Pasireotide

What is Pasireotide?

• Pasireotide (Signifor) is a somatostatin analog used to treat Cushing's disease in adults who cannot be treated with surgery or who did not respond to surgery.
• Pasireotide injection (Signifor Lar) is also used to decrease the amount of growth hormone produced by people with acromegaly who cannot be treated with surgery or who did not respond to surgery.

Pasireotide

What are the uses of this medicine?

• Pasireotide (Signifor) is a prescription medicine used to treat Cushing's disease in adults who cannot have surgery or have failed surgery.

Pasireotide injection (Signifor Lar) is a prescription medicine used to treat people with:

• acromegaly for whom surgery has not worked well enough or who cannot have surgery.
• Cushing's disease for whom surgery has not worked well enough or who cannot have surgery.

How does this medicine work?

• Pasireotide (pa" ze ree' oh tide) is a synthetic octapeptide and analogue of somatostatin that is used for its ability to suppress levels and activities of hormones (growth hormone, insulin, gastrin, secretin, glucagon) or active neuropeptides (serotonin, vasoactive intestinal polypeptide [VIP]).
• Natural somatostatin is produced in the hypothalamus and acts to suppress growth hormone release from the pituitary.
• Somatostatin is also found in other neurons throughout the body and particularly in intestinal and pancreatic neurons, where it is active in suppressing release of hormones and neuropeptides such as insulin, glucagon, ACTH, gastrin, secretin, motilin, VIP, serotonin and cholecystokinin. Because of its short half-life (~3 minutes), somatostatin is impractical as a therapeutic agent, and analogues have been developed that have a more favorable pharmacological profile such as octreotide, pasireotide and lanreotide, all three of which have been marketed in long acting release (LAR) forms to allow once weekly or monthly administration.
• Pasireotide appears to interact largely with the somatostatin subtypes 1, 2 and 3 and possibly subtype 5 receptors, but otherwise acts in a similar manner to somatostatin.
• Pasireotide therapy has been shown to improve symptoms and complications of several neuroendocrine tumors including abnormal growth in acromegaly due to growth hormone secreting pituitary tumors and symptoms of excessive glucocorticoid production due to ACTH secreting pituitary tumors.

Who Should Not Use this medicine ?

• This medicine have no usage limitations.

What drug interactions can this medicine cause?

• Tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.

Be sure to mention any of the following:

• amiodarone (Pacerone)
• beta blockers such as atenolol (Tenormin), labetalol (Trandate), metoprolol (Kapspargo sprinkle, Lopressor, Toprol XL), nadolol (Corgard), and propranolol (Hemangeol, Inderal)
• bromocriptine (Cycloset, Parlodel)
• calcium channel blockers such as amlodipine (Katerzia, Norvasc; in Caduet, Lotrel, others), diltiazem (Cardizem, Cartia, Tiazac, others), felodipine, nifedipine (Procardia), nisoldipine (Sular), and verapamil (Calan, Verelan)
• cyclosporine (Gengraf, Neoral, Sandimmune)
• digoxin (Lanoxin)
• diuretics ('water pills')
• insulin and oral medications for diabetes
• procainamide
• quinidine (in Nuedexta)
• sotalol (Betapace, Sorine, Sotylize)

Is this medicine FDA approved?

• Pasireotide was approved for use in treating Cushing disease in the United States in 2012 and a long acting form for as treatment of acromegaly in 2014.

How should this medicine be used?

Prior to the start of Signifor, patients should have baseline levels of the following:

• fasting plasma glucose (FPG)
• hemoglobin A1c (HbA1c)
• liver tests
• serum potassium and magnesium levels

• Patients should also have a baseline electrocardiogram (ECG) and gallbladder ultrasound.

Recommended dosage: Signifor:

• Recommended initial dosage is either 0.6 mg or 0.9 mg by subcutaneous injection twice a day; recommended dosage range is 0.3 mg to 0.9 mg twice a day.
• Titrate dosage based on treatment response [clinically meaningful reduction in 24-hour urinary free cortisol (UFC) and/or improvements in signs and symptoms of disease] and tolerability.

Patients With Hepatic Impairment:

• Child-Pugh B: Recommended initial dosage is 0.3 mg twice a day and maximum dosage is 0.6 mg twice a day.
• Child-Pugh C: Avoid use in these patients.

Signifor Lar: Initial Dose:

• Acromegaly: The initial dose is 40 mg by intramuscular injection once every 4 weeks (every 28 days).
• Cushing's Disease: The initial dose is 10 mg by intramuscular injection once every 4 weeks (every 28 days).

Patients with Hepatic Impairment: Child-Pugh B:

• Acromegaly: Recommended initial dose is 20 mg once every 4 weeks and maximum dose is 40 mg once every 4 weeks.
• Cushing's Disease: Recommended initial dose is 10 mg once every 4 weeks and maximum dose is 20 mg once every 4 weeks.

• Child-Pugh C: Avoid use in these patients.

Administration:

• Pasireotide comes a solution (Signifor) to be injected subcutaneously.
• Pasireotide also comes as a suspension(Signifor Lar) to be mixed with another solution and injected into the muscles of the buttocks by a doctor or nurse.

