Tesamorelin

Tesamorelin
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Overview

Tesamorelin is a Growth hormone secretagogues that is FDA approved for the treatment of reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Common adverse reactions include arthralgia, injection site erythema, injection site pruritis, pain in extremity, peripheral edema, myalgia..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• EGRIFTA® (tesamorelin for injection) is indicated for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy.

Limitations of Use:

• Since the long-term cardiovascular safety and potential long-term cardiovascular benefit of EGRIFTA® treatment have not been studied and are not known, careful consideration should be given whether to continue EGRIFTA® treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue measured by waist circumference or CT scan.

• EGRIFTA® is not indicated for weight loss management (weight neutral effect).

• There are no data to support improved compliance with anti-retroviral therapies in HIV-positive patients taking EGRIFTA®.

Dosage

General Dosing Information

• The recommended dose of EGRIFTA® is 2 mg injected subcutaneously once a day.

• The recommended injection site is the abdomen. Injection sites should be rotated to different areas of the abdomen. Do not inject into scar tissue, bruises or the navel.

DOSAGE FORMS AND STRENGTHS

• EGRIFTA® (tesamorelin for injection) is supplied in a vial containing 2 mg of tesamorelin as a lyophilized powder. The diluent (Sterile Water for Injection, USP 10 mL) is provided in a separate bottle.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tesamorelin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tesamorelin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Tesamorelin in pediatric patients.

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Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tesamorelin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tesamorelin in pediatric patients.

Contraindications

Disruption of the Hypothalamic-pituitary Axis

• EGRIFTA® is contraindicated in patients with disruption of the hypothalamic-pituitary axis due to hypophysectomy, hypopituitarism, pituitary tumor/surgery, head irradiation or head trauma.

Active Malignancy

• EGRIFTA® is contraindicated in patients with active malignancy (either newly diagnosed or recurrent). Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with EGRIFTA®.

Hypersensitivity

• EGRIFTA® is contraindicated in patients with known hypersensitivity to tesamorelin and/or mannitol (an excipient).

Pregnancy

• EGRIFTA® is contraindicated in pregnant women. During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying this physiologic change of pregnancy with EGRIFTA® offers no known benefit and could result in fetal harm. Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephalus in offspring at a dose approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue EGRIFTA® therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Warnings

There is limited information regarding Tesamorelin Warnings' in the drug label.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Tesamorelin in the drug label.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Tesamorelin in the drug label.

Drug Interactions

There is limited information regarding Tesamorelin Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tesamorelin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Tesamorelin during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Tesamorelin with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Tesamorelin with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Tesamorelin with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Tesamorelin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Tesamorelin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Tesamorelin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Tesamorelin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Tesamorelin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Tesamorelin in patients who are immunocompromised.

Administration and Monitoring

Administration

• Intravenous

• Reconstituted EGRIFTA® solution should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. EGRIFTA® must be injected only if the solution is clear, colorless and without particulate matter.

• EGRIFTA® should be injected subcutaneously into the skin on the abdomen. Injection sites should be rotated to different areas of the abdomen. Do not inject into scar tissue, bruises or the navel.

Monitoring

There is limited information regarding Monitoring of Tesamorelin in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Tesamorelin in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Tesamorelin in the drug label.

Pharmacology

Mechanism of Action

• In vitro, tesamorelin binds and stimulates human GRF receptors with similar potency as the endogenous GRF.

• Growth Hormone-Releasing Factor (GRF), also known as growth hormone-releasing hormone (GHRH), is a hypothalamic peptide that acts on the pituitary somatotroph cells to stimulate the synthesis and pulsatile release of endogenous growth hormone (GH), which is both anabolic and lipolytic. GH exerts its effects by interacting with specific receptors on a variety of target cells, including chondrocytes, osteoblasts, myocytes, hepatocytes, and adipocytes, resulting in a host of pharmacodynamic effects. Some, but not all these effects, are primarily mediated by IGF-1 produced in the liver and in peripheral tissues.

Structure

There is limited information regarding Tesamorelin Structure in the drug label.

