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Pasireotide

Pronunciation

(pas i REE oh tide)

Index Terms

  • Pasireotide Diaspartate
  • SOM230

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Subcutaneous:

Signifor: 0.3 mg/mL (1 mL); 0.6 mg/mL (1 mL); 0.9 mg/mL (1 mL)

Suspension Reconstituted, Intramuscular, as pamoate [strength expressed as base]:

Signifor LAR: 20 mg (1 ea); 40 mg (1 ea); 60 mg (1 ea)

Brand Names: U.S.

  • Signifor
  • Signifor LAR

Pharmacologic Category

  • Somatostatin Analog

Pharmacology

Pasireotide is a cyclohexapeptide somatostatin analog, which is a peptide inhibitor of multiple endocrine, neuroendocrine, and exocrine mechanisms. In patients with Cushing disease, pasireotide binds to somatostatin receptor (sst1-5), with high affinity for the sst1, sst2, sst3 subtypes, and highest affinity for the sst5 subtype, resulting in inhibition of ACTH secretion which leads to decreased cortisol secretion. In patients with acromegaly, pasireotide binds to sst2 and sst5, resulting in decreased GH and IGF-1.

Distribution

Vd: >100 L

Metabolism

Primarily eliminated as unchanged drug hepatically (via biliary excretion)

Excretion

Feces (~40% to 56%, primarily as unchanged drug); urine (~6% to 10%, primarily as unchanged drug)

Time to Peak

Plasma: Subcutaneous: 0.25 to 0.5 hours

Half-Life Elimination

Subcutaneous: ~12 hours

Protein Binding

88%

Special Populations: Hepatic Function Impairment

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).

Use: Labeled Indications

Acromegaly (Signifor LAR): Treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

Cushing disease (Signifor): Treatment of Cushing disease in patients for whom pituitary surgery is not an option or has not been curative

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to pasireotide or any component of the formulation; moderate or severe hepatic impairment (Child-Pugh B or C); uncontrolled diabetes (HbA1c ≥8%) despite receiving anti-diabetic therapy; NYHA Class III to IV heart failure; cardiogenic shock; second- or third-degree atrioventricular (AV) block, sinoatrial block, sick sinus syndrome (unless patient has a functioning pacemaker); severe bradycardia; congenital long QT syndrome or baseline QTc interval ≥500 ms.

Dosing: Adult

Acromegaly (Signifor LAR): IM: Initial: 40 mg once every 28 days; for patients who have not normalized GH and/or IGF-1 levels after 3 months, increase to a maximum of 60 mg. If adverse reactions occur or IFG-1 level decreases to less than lower limit of normal, decrease dosage (temporarily or permanently) by 20 mg decrements.

Missed dose: If a dose is missed, dose may be given up to but no later than 14 days prior to the next dose.

Cushing disease (Signifor): SubQ:

Initial:

US labeling: 0.6 mg or 0.9 mg twice daily.

Canadian labeling: 0.6 mg twice daily.

Titrate based on response and tolerability. If adverse reactions occur, temporarily decrease dose by 0.3 mg increments. Recommended maintenance dosage range: 0.3 to 0.9 mg twice daily. Note: Maximum urinary free cortisol reductions are usually observed by 2 months of treatment. The Canadian labeling recommends to consider discontinuation if clinical improvement is not observed after 2 months of therapy.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Acromegaly (Signifor LAR):

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate hepatic impairment (Child-Pugh class B): Initial: 20 mg every 28 days (maximum: 40 mg every 28 days).

Severe hepatic impairment (Child-Pugh class C): Avoid use.

Cushing disease (Signifor):

Prior to initiation:

US labeling:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Initial: 0.3 mg twice daily (maximum: 0.6 mg twice daily)

Severe impairment (Child-Pugh class C): Use not recommended.

Canadian labeling:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe impairment (Child-Pugh class B or C): Use is contraindicated.

During therapy:

US labeling:

If ALT increases >3 times ULN or baseline value: Recheck ALT during recommended timeframe per recommendations in manufacturer’s labeling for confirmation. If ALT level confirmed or increasing, interrupt therapy and investigate potential cause.

If any liver test ≥5 times ULN (with a normal baseline) OR >5 times the baseline value (with an abnormal baseline): Interrupt therapy and monitor liver tests more frequently per recommendations in manufacturer’s labeling. If values return to normal or near normal, therapy may be reinitiated with extreme caution/monitoring only if another likely cause for hepatic effects is discovered.

