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Pegvisomant

Class: Somatotropin Antagonists
VA Class: HS701
Brands: Somavert

Introduction

Selective, competitive somatotropin receptor antagonist; biosynthetic analog of human growth hormone (somatotropin).1 3 5 6 7

Uses for Pegvisomant

Acromegaly

Treatment of acromegaly in patients who have had inadequate responses to or are not candidates for surgical resection, pituitary irradiation, and/or other medical therapies (e.g., bromocriptine mesylate, octreotide).1 3 4 4

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Improves certain manifestations of acromegaly (decreases in ring size and a composite measure of soft tissue swelling, arthralgia, headache, excessive perspiration, and fatigue).1 3 6

Pegvisomant Dosage and Administration

General

  • The goal of therapy in patients with acromegaly is to reduce serum insulin growth factor-I (IGF-I) concentrations to normal levels.1 3 4 Monitor serum IGF-I concentrations at least semiannually after such concentrations have normalized.1 10

Administration

Sub-Q Administration

Administer by sub-Q injection into the upper arm, upper thigh, abdomen, or buttocks.1 2

Reconstitution

Reconstitute by adding 1 mL of the manufacturer-supplied diluent (sterile water for injection) to a vial labeled as containing 10, 15, or 20 mg of pegvisomant protein to provide a solution containing 10, 15, or 20 mg/mL, respectively.1 2 Roll vial gently between the palms until powder is completely dissolved and a clear solution is attained;1 2 discard any unused diluent.2 10 Do not shake vial since denaturation of the protein may occur.1 2 10

Dosage

Dosage of pegvisomant is expressed in terms of pegvisomant protein.1 Each mg of pegvisomant protein contains approximately 1 unit of activity.1 10

Adults

Acromegaly
Sub-Q

Loading dose: 40 mg; administer under medical supervision.1 2 6 Subsequently, self-inject 10 mg once daily.1 2 6

Adjust dosage in 5-mg increments (or 5-mg decrements, if serum IGF-I concentrations are below normal) at intervals of no less than 4–6 weeks until the desired effect on serum IGF-I concentrations is observed or a maximum dosage of 30 mg daily is reached.1 5 6

Not known if an increased dosage would be of benefit in patients who continue to have symptoms after achieving normal IGF-I levels.1

Prescribing Limits

Adults

Acromegaly
Sub-Q

Maximum daily dosage 30 mg.1 5 6

Special Populations

No special population recommendations at this time.1 10

Cautions for Pegvisomant

Contraindications

  • Known hypersensitivity to pegvisomant or any ingredient in the formulation.1 Vial stopper contains natural rubber latex,1 2 which may cause sensitivity reactions in susceptible individuals.8 9

Warnings/Precautions

General Precautions

Hepatic Effects

Elevations in serum aminotransferase (transaminase) concentrations (i.e., AST [SGOT], ALT [SGPT]) >3 times but not >10 times the ULN1 3 reported.1

Perform periodic liver function tests (i.e., serum aminotransferase, total bilirubin, and alkaline phosphatase concentrations) prior to and during therapy (i.e., monthly for first 6 months, every 3 months for the next 6 months, then every 6 months for the next year) in patients with normal liver function at baseline.1 In patients who develop certain abnormalities in liver function tests (elevations 3–5 times the ULN without signs or symptoms of hepatotoxicity or an increase in total bilirubin) during therapy, continue the drug with caution.1 Monitor liver function tests weekly, and perform a comprehensive hepatic examination to investigate possible alternative causes of liver dysfunction.1

If serum aminotransferase elevations ≥3 times the ULN occur in conjunction with any increase in total bilirubin concentration or if liver function test elevations of ≥5 times the ULN occur (with or without manifestations of hepatitis or liver injury), discontinue therapy immediately.1 In addition, undertake a thorough examination of hepatic function in such patients, including serial liver function tests to determine if and when liver dysfunction resolves.1 If liver function test results normalize, consider cautious reinitiation of pegvisomant therapy, with frequent monitoring of liver function tests.1

In patients who develop manifestations suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, upper right quadrant pain, ascites, unexplained edema, easy bruising), a comprehensive hepatic examination should be performed and the drug discontinued if liver injury is confirmed.1 2

For information about initiation of treatment in patients with hepatic impairment, see Hepatic Impairment under Cautions.

