Pasireotide (Monograph)

Brand name: Signifor
Drug class: Somatostatin Agonists
Chemical name: Cyclo[(2S)-2-phenylglycyl-d-tryptophyl-l-lysyl-O-(phenylmethyl)-l-tyrosyl-l-phenylalanyl-(4R)-4-[[[(2-aminoethyl)amino]carbonyl]oxy]-l-prolyl]
Molecular formula: C₅₈H₆₆N₁₀O₉
CAS number: 396091-73-9

Medically reviewed by Drugs.com on Nov 22, 2022. Written by ASHP.

Introduction

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

Uses for Pasireotide

Cushing's Disease

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.

Pasireotide Dosage and Administration

General

• Prior to initiating therapy, measure fasting plasma glucose and HbA_1c, and perform liver function tests, ECG, and gallbladder ultrasound to establish baseline values. Generally repeat these tests at periodic intervals during therapy to monitor for potentially serious adverse effects. (See Warnings/Precautions under Cautions.)

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

Administration

Sub-Q Administration

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

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

Dosage

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

Adults

Cushing's Disease

Sub-Q

Initially, 0.6 or 0.9 mg twice daily. Adjust subsequent dosage based on response (e.g., urinary free cortisol concentrations, symptoms) and tolerance. 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 dose is suggested.

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. Response usually evident by 2 months of therapy.

Special Populations

Hepatic Impairment

Sub-Q

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

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

Renal Impairment

Dosage adjustments not required.

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.

Cautions for Pasireotide

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Warnings

Hypocortisolism

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

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

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

Cardiovascular Effects

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

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. (See Drugs that Prolong the QT Interval under Interactions.)

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

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).

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.

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 or ULN, perform serial measurements of these tests at least weekly.

Biliary Effects

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

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

Pituitary Hormone Deficiency

Deficiencies of pituitary hormones other than ACTH (e.g., thyrotropin [thyroid-stimulation hormone; TSH], GH, insulin-like growth factor I [IGF-I]) 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.

Specific Populations

Pregnancy

Category C.

Lactation

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

Pediatric Use

Safety and efficacy not established.

Geriatric Use

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

Hepatic Impairment

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

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

Renal Impairment

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

Common Adverse Effects

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

Interactions for Pasireotide

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

Also not 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 Metabolized by Hepatic Microsomal Enzymes

CYP substrates: Potential pharmacokinetic interaction (decreased substrate clearance).

Drugs that Cause Bradycardia

Potential for additive 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.

Specific Drugs

Pasireotide Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed; peak plasma concentrations achieved within 0.25–0.5 hours.

Special Populations

Moderate or severe hepatic impairment (Child-Pugh class B or C) increases AUC by 56 or 42%, respectively. Mild hepatic impairment does not substantially affect AUC.

Distribution

Extent

Not known whether distributed into 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.

Stability

Storage

Parenteral

Injection, for Sub-Q Use

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

Actions

• Synthetic polypeptide pharmacologically related to natural endocrine hormone somatostatin.

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

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

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

Advice to Patients

• 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; importance of patients contacting 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 periodically during therapy.

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

• Importance of patients reviewing the manufacturer's medication guide; importance of clinicians instructing patients on proper injection technique and disposal of unused medication.

• 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 patients of other important precautionary information. (See Cautions.)

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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