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warnings and cautions
5 WARNINGS AND PRECAUTIONS Increased risk of neoplasms: Preexisting malignancy should be inactive and its treatment complete prior to starting EGRIFTA . Discontinue EGRIFTA if there is any evidence of recurrent malignancy. ( 5.1 ) Elevated IGF-1: EGRIFTA stimulates GH production and increases serum IGF-1, a growth factor. The effects of prolonged elevations in IGF-1 levels are unknown. Monitor IGF-1 levels during EGRIFTA therapy. Consider discontinuing in patients with persistent elevations. ( 5.2 ) Fluid retention: May occur with EGRIFTA and may include edema, arthralgia, and carpal tunnel syndrome. ( 5.3 ) Glucose intolerance or diabetes mellitus: May develop with EGRIFTA use. Evaluate glucose prior to and during therapy. ( 5.4 ) Hypersensitivity reactions: Have occurred in clinical trials. Advise patients to seek immediate medical attention and discontinue treatment if suspected. ( 5.5 ) Increased mortality in patients with acute critical illness: Consider discontinuation in critically ill patients . ( 5.7 ) 5.1 Increased Risk of Neoplasms New Malignancy Carefully consider the decision to start treatment with EGRIFTA based on the increased background risk of malignancies in HIV-positive patients. Active Malignancy EGRIFTA induces the release of endogenous growth hormone (GH), a known growth factor. Do not treat patients with active malignancy with EGRIFTA [see Contraindications ( 4 )] . History of Malignancy For patients with a history of non-malignant neoplasms, initiate EGRIFTA therapy after careful evaluation of the potential benefit of treatment. For patients with a history of treated and stable malignancies, initiate EGRIFTA therapy only after careful evaluation of the potential benefit of treatment relative to the risk of re-activation of the underlying malignancy. Discontinue EGRIFTA if there is any evidence of recurrent malignancy. 5.2 Elevated IGF-1 Levels EGRIFTA stimulates GH production and increases serum IGF-1, a growth factor. The effects of prolonged elevations in IGF-1 levels are unknown. Monitor IGF-1 levels during EGRIFTA therapy. Consider discontinuing EGRIFTA in patients with persistent elevations of IGF-1 levels (e.g., >3 SDS), particularly if the efficacy response is not robust. Among patients who received EGRIFTA for 26 weeks, 47% had IGF-1 levels greater than 2 standard deviation scores (SDS), and 36% 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 34% had IGF-1 SDS >2 and 23% had IGF-1 SDS >3. 5.3 Fluid Retention Fluid retention may occur during EGRIFTA therapy and is thought to be related to the induction of GH secretion. This manifests as increased tissue turgor and musculoskeletal discomfort resulting in adverse reactions (e.g. edema, arthralgia, carpal tunnel syndrome) which are either transient or resolve with discontinuation of treatment. 5.4 Glucose Intolerance or Diabetes Mellitus EGRIFTA treatment can result in glucose intolerance. During clinical trials, the percentages of patients with elevated HbA 1c (≥ 6.5%) from baseline to Week 26 were 5% and 1% in the EGRIFTA and placebo groups, respectively. An increased risk of developing diabetes with EGRIFTA (HbA 1c level ≥ 6.5%) relative to placebo was observed [intent-to-treat hazard odds ratio of 3.3 (CI 1.4, 9.6)]. Evaluate glucose status prior to initiating EGRIFTA. Monitor all patients treated with EGRIFTA periodically to diagnose those who develop impaired glucose tolerance or diabetes. If patients treated with EGRIFTA develop glucose intolerance or diabetes, consider discontinuing EGRIFTA in patients who do not show a clear efficacy response. EGRIFTA increases IGF-1, monitor patients with diabetes who are receiving treatment with EGRIFTA at regular intervals for potential development or worsening of retinopathy. 5.5 Hypersensitivity Reactions Hypersensitivity reactions occurred in 4% of patients treated with EGRIFTA in clinical trials. Reactions included pruritus, erythema, flushing, urticaria, and rash. In cases of suspected hypersensitivity reactions, advise patients to seek prompt medical attention and immediately discontinue treatment with EGRIFTA. 5.6 Injection Site Reactions EGRIFTA may cause injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. The incidence of injection site reactions was 25% in EGRIFTA-treated patients and 14% in placebo-treated patients during the first 26 weeks of treatment in clinical trials. Rotate injection sites to different areas of the abdomen to decrease injection site reactions [see Dosage and Administration ( 2.1 )]. 5.7 Increased Mortality in Patients with 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 is a Growth Hormone-Releasing Hormone (GHRH) and since EGRIFTA stimulates growth hormone production, consider discontinuing EGRIFTA in critically ill patients.
