Egrifta: Indications, Dosage, Precautions, Adverse Effects
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Egrifta - Product Information

Manufacture: EMD Serono, Inc
Country: United States
Condition: Lipodystrophy
Class: Metabolic agents
Form: Liquid solution, Subcutaneous (SC), Powder
Ingredients: tesamorelin, mannitol and sterile water for injection

Indications and Usage

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

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 and Administration

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

Egrifta must be reconstituted with the diluent provided with the product.

Reconstitute the 2 mg vial of Egrifta with 2.1 mL of diluent. Mix by rolling the vial gently in your hands for 30 seconds. Do not shake.

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

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.

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.

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) [see Warnings and Precautions].

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 [see Use in Specific Populations].

Warnings and Precautions

Neoplasms

Egrifta induces the release of endogenous growth hormone (GH), a known growth factor. Thus, patients with active malignancy should not be treated with Egrifta [see Contraindications].

For patients with a history of non- malignant neoplasms, Egrifta therapy should be initiated after careful evaluation of the potential benefit of treatment. For patients with a history of treated and stable malignancies, Egrifta therapy should be initiated only after careful evaluation of the potential benefit of treatment relative to the risk of re-activation of the underlying malignancy.

In addition, the decision to start treatment with Egrifta should be considered carefully based on the increased background risk of malignancies in HIV-positive patients.

Elevated IGF-1

Egrifta stimulates GH production and increases serum IGF-1. Given that IGF-1 is a growth factor and the effect of prolonged elevations in IGF- 1 levels on the development or progression of malignancies is unknown, IGF -1 levels should be monitored closely during Egrifta therapy. Careful consideration should be given to discontinuing Egrifta in patients with persistent elevations of IGF-1 levels (e.g., >3 SDS), particularly if the efficacy response is not robust (e.g., based on visceral adipose tissue changes measured by waist circumference or CT scan).

During the clinical trials, patients were monitored every three months. Among patients who received Egrifta for 26 weeks, 47.4% had IGF- 1 levels greater than 2 standard deviation scores (SDS), and 35.6% had SDS >3, with this effect seen as early as 13 weeks of treatment. Among those patients who remained on Egrifta for a total of 52 weeks, at the end of treatment 33.7% had IGF-1 SDS >2 and 22.6% had IGF-1 SDS >3.

Fluid Retention

Fluid retention may occur during Egrifta therapy and is thought to be related to the induction of GH secretion. It manifests as increased tissue turgor and musculoskeletal discomfort resulting in a variety of adverse reactions (e.g. edema, arthralgia, carpal tunnel syndrome) which are either transient or resolve with discontinuation of treatment.

Glucose Intolerance

Egrifta treatment may result in glucose intolerance. During the Phase 3 clinical trials, the percentages of patients with elevated HbA1c (≥ 6.5%) from baseline to Week 26 were 4.5% and 1.3% in the Egrifta and placebo groups, respectively. An increased risk of developing diabetes with Egrifta (HbA1c level ≥ 6.5%) relative to placebo was observed [intent-to-treat hazard odds ratio of 3.3 (CI 1.4, 9.6)]. Therefore, glucose status should be carefully evaluated prior to initiating Egrifta treatment. In addition, all patients treated with Egrifta should be monitored periodically for changes in glucose metabolism to diagnose those who develop impaired glucose tolerance or diabetes. Diabetes is a known cardiovascular risk factor and patients who develop glucose intolerance have an elevated risk for developing diabetes. Caution should be exercised in treating HIV-positive patients with lipodystrophy with Egrifta if they develop glucose intolerance or diabetes, and careful consideration should be given to discontinuing Egrifta treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue by waist circumference or CT scan measurements.

Since Egrifta increases IGF- 1, patients with diabetes who are receiving ongoing treatment with Egrifta should be monitored at regular intervals for potential development or worsening of retinopathy.

Hypersensitivity Reactions

Hypersensitivity reactions may occur in patients treated with Egrifta. Hypersensitivity reactions occurred in 3.6% of patients with HIV-associated lipodystrophy treated with Egrifta in the Phase 3 clinical trials. These reactions included pruritus, erythema, flushing, urticaria, and other rash. In cases of suspected hypersensitivity reactions, patients should be advised to seek prompt medical attention and treatment with Egrifta should be discontinued immediately.

