Egrifta

Tesamorelin injection is used to decrease the amount of extra fat in the stomach area in adults with human immunodeficiency virus (HIV) who have lipodystrophy (increased body fat in certain areas of the body). Tesamorelin injection is not used to help with weight loss. Tesamorelin injection is in a class of medications called human growth hormone-releasing factor (GRF) analogs. It works by increasing the production of a certain natural substance that can decrease the amount of body fat.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Contraindications

Hypersensitivity to tesamorelin or mannitol

Disruption of HP axis caused by hypophysectomy, hypopituitarism, pituitary tumor/surgery, head irradiation, or head trauma

Active malignancy

Pregnancy

Cautions

Caution with history of nonmalignant neoplasms; preexisting malignancy should be inactive and treatment complete prior to initiating therapy

If hypersensitivity suspected, discontinue and provide immediate medical attention

Consider discontinuing with persistent elevations of IGF-I levels (eg, >3 SDS), particularly if efficacy response is not robust

Fluid retention may occur and may include edema, arthralgia, and carpal tunnel syndrome

Increased mortality with acute critical illness due to complications following open heart surgery, abdominal surgery, multiple accidental trauma, or acute respiratory failure following treatment with pharmacologic amounts of growth hormone

May modulate CYP450-mediated antipyrine clearance

Not for use in children when epiphyses open because may cause excessive growth

Inhibits 11-beta-hydroxysteroid dehydrogenase type-1, a microsomal enzyme required for conversion of cortisone and prednisone to their active metabolites

Injections site reactions including irritation, erythema, pain, and bruising may occur; rotate site of injection to different areas of abdomen to reduce incidence of injection site reactions

May increase risk of development of diabetes due to glucose intolerance; evaluate glucose status prior to and during therapy

Not indicated for weight loss management

Egrifta is a prescription medication used to reduce excess abdominal fat in HIV-infected patients with lipodystrophy.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Egrifta is part of the drug class:

• Somatropin and somatropin agonists

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• steroids such as prednisone (Cortan, Deltasone, Orasone, Sterapred), budesonide (Entocort), dexamethasone (Decadron), triamcinolone (Kenacort, Aristocort), flunisolide (AeroBid. Aerospan), ciclesonide (Alvesco), mometasone (Asmanex, Dulera), fluticasone (Flovent), methylprednisolone (Medrol, Solu-Medrol), fludrocortisone (Florinef), and hydrocortisone (Cortef, Cortril, Hydrocortone)
• ritonavir (Norvir)

This is not a complete list of Egrifta drug interactions. Ask your doctor or pharmacist for more information.

Before taking Egrifta, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Egrifta or to any of its ingredients
• have or have had cancer
• have diabetes
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed
• have kidney or liver problems
• have any other medical condition

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

The recommended dose of Egrifta is 2 mg injected directly under the skin (subcutaneously) once a day.

Tesamorelin is made with growth hormone-releasing factor (GRF).

Tesamorelin is used to reduce excess fat around the stomach that is caused by taking certain HIV medications. This condition is also called lipodystrophy (LYE-poe-DIS-troe-fee).

Tesamorelin is not a weight-loss medication and should not be used to treat obesity.

Do not inject this medicine into scar tissue or on skin that is bruised. Do not inject directly into your navel (belly-button).

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

• 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.)

A nurse or other trained health professional will give you this medicine. You may also be taught how to give your medicine at home. This medicine is given as a shot under your skin, usually in the abdomen or stomach. Do not inject the medicine into a bruise, scar tissue, or the navel.

Tesamorelin injection comes with a patient instructions. Read the instructions and make sure you understand:

• How to prepare the injection.
• Proper use of disposable syringes.
• How to give the injection.
• How long the injection is stable.

If you have any questions about any of this, check with your doctor.

You will be shown the body areas where this shot can be given. Use a different body area each time you give yourself a shot. Keep track of where you give each shot to make sure you rotate body areas. This will help prevent skin problems from the injections.