Canadian labeling:

If ALT increases >3 times ULN to <5 times ULN: Recheck ALT in 48 hours and if value remains <5 times ULN, continue monitoring ALT every 48 hours. If levels increase >5 times ULN, discontinue therapy and do not reinitiate.

If ALT increases >5 times ULN or if ALT or AST increase >3 times ULN concurrently with an increased bilirubin >2 times ULN or if jaundice or other signs of clinically significant hepatic impairment: Discontinue therapy and investigate potential cause; monitor until resolution. Do not reinitiate therapy.

Reconstitution

Signifor LAR: Allow to stand at room temperature for at least 30 minutes before reconstitution (maximum: 24 hours at room temperature). Reconstitute vials with provided diluent. Shake the vial moderately in a horizontal direction for at least 30 seconds until suspension is uniform; repeat moderate shaking for an additional 30 seconds if the powder is not completely suspended. Administer immediately after reconstitution.

Administration

Intramuscular (IM): Acromegaly (Signifor LAR): Administer IM into the left or right gluteus immediately after reconstitution; do not administer IV.

Subcutaneous (SubQ): Cushing disease (Signifor): Administer subcutaneously into the top of the thigh or abdomen (excluding the navel and waistline). Do not inject into inflamed or irritated skin. Alternate the injection site.

Storage

Signifor: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Signifor LAR: Prior to reconstitution: Store at 2°C to 8°C (36°F to 46°F). Do not freeze. Allow to stand at room temperature for at least 30 minutes before reconstitution (maximum: 24 hours at room temperature); administer immediately after reconstitution. The unreconstituted kit may be re-refrigerated, if needed.

Drug Interactions

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Bromocriptine: Somatostatin Analogs may increase the serum concentration of Bromocriptine. Somatostatin Analogs may also delay bromocriptine absorption and time to maximum plasma concentrations. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Codeine: Somatostatin Analogs may decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Monitor therapy

CycloSPORINE (Systemic): Somatostatin Analogs may decrease the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Gallium Ga 68 Dotatate: Somatostatin Analogs may diminish the therapeutic effect of Gallium Ga 68 Dotatate. Specifically, a false negative PET scan may occur if Gallium GA 68 Dotatate is used during treatment with somatostatin analogs. Management: Imaging with gallium Ga 68 dotatate positron emission tomography (PET) should be performed just prior to dosing with long-acting somatostatin analogs. Short-acting somatostatin analogs can be used up to 24 hours before imaging with gallium Ga 68 dotatate. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Pegvisomant: Somatostatin Analogs may enhance the adverse/toxic effect of Pegvisomant. Specifically, this combination may increase the risk for significant elevations of liver enzymes. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (10% to 11%)

Central nervous system: Headache (3% to 29%), fatigue (10% to 24%), insomnia (4% to 14%), anxiety (6% to 11%)

Dermatologic: Alopecia (2% to 18%)

Endocrine & metabolic: Hyperglycemia (29% to 43%), diabetes mellitus (6% to 31%), hypoglycemia (3% to 15%), increased gamma-glutamyl transferase (9% to 12%), hypercholesterolemia (9% to 11%)

Gastrointestinal: Diarrhea (16% to 59%), nausea (3% to 58%), cholelithiasis (10% to 30%), increased serum lipase (1% to 30%), abdominal pain (8% to 25%), increased serum amylase (2% to 20%), upper abdominal pain (6% to 12%), abdominal distension (5% to 12%), decreased appetite (9% to 11%)

Hematologic & oncologic: Prolonged prothrombin time (2% to 47%; minimal elevation), elevated glycosylated hemoglobin (6% to 12%)

Hepatic: Increased serum ALT (≤13%)

Infection: Influenza (6% to 11%)

Local: Injection site reactions (7% to 18%; including pain, erythema, hematoma, hemorrhage, pruritus)

Neuromuscular & skeletal: Weakness (6% to 16%), increased creatine phosphokinase (13%), myalgia (5% to 12%)

Respiratory: Nasopharyngitis (6% to 16%)

1% to 10%:

Cardiovascular: Hypertension (8% to 10%), sinus bradycardia (3% to 10%), hypotension (6% to 8%), atrioventricular block (6%), prolonged Q-T interval on ECG (4% to 6%)

Central nervous system: Dizziness (2% to 10%), vertigo (5% to 8%)

Dermatologic: Pruritus (7% to 9%), xeroderma (6%)

Endocrine & metabolic: Increased serum glucose (4% to 8%), hypokalemia (5% to 7%), adrenal insufficiency (≤6%), weight loss (5%), impaired glucose tolerance (1% to 5%), hypothyroidism (4%)

