Pasireotide

Do not inject this medicine into skin that is red or irritated.

Many drugs can interact with pasireotide. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with pasireotide, especially:

• bromocriptine;
• cyclosporine;
• anagrelide;
• droperidol;
• methadone;
• ondansetron;
• an antibiotic--azithromycin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, pentamidine;
• cancer medicine--arsenic trioxide, vandetanib;
• an antidepressant--citalopram, escitalopram;
• anti-malaria medication--chloroquine, halofantrine;
• heart or blood pressure medicine--amlodipine, atenolol, carvedilol, labetalol, metoprolol, nebivolol, sotalol, verapamil, and others;
• heart rhythm medicine--amiodarone, disopyramide, dofetilide, dronedarone, flecainide, ibutilide, quinidine, sotalol;
• medicines to control electrolyte disorders--calcium gluconate, sodium polystyrene sulfonate, tolvaptan; or
• medicine to treat a psychiatric disorder--chlorpromazine, haloperidol, pimozide, thioridazine.

This list is not complete and many other drugs can interact with pasireotide. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Pasireotide may be found in some form under the following brand names:

• Signifor

• Signifor LAR

Tell your doctor if you are pregnant or plan to become pregnant. It is not known if pasireotide will harm your unborn baby.

Pasireotide Usage for Cushing's Disease:

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

Pasireotide LAR for Acromegaly:

• Your healthcare provider will inject pasireotide once a month into your buttock muscle.
• Keep all appointments.
• If you must miss a regularly scheduled appointment for an injection, reschedule as soon as possible.

You should not use pasireotide if you are allergic to it.

Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using pasireotide.

To make sure pasireotide is safe for you, tell your doctor if you have:

• diabetes;

• liver disease;

• a heart rhythm disorder;

• personal or family history of long QT syndrome;

• gallbladder disease; or

• a history of an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

It is not known whether pasireotide will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether pasireotide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Do not inject this medicine into skin that is red or irritated.

Cushing's Disease

Treatment of Cushing's disease in adults who are not candidates for pituitary surgery or in whom surgery was not curative.1 3

Designated an orphan drug by FDA for use in this condition.4

Treatment of choice for patients with Cushing's disease is pituitary (transsphenoidal) surgery; pasireotide considered a second-line treatment option.7 8 9 10 12

General

• Prior to initiating therapy, measure fasting plasma glucose and HbA1c, and perform liver function tests, ECG, and gallbladder ultrasound to establish baseline values.1 Generally repeat these tests at periodic intervals during therapy to monitor for potentially serious adverse effects.1 (See Warnings/Precautions under Cautions.)

• Prior to therapy, initiate intensive and optimal antidiabetic therapy in patients with poorly controlled diabetes mellitus at baseline.1 (See Hyperglycemia and Diabetes Mellitus under Cautions.)

Administration

Sub-Q Administration

Administer by sub-Q injection.1 Patients may self-administer drug after appropriate training.1

Recommended sites of injection include upper thigh or abdomen; avoid areas that are red, inflamed, or irritated.1 Gently pinch skin at injection site and quickly insert needle at an approximately 45° angle.1 Rotate injection site with each dose.1

Dosage

Available as pasireotide diaspartate; dosage expressed in terms of pasireotide.1

Adults

Initially, 0.6 or 0.9 mg twice daily.1 Adjust subsequent dosage based on response (e.g., urinary free cortisol concentrations, symptoms) and tolerance.1 Recommended dosage range is 0.3–0.9 mg twice daily.1

For patients initially receiving 0.6 mg twice daily, may consider dosage increase to 0.9 mg twice daily to improve treatment response depending on patient tolerance.1

May temporarily reduce dosage to manage adverse effects; dosage reduction by 0.3-mg decrements per dose is suggested.1

Continuation of treatment as long as patient is deriving benefit (i.e., as assessed by clinically meaningful reductions in 24-hour urinary free cortisol concentrations and/or improvements in clinical manifestations) is recommended.1 Response usually evident by 2 months of therapy.1 12 13

Special Populations

Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh class B): Initially, 0.3 mg twice daily; recommended maximum dosage is 0.6 mg twice daily.1

Patients with severe hepatic impairment (Child-Pugh class C): Avoid use.1

Renal Impairment

Dosage adjustments not required.1

Geriatric Patients

Select dosage with caution because of greater frequency of decreased hepatic, renal, and/or cardiac function, and of concomitant disease or other drug therapy in geriatric patients.1

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Warnings

Risk of hypocortisolism since pasireotide suppresses corticotropin (ACTH) secretion.1

Monitor for manifestations of hypocortisolism.1 (See Advice to Patients.) If hypocortisolism occurs, consider temporary dosage reduction, interruption in therapy, or temporary use of glucocorticoid replacement therapy.1

