Pasireotide (Monograph)

Brand names: Signifor, Signifor LAR
Drug class: Somatostatin Agonists

Medically reviewed by Drugs.com on Dec 17, 2023. Written by ASHP.

Introduction

Synthetic polypeptide pharmacologically related to somatostatin (growth hormone [GH, somatropin] release-inhibiting factor).

Commercially available as pasireotide diaspartate (Signifor) in a sub-Q formulation for treatment of Cushing's disease. Also available as pasireotide pamoate in a long-acting IM formulation (Signifor LAR) for treatment of acromegaly or Cushing's disease.

Uses for Pasireotide

Cushing's Disease

Sub-Q injection and long-acting injectable IM suspension are used for treatment of Cushing's disease in adults who are not candidates for pituitary surgery or in whom surgery was not curative.

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

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

Acromegaly

Treatment of acromegaly in patients who have had an inadequate response to or are not candidates for surgical resection (designated an orphan drug by FDA for this use).

Goal of therapy is to normalize concentrations of growth hormone (GH) and insulin-like growth factor-1 (IGF-1).

Related/similar drugs

dexamethasone, Decadron, cyproheptadine, octreotide, bromocriptine, mifepristone, lanreotide

Pasireotide Dosage and Administration

General

Pretreatment Screening

• Obtain baseline fasting plasma glucose, glycosylated hemoglobin (hemoglobin A_1c[HbA_1c]), serum potassium and magnesium levels, liver function tests, electrocardiogram (ECG), and gallbladder ultrasound.

• Monitor pituitary function (e.g., thyrotropin, free thyroxine, growth hormone [GH], and insulin-like growth hormone factor-1 [IGF-1] concentrations).

• Patients with poorly controlled diabetes mellitus at baseline should be intensively managed with optimal antidiabetic therapy prior to initiating pasireotide.

Patient Monitoring

• Monitor fasting plasma glucose, HbA_1c, serum potassium and magnesium levels, liver function tests, and ECG at regular intervals during therapy or as clinically indicated.

• Periodically monitor for gallstones or complications of gallstones.

• Monitor pituitary function (e.g., thyrotropin, free thyroxine, GH, and IGF-1 concentrations) as clinically indicated.

• Cushing's Disease: Individualize dosage based on patient’s response (concentrations of urinary free cortisol [UFC], clinical symptoms) and tolerance; monitor 24- hour UFC concentrations and clinical symptoms and adjust dosage accordingly.

• Acromegaly: Individualize dosage based on patient’s response (GH and IGF-1 concentrations, clinical symptoms); monitor serum GH and IGF-1 concentrations and adjust dosage accordingly.

Administration

Pasireotide diaspartate injection: Administer by sub-Q injection only.

Pasireotide pamoate long-acting injectable suspension: Administer by IM injection. Do not administer IV.

Sub-Q Administration

Administer pasireotide diaspartate by sub-Q injection into the top of thigh or abdomen; avoid areas that are red, inflamed, or irritated. Patients may self-administer drug after appropriate training.

Gently pinch skin at injection site and quickly insert needle at an approximately 45° angle. Rotate injection sites with each dose.

If a dose is missed, skip missed dose and administer next dose at scheduled time; do not administer 2 doses to make up for a missed dose.

IM Injection

Administer long-acting injectable pasireotide pamoate suspension by IM injection into left or right gluteal muscle; do not administer IV. Intended for administration only by a trained healthcare professional.

Commercially available as a lyophilized powder that must be reconstituted by a trained healthcare professional immediately prior to administration.

Prior to reconstitution, allow vial and diluent syringe to reach room temperature for a minimum of 30 minutes (not to exceed 24 hours).

Reconstitute the powder with manufacturer-supplied diluent. After addition of diluent, moderately shake vial in a horizontal direction for at least 30 seconds until a uniform suspension is formed. If powder is not completely suspended, repeat and moderately shake vial for another 30 seconds.

If a dose is missed and the patient returns prior to the next scheduled dose, a dose may be administered up to but no later than 14 days prior to the next dose.

Dosage

Available as pasireotide diaspartate and pasireotide pamoate; dosage expressed in terms of pasireotide.