Use a new needle and syringe each time you inject your medicine.

You might not use all of the medicine in each vial (glass container). Use each vial only one time. Do not save an open vial. If the medicine in the vial has changed color, or if you see particles in it, do not use it.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For injection dosage form:
  • For HIV-infected lipodystrophy:
    • Adults—2 milligrams (mg) injected under your skin once a day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medication box of Egrifta™ vials in the refrigerator. Protect the medicine from direct light. Do not freeze. You must store the box of sterile water for injection, syringes, and needles at room temperature.

Use the mixed solution right away and throw any unused solution or mixture.

Throw away used needles and syringes in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

• It is used to lower belly fat in patients with HIV.

Egrifta® (tesamorelin for injection) is indicated for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy [see Clinical Studies (14)].

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®.

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.

Reconstitution Procedure

Detailed instructions for reconstituting Egrifta® are provided in the INSTRUCTIONS FOR USE leaflet enclosed in the boxes containing Egrifta® and diluent.

Two vials of 1 mg of Egrifta® must be reconstituted with the diluent provided with the product.

Reconstitute the first 1 mg vial of Egrifta® with 2.2 mL of diluent. Mix by rolling the vial gently in your hands for 30 seconds. Do not shake. Reconstitute the second 1 mg vial of Egrifta® with the entire solution from the first vial. Mix by rolling the vial gently in your hands for 30 seconds. Do not shake.

Administer Egrifta® immediately following reconstitution and throw away any unused Egrifta® solution. If not used immediately, the reconstituted Egrifta® solution should be discarded. Do not freeze or refrigerate the reconstituted Egrifta® solution.

Administration

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.

The most commonly reported adverse reactions are hypersensitivity (e.g., rash, urticaria) reactions due to the effect of GH (e.g., arthralgia, extremity pain, peripheral edema, hyperglycemia, carpal tunnel syndrome), injection site reactions (injection site erythema, pruritus, pain, urticaria, irritation, swelling, hemorrhage).

During the first 26 weeks of treatment (main phase), discontinuations as a result of adverse reactions occurred in 9.6% of patients receiving Egrifta® and 6.8% of patients receiving placebo. Apart from patients with hypersensitivity reactions identified during the studies and who were discontinued per protocol (2.2%), the most common reasons for discontinuation of Egrifta® treatment were adverse reactions due to the effect of GH (4.2%) and local injection site reactions (4.6%).

During the following 26 weeks of treatment (extension phase), discontinuations as a result of adverse events occurred in 2.4% of patients in the T-T group (patients treated with tesamorelin for Week 0-26 and with tesamorelin for Week 26-52) and 5.2% of patients in the T-P group (patients treated with tesamorelin for Week 0-26 and with placebo for Week 26-52).

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Seven hundred and forty HIV-infected patients with lipodystrophy and excess abdominal fat were exposed to Egrifta® in the Phase 3 clinical trials; of these 543 received Egrifta® during the initial 26-week placebo-controlled phase [see Clinical Studies (14)].

Adverse reactions that occurred more frequently with Egrifta® relative to placebo and had an incidence ≥1% during the first 26 weeks across all studies are presented in Table 1.

Mean levels of fasting blood glucose and fasting insulin were not significantly different between Egrifta® -treated and placebo-treated patients after 26 weeks of treatment.

In the Egrifta® Phase 3 clinical trials, mean baseline (Week 0) HbA1c was 5.26% among patients in the Egrifta® group and 5.28% among those in the placebo group. At Week 26, mean HbA1c was higher among patients treated with Egrifta® compared with placebo (5.39% vs. 5.28% for the Egrifta® and placebo groups, respectively, mean treatment difference of 0.12%, p=0.0004). Patients receiving Egrifta® had an increased risk of developing diabetes (HbA1c level ≥ 6.5%) compared with placebo (4.5% vs. 1.3%), with a hazard ratio of 3.3 (CI 1.4, 9.6).

