Egrifta

Generic Name: Tesamorelin Acetate
Class: Somatotropin Agonists
Molecular Formula: C221H366N72O67S•C2H4O2
CAS Number: 901758-09-6

Introduction

Synthetic analog of human growth hormone-releasing factor (GHRF, growth hormone-releasing hormone [GHRH]).1 2 3 4 5 6 7 12 18 19

Uses for Egrifta

HIV-associated Lipodystrophy

Reduction of excess abdominal fat in patients with HIV-associated lipodystrophy.1 2 3 4 6 9 17 Selectively reduces visceral adipose tissue, preserves subcutaneous fat, and improves body image.1 2 3 4 5 6 12 13

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Long-term cardiovascular benefits and safety not known; carefully consider whether to continue the drug in patients who fail to achieve a substantial clinical response (based on degree of visceral adipose tissue reduction as measured by waist circumference or computed tomography [CT] scan).1 17 19

Not indicated for weight loss management.1 5 9

Insufficient evidence to support improved compliance with antiretroviral therapies in HIV-infected patients.1 9 17

Egrifta Dosage and Administration

General

Restricted Distribution Program

Tesamorelin acetate is available in the US through a restricted distribution program.23 24 25 The drug can only be obtained through a targeted network of contracted pharmacies via the AXIS Center, a manufacturer-sponsored support service that facilitates access to therapy and provides reimbursement support and patient education.23 24 25 Contact AXIS at 877-714-2947or for further information.9 23 25

Administration

Sub-Q Administration

Administer sub-Q into the abdomen.1

Rotate injection sites daily (e.g., between left and right anterolateral or posterolateral abdominal wall).1 10

Do not inject into scarred, bruised, reddened, infected, or irritated sites; avoid the navel.1 9 10

Reconstitution

Reconstitute 2 vials each containing 1 mg of tesamorelin with a total of 2.2 mL of sterile water for injection (supplied by manufacturer) to provide a solution containing 1 mg/mL.1 10

Direct diluent toward sides of vials rather than directly onto powder to avoid foaming; roll each vial gently between the hands for 30 seconds to dissolve powder (do not shake).10

Combine reconstituted contents of both vials (total volume of approximately 2.2 mL) and administer immediately as a single sub-Q injection.10 Discard reconstituted vials if not used immediately; do not refrigerate or freeze.1

Consult manufacturer’s patient instructions for use for complete information on preparation, reconstitution, and administration of tesamorelin.1 10

Dosage

Available as tesamorelin acetate; dosage expressed in terms of tesamorelin.1

Adults

HIV-associated Lipodystrophy
Sub-Q

2 mg once daily.1

Data suggest that maintenance therapy is required to sustain the drug’s effects on visceral adipose tissue; optimal duration of therapy unknown.1 3 4 6 18 Safety and efficacy beyond 1 year not established.1 3 4

Special Populations

No special population dosage recommendations at this time.1

Cautions for Egrifta

Contraindications

  • Known hypersensitivity to tesamorelin acetate, mannitol, or any ingredient in the formulation.1 9

  • Pregnancy.1 9 (See Pregnancy and Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Patients with disruption of the hypothalamic-pituitary axis due to hypophysectomy, hypopituitarism, pituitary tumor/surgery, head irradiation, or head trauma.1 9

  • Active (newly diagnosed or recurrent) malignancy.1 9 (See Malignancy under Cautions.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; fetal anomalies (i.e., hydrocephaly, delayed skull ossification) demonstrated in rats.1

Contraindicated during pregnancy.1 If used during pregnancy or patient becomes pregnant, discontinue drug and apprise of potential fetal hazard.1 (See Pregnancy under Cautions.)

Malignancy

Possible risk of malignancies; do not use in patients with active malignancy (newly diagnosed or recurrent).1 Confirm that any preexisting malignancy is inactive and its treatment completed prior to initiating therapy.1

Initiate therapy in patients with a history of treated and stable malignancies only after careful consideration of the potential benefits versus risks of reactivation of the underlying malignancy.1

Initiate therapy in patients with a history of nonmalignant neoplasms after carefully considering potential benefits of therapy.1

Consider increased background risk of malignancies in HIV-positive patients before initiating therapy.1

Increased Insulin-like Growth Factor I (IGF-I) Concentrations

Tesamorelin increases serum concentrations of insulin-like growth factor I (IGF-I), which has an unknown effect on the development or progression of malignancies.1 3 5 7 11 19

Monitor IGF-I concentrations closely (e.g., every 3 months).1 11 Consider discontinuance of therapy in patients who experience persistent IGF-I elevations >3 standard deviations above mean value in a population of similar age and gender, particularly if a substantial response to therapy not achieved.1

Fluid Retention

Fluid retention (possibly related to excess growth hormone [GH] secretion) reported.1 Typically manifests as increased tissue turgor and musculoskeletal discomfort resulting in adverse effects such as edema, arthralgia, and carpal tunnel syndrome.1 2 3 4 5 6 Symptoms usually are transient and resolve with drug discontinuance.1