Injection Site Reactions

Egrifta treatment may cause injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. The incidence of injection site reactions was 24.5% in Egrifta -treated patients and 14.4% in placebo-treated patients during the first 26 weeks of treatment in the Phase 3 clinical trials. For patients who continued Egrifta for an additional 26 weeks, the incidence of injection site reactions was 6.1%. In order to reduce the incidence of injection site reactions, it is recommended to rotate the site of injection to different areas of the abdomen.

Acute Critical Illness

Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of growth hormone. Egrifta has not been studied in patients with acute critical illness. Since Egrifta stimulates growth hormone production, careful consideration should be given to discontinuing Egrifta in critically ill patients.

Adverse Reactions

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, pruritis, 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].

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.

Table 1. Adverse Reactions Reported in ≥ 1% and More Frequent in Egrifta -treated than Placebo Patients during the 26-Week Main Phase (Combined Studies)
  Incidence of patients (%) with adverse drug reactions
System Organ Class
Preferred Term
EGRIFTA
(N=543)
Placebo
(N=263)
Musculoskeletal and connective tissue disorders
Arthralgia 13.3 11.0
Pain in extremity 6.1 4.6
Myalgia 5.5 1.9
Musculoskeletal pain 1.8 0.8
Musculoskeletal stiffness 1.7 0.4
Joint stiffness 1.5 0.8
Muscle spasms 1.1 0.8
Joint swelling 1.1 0.0
General disorders and adminis tration site conditions
Injection site erythema 8.5 2.7
Injection site pruritus 7.6 0.8
Edema peripheral 6.1 2.3
Injection site pain 4.1 3.0
Injection site irritation 2.9 1.1
Pain 1.7 1.1
Injection site hemorrhage 1.7 0.4
Injection site urticaria 1.7 0.4
Injection site swelling 1.5 0.4
Injection site reaction 1.3 0.8
Chest pain 1.1 0.8
Injection site rash 1.1 0.0
Nervous system disorders
Paresthesia 4.8 2.3
Hypoesthesia 4.2 1.5
Carpal tunnel syndrome 1.5 0.0
Gastrointestinal disorders
Nausea 4.4 3.8
Vomiting 2.6 0.0
Dyspepsia 1.7 0.8
Abdominal pain upper 1.1 0.8
Cardiac disorders
Palpitations 1.1 0.4
Psychiatric disorders
Depression 2.0 1.5
Skin and subcutaneous tissue disorders
Rash 3.7 1.5
Pruritus 2.4 1.1
Night sweats 1.1 0.4
Vas cular dis orders
Hypertension 1.3 0.8
Injury, poisoning and procedural complications
Muscle strain 1.1 0.0
Inves tigations
Blood creatine phosphokinase increased 1.5 0.4

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:

Table 2. Adverse Reactions Reported in ≥ 1% and More Frequent in Egrifta-treated than Placebo Patients during the 26-Week Extension Phase of the Combined Studies (Week 26 to Week 52 of the studies )
  Incidence of patients (%) with adverse drug reactions
System Organ Class Preferred Term T-T* (Week 26-52)
(N=246)
T-P (Week 26-52)
(N=135)
Musculoskeletal and connective tissue disorders
Pain in extremity 3.3 0.7
Myalgia 1.2 0.0
General disorders and adminis tration site conditions
Injection site pruritus 2.0 0.0
Edema peripheral 2.0 0.0
Injection site erythema 1.2 0.0
Nervous system disorders
Paresthesia 1.6 1.5
Hypoesthesia 1.6 0.7
Neuropathy peripheral 1.6 1.5
Gastrointestinal disorders
Vomiting 2.0 0.7
Psychiatric disorders
Depression 1.6 0.7
Insomnia 1.2 0.0
Skin and subcutaneous tissue disorders
Pruritus 1.2 0.7
Urticaria 1.2 0.0
Night sweats 1.2 0.0
Vascular disorders
Hypertension 1.6 1.5
Hot flush 1.2 0.7

* T-T = tesamorelin for Week 0-26 and tesamorelin for Week 26-52

T-P = tesamorelin for Week 0-26 and placebo for Week 26-52

For patients who continued from Week 26-52, mean levels of fasting blood glucose, fasting insulin, and HbA1c were not different between the T-T and T-P groups.

