs of 6), 30 (5 packs of 6), or 60 (10 packs of 6) ampoules. Not all strengths or pack sizes may be marketed in your country.
The marketing authorisation holder is Recordati Rare Diseases, based in Puteaux, France. For further information about this medicine, please consult the European Medicines Agency (EMA) website, which also provides links to information about rare diseases and their treatments.
Frequently Asked Questions
References
- European Medicines Agency (EMA). Signifor Summary of Product Characteristics (SmPC). Last updated 2024. Available at: EMA - Signifor
- Colao A, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med. 2012;366(10):914-924. doi:10.1056/NEJMoa1105743
- Nieman LK, et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. doi:10.1210/jc.2015-1818
- Pivonello R, et al. Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing's disease: results from a Phase III study. Clin Endocrinol. 2014;81(3):408-417. doi:10.1111/cen.12431
- Fleseriu M, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/S2213-8587(21)00235-7
- World Health Organization (WHO). Model List of Essential Medicines, 23rd edition. 2023.
- Lacroix A, et al. Management of hyperglycaemia associated with pasireotide: expert consensus recommendations. Pituitary. 2020;23(3):263-276. doi:10.1007/s11102-019-01012-9
- Feelders RA, et al. Advances in the medical treatment of Cushing's syndrome. Lancet Diabetes Endocrinol. 2019;7(4):300-312. doi:10.1016/S2213-8587(18)30155-4
Editorial Team & Review Process
This article was written by the iMedic Medical Editorial Team, comprising specialists in endocrinology and clinical pharmacology. All content is based on current EMA-approved prescribing information, peer-reviewed clinical studies, and international treatment guidelines.
Our editorial process follows the GRADE evidence framework to ensure the highest quality of medical information. All claims are supported by Level 1A evidence where available, based on systematic reviews and randomised controlled trials.
Medical Review Board: Content independently reviewed by board-certified endocrinologists and clinical pharmacologists in accordance with WHO, EMA, and Endocrine Society guidelines.
Conflict of Interest: None. iMedic receives no commercial funding and accepts no pharmaceutical company sponsorship.
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