EGRIFTA Powder for solution fot injection Ref.[10721] Active ingredients: Tesamorelin

A 1.0 cm reduction in waist circumference should be considered as the minimal acceptable decrease for a satisfactory response following a 6-month treatment with EGRIFTA.

Carcinogenesis and Mutagenesis

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.

Endocrine and Metabolism

Elevated IGF-1 levels

EGRIFTA stimulates GH production and increases serum insulin-like growth factor-1 (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, and treatment should be discontinued in patients with IGF-1 standard deviation scores (SDS) greater than 2 after 26 weeks.

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.

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.

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 GH. EGRIFTA has not been studied in patients with acute critical illness. Since EGRIFTA stimulates GH production, careful consideration should be given to discontinuing EGRIFTA in critically ill patients.

Immune

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 discontinue treatment with EGRIFTA immediately and seek prompt medical attention.

As with all therapeutic proteins and peptides, there is a potential for in vivo development of antiEGRIFTA 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% (See ADVERSE REACTIONS, Immunogenicity)

Skin

Injection of EGRIFTA may be associated with 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. Do not inject into scar tissue, bruises or the navel.

Special Populations

Pregnant Women

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 equal to the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue EGRIFTA therapy. If EGRIFTA is used during pregnancy, or if the patient becomes pregnant while taking EGRIFTA, the patient should be apprised of the potential hazard to the fetus.

Nursing Women

It is recommended that HIV-infected mothers not breast-feed their infants, to avoid risking postnatal transmission of HIV. Because of both the potential for transmission of HIV infection and the risk of serious adverse reactions in nursing infants, mothers receiving EGRIFTA should not feed their infants breast milk.

Pediatrics (<18 years of age)

EGRIFTA is contraindicated in patients below 18 years of age. Safety and effectiveness of EGRIFTA in pediatric patients have not been established, and there is potential for excess GH and IGF-1 to result in linear growth acceleration and excessive growth in children with open epiphyses.

Geriatrics (>65 years of age)

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.

Monitoring and Laboratory Tests

Blood Glucose

Patients treated with EGRIFTA should be monitored periodically for changes in glucose metabolism.

Caution should be exercised in treating HIV-infected 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.

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.

IGF-1

IGF-1 levels should be monitored during treatment with EGRIFTA and treatment should be discontinued in patients with IGF-1 SDS greater than 2 after 26 weeks.

Adverse Drug Reaction Overview

During the initial 26-week treatment period (Main Phase) of both placebo-controlled studies combined, the most frequently observed adverse drug reactions were those thought to be related to the induction of GH secretion, such as arthralgia, extremity pain, peripheral edema and myalgia (25.6% in EGRIFTA group vs. 13.7% in placebo group), and local injection site reactions, such as injection site erythema and pruritus (24.5% in the EGRIFTA group vs. 14.4% in the placebo group). Hypersensitivity reactions occurred in 2.9% of EGRIFTA-treated patients. Discontinuations as a result of adverse events occurred in 9.6% of patients receiving EGRIFTA and 6.8% of patients receiving placebo. Also, 4.2% and 4.6% EGRIFTA-treated patients discontinued the study due to adverse event(s) (AE) and experienced a GH-related AE and injection site reactions, respectively. The incidence of serious adverse events was similar between EGRIFTA and placebo groups (3.7% vs. 4.2%).

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 EGRIFTA for Week 0-26 and with EGRIFTA for Week 26-52) and 5.2% of patients in the T-P group (patients treated with EGRIFTA for Week 0-26 and with placebo for Week 26-52).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Seven hundred and forty (740) HIV-infected patients with excess abdominal fat were exposed to EGRIFTA in two randomized, double-blind, placebo-controlled Phase 3 studies. Specifically, these patients included 543 patients who initially received EGRIFTA during the initial 26-week placebo-controlled Main Phase of these studies and who then received EGRIFTA (N=246) or placebo (N=135) during the 26-week Extension Phase, and 197 patients who initially received placebo during the Main Phase and then received EGRIFTA during the Extension Phase (see Clinical Trials).

Adverse drug reactions were defined as all treatment-emergent adverse events occurring at a greater incidence in the active treatment group compared to the placebo group and considered to be related to EGRIFTA or having a potential pharmacological relationship. Common and very common adverse drug reactions during the 26-week Main Phase of both studies combined and those that occurred between Weeks 26 and 52 of the Extension Phase of both studies combined are presented in Table 1 and Table 2, while less common adverse drug reactions that occurred in greater than one EGRIFTA-treated patients are presented in Table 3 and Table 4. Because there was not a group of patients receiving placebo for 52 weeks, only adverse drug reactions occurring at a greater incidence between Weeks 26 and 52 in patients who were randomized to receive EGRIFTA for 52 weeks as compared to the group of patients who discontinued EGRIFTA treatment at Week 26 are reported in Table 2 and Table 4. Patients experiencing the same adverse event multiple times were counted only once according to the maximum severity for the corresponding preferred term.

