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 ER, Intramuscular, as pamoate [strength expressed as base]:
Signifor LAR: 10 mg (1 ea); 30 mg (1 ea); 20 mg (1 ea); 40 mg (1 ea); 60 mg (1 ea)
Pharmacology
Mechanism of Action
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.
Pharmacokinetics/Pharmacodynamics
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%
Use in Specific Populations
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.
The Endocrine Society suggests use of a somatostatin analog in select patients preoperatively to reduce surgical risk from severe comorbidities and as initial adjuvant therapy in patients with persistent, significant disease (ie, moderate to severe signs/symptoms of growth hormone excess and without local mass effects) postoperatively. Alternative agents are suggested for patients with mild disease postoperatively (Endocrine Society [Katznelson 2014]).
Cushing disease (Signifor and Signifor LAR): 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.
Dosage and Administration
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, may increase to a maximum of 60 mg once every 28 days. 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: 0.6 mg or 0.9 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.
Signifor LAR: IM: Initial: 10 mg once every 28 days; for patients who have not normalized 24-hour urinary free cortisol after 4 months, may increase dose (maximum: 40 mg once every 28 days). If adverse reactions occur or if cortisol level decreases to less than lower limit of normal or is in the lower normal range in patients with symptoms suggestive of adrenal insufficiency, may interrupt therapy (temporarily or permanently) or decrease to a previously tolerated dose.
Missed dose: If a dose is missed, dose may be given up to but no later than 14 days prior to the next dose.
Dosing: Geriatric
Refer to adult dosing.
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
IM: Signifor LAR: Administer only by IM injection into the left or right gluteus immediately after reconstitution.
SubQ: Signifor: Administer only by subcutaneous injection 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
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. Exceptions are discussed in separate monographs. Consider therapy modification
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
Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Avoid combination
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
Gallium Ga 68 Dotatoc: Somatostatin Analogs may diminish the therapeutic effect of Gallium Ga 68 Dotatoc. Management: Imaging with gallium Ga 68 dotatoc 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 dotatoc. Consider therapy modification
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
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
Lutetium Lu 177 Dotatate: Somatostatin Analogs may diminish the therapeutic effect of Lutetium Lu 177 Dotatate. Specifically, the therapeutic effect of Lutetium Lu 177 Dotatate may be diminished if the timing of Somatostatin Analog administration is not carried out as recommended. Management: Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each lutetium Lu 177 dotatate dose. Administer short- and long-acting octreotide during treatment as recommended. See full monograph. Consider therapy modification
Macimorelin: Somatostatin Analogs may diminish the diagnostic effect of Macimorelin. Avoid combination
Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering 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
Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Consider therapy modification
Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Adverse Reactions
>10%:
Cardiovascular: Peripheral edema (10% to 14%)
Central nervous system: Headache (immediate release: 28% to 29%; long-acting release: 3% to 19%), fatigue (10% to 27%), hypertension (8% to 15%), insomnia (immediate release: 4% to 14%), anxiety (immediate release: 6% to 11%)
Dermatologic: Alopecia (2% to 18%)
Endocrine & metabolic: Hyperglycemia (29% to 47%), diabetes mellitus (long-acting release: 21% to 31%; immediate release: 6% to 20%), hypoglycemia (3% to 15%), increased gamma-glutamyl transferase (9% to 12%), hypercholesterolemia (6% to 11%)
Gastrointestinal: Diarrhea (immediate release: 58% to 59%; long-acting release: 16% to 39%), nausea (immediate release: 46% to 58%; long-acting release: 3% to 21%), cholelithiasis (10% to 33%), increased serum lipase (long-acting release: 1% to 30%; immediate release: 6% to 9%), abdominal pain (8% to 25%), increased serum amylase (long-acting release: 1% to 20%; immediate release: 2%), upper abdominal pain (6% to 12%), abdominal distension (5% to 12%), decreased appetite (9% to 11%)
Hematologic & oncologic: Prolonged partial thromboplastin time (immediate release: 47%), prolonged prothrombin time (immediate release: 2% to 33%; long-acting release: 1%), elevated glycosylated hemoglobin (5% to 12%)