Tumor Growth

Progressive tumor growth occurred in 2 patients with underlying somatotropin-secreting pituitary tumors receiving pegvisomant in clinical trials.1 5

Carefully monitor patients who have pituitary growth hormone-secreting neoplasms with periodic imaging scans of the sella turcica.1 10

Endocrine and Metabolic Effects

Monitor patients with acromegaly and diabetes mellitus carefully for hypoglycemia and reduce dosage of insulin and/or antidiabetic drugs as necessary.1

Functional growth hormone deficiency may occur despite the presence of elevated serum growth hormone concentrations.1 Monitor patients for signs and symptoms of growth hormone deficiency.1 Adjust dosage using serum IGF-I concentrations to maintain such concentrations within the age-adjusted normal range.1

Specific Populations

Pregnancy

Category B.

Lactation

Not known whether pegvisomant is distributed in milk.1 Use with caution.1

Pediatric Use

Safety and efficacy not established in children.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently from younger adults.1

Hepatic Impairment

Use with caution in patients with preexisting mild hepatic impairment (elevations in serum aminotransferase, total bilirubin, or alkaline phosphatase concentrations not >3 times the ULN).1 Monitor liver function tests frequently (monthly for at least 1 year after initiation of therapy, then every 6 months for the next year) during therapy in such patients.1 Do not initiate therapy in patients with liver function test elevations >3 times the ULN until a comprehensive examination establishes the cause of liver dysfunction.1 Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs.1 10 If therapy is implemented in these patients, monitor liver function tests and clinical symptoms very closely.1 (See Hepatic Effects under Cautions.)

Common Adverse Effects

Abnormal liver function test results,1 accidental injury,1 5 back pain,1 5 chest pain,1 diarrhea,1 3 5 dizziness,1 flu syndrome,1 5 hypertension,1 infection, 1 5 injection site reaction,1 3 5 nausea,1 3 pain, 1 3 5 paresthesia,1 peripheral edema,1 sinusitis.1 5

Interactions for Pegvisomant

Specific Drugs or Laboratory Tests

Drug or Test

Interaction

Comments

Antidiabetic agents

Improved insulin sensitivity and glucose tolerance resulting from reduction in IGF-I concentrations1 6 10 11

Adjust dosage of concurrent antidiabetic therapy as necessary in patients with acromegaly and diabetes mellitus1 10

Opiate agonists

Decreased efficacy (higher serum concentrations of pegvisomant needed to produce appropriate suppression of IGF-I)1 10

Increased dosage of pegvisomant may be required1 10

Test, growth hormone concentrations

Pegvisomant cross-reacts with endogenous growth hormone, causing overestimation of endogenous growth hormone concentrations1 10

Even when accurately measured, growth hormone concentrations usually increase during pegvisomant therapy1 6 11

Monitor treatment and adjust dosage based on serum IGF-I concentrations1

Pegvisomant Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations usually attained 33–77 hours after administration.1 The relative bioavailability of a 20-mg sub-Q dose was 57% compared with a 10-mg IV dose.1

Onset

Reduction in serum IGF-I concentrations and increase in GH concentrations by week 2 of therapy.1

Duration

Serum GH concentrations remained stable during 18 months of therapy.1 5

Distribution

Extent

Mean apparent volume of distribution is 7L, suggesting that the drug does not distribute extensively into tissues.1

Elimination

Elimination Route

<1% of an administered dose is recovered in urine over 96 hours.1 Elimination route not determined in humans.1