Pharmacodynamics

Effects on IGF-1 and IGFBP-3 levels

• Tesamorelin stimulates growth hormone secretion, and subsequently increases IGF-1 and IGFBP-3 levels.

Other Pituitary Hormones

• No clinically significant changes in the levels of other pituitary hormones, including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH) and prolactin, were observed in subjects receiving EGRIFTA® in Phase 3 clinical trials.

Pharmacokinetics

Absorption

• The absolute bioavailability of EGRIFTA® after subcutaneous administration of a 2 mg dose was determined to be less than 4% in healthy adult subjects. Single and multiple dose pharmacokinetics of EGRIFTA® have been characterized in healthy subjects and HIV-infected patients without lipodystrophy following 2 mg subcutaneous administration.

• The mean values [coefficient of variation (CV)] of the extent of absorption (AUC) for tesamorelin were 634.6 (72.4) and 852.8 (91.9) pg.h/mL in healthy subjects and HIV-infected patients, respectively, after a single subcutaneous administration of a 2 mg EGRIFTA® dose. The mean (CV) peak tesamorelin concentration (Cmax) values were 2874.6 (43.9) pg/mL in healthy subjects and 2822.3 (48.9) pg/mL in HIV-infected patients. The median peak plasma tesamorelin concentration (Tmax) was 0.15 h in both populations.

Distribution

• The mean volume of distribution (±SD) of tesamorelin following a single subcutaneous administration was 9.4±3.1 L/kg in healthy subjects and 10.5±6.1 L/kg in HIV-infected patients.

Metabolism

• No formal metabolism studies have been performed in humans.

Elimination

• Mean elimination half-life (T1/2) of tesamorelin was 26 and 38 minutes in healthy subjects and HIV-infected patients, respectively, after subcutaneous administration for 14 consecutive days.

Drug Interactions

Simvastatin

• The effect of multiple dose administration of EGRIFTA® (2 mg) on the pharmacokinetics of simvastatin and simvastatin acid was evaluated in healthy subjects. Co-administration of EGRIFTA® and simvastatin (a sensitive CYP3A substrate) resulted in 8% decrease in extent of absorption (AUCinf) and 5% increase in rate of absorption (Cmax) of simvastatin. For simvastatin acid there was a 15% decrease in AUCinf and 1% decrease in Cmax.

Ritonavir

• The effect of multiple dose administration of EGRIFTA® (2 mg) on the pharmacokinetics of ritonavir was evaluated in healthy subjects. Co-administration of EGRIFTA® with ritonavir resulted in 9% decrease in AUCinf and 11% decrease in Cmax of ritonavir.

Specific Populations

• Pharmacokinetics of tesamorelin in patients with renal or hepatic impairment, in pediatric patients, or in elderly patients has not been established.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Life-time carcinogenicity studies in rodents have not been conducted with tesamorelin acetate. No potential mutagenicity of tesamorelin acetate was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (hamster CHOK1 cells), and chromosomal damage in intact animals (bone marrow cells in mice). There was no effect on fertility in male or female rats following administration of tesamorelin acetate at doses up to 0.6 mg/kg (approximately equal to clinical exposure) for 28 days in males or 14 days in females. In the 26-week toxicity study in rats, females given approximately 16 and 25 times the clinical dose were more likely to be in diestrus.