Adverse reactions observed during Week 26 to 52 of the Phase 3 clinical trials which had an incidence of ≥1% and were seen more frequently with Egrifta® relative to placebo are presented in Table 2:

Immunogenicity

As with all therapeutic proteins and peptides, there is a potential for in vivo development of anti- Egrifta® antibodies. In the combined Phase 3 clinical trials anti-tesamorelin IgG antibodies were detected in 49.5% of patients treated with Egrifta® for 26 weeks and 47.4% of patients who received Egrifta® for 52 weeks. In the subset of patients with hypersensitivity reactions, anti-tesamorelin IgG antibodies were detected in 85.2%. Cross-reactivity to endogenous growth hormone-releasing hormone (GHRH) was observed in approximately 60% of patients who developed anti-tesamorelin antibodies. Patients with and without anti-tesamorelin IgG antibodies had similar mean reductions in visceral adipose tissue (VAT) and IGF-1 response suggesting that the presence of antibodies did not alter the efficacy of Egrifta®. In a group of patients who had antibodies to tesamorelin after 26 weeks of treatment (56%) and were re-assessed 6 months later, after stopping Egrifta® treatment, 18% were still antibody positive.

Neutralizing antibodies to tesamorelin and hGHRH were detected in vitro at Week 52 in 10% and 5% of Egrifta®-treated patients, respectively. They did not appear to have an impact on efficacy, as evidenced by comparable changes in VAT and IGF-1 level in patients with or without in vitro neutralizing antibodies.

The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, methodology, sample handling, timing of sample collection, concomitant medication and underlying disease. For these reasons, comparison of the incidence of antibodies to Egrifta® with the incidence of antibodies to other products may be misleading.

Cytochrome P450-Metabolized Drugs

Co-administration of Egrifta® with simvastatin, a sensitive CYP3A substrate, showed that Egrifta® had no significant impact on the pharmacokinetics profiles of simvastatin in healthy subjects. This result suggests that Egrifta® may not significantly affect CYP3A activity. Other isoenzymes of CYP450 have not been evaluated with Egrifta®. Published data, however, indicate that GH may modulate cytochrome P450 (CYP450) mediated antipyrine clearance in man. These data suggest that GH may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Because tesamorelin stimulates GH production, careful monitoring is advisable when Egrifta® is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes [see Clinical Pharmacology (12.3)].

11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)

GH is known to inhibit 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1), a microsomal enzyme required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Because tesamorelin stimulates GH production, patients receiving glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses following initiation of Egrifta®, particularly in patients treated with cortisone acetate and prednisone because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.

Applies to tesamorelin: subcutaneous powder for solution

Along with its needed effects, tesamorelin (the active ingredient contained in Egrifta) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking tesamorelin:

• Difficulty with moving
• muscle pain or stiffness
• pain in the arms or legs
• pain in the joints

• Blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• burning, numbness, pain, or tingling in all fingers except the smallest finger
• chest pain
• dizziness
• fast, irregular, pounding, or racing heartbeat or pulse
• headache
• nervousness
• pounding in the ears
• slow or fast heartbeat
• swelling of the joints
• unsteadiness or awkwardness
• weakness in the arms, hands, legs, or feet

Some side effects of tesamorelin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at injection site
• muscle aching or cramping

• Acid or sour stomach
• belching
• bone pain
• discouragement
• feeling of warmth
• feeling sad or empty
• heartburn
• indigestion
• irritability
• itching skin
• lack of appetite
• loss of interest or pleasure
• muscle spasms
• nausea
• night sweats
• rash
• redness of the face, neck, arms, and occasionally, upper chest
• sleeplessness
• stiffness of the joints
• stomach discomfort, upset, or pain
• strain in the muscles
• sudden sweating
• tiredness
• trouble concentrating
• trouble sleeping
• unable to sleep
• upper abdominal or stomach pain
• vomiting

There are no data on the excretion of tesamorelin into human milk. HIV infected mothers should not feed human milk to avoid potential postnatal transmission of HIV.