Risk of hyperglycemia and diabetes mellitus.1 3 5 8 12 15 16 17 18 Cushing's disease may contribute to this risk.1 3 10 15 Hyperglycemia-related adverse effects reported frequently in clinical studies.1 3 12 13 Usually occurs shortly after drug initiation, and persists throughout duration of therapy; glucose concentrations may be stabilized with use of antidiabetic agents.1 3 12 13

Closely monitor glycemic status, particularly in patients with preexisting diabetes mellitus or impaired glucose tolerance.1 3 5 9 13 15 16 Assess baseline glycemic status prior to initiating therapy; ensure that optimal glycemic control is achieved.1 16 (See General under Dosage and Administration.) Monitor blood glucose concentrations weekly for the first 2–3 months of therapy, then periodically thereafter as clinically indicated.1

Initiate or adjust antidiabetic therapy if hyperglycemia develops.1 3 15 16 If uncontrolled hyperglycemia persists despite appropriate medical management, reduce pasireotide or discontinue treatment.1 16 After discontinuance of therapy, monitor glycemic status according to current standards of care.1

Risk of bradycardia.1 Closely monitor patients with cardiac disease and/or other risk factors for bradycardia.1 (See Drugs that Cause Bradycardia under Interactions.)

Risk of QT-interval prolongation.1 3 Observed following administration of therapeutic and supratherapeutic dosages of pasireotide.1 Use with caution in patients with a substantial risk for QT-interval prolongation.1 (See Drugs that Prolong the QT Interval under Interactions.)

Obtain baseline ECG; consider periodic monitoring of QT interval during therapy.1 Correct hypokalemia and hypomagnesemia (if present) prior to initiating therapy; monitor potassium and magnesium concentrations periodically during therapy.1

Elevations in ALT or AST concentrations reported; generally transient and not associated with clinically important effects.1

Perform liver function tests at baseline and at periodic intervals during therapy (i.e., after 1–2 weeks of treatment, then monthly for 3 months, every 6 months thereafter).1

If ALT is elevated, repeat test as follows: in patients with normal ALT concentrations at baseline, perform repeat test within 1 week if ALT is 3–5 times ULN or within 48 hours if ALT >5 times ULN; in patients with abnormal ALT concentrations at baseline, perform repeat test within 1 week if ALT is 3–5 times ULN or sooner if ALT >5 times ULN.1

If ALT concentrations remain elevated or continue to rise upon a repeat test, temporarily interrupt therapy and investigate probable cause.1 May reinitiate pasireotide therapy cautiously and with close observation once abnormalities resolve to normal or near-normal values and if some other likely cause found.1

If results of any liver function tests (e.g., ALT, AST, alkaline phosphatase, total bilirubin) are >5 times the baseline value or ULN, perform serial measurements of these tests at least weekly.1

Cholelithiasis reported; in some cases, hospitalization or intervention (e.g., cholecystectomy) required.1 3 12

Perform gallbladder ultrasound prior to therapy and periodically thereafter (i.e., every 6–12 months during therapy).1

Deficiencies of pituitary hormones other than ACTH (e.g., thyrotropin [thyroid-stimulation hormone; TSH], GH, insulin-like growth factor I [IGF-I]) may occur.1 8 17 Risk is particularly high in patients following transsphenoidal surgery and/or pituitary irradiation.1

Evaluate pituitary function prior to initiation of therapy; consider periodic monitoring during therapy if clinically indicated.1

Specific Populations

Category C.1

Distributed into milk in rats; not known whether distributed into human milk. 1 Avoid use in nursing women; if use is necessary, exercise caution.1

Safety and efficacy not established.1

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 (See Geriatric Populations under Dosage and Administration.)

Systemic exposure to pasireotide substantially increased in patients with moderate or severe hepatic impairment.1 14 (See Special Populations under Pharmacokinetics.)

Dosage adjustment required for patients with moderate hepatic impairment.1 14 (See Hepatic Impairment under Dosage and Administration.) Avoid use in patients with severe hepatic impairment.1

Renal impairment not expected to substantially affect systemic exposure of pasireotide because drug only minimally eliminated in urine.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, diabetes mellitus.1 3

Storage

Parenteral

25°C (may be exposed to 15–30°C); protect from light.1

• Pasireotide Diaspartate
• SOM230

AUCinf was increased by 12%, 56%, and 42% and Cmax was increased by 3%, 46%, and 33% respectively, in mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C).

Refer to adult dosing.

Adverse events have been observed in animal reproduction studies.

Consult WARNINGS section for dosing related precautions.

Safety and efficacy have not been established in patients younger than 18 years.

Use is not recommended. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: Breastfeeding should be discontinued during treatment.

Animal studies showed excretion of this drug in milk at levels 30% of the plasma level; growth retardation was seen in pre- and post-natal studies, but after weaning body weight gains were comparable to control groups, showing reversibility.