Clinical Studies

• Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in HIV-infected patients with lipodystrophy and excess abdominal fat (abdominal lipohypertrophy). Both studies (Study 1 and 2) consisted of a 26-week Main Phase and a 26-week Extension Phase. Main inclusion criteria were age 18-65 years, a waist circumference ≥95 cm (37.4 inches) and a waist-to-hip ratio ≥0.94 for men and ≥94 cm (37.0 inches) and ≥0.88 for women, respectively, and fasting blood glucose (FBG) <150 mg/dL (8.33 mmol/L). Main exclusion criteria included BMI ≤ 20 kg/m2, type 1 diabetes, type 2 diabetes, if previously treated with insulin or with oral hypoglycemic or insulin-sensitizing agents, history of malignancy, and hypopituitarism. Patients were on a stable anti-retroviral regimen for at least 8 weeks prior to randomization. Patients meeting the inclusion/exclusion criteria were randomized in a 2:1 ratio to receive 2 mg EGRIFTA® or placebo subcutaneously daily for 26 weeks. The primary efficacy assessment for each of these studies was the percent change from baseline to Week 26 (Main Phase) in visceral adipose tissue (VAT), as assessed by computed tomography (CT) scan at L4-L5 vertebral level. Secondary endpoints included changes from baseline in patient-reported outcomes related to body image, triglycerides, ratio of total cholesterol to HDL cholesterol, IGF-1 levels, and safety parameters. Other endpoints included changes from baseline in waist circumference, abdominal subcutaneous tissue (SAT), trunk fat, and lean body mass. In both studies, EGRIFTA®-treated patients completing the 26-week treatment period were re-randomized to blinded therapy with either daily placebo or 2 mg EGRIFTA® for an additional 26-week treatment period (Extension Phase) in order to assess maintenance of VAT reduction and to gather long-term safety data. For inclusion in the Extension Phase studies, subjects must have completed the Main Phase with FBG ≤ 150 mg/dL.

Main Phase (Baseline to Week 26):

Study 1

• This study randomized 412 HIV-infected patients with lipodystrophy and excess abdominal fat to receive either EGRIFTA® (N=273) or placebo (N=137). At baseline for the two groups combined, mean age was 48 years; 86% were male; 75% were white, 14% were Black/African American, and 8% were Hispanic; mean weight was 90 kg; mean BMI was 29 kg/m2; mean waist circumference was 104 cm; mean hip circumference was 100 cm; mean VAT was 176 cm2; mean CD4 cell count was 606 cells/mm3; 69% had undetectable viral load (<50 copies/mL); and 33.7% randomized to EGRIFTA® and 36.6% randomized to placebo had impaired glucose tolerance, while 5.6% randomized to EGRIFTA® and 6.7% randomized to placebo had diet-controlled diabetes mellitus. The twenty-six week completion rate in Study 1 was 80%.

Study 2

• This study randomized 404 HIV-infected patients with lipodystrophy and excess abdominal fat to receive either EGRIFTA® (N=270) or placebo (N=126). At baseline for the two groups combined, mean age was 48 years; 84% were male; 77% were white, 12% were Black/African American, and 9% were Hispanic; mean weight was 88 kg; mean BMI was 29 kg/m2; mean waist circumference was 105 cm; mean hip circumference was 100 cm; mean VAT was 189 cm2; mean CD4 cell count was 592 cells/mm3; 83% had undetectable viral load (<50 copies/mL); and 44.1% randomized to EGRIFTA® and 39.7% randomized to placebo had impaired glucose tolerance, while 9.3% randomized to EGRIFTA® and 9.5% randomized to placebo had diet-controlled diabetes mellitus. The twenty-six week completion rate in Study 2 was 74%.

• Results for the Main Phases of Studies 1 and 2 are presented in Tables 3 and 4.

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• A subgroup analysis by gender showed that there were no statistical differences in the percent change from baseline in visceral adipose tissue (VAT) and IGF-1 responses, respectively, between males and females.

• At Week 26, treatment with EGRIFTA® resulted in a reduction from baseline in mean trunk fat of 1.0 kg in Study 1 and 0.8 kg in Study 2, respectively (compared with an increase of 0.4 kg in Study 1 and of 0.2 kg in Study 2, respectively, in patients receiving placebo). Treatment with EGRIFTA® resulted in an increase from baseline in mean lean body mass of 1.3 kg in Study 1 and of 1.2 kg in Study 2, respectively (compared with a decrease of 0.2 kg in Study 1 and of 0.03 kg in Study 2, respectively, in patients receiving placebo).

• On average, there were no adverse effects of EGRIFTA® on lipids or subcutaneous adipose tissue (SAT). EGRIFTA® did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).

Patient Reported Outcomes

• Patients rated the degree of distress associated with their belly appearance on a 9-point rating scale that was then transformed to a score from 0 (extremely upsetting and distressing) to 100 (extremely encouraging). A score of 50 indicated neutral (no feeling either way). A positive change from baseline score indicated improvement, i.e., less distress.