6 ADVERSE REACTIONS The following important adverse reactions are also described elsewhere in the labeling: Increased risk of neoplasms [see Warnings and Precautions ( 5.1 )] Elevated IGF-1 levels [see Warnings and Precautions ( 5.2 )] Fluid retention [see Warnings and Precautions ( 5.3 )] Glucose intolerance or diabetes mellitus [see Warnings and Precautions ( 5.4 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] Injection site reactions [see Warnings and Precautions ( 5.6 )] Most commonly reported adverse reactions (>5%): Arthralgia, injection site erythema, injection site pruritus, pain in extremity, peripheral edema, and myalgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact THERA patient support TM toll free at 1-833-23THERA (1-833-238-4372) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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. The safety of the EGRIFTA 2 mg/vial formulation has been established based on clinical trials conducted with the EGRIFTA 1 mg/vial formulation. Adverse reactions for the 1.4 mg dose (2 mg/vial formulation) of EGRIFTA are expected to be similar to those observed with the 2 mg dose (1 mg/vial formulation) of EGRIFTA [see Clinical Pharmacology ( 12.3 )]. Seven hundred and forty HIV-infected patients with lipodystrophy and excess abdominal fat were treated with EGRIFTA in clinical trials; of these, 543 received EGRIFTA during the initial 26-week placebo-controlled phase. The most commonly reported adverse reactions were hypersensitivity reactions (e.g., rash, urticaria), edema-related reactions (e.g., arthralgia, extremity pain, peripheral edema, carpal tunnel syndrome), hyperglycemia, and injection site reactions (injection site erythema, pruritus, pain, urticaria, irritation, swelling, hemorrhage). Adverse reactons 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 Phase (Combined Studies) * Injection site reaction includes: Injection site erythema, Injection site pruritus, Injection site rash, Injection site urticaria, Injection site pain, Injection site swelling, Injection site irritation, Injection site hemorrhage. Preferred Term Placebo (N=263) EGRIFTA (N=543) Injection site reaction* Arthralgia Pain in extremity Myalgia Edema peripheral Paresthesia Hypoesthesia Rash Dyspepsia Musculoskeletal pain Pain Pruritus Vomiting Musculoskeletal stiffness Blood creatine phosphokinase increased Carpal tunnel syndrome Joint swelling Muscle strain Night sweats Palpitations 6 11 5 2 2 2 2 2 1 1 1 1 0 0 0 0 0 0 0 0 17 13 6 6 6 5 4 4 2 2 2 2 3 2 1 1 1 1 1 1 In the EGRIFTA clinical trials, mean baseline HbA 1c was 5.3% among patients in both the EGRIFTA and placebo groups. Patients receiving EGRIFTA had an increased risk of developing diabetes (HbA 1c level ≥ 6.5%) compared with placebo (5% vs. 1%), with a hazard ratio of 3.3 (CI 1.4, 9.6). 6.2 Immunogenicity As with all therapeutic proteins and peptides, there is a potential for development of anti- EGRIFTA 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. In the clinical trials with the EGRIFTA 1 mg/vial formulation, anti-tesamorelin IgG antibodies were detected in 50% of patients treated with EGRIFTA for 26 weeks and 47% of patients who received EGRIFTA for 52 weeks. In the subset of patients with hypersensitivity reactions, anti-tesamorelin IgG antibodies were detected in 85%. 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. 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. Changes in VAT and IGF-1 levels in patients with or without in vitro neutralizing antibodies were comparable.