Gastrointestinal: Increased serum amylase (2% to 20%), vomiting (4% to 10%), constipation (5% to 9%), pancreatitis (1%)

Hematologic & oncologic: Anemia (3% to 6%)

Hepatic: Increased serum AST (≤7%), increased serum bilirubin (2%)

Neuromuscular & skeletal: Arthralgia (6% to 10%), back pain (5% to 8%), limb pain (5% to 7%)

Respiratory: Upper respiratory tract infection (7%), cough (5%)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiac disorders: Bradycardia and QT prolongation have been observed with therapy. Use with caution in patients with preexisting cardiac disease, patients with risk factors for bradycardia (eg, high-grade heart block, history of significant bradycardia, receiving concomitant drugs known to cause bradycardia), and/or patients at risk for QT prolongation (eg, congenital long QT, recent MI, heart failure, unstable angina, hypokalemia, hypomagnesemia, receiving concomitant drugs known to cause QT prolongation). The Canadian labeling contraindicates use in several of these disorders (refer to Contraindications). Obtain baseline electrocardiogram (ECG) prior to therapy and consider continued monitoring during therapy for an effect on the QTc interval. Correct hypokalemia, hypomagnesemia, and/or hypocalcemia prior to therapy and monitor during therapy.

• Cholelithiasis: May impair gallbladder, leading to gallstone formation; monitor patients for cholelithiasis.

• Hepatic effects: Increased liver enzymes have been reported; ALT, AST, and bilirubin should be monitored per recommendations in manufacturer’s labeling. May require dosage interruption to investigate probable cause of confirmed or rising liver enzyme values; patients with significant elevations in liver function tests require more frequent monitoring and extensive monitoring (ALT, AST, alkaline phosphatase, total bilirubin).

• Hyperglycemia/diabetes: Inhibition of insulin and glucagon secretion may affect glucose regulation, leading to hyperglycemia (sometimes severe). Exacerbation of glycemia occurred in the majority of patients during the initial months of therapy, including patients with normal glucose levels at baseline; diabetes and prediabetes has also been observed. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Assess fasting blood glucose (FBG) levels and/or hemoglobin A1c (HbA1c) prior to initiation of therapy. Patients should also do self-monitoring of blood glucose and/or FBG for the first few months of therapy, after dose increases, and periodically during use. If hyperglycemia occurs, initiation or dosage adjustment of antidiabetic therapy is recommended; if uncontrolled hyperglycemia persists despite antidiabetic therapy, consider dosage reduction or discontinuation of pasireotide.

• Hypocortisolism: Suppression of the adrenocorticotropic hormone (ACTH) from therapy may lead to hypocortisolism in Cushing disease. Monitor all patients for signs or symptoms of hypocortisolism (eg, anorexia, fatigue, hypoglycemia, hyponatremia, hypotension, nausea, vomiting, weakness). If symptoms occur, consider stopping or reducing the dose until symptoms improve. Glucocorticoid replacement therapy may also be needed temporarily.

• Hypothyroidism: Decreases (slight) in thyroid function have been observed during therapy; monitor thyroid function tests prior to therapy and periodically during therapy.

Disease-related concerns:

• Diabetes: Prior to initiation, patients with poorly controlled or uncontrolled diabetes should have antidiabetic therapy optimized; exacerbation of glycemia commonly occurs with pasireotide use. The Canadian labeling contraindicates use in patients with uncontrolled diabetes (≥8% HbA1c) despite receiving antidiabetic therapy.

• Hepatic impairment: Use with caution in patients with hepatic impairment; lower doses are recommended at therapy initiation in patients with moderate impairment (Child-Pugh class B). Use not recommended in patients with severe impairment (Child-Pugh class C). Canadian labeling contraindicates use in moderate or severe impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Acromegaly: Signifor LAR: For intramuscular (IM) use; do not administer intravenously (IV). Must be reconstituted and administered by a trained health care provider. Therapy may cause inhibition of additional pituitary hormones (other than GH/IGF-1); additional monitoring for pituitary deficiency is advised (eg, thyroid, adrenal, gonadal) prior to initiation of therapy and periodically thereafter.

• Appropriate use: Cushing disease: Signifor: For subcutaneous injection. Evaluate for treatment response with 24-hour urinary free cortisol levels and/or improvement in symptoms. Maximum reduction in urinary free cortisol levels is usually seen by 2 months of therapy. Therapy may cause inhibition of additional pituitary hormones (other than ACTH); additional monitoring for pituitary deficiency is advised (eg, thyroid-stimulating hormone [TSH], free T4, GH, IGF-1), particularly in patients who have undergone transsphenoidal surgery and pituitary irradiation who are at an increased risk for deficiency.