Signifor:

• Use Signifor exactly as your doctor tells you to.
• Your doctor may change your dose if needed.
• Before you use Signifor for the first time, your doctor should do a blood test to check your blood sugar levels and your liver tests.
• Before you use Signifor for the first time, your doctor should do a test to check your heart (electrocardiogram) and your gallbladder (ultrasound).
• Signifor should be clear and colorless. Before you inject your dose, check to make sure that Signifor is clear and colorless, and does not have any clumps or particles in it.
• Signifor is given as an injection into the fat just under your skin (subcutaneous injection).
• Do not inject Signifor into skin that is red or irritated.
• The recommended injection sites for Signifor are the top of your thigh or stomach area (abdomen).
• Change (rotate) your injection site with each dose. Do not inject Signifor into the exact same spot for each injection.
• Your doctor should show you how to prepare and give your dose of Signifor before you use it for the first time.
• You should not inject Signifor until your doctor has shown you how to use it the right way.

Signifor Lar:

• Signifor Lar must be given by a trained healthcare provider as an injection into the muscle of your buttocks (intramuscularly).
• Your healthcare provider will tell you how much Signifor Lar you will receive and when you will receive it.
• Your healthcare provider may change your dose of Signifor Lar or the length of time between your injections. Your healthcare provider will tell you how long you need to receive Signifor Lar.
• Before you receive Signifor Lar for the first time, your healthcare provider should do a blood test to check your fasting blood sugar level, hemoglobin A1c level, electrolyte levels, and your liver function.
• You will need to check your blood sugar levels during treatment with Signifor Lar, especially after you start treatment with Signifor Lar and after your dose is increased. Your healthcare provider will tell you how often you should check your blood sugar levels.
• Before you receive Signifor Lar for the first time and during your treatment, your healthcare provider should do a test to check your heart (electrocardiogram).
• If you miss a dose of Signifor Lar, you may receive your missed dose up to 14 days before your next dose.
• It is important that you keep your scheduled appointments with your healthcare provider during treatment with Signifor Lar.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form:

• As Injection: 0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL in a single-dose ampule
• As Signifor Lar for injectable suspension: 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg, powder in a vial to be reconstituted with the provided 2 mL diluent.

This medicine is available in fallowing brand namesː

• Signifor; Signifor Lar

What side effects can this medication cause?

The most common side effects of this medicine include:

• diarrhea
• nausea
• high blood sugar
• headache
• abdominal pain
• fatigue
• diabetes mellitus
• injection-site reactions
• common cold
• hair loss
• weakness
• fluid retention
• Abnormal blood test result for glycosylated hemoglobin (the level of glycosylated hemoglobin indicates the average blood sugar level over the previous months)

Pasireotide may cause serious side effects, including:

• hypocortisolism
• hyperglycemia
• bradycardia
• QT interval prolongation
• elevation of your liver tests
• gallstones (cholelithiasis)

What special precautions should I follow?

• Decreases in circulating levels of cortisol may occur resulting in biochemical and/or clinical hypocortisolism. Signifor/Signifor Lar dose reduction or interruption and/or adding a low-dose short-term glucocorticoid may be necessary.
• Blood glucose elevations have been seen in healthy volunteers and patients treated with Signifor/Signifor Lar.
• Bradycardia has been reported with the use of Signifor/Signifor Lar. Dose adjustments of beta-blockers, calcium channel blockers, or correction of electrolyte disturbances may be necessary.
• Signifor is associated with QT prolongation. A baseline ECG is recommended prior to initiating therapy with Signifor and monitoring for an effect on the QTc interval is advisable. Hypokalemia and hypomagnesemia must be corrected prior to Signifor administration and should be monitored periodically during therapy.
• Increases in liver enzymes have been observed with Signifor/Signifor Lar. Evaluate liver enzyme tests prior to and during treatment.
• Cholelithiasis has been frequently reported in clinical studies with Signifor/Signifor Lar. Ultrasonic examination of the gallbladder before, and periodically during Signifor therapy is recommended. If complications of cholelithiasis are suspected, discontinue Signifor and treat appropriately.
• As the pharmacological activity of Signifor/Signifor Lar mimics that of somatostatin, inhibition of pituitary hormones, other than ACTH, may occur. Patients who have undergone transsphenoidal surgery and pituitary irradiation are particularly at increased risk for deficiency of pituitary hormones.
• Pasireotide has many side effects including suppression of gall bladder contractility and bile production, and maintenance therapy can cause cholelithiasis and accompanying elevations in serum enzymes and bilirubin.

What to do in case of emergency/overdose?

• In case of overdose, call the poison control helpline of your country. In the United States, call 1-800-222-1222.

• Overdose related information is also available online at poisonhelp.org/help.
• In the event that the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services. In the United States, call 911.
• In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient's clinical status, until resolution of the symptoms.

Can this medicine be used in pregnancy?

• The limited data with Pasireotide in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
• Pasireotide may harm your unborn baby.

Can this medicine be used in children?

• Safety and effectiveness of Pasireotide have not been established in pediatric patients.

What are the active and inactive ingredients in this medicine?

Signifor:

• Active ingredient: Pasireotide
• Inactive ingredients: Mannitol, sodium hydroxide, tartaric acid, and water for injection.

Signifor Lar:

• Active ingredient: pasireotide pamoate
• Inactive ingredients:
• Vial: Poly(D,L-lactide-co-glycolide)
• Prefilled syringe: Mannitol, carboxymethylcellulose sodium, poloxamer 188, and water for injections

Who manufactures and distributes this medicine?

Signifor: Distributed by:

• Recordati Rare Diseases Inc., Lebanon, NJ U.S.A

Signifor Lar: Distributed by:

• Recordati Rare Diseases Inc., Lebanon, NJ U.S.A

What should I know about storage and disposal of this medication?

Signifor:

• Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F), protect from light.

Signifor Lar:

• Store at 2°C to 8°C (36°F-46°F).
• Do not freeze.

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• Dailymed label info on Pasireotide
• FDA Pasireotide

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