Adults

Cushing's Disease

Sub-Q (Pasireotide Diaspartate Injection)

Initially, 0.6 or 0.9 mg twice daily. Adjust subsequent dosage based on response (e.g., clinically meaningful reduction in 24-hour UFC concentrations, improvement in clinical manifestations) and tolerability. Recommended dosage range is 0.3–0.9 mg twice daily.

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.

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

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

IM Injection (Pasireotide Pamoate Long-acting Injectable Suspension)

Initially, 10 mg once every 4 weeks.

After 4 months, may consider a dosage increase in patients who do not have normalized 24-hour UFC levels and who tolerate the dosage up to a maximum dosage of 40 mg once every 4 weeks to improve treatment response.

To manage adverse effects or over-response to treatment (e.g., cortisol levels below the lower limit of normal or in the low part of the normal range with symptoms suggestive of adrenal insufficiency), may temporarily reduce dosage to previously tolerated dosage, temporarily interrupt therapy, or discontinue therapy. For patients on a dosage of 10 mg once every 4 weeks, therapy can either be interrupted or discontinued.

Acromegaly

IM Injection (Pasireotide Pamoate Long-acting Injectable Suspension)

Initially, 40 mg once every 4 weeks.

In patients who do not have normalized GH concentrations and/or age- and sex-adjusted IGF-1 concentrations after 3 months of treatment at the initial dosage and who tolerate the initial dosage, may consider dosage increase up to a maximum dosage of 60 mg IM once every 4 weeks.

To manage adverse effects or over-response to treatment (e.g., age- and sex-adjusted IGF-1 levels below the lower limit of normal), may reduce dosage, either temporarily or permanently, by 20-mg decrements.

Special Populations

Hepatic Impairment

Sub-Q Injection (Pasireotide Diaspartate Injection)

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

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

IM Injection (Pasireotide Pamoate Long-acting Injectable Suspension)

Cushing's disease: Patients with moderate hepatic impairment (Child-Pugh class B): Initially, 10 mg once every 4 weeks; maximum recommended dosage is 20 mg once every 4 weeks.

Acromegaly: Patients with moderate hepatic impairment (Child-Pugh class B): Initially, 20 mg once every 4 weeks; maximum recommended dosage is 40 mg once every 4 weeks.

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

Renal Impairment

Dosage adjustments not required.

Geriatric Use

Select dosage with caution, generally starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy in geriatric patients.

Cautions for Pasireotide

Contraindications

• None.

Warnings/Precautions

Warnings

Hypocortisolism

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

Monitor for manifestations of hypocortisolism. If hypocortisolism occurs, consider temporary dosage reduction or interruption of therapy and temporary glucocorticoid replacement therapy.

Hyperglycemia and Diabetes Mellitus

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

Closely monitor glycemic status, particularly in patients with preexisting diabetes mellitus or impaired glucose tolerance. Assess baseline glycemic status prior to initiating therapy; ensure that optimal glycemic control is achieved.

Sub-Q therapy: Monitor blood glucose concentrations weekly for the first 2–3 months of therapy, for the first 2 to 4 weeks after dosage is increased, then periodically thereafter as clinically indicated.

IM therapy: Monitor blood glucose concentrations weekly for the first 3 months of therapy, for the first 4–6 weeks after dosage is increased, then periodically thereafter as clinically indicated.

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

Postmarketing cases of ketoacidosis with long-acting pasireotide in patients with and without a history of diabetes reported. Evaluate patients who present with signs and symptoms consistent with severe metabolic acidosis for ketoacidosis. If ketoacidosis is suspected, discontinue therapy and initiate prompt evaluation and treatment.

Cardiovascular Effects

Risk of bradycardia. Closely monitor patients with cardiac disease and/or other risk factors for bradycardia (e.g., clinically important bradycardia, high-grade heart block, concomitant use of drugs that cause bradycardia).

Risk of QT-interval prolongation. Observed following administration of therapeutic and supratherapeutic dosages of pasireotide. Use with caution in patients with a substantial risk for QT-interval prolongation such as those with congenital QT prolongation, uncontrolled or substantial cardiac disease (e.g., recent MI, CHF, unstable angina, clinically important bradycardia), hypokalemia and/or hypomagnesemia, and those receiving concomitant antiarrhythmic drugs or other agents that prolong the QT interval.

