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Egrifta

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Egrifta

Egrifta

SIDE EFFECTS

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 HTV-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 administration 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
Vascular disorders
  Hypertension 1.3 0.8
Injury, poisoning and procedural complications
  Muscle strain 1.1 0.0
Investigations
  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 HbAic 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)

System Organ Class
Preferred Term
Incidence of patients (%) with adverse drug reactions
T-T1 (Week 26-52)
(N=246)
T-P2 (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 administration 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
1 T-T = tesamorelin for Week 0-26 and tesamorelin for Week 26-52
2 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.

Read the Egrifta (tesamorelin injection) Side Effects Center for a complete guide to possible side effects

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 CLINICAL PHARMACOLOGY].

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.

Read the Egrifta Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 12/12/2011
This monograph has been modified to include the generic and brand name in many instances.

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