Half-life

Mean serum half-life approximately 6 days.1

Stability

Storage

Parenteral

Powder for Sub-Q Injection

2–8°C; protect from freezing.1 Use within 6 hours following reconstitution.1

Actions

  • Binds to somatotropin receptors and competitively blocks binding of endogenous growth hormone, thereby interfering with signal transduction and the subsequent production of insulin-like growth factor I (IGF-I).1 3 6 7 IGF-I mediates most of the somatotropic effects of growth hormone.1 3 6 7

  • Produces a rapid decrease in serum IGF-I and other growth hormone-responsive serum proteins (e.g., IGF binding protein-3 [IGFBP-3], acid labile subunit of IGFBP-3) in patients with acromegaly.1 3 5 6

Advice to Patients

  • Importance of patients understanding instructions for proper storage, preparation, and injection technique.2

  • Importance of omitting missed dose and administering next dose at regularly scheduled time.2

  • Importance of monitoring for signs and symptoms of functional growth hormone deficiency.1 2 Importance of obtaining periodic determinations of serum insulin growth factor-I (IGF-I) concentrations in order to achieve and maintain therapeutic response.1 2

  • Importance of obtaining serial monitoring of liver function tests and of discontinuing therapy and reporting signs or symptoms of possible liver dysfunction (e.g., jaundice, dark urine, light stools, loss of appetite, nausea, fatigue, abdominal pain) to clinicians immediately.1 2

  • Importance of alerting clinician about allergy to latex.1 2

  • Importance of informing clinicians of concomitant conditions (e.g., diabetes mellitus, history of or current liver dysfunction) and existing or contemplated concomitant therapy, including prescription and OTC drugs (particularly insulin, other antidiabetic agents, or opiate agonists).1 2 10 (See Specific Drugs under Interactions.)

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing patients of other important precautionary information.1 (See Cautions).

Preparations

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

Pegvisomant

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for subcutaneous use

10 mg (as protein)

Somavert (with 10 mL sterile water for injection diluent; may contain natural latex components in packaging)

Pfizer

15 mg (as protein)

Somavert (with 10 mL sterile water for injection diluent; may contain natural latex components in packaging)

Pfizer

20 mg (as protein)

Somavert (with 10 mL sterile water for injection diluent; may contain natural latex components in packaging)

Pfizer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Somavert (pegvisomant) for injection prescribing information. Kalamazoo, MI; 2003 Jun.

2. Pfizer. Somavert (pegvisomant) for injection patient information. Kalamazoo, MI; 2003 Jun.

3. Trainer PJ, Drake WM, Katznelson L et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000; 342:1171-7. [IDIS 444363] [PubMed 10770982]

4. Utiger RD. Treatment of acromegaly. N Engl J Med. 2000; 342:1210-1. [IDIS 444364] [PubMed 10770989]

5. van der Lely AJ, Hutson RK, Trainer PJ et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001; 358:1754-9. [PubMed 11734231]

6. Pfizer. Somavert (pegvisomant) for injection general review. Kalamazoo, MI; 2003 Mar.

7. Friend KE. Cancer and the potential place for growth hormone receptor antagonist therapy. Growth Horm IGF Res. 2001; 11(Suppl A):S121-3.

8. Food and Drug Administration. Amended economic impact analysis of final rule requiring use of labeling on natural rubber containing devices; 21 CFR Part 801. Final rule. (Docket no. 96N-0119). Fed Regist. 1998; 63:50660-704.

9. Food and Drug Administration. Latex-containing devices; user labeling. 21 CFR Part 801. Proposed rule. (Docket No. 96N-0119). Fed Regist. 1996; 61:32617-21.

10. Pfizer, New York, NY: Personal communication.

11. Parkinson C, Drake WM, Roberts ME et al. A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal. J Endocrinol Metab. 2002; 87:1797-1804.

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