Obtain baseline ECG; periodic monitoring of QT interval is advisable during therapy. Patients at risk for QT-interval prolongation who are receiving pasireotide extended-release IM injection should be monitored for QT-interval prolongation at the time of maximum drug concentration (21 days after injection). Correct hypokalemia and hypomagnesemia (if present) prior to initiating pasireotide therapy; monitor potassium and magnesium concentrations periodically during therapy.

Hepatic Effects

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

Sub-Q therapy: 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, and every 6 months thereafter). 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 is >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 is >5 times ULN. If ALT concentrations remain elevated or continue to rise upon a repeat test, temporarily interrupt therapy and investigate probable cause. 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. If results of any liver function tests (e.g., ALT, AST, alkaline phosphatase, total bilirubin) are >5 times the baseline value (if abnormal baseline) or ULN (if baseline is normal), perform serial measurements of these tests weekly or more frequently.

IM therapy: Monitor liver function tests at baseline, after 2–3 weeks of treatment, then monthly for 3 months, and periodically thereafter as clinically indicated. If ALT or AST concentrations are elevated, monitor liver function until ALT/AST concentrations return to pre-treatment values. If signs or symptoms suggestive of significant hepatic impairment occur, temporarily interrupt IM therapy and investigate probable cause. Monitor patients until resolution. If hepatic impairment is suspected to be related to drug, discontinue pasireotide therapy.

Biliary Effects

Cholelithiasis reported frequently in pasireotide-treated patients; in some cases, complications (e.g., cholecystitis, cholangitis) requiring hospitalization or intervention (e.g., cholecystectomy) required.

Sub-Q therapy: Perform gallbladder ultrasound prior to therapy and monitor patients periodically during therapy.

IM therapy: Periodically monitor patients during therapy.

If complications of cholelithiasis suspected, discontinue pasireotide therapy and institute appropriate treatment.

Pituitary Hormone Deficiency

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

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

If adrenal insufficiency occurs, treat in accordance with current standard of care; replacement doses of exogenous glucocorticoids may be required.

Specific Populations

Pregnancy

Limited data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal studies, findings indicating developmental delay and retardation of physiologic growth were observed.

Lactation

Distributed into milk in rats; not known whether pasireotide is distributed into human milk, affects milk production, or has any effects on breast-fed infants. Consider benefits of breast-feeding and importance of pasireotide to the woman along with potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

Females and Males of Reproductive Potential

Reduced or normalized serum cortisol levels, reduced GH levels, and normalized IGF-1 levels may improve female fertility and potentially result in unintended pregnancy.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Other clinical experience has not identified differences in responses between geriatric and younger patients.

Age is not expected to substantially affect circulating levels of pasireotide.

Hepatic Impairment

Systemic exposure to pasireotide substantially increased in patients with moderate or severe hepatic impairment.

Dosage adjustment not required for patients with mild hepatic impairment. Dosage adjustment required for patients with moderate hepatic impairment. Safety and efficacy of pasireotide not established in patients with severe hepatic impairment; avoid use in such patients.

Renal Impairment

Sub-Q injection: Pharmacokinetics not substantially affected by mild, moderate, or severe renal impairment or end-stage renal failure. Pasireotide is minimally eliminated in urine.

Long-acting IM injection: Clinical studies not conducted in patients with renal impairment; renal impairment not expected to significantly affect pasireotide pharmacokinetics.

Common Adverse Effects

Sub-Q injection (≥20%): Diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, diabetes mellitus.

Long-acting IM injection (≥20%): Diarrhea, cholelithiasis, hyperglycemia, diabetes mellitus.

Drug Interactions

Not a substrate, inhibitor, or inducer of any major CYP isoenzymes. May indirectly decrease metabolic clearance of CYP substrates via suppression of GH secretion (which is known to increase CYP enzyme activity).

Also not likely to be a substrate of breast cancer resistance protein (BCRP), organic cation transporter 1 (OCT1), or organic anion-transporting polypeptide (OATP) 1B1, 1B3, or 2B1.