• The cumulative distribution of response (change from baseline to 26 weeks) is shown in Figure 1 for both treatment groups. A curve shifted to the right on this scale indicates a greater percentage of patients reporting improvement.

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Extension Phase (Weeks 26-52):

• In the double-blind Extension Phase, patients on EGRIFTA® completing the 26-week Main Phase were re-randomized to receive 2 mg EGRIFTA® or placebo.

Study 1

• This study re-randomized 207 HIV-infected patients with lipodystrophy who completed EGRIFTA® treatment in the Main Phase to receive either EGRIFTA® (N=154) or placebo (N=50) for an additional 26-week duration (3:1 randomization ratio). At baseline (Week 26) for the two groups combined, mean age was 48 years; 88% were male; 78% were white, 12% were Black/African American, and 8% were Hispanic; mean weight was 90 kg; mean BMI was 29 kg/m2; mean waist circumference was 102 cm; mean hip circumference was 100 cm; mean VAT was 145 cm2; mean CD4 cell count was 639 cells/mm3; 68% had undetectable viral load (<50 copies/mL); and for those EGRIFTA®-treated patients completing the 26-week treatment period that were re-randomized to EGRIFTA® (T-T group) or re-randomized to placebo, 36.6% and 32.0%, respectively, had impaired glucose tolerance, while 2.0% re-randomized to EGRIFTA® and 6.0% re-randomized to placebo had diet-controlled diabetes mellitus. The completion rate for patients randomized into the extension phase of Study 1 was 83%.

Study 2

• This study re-randomized 177 HIV-infected patients with lipodystrophy who completed EGRIFTA® treatment in the Main Phase to receive either EGRIFTA® (N=92) or placebo (N=85) for an additional 26-week duration (1:1 randomization ratio). At baseline (Week 26) for the two groups combined, mean age was 48 years; 90% were male; 84% were white, 9% were Black/African American, and 7% were Hispanic; mean weight was 89 kg; mean BMI was 28 kg/m2; mean waist circumference was 105 cm; mean hip circumference was 100 cm; mean VAT was 172 cm2; mean CD4 cell count was 579 cells/mm3; 82% had undetectable viral load (<50 copies/mL); and for those EGRIFTA®-treated patients completing the 26-week treatment period that were re-randomized to EGRIFTA® (T-T group) or re-randomized to placebo, 48.9% and 50.6%, respectively, had impaired glucose tolerance, while 4.3% re-randomized to EGRIFTA® and 12.9% re-randomized to placebo had diet-controlled diabetes mellitus. The completion rate for patients randomized into the extension phase of Study 2 was 81%.

• Results for the Extension Phases of Studies 1 and 2 are presented in Tables 5 and 6.

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• Data in Figure 2 are expressed as mean values. T-T (tesamorelin to tesamorelin) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to tesamorelin for Weeks 26-52. T-P (tesamorelin to placebo) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to placebo for Weeks 26-52. P-T (placebo to tesamorelin) refers to the group of patients who received placebo for Weeks 0-26 and were switched to tesamorelin (treated open label) for Weeks 26-52.

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This image is provided by the National Library of Medicine.

• Patients treated with EGRIFTA® for 52 weeks (T-T group) showed no change between Weeks 26 and 52 in mean trunk fat (increase of 0.1 kg in Study 1 and decrease of 0.5 kg in Study 2, respectively, compared with an increase of 1.4 kg in patients in the T-P group in Study 1 and an increase of 1.09 kg in Study 2, respectively) nor was there a change from Week 26 baseline in mean lean body mass (decrease of 0.1 kg in Study 1 and increase of 0.1 kg in Study 2, respectively, compared with a decrease of 1.8 kg in patients in the T-P group in Study 1 and a decrease of 1.7 kg in Study 2, respectively).

• There was no adverse effect of EGRIFTA® on lipids or subcutaneous adipose tissue (SAT). EGRIFTA® did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).

How Supplied

Storage

There is limited information regarding Tesamorelin Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Tesamorelin in the drug label.

Precautions with Alcohol

• Alcohol-Tesamorelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• EGRIFTA

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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