Table 1. Common and Very Common Adverse Drug Reactions (Frequency ≥1% during the 26-Week Main Phase of the Combined Studies):

^§ Note: all patients entered the study with high baseline triglyceride levels (range from 4.2 to 37 mmol/L).

In the EGRIFTA Phase 3 clinical trials, mean baseline (Week 0) HbA_1c was 5.26% among patients in the EGRIFTA group and 5.28% among those in the placebo group. At Week 26, mean HbA_1c 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 (HbA_1c level ≥6.5%) compared with placebo (4.5% vs. 1.3%), with a hazard ratio of 3.3 (CI 1.4, 9.6).

Table 2. Adverse Reactions Reported in ≥1% of Patients and More Frequent in EGRIFTA–treated than Placebo Patients during the 26-Week Extension Phase of the Combined Studies (Week 26 to Week 52):

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Table 3. Less Common Clinical Trial Adverse Drug Reactions (occurred in greater than one study subject during the 26-Week Main Phase of the Combined Studies):

Table 4. Less Common Clinical Trial Adverse Drug Reactions (occurred in greater than one study subject during the 26-Week Extension Phase of the Combined Studies):

Abnormal Hematologic and Clinical Chemistry Findings

Table 5. Notable Changes or Abnormalities in Biochemistry and Hematology Laboratory Tests at Week 26:

Table 6. Notable Changes or Abnormalities in Biochemistry and Hematology Laboratory Tests at Week 52:

Immunogenicity

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 TM 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 antitesamorelin 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.

Post-Market Adverse Drug Reactions

The most common adverse events reported during post-marketing experience with EGRIFTA, regardless of causality assessment, are the following:

Gastrointestinal disorders: Nausea, diarrhoea, abdominal distension.

General disorders and administration site conditions: Drug ineffective, injection site bruising, injection site erythema, injection site haemorrhage, injection site pain, injection site pruritus, injection site rash, injection site swelling, injection site mass, local swelling, pain, oedema peripheral, fatigue.

Investigations: Blood glucose increased, weight increased.

Musculoskeletal and connective tissue disorders: Arthralgia, joint swelling, myalgia, pain in extremity, back pain.

Nervous system disorders: Headache, hypoaesthesia, paraesthesia, carpal tunnel syndrome, dizziness, neuropathy peripheral.

Psychiatric disorders: Insomnia, depression.

Skin and subcutaneous tissue disorders: Rash, pruritus.

Vascular disorders: Hypertension.

During post-marketing surveillance with EGRIFTA, reports of adverse reactions also included:

• Diabetes mellitus, glucose intolerance, blood glucose abnormal and impaired fasting glucose (see WARNINGS AND PRECAUTIONS).
• Hypersensitivity (see WARNINGS AND PRECAUTIONS)

Drug-Drug Interactions

Published data indicate that GH may modulate cytochrome P450 (CYP450) activity.

Simvastatin

The effect of multiple dose administration of EGRIFTA (2 mg) on the pharmacokinetics of simvastatin (a CYP3A4 substrate) and simvastatin acid was evaluated in healthy subjects. Coadministration of EGRIFTA and simvastatin (a sensitive CYP3A substrate) resulted in 8% decrease in extent of absorption (AUC_inf) and 5% increase in rate of absorption (C_max) of simvastatin. For simvastatin acid there was a 15% decrease in AUC_inf and 1% decrease in C_max.

Ritonavir

The effect of multiple dose administration of EGRIFTA (2 mg) on the pharmacokinetics of ritonavir (a CYP3A4 inhibitor) was evaluated in healthy subjects. Co-administration of EGRIFTA with ritonavir resulted in 9% decrease in AUC_inf and 11% decrease in C_max of ritonavir.

These results suggest that EGRIFTA TM does not significantly affect CYP3A activity. Therefore, either medicinal product may be co-administered with EGRIFTA without changing their dosing regimen. However, other isoenzymes of CYP450 have not been evaluated with EGRIFTA. The available data suggest that GH may alter (increase) the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine) resulting in lower plasma levels of these compounds. The clinical significance of this effect is unknown; however, patients being treated concomitantly with CYP450 substrates should be monitored to ensure that the therapeutic efficacy of these drugs is maintained.

With respect to patients with ACTH deficiency receiving glucocorticoid replacement therapy, such replacement therapy should be monitored and adjusted to maintain adequate dosing, since patients may require an increase in maintenance or stress doses following initiation of EGRIFTA.

No other drug-drug interaction studies were conducted. However, during clinical trials, administration of EGRIFTA for up to 52 weeks did not adversely alter antiretroviral effectiveness, as shown by unaffected mean circulating levels of CD4 counts or viral load.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.