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.

Drug Interactions

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 ClinicalPharmacology].

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.

Use in Specific Populations

Pregnancy

Pregnancy Category X [see Contraindications].

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 hydrocephaly in offspring at a dose of 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.

Tesamorelin acetate administration to rats during organogenesis and lactation produced hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). Actual animal dose was 1.2 mg/kg. During organogenesis, lower doses approximately 0.1 to 1 times the clinical dose caused delayed skull ossification in rats. Actual animal doses were 0.1 to 0.6 mg/kg. No adverse developmental effects occurred in rabbits using doses up to approximately 500 times the clinical dose.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not human milk-feed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 infection transmission and serious adverse reactions in nursing infants, mothers receiving Egrifta should be instructed not to human milk-feed.

It is not known whether Egrifta is excreted in human milk. Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). Actual animal dose was 1.2 mg/kg.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Egrifta should not be used in children with open epiphyses, among whom excess GH and IGF-1 may result in linear growth acceleration and excessive growth.

Geriatric Use

There is no information on the use of Egrifta in patients greater than 65 years of age with HIV and lipodystrophy.

Renal and Hepatic Impairment

Safety, efficacy, and pharmacokinetics of Egrifta in patients with renal or hepatic impairment have not been established.

Overdosage

No data are available on overdosage.

How Supplied/storage and Handling

Egrifta (tesamorelin for injection) is supplied as a sterile, white to off-white lyophilized powder. Each single-use vial of Egrifta contains 2 mg of tesamorelin as the free base (2.2 mg tesamorelin acetate, anhydrous) and the following inactive ingredient: 100 mg mannitol, USP.

Egrifta is available in a package comprised of two boxes. One box contains 30 vials of Egrifta and a second box contains 30 single-use 10 mL bottles of reconstitution diluent (Sterile Water for Injection, USP), disposable syringes, and needles sufficient for a 30 day supply.

After reconstitution with Sterile Water for Injection, USP the reconstituted solution concentration is 1 mg/mL and should be injected immediately.

Egrifta vials should be protected from light and be kept in the original box until time of use. Non-reconstituted Egrifta must be stored at refrigerated temperature, between 2°C and 8°C (36°F and 46°F) until dispensed. Upon dispensing, the patient may store non-reconstituted Egrifta at refrigerated temperature until the expiration date, or at or below 25°C (77°F) for 3 months or until the expiration date, whichever occurs first. The reconstitution diluent (Sterile Water for Injection, USP), syringes and needles should be stored at controlled room temperature of 20ºC to 25ºC (68°F to 77°F).

Syringes and needles are for single-use by a single patient and should never be shared between patients.

NDC 44087-2011-2

Patient Counseling Information

See FDA-approved patient labeling (Patient Information and Patient Instructions for Use).

  • Fluid retention (5.3) - Advise patients that treatment with Egrifta may cause symptoms consistent with fluid retention, including edema, arthralgia, and carpal tunnel syndrome. These reactions are either transient or resolve with discontinuation of treatment.
  • Hypersensitivity Reactions (5.5) - Advise patients that hypersensitivity reactions (e.g., rash, urticaria) may occur during treatment with Egrifta. Advise patients to seek prompt medical attention and to immediately discontinue treatment with Egrifta.
  • Injection Site Reactions (5.6) - Advise patients of possible injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. To reduce the incidence of injection site reactions, advise patients to rotate the site of injection.
  • Counsel patients that they should never share an Egrifta syringe with another person, even if the needle is changed. Sharing of syringes or needles between patients may pose a risk of transmission of infection.

Pregnancy

Advise women to discontinue Egrifta if pregnancy occurs, as the drug offers no known benefit to pregnant women and could result in fetal harm [see Contraindications and Use in Specific Populations].

Nursing Mothers

Because of both the potential for HIV-1 infection transmission and serious adverse reactions in nursing infants, mothers receiving Egrifta should be instructed not to human milk-feed [see Use in SpecificPopulations].