Glucose Intolerance

Risk of glucose intolerance and diabetes mellitus.1 6 17 18

Evaluate glucose status carefully prior to initiating therapy and periodically thereafter.1 6 18 Exercise caution in patients who develop glucose intolerance or diabetes mellitus; consider discontinuance of therapy in such patients who fail to demonstrate a clear response to therapy.1

Monitor patients with diabetes mellitus at regular intervals for potential development or worsening of retinopathy.1

Injection Site Reactions

Injection site reactions (e.g., erythema, pruritus, pain, irritation, bruising) reported frequently.1 2 3 4 6 17 19

Rotate injection sites daily to reduce incidence of such reactions.1

Critical Illness

Increased mortality reported in patients with acute critical illness resulting from complications following cardiac or abdominal surgery or multiple accidental trauma or from acute respiratory failure following pharmacologic dosages of GH.1 14

Consider discontinuance of therapy in patients with acute critical illness, since tesamorelin increases GH production.1

Sensitivity Reactions

Hypersensitivity Reactions

Risk of hypersensitivity reactions (e.g., pruritus, erythema, flushing, urticaria, rash).1 2 3 4 6 May occur after first dose or up to 26 weeks later.11

Symptoms generally resolve spontaneously with discontinuance of therapy or with administration of an antihistamine or topical corticosteroid.6 11

If a hypersensitivity reaction is suspected, patient should immediately discontinue drug and promptly seek medical attention.1 3 4 6

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.1 Possible development of antibodies to tesamorelin acetate.1 Presence of anti-tesamorelin IgG antibodies does not appear to affect clinical response.1 3 4 6

Specific Populations

Pregnancy

Category X.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Visceral adipose tissue increases during pregnancy as a result of normal metabolic and hormonal changes; modification of this process offers no known clinical benefit and may result in fetal harm.1 17

Lactation

Not known whether tesamorelin is distributed into milk.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1 9 Do not use in children with open epiphyses since increased GH and IGF-I concentrations may result in excessive linear growth.1

Geriatric Use

Information not available in patients ≥65 years of age with HIV-associated lipodystrophy.1

Hepatic Impairment

Safety and efficacy not established in patients with hepatic impairment.1

Renal Impairment

Safety and efficacy not established in patients with renal impairment.1

Common Adverse Effects

Arthralgia, injection site reactions (erythema, pruritus), extremity pain, peripheral edema, myalgia.1 2 3 4 6

Interactions for Egrifta

Drugs Metabolized by Hepatic Microsomal Enzymes

Not likely to substantially affect CYP3A activity.1 Effect on other CYP isoenzymes not evaluated.1

GH may alter clearance of drugs known to be metabolized by CYP isoenzymes; carefully monitor if used concomitantly with these drugs.1 15

Drugs Metabolized by 11β-Hydroxysteroid Dehydrogenase Type 1

GH inhibits 11β-hydroxysteroid dehydrogenase type 1, the enzyme required for conversion of cortisone to cortisol; therefore, patients receiving glucocorticoid replacement therapy for hypoadrenalism may require increase in maintenance glucocorticoid dosage or supplemental stress-related glucocorticoid doses following initiation of tesamorelin.1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)

Possible interference with clearance of anticonvulsants 1 22

Corticosteroids (e.g., cortisone acetate, prednisone)

Possible interference with clearance of corticosteroids1 22

Glucocorticoids: Possible decreased concentrations of the active glucocorticoid metabolite1

Glucocorticoids: Increased stress or maintenance dosages of the glucocorticoid may be required1

Cyclosporine

Possible interference with clearance of cyclosporine1 22

Ritonavir

Slight decreases in AUC and peak plasma concentrations of ritonavir1

Sex hormones (e.g., testosterone, estrogens [oral contraceptives])

Possible interference with clearance of sex hormones1 22

Simvastatin

Slight decrease in extent and slight increase in rate of simvastatin absorption1

Egrifta Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability <4% in healthy adults following sub-Q administration.1

Peak plasma concentrations achieved in approximately 0.15 hours.1

Distribution

Extent

Not known whether tesamorelin is distributed into milk.1

Elimination

Metabolism

No formal drug metabolism studies performed to date in humans.1

Half-life

Adults with HIV: Approximately 38 minutes.1

Healthy individuals: Approximately 26 minutes.1

Stability

Storage

Parenteral

Powder for Injection

2–8°C; protect from light.1 Store in original carton prior to use.1

Store diluent and other supplies at 20–25°C.1

Actions

  • Synthetic analog of human GHRF; stimulates synthesis and release of GH from pituitary somatotroph cells.1 2 3 4 5 6 7 12 18 19 Also increases production of IGF-I by the liver and peripheral tissues.1 2 4 7 11

  • GH (deficient in patients with HIV-associated lipodystrophy) produces anabolic and lipolytic effects by interacting with specific receptors on target cells (e.g., chondrocytes, osteoblasts, myocytes, hepatocytes, adipocytes).1 4 7 13 20 Some of these effects are mediated by IGF-I.1

  • Shown in vitro to bind to and stimulate GHRF receptors with similar potency to that of the native protein.1 11