Likely to be a substrate of P-glycoprotein (P-gp), but effect of P-gp on pharmacokinetics expected to be limited.

Drugs that Cause Bradycardia

Potential additive effects on bradycardia; closely monitor patients receiving concomitant therapy. Dosage adjustment of concomitant drug may be necessary.

Drugs that Prolong the QT Interval

Potential additive effects on QT-interval prolongation. Use concomitantly with caution; monitor for QT-interval prolongation. Monitor patients receiving extended-release IM pasireotide pamoate for QT-interval prolongation at the time of maximum drug concentration (21 days after injection).

Specific Drugs

Pasireotide Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration, rapidly absorbed; peak plasma concentrations achieved within 0.25–0.5 hours.

Following IM injection of long-acting suspension, drug is released slowly and gradually from its polymer vehicle (after an initial, rapid absorption of immediately available drug).

Peak plasma concentrations usually attained around day 21 following IM injection of long-acting suspension.

Duration

Following IM injection of long-acting suspension, steady-state plasma concentrations achieved after 3 monthly doses.

Special Populations

Moderate or severe hepatic impairment (Child-Pugh class B or C) increases exposure by 56 or 42%, respectively; peak concentrations increase by 46 or 33%, respectively. Mild hepatic impairment does not substantially affect exposure.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 88%.

Elimination

Metabolism

Not appreciably metabolized; detected mostly as unchanged drug in plasma, urine, and feces.

Elimination Route

Elimination occurs principally via hepatic clearance, with minor renal contribution.

Half-life

Effective half-life: Approximately 12 hours in healthy individuals following sub-Q administration.

Stability

Storage

Parenteral

Injection, for Sub-Q Use

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

Long-acting Injectable Suspension, for IM Use

2–8°C. May store at 25°C for up to 24 hours.

Must allow to reach room temperature before administration. If not used immediately after mixing, discard drug.

Actions

• Synthetic polypeptide pharmacologically related to natural endocrine hormone somatostatin.

• Binds to and activates somatostatin receptors in the anterior pituitary, resulting in inhibition of ACTH secretion and decreased cortisol secretion from adrenal glands.

• Binds preferentially to somatostatin receptor subtypes 1, 2, 3, and 5 with greatest affinity for receptor subtype 5 (frequently overexpressed in corticotroph tumor cells from patients with Cushing's disease).

• In acromegaly, binds to somatostatin receptor subtypes 2 and 5, which may be relevant for inhibition of GH secretion. In vivo studies demonstrate that pasireotide lowers GH and IGF-1 concentrations in patients with acromegaly.

• Differs from other currently available somatostatin analogs (lanreotide, octreotide) in its distinct somatostatin receptor-binding profile.

Advice to Patients

• Advise patients to review the manufacturer's medication guide and instructions for use for pasireotide diaspartate; instruct patients on proper injection technique and disposal of unused medication.

• Risk of hypocortisolism; importance of patients contacting clinician immediately if weakness, fatigue, loss of appetite, nausea, vomiting, hypotension, hyponatremia, or hypoglycemia occurs.

• Risk of hyperglycemia and diabetes mellitus; importance of monitoring for excessive thirst, increased appetite with weight loss, high urine output, or fatigue. Importance of close monitoring of blood glucose concentrations prior to and during therapy.

• Risk of bradycardia and QT-interval prolongation; advise patients that an electrocardiogram (ECG) will be taken before treatment and periodically thereafter. Importance of advising patients with cardiac disease and with risk factors for QT-interval prolongation and bradycardia that adjustments in cardiac medications may be made and electrolyte disturbances may require correction. Importance of patients contacting a clinician immediately if abnormal heart beats, dizziness, or fainting occurs.

• Risk of liver enzyme elevations; importance of monitoring liver function tests prior to and during therapy.

• Risk of cholelithiasis; importance of gallbladder ultrasound prior to and periodic monitoring during therapy.

• Risk of pituitary hormone deficiency; importance of monitoring pituitary function prior to and periodically during therapy.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of informing premenopausal women that pasireotide therapy may improve fertility and increase the possibility of unplanned pregnancy. Importance of clinicians talking to patients about effective birth control methods.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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