Hepatic: Increased serum alanine aminotransferase (≤14%), increased serum aspartate aminotransferase (≤14%)
Infection: Influenza (6% to 11%)
Local: Injection site reactions (immediate release: 17% to 18%; long-acting release: 2% to 7%)
Neuromuscular & skeletal: Asthenia (immediate release: 6% to 16%), increased creatine phosphokinase in blood specimen (long-acting release: 13%), myalgia (5% to 12%), back pain (5% to 11%)
Respiratory: Nasopharyngitis (6% to 16%)
1% to 10%:
Cardiovascular: Sinus bradycardia (3% to 10%), hypotension (6% to 8%), atrioventricular block (long-acting release: 6%), prolonged Q-T interval on ECG (1% to 6%)
Central nervous system: Dizziness (2% to 10%), vertigo (immediate release: 5% to 8%)
Dermatologic: Pruritus (immediate release: 7% to 9%), xeroderma (immediate release: 6%)
Endocrine & metabolic: Hyperuricemia (long-acting release: 7%), hypokalemia (immediate release: 5% to 7%), adrenocortical insufficiency (2% to 7%), decreased cortisol (long-acting release: 5%), weight loss (long-acting release: 5%), impaired glucose tolerance/prediabetes (long-acting release: 1% to 5%), hypothyroidism (immediate release: 4%)
Gastrointestinal: Vomiting (3% to 10%), constipation (5% to 9%), flatulence (long-acting release: 5%), cholestasis (long-acting release: 4%), cholecystitis (long-acting release: 1%), pancreatitis (long-acting release: ≤1%)
Hematologic & oncologic: Anemia (3% to 6%)
Neuromuscular & skeletal: Arthralgia (6% to 10%), limb pain (5% to 7%)
Respiratory: Upper respiratory tract infection (long-acting release: 7%), cough (long-acting release: 5%)
<1%, postmarketing, and/or case reports: Bradycardia, diabetic ketoacidosis, increased serum bilirubin, pancreatitis
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). Obtain baseline 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: Cholelithiasis and complications of cholelithiasis (eg, cholecystitis, cholangitis, pancreatitis) requiring cholecystectomy have been reported; monitor periodically for cholelithiasis; discontinue and treat appropriately if suspected.
- 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. Prior to initiation, assess fasting blood glucose (FBG) levels and/or hemoglobin A1c (HbA1c), and optimize antidiabetic therapy in diabetic patients with poor baseline glycemic control. 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.
- Pituitary hormone deficiency (anterior): May cause inhibition of anterior pituitary hormones; monitoring for pituitary deficiency is advised (eg, thyroid, adrenal, gonadal) prior to initiation of therapy and periodically thereafter. Patients who have undergone transsphenoidal surgery and pituitary irradiation are at an increased risk for deficiency.
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.
- 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).
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.
Monitoring Parameters
Acromegaly (Signifor LAR): Serum GH and IGF-1 (at 3 months prior to dosage adjustment); 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: 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), 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.
Liver function tests:
Signifor: 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.
Signifor LAR: 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.
Pregnancy
Pregnancy Considerations
If treatment for acromegaly is required during pregnancy for worsening symptoms (eg, headaches or evidence of worsening tumor), alternative agents are recommended. Monitoring of insulin-like growth factor 1 (IGF-1) and/or growth hormone (GH) is not recommended during pregnancy, as an active placental GH variant present in maternal blood limits the usefulness of the results (Endocrine Society [Katznelson 2014]).
Fertility may be improved with treatment in females of reproductive potential following normalization of serum cortisol in patients with Cushing disease and normalization of IGF-1 and GH in women with acromegaly. The Endocrine Society acromegaly guidelines recommend women of childbearing potential use adequate contraception during treatment, and suggest discontinuing long-acting formulations of somatostatin analogs approximately 2 months prior to a planned pregnancy; short-acting octreotide may be used until conception if needed (Endocrine Society [Katznelson 2014]).
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, passing gas, common cold symptoms, painful extremities, diarrhea, hair loss, stuffy nose, sore throat, injection site irritation, trouble sleeping, flu-like symptoms, back pain, muscle pain, anxiety, constipation, dry skin, or joint pain. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating), signs of gallstones (pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; yellow skin; 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), abnormal heartbeat, fast heartbeat, slow heartbeat, vision changes, severe dizziness, passing out, severe headache, 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.