  • Does not substantially affect other pituitary hormones (i.e., thyroid-stimulating hormone [TSH], luteinizing hormone [LH], adrenocorticotropic hormone [ACTH], prolactin).1

Advice to Patients

  • Risk of fluid retention; importance of advising patients of possible manifestations including edema, arthralgia, and carpal tunnel syndrome.1 9

  • Risk of hypersensitivity; importance of advising patients to immediately discontinue treatment and seek medical attention if a hypersensitivity reaction (e.g., rash, hives, swelling of the face or throat, breathing difficulties, fast heartbeat, feelings of faintness or fainting) occurs.1 9

  • Importance of advising patients of the possibility of injection site reactions (e.g., redness, itching, pain, irritation, bruising, bleeding, rash, swelling) and to rotate injection sites daily.1 9

  • Importance of not sharing syringes and needles used to administer the drug with other individuals since this may result in transmission of infectious diseases, including HIV infection.1 9

  • Importance of women informing clinicians if they are, or plan to become, pregnant or plan to breast-feed.1 9 Risk of fetal harm if administered to pregnant women; if pregnancy occurs during therapy, discontinue drug immediately and apprise patient of potential harm to the fetus.1 9 Importance of advising women to discontinue nursing because of the potential for HIV transmission and serious adverse effects in nursing infants.1 9

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illness (e.g., cancer, diabetes).1 9

  • Importance of informing patients of other important precautionary information.1 9 (See Cautions.)

Preparations

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

Tesamorelin Acetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for subcutaneous use

1 mg (of tesamorelin)

Egrifta (available with sterile water for injection diluent, syringes, and needles)

EMD Serono

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Egrifta 1MG Solution (SERONO): 1/$45.99 or 2/$80.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 27, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. EMD Serono. Egrifta (tesamorelin for injection) prescribing information. Rockland, MA; 2010 Nov.

2. Falutz J, Allas S, Blot K et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007; 357:2359-70. [PubMed 18057338]

3. Falutz J, Allas S, Mamputu JC et al. Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation. AIDS. 2008; 22:1719-28. [PubMed 18690162]

4. Falutz J, Potvin D, Mamputu JC et al. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension. J Acquir Immune Defic Syndr. 2010; 53:311-22. [PubMed 20101189]

5. Falutz J, Allas S, Kotler D et al. A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation. AIDS. 2005; 19:1279-87. [PubMed 16052083]

6. Falutz J, Mamputu JC, Potvin D et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. J Clin Endocrinol Metab. 2010; 95:4291-304. [PubMed 20554713]

7. Wang Y, Tomlinson B. Tesamorelin, a human growth hormone releasing factor analogue. Expert Opin Investig Drugs. 2009; 18:303-10. [PubMed 19243281]

8. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005; 352:48-62. [PubMed 15635112]

9. EMD Serono. Egrifta (tesamorelin for injection) patient information. Rockland, MA; 2010 Nov.

10. EMD Serono. Egrifta (tesamorelin for injection) patient instructions for use. Rockland, MA; 2010 Nov.

11. US Food and Drug Administration. Briefing document from the endocrinologic and metabolic drugs advisory committee. May 27, 2010. From FDA website .

12. Moyle G, Moutschen M, Martínez E et al. Epidemiology, assessment, and management of excess abdominal fat in persons with HIV infection. AIDS Rev. 2010 Jan-Mar; 12:3-14.

13. Koutkia P, Canavan B, Breu J et al. Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial. JAMA. 2004; 292:210-8. [PubMed 15249570]

14. Takala J, Ruokonen E, Webster NR et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999; 341:785-92. [PubMed 10477776]

15. Cheung NW, Liddle C, Coverdale S et al. Growth hormone treatment increases cytochrome P450-mediated antipyrine clearance in man. J Clin Endocrinol Metab. 1996; 81:1999-2001. [PubMed 8626872]

16. Malgarini RB, Pimpinella G. Effects of growth hormone-releasing factor in HIV-infected patients. N Engl J Med. 2008; 358:969; author reply 969-70.

17. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 22-505: Summary review for tesamorelin. From FDA website .

18. Leung VL, Glesby MJ. Pathogenesis and treatment of HIV lipohypertrophy. Curr Opin Infect Dis. 2011; 24:43-9. [PubMed 21124215]

19. Grunfeld C, Dritselis A, Kirkpatrick P. Tesamorelin. Nat Rev Drug Discov. 2011; 10:95-6. [PubMed 21283099]

20. EMD Serono, Rockland, MA: Personal communication.

21. Ferdinandi ES, Brazeau P, High K et al. Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic Clin Pharmacol Toxicol. 2007; 100:49-58. [PubMed 17214611]

22. Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy. 1998 Jan-Feb; 18:84-112.

23. EMD Serono. The AXIS Center. Available at: . Accessed 2011 Jun 17.

24. EMD Serono. Patient support with the AXIS center. Available at: . Accessed 2011 Jun 17.

25. Health Education Online, Inc. Tesamorelin (Egrifta) now available to manage HIV-related lipodystrophy. Available at: . Accessed 2011 Jun 20.

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