Tesamorelin Injection

Tesamorelin injection comes as a powder to be mixed with the liquid provided with your medication and injected subcutaneously (under the skin). It is usually injected once a day. Use tesamorelin injection at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use tesamorelin injection exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor.

Before you use tesamorelin injection for the first time, read the manufacturer's information for the patient that comes with the medication. Your medication comes in 2 boxes: one box with tesamorelin injection vials and another with vials containing liquid to mix with the medication, needles, and syringes. Ask your pharmacist or doctor to show you how to mix and inject the medication. Be sure to ask your pharmacist or doctor if you have any questions about how to inject this medication.

You should inject tesamorelin into the skin of your stomach area below the navel (belly button). Do not inject tesamorelin into the navel or into any scarred, reddened, irritated, infected, or bruised areas of skin. Do not inject tesamorelin into any areas with hard bumps from previous injections. Choose a different area for each injection to help prevent bruising and irritation. Keep track of the areas where you inject tesamorelin, and do not give an injection into the same spot two times in a row.

After mixing tesamorelin injection, use the medication right away. Do not store tesamorelin injection after mixing. Dispose of any used tesamorelin injection and any extra liquid used to mix the injection.

You should always look at tesamorelin injection solution (liquid) after mixing and before you inject it. The solution should be clear and colorless with no particles in it. Do not use tesamorelin injection solution if it is colored, cloudy, contains particles, or if the expiration date on the bottle has passed.

Never reuse syringes or needles, and never share needles with another person. Do not share syringes with another person even if the needle was changed. Sharing needles and syringes can cause the spread of certain diseases, such as HIV. If you accidently prick someone with a used needle, tell him to talk to his healthcare provider right away. Dispose of any remaining tesamorelin injection, extra liquid used to mix the injection, and used needles and syringes in a puncture-resistant container made of hard plastic or metal that has a lid. Never throw used needles or syringes into the trash. Ask your doctor or pharmacist how to dispose of the puncture-resistant container and all other used materials.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

Inject the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not inject a double dose to make up for a missed one.

Store the medication box containing the tesamorelin injection vials in the refrigerator. Do not freeze. Store the box containing the provided liquid, needles, and syringes at room temperature away from light, excess heat, and moisture (not in the bathroom). Keep each box tightly closed and out of reach of children.

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before and during your treatment to check your body's response to tesamorelin injection.

Do not let anyone else use your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• Egrifta^®

Included as part of the PRECAUTIONS section.

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.

Pharmacodynamics

Tesamorelin stimulates growth hormone secretion, and subsequently increases IGF-1 and IGFBP-3 levels [see Clinical Studies].

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

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 HTV-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 HTV-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 HTV-infected patients. The median peak plasma tesamorelin concentration (Tmax)was 0.15 h in both populations.

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 HTV-infected patients.

No formal metabolism studies have been performed in humans.

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

Drug Interactions

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 [see DRUG INTERACTIONS].

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 [see DRUG INTERACTIONS].

Specific Populations

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

Clinical Studies

Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in HTV-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.

This study randomized 412 HlV-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%.

This study randomized 404 HlV-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.

Table 3: Changes from Baseline to Week 26 in Visceral Adipose Tissue (cm2) by Treatment Group (Intent-To-Treat Population with Last Observation Carried Forward)

Table 4: Changes from Baseline to Week 26 in IGF-1, IGFBP-3, Weight, and Waist Circumference by Treatment Group (Intent-To-Treat Population with Last Observation Carried Forward)

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).

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.

Figure 1. Cumulative Distribution of Response for Belly Appearance Distress

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.

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%.

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.

Table 5: Changes from Week 26 Baseline to Week 52 in Visceral Adipose Tissue (cm2) by Treatment Group (Intent-To-Treat Population with Last Observation Carried Forward)

Figure 2. shows the percent change in VAT from baseline (Week 0) over time until 52 weeks in completer patients.

Figure 2. Percent Change from Baseline in VAT over Time

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.

Table 6: Changes from Week 26 Baseline to Week 52 in IGF-1, IGFBP-3, Weight, and Waist Circumference by Treatment Group (Intent-To-Treat Population with Last Observation Carried Forward)

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).

Your pharmacist can provide more information about tesamorelin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 1.01. Revision date: 6/14/2011.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.