Monitoring Parameters

Acromegaly (Signifor LAR): Serum GH and IGF-1; fasting plasma glucose (FBG) and hemoglobin A1c (HbA1c) (prior to initiation and after treatment discontinuation as clinically appropriate); plasma glucose (weekly for the first 3 months of therapy, the first 4 to 6 weeks after dose increases, and periodically thereafter); ECG (baseline; 21 days after injection in patients at high risk; consider continued monitoring during treatment); serum potassium and magnesium (prior to and periodically during therapy); thyroid function (baseline then periodically); adrenal function (prior to and periodically during therapy); gonadal function (prior to and periodically during therapy); signs and symptoms of adrenal insufficiency; heart rate (patients with cardiac disease and/or risk factor for bradycardia); monitor periodically for cholelithiasis.

Liver function tests: Prior to initiation, after the first 2 to 3 weeks, then monthly for 3 months and as clinically indicated; during therapy, discontinue if clinically significant liver impairment develops and monitor liver function until resolution.

Cushing disease (Signifor): Urinary free cortisol (24-hour); FBG and HbA1c (prior to initiation); FBG and/or self-monitoring glucose (weekly for first 2 to 3 months, as well as over the first 2 to 4 weeks after any dose increase, then periodically during therapy; Canadian labeling recommends resuming weekly monitoring for 2 to 3 months after dose increases), and FBG or HbA1c (following discontinuation as clinically appropriate); serum GH and IGF-1 (baseline then periodically); thyroid function (baseline then periodically); potassium and magnesium (prior to therapy then periodically during therapy); ECG (baseline and consider continued monitoring during treatment); gall bladder ultrasonography (baseline, then every 6 to 12 months during therapy); signs and symptoms of hypocortisolism (eg, weakness, fatigue, nausea, vomiting); heart rate. Additional Canadian labeling recommendations include calcium and lipase prior to therapy and then periodically during therapy.

Liver function tests:

US labeling: Prior to therapy, 1 to 2 weeks after initiation, then monthly for 3 months, then every 6 months thereafter; more frequent testing may be necessary:

If ALT normal at baseline and ALT increases 3 to 5 times ULN on therapy: Repeat ALT within 1 week

If ALT normal at baseline and ALT increases >5 times ULN on therapy: Repeat ALT within 48 hours

If ALT abnormal at baseline and ALT increases 3 to 5 times baseline values on therapy: Repeat ALT within 1 week

If ALT abnormal at baseline and ALT increases >5 times ULN on therapy: Repeat ALT <1 week

Note: ALT levels should be done in a laboratory capable of same-day results; if ALT levels are confirmed or rising, interrupt therapy and investigate cause.

During therapy, if any liver test ≥5 times ULN (with a normal baseline) OR >5 times the baseline value (with an abnormal baseline), interrupt therapy and monitor ALT, AST, alkaline phosphatase, and total bilirubin weekly or more frequently. If values return to normal or near normal, therapy may be reinitiated with extreme caution/monitoring only if another likely cause for hepatic effects discovered.

Canadian labeling: Baseline, weekly for the first month, then every 2 weeks for the next 3 months, then every 3 months thereafter. More frequent testing may be necessary with dose increase or:

If ALT increases >3 times ULN < 5 times ULN: Recheck ALT in 48 hours and if value remains <5 times ULN continue monitoring ALT every 48 hours. If levels increase >5 times ULN or if ALT or AST increase >3 times ULN concurrently with an increased bilirubin >2 times ULN or if jaundice or other signs of clinically significant hepatic impairment occur, discontinue therapy and monitor until resolution of hepatic function. Do not reinitiate therapy.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. The Canadian labeling recommends avoiding use during pregnancy or in women of childbearing potential who are not using contraception.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, loss of strength and energy, nausea, diarrhea, hair loss, rhinitis, pharyngitis, injection site irritation, insomnia, flu-like symptoms, muscle pain, or joint pain. Have patient report immediately to prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of low sodium (headache, trouble focusing, memory problems, illogical thinking, weakness, seizures, or change in balance), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of gallstones (pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; yellow skin or eyes; or fever with chills), signs of decreased hormones (abnormal diarrhea; dizziness; loss of strength and energy; lack of appetite; passing out; vomiting; or weight loss), arrhythmia, bradycardia, severe dizziness, passing out, severe headache, muscle cramps, swelling of arms or legs, or abdominal edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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