Egrifta (Tesamorelin) Side Effects: Incidence Rates Across Clinical Trials

Which trials produced these incidence rates?

The numbers come from two randomized, double-blind, placebo-controlled phase 3 trials in HIV-infected adults with excess abdominal fat: 412 patients in the first [3] and 404 in the second [4], each treated for 26 weeks with tesamorelin 2 mg subcutaneously once daily or placebo. The pooled safety analysis covers 806 patients, 543 on tesamorelin and 263 on placebo [2], and the labels state that 740 patients received tesamorelin across the clinical program [1].

That 2 mg dose was given with the original 1 mg-per-vial Egrifta product. The current products are dosed differently: Egrifta SV at 1.4 mg and Egrifta WR at 1.28 mg, both once daily [1][5]. Both labels state that adverse reactions at these doses are expected to be similar to those seen with the 2 mg dose, and that systemic exposure is similar [1][5].

Injection-site reactions

The labels put the incidence of injection-site reactions at 25% with tesamorelin and 14% with placebo during the first 26 weeks [1].

The reactions described are local: redness, itching, pain, irritation and bruising [1]. To reduce them, the label directs rotating injection sites to different areas of the abdomen [1].

Joint pain, muscle pain and fluid retention

Apart from the injection site, the most frequently reported reactions were joint, muscle and limb symptoms and edema. Arthralgia was reported in 13% on tesamorelin versus 11% on placebo, peripheral edema 6% versus 2%, myalgia 6% versus 2%, pain in an extremity 6% versus 5%, paresthesia 5% versus 2%, and hypoesthesia 4% versus 2% [1]. Less common entries in the same table include musculoskeletal pain at 2% versus 1%, joint swelling at 1% versus 0% and carpal tunnel syndrome at 1% versus 0% [1].

The label describes fluid retention as increased tissue turgor and musculoskeletal discomfort producing edema, arthralgia and carpal tunnel syndrome, and states that these reactions are either transient or resolve when treatment is discontinued [1]. It states that the fluid retention is thought to be related to the induction of growth hormone secretion [1].

Glucose

In the trials, 5% of tesamorelin patients and 1% of placebo patients moved from baseline to an HbA1c of 6.5% or higher by week 26, a hazard ratio of 3.3 (95% CI 1.4 to 9.6) [1]. Mean glycemic measures, by contrast, differed little between the groups in the pooled phase 3 analysis [2].

A separate 50-patient trial looked at timing: fasting glucose was higher with tesamorelin at 2 weeks, up 9 versus 2 mg/dL, but no different at 6 months [6]. The label directs evaluating glucose before starting and monitoring periodically during treatment, considering discontinuation in patients who develop glucose intolerance without a clear efficacy response, and monitoring patients who have diabetes for development or worsening of retinopathy [1].

IGF-1

Tesamorelin stimulates growth hormone production and raises IGF-1. Among patients treated for 26 weeks, 47% had IGF-1 above 2 SDS and 36% above 3 SDS, an effect seen as early as week 13; among those treated for a full 52 weeks, 34% were above 2 SDS and 23% above 3 SDS at the end of treatment [1]. The label states that the effects of prolonged IGF-1 elevation are unknown, and directs monitoring IGF-1 with consideration of discontinuation for persistent elevations such as above 3 SDS, particularly when the fat-loss response is not robust [1].

Hypersensitivity reactions

Hypersensitivity reactions occurred in 4% of tesamorelin-treated patients in the trials and included pruritus, erythema, flushing, urticaria and rash [1]. The label advises patients with a suspected reaction to seek prompt medical attention and to stop treatment, and lists known hypersensitivity to tesamorelin or the excipients as a contraindication [1][5]. Among patients who had a hypersensitivity reaction, 85% had anti-tesamorelin antibodies [1].

Antibodies

Anti-tesamorelin IgG antibodies were found in 50% of patients at 26 weeks and 47% at 52 weeks in the original product's trials; neutralizing antibodies were present in about 10% at week 52, compared with about 5% for human GHRH [1]. Fat loss and the IGF-1 response were similar in patients with and without antibodies [1]. Antibody incidence depends heavily on the sensitivity and specificity of the assay, and the label notes that differences in assay methods preclude meaningful comparisons across studies [1].

Cancer warning and contraindications

Tesamorelin induces release of growth hormone, a known growth factor. The label lists neoplasm risk as a warning; it does not appear in the adverse-reaction table [1]. The label asks prescribers to weigh the higher background cancer risk in HIV-positive patients, to start only when any preexisting malignancy is inactive and its treatment complete, and to stop if malignancy recurs [1].

The contraindications are disruption of the hypothalamic-pituitary axis (hypophysectomy, hypopituitarism, pituitary tumor or surgery, head irradiation or head trauma), active malignancy, known hypersensitivity to tesamorelin or its excipients, and pregnancy [1][5].

Adverse reaction rates from the label

Table 1 of the labels lists reactions reported in at least 1% of patients and more often with tesamorelin than placebo during the 26-week phase, from trials of the 1 mg-per-vial product [1][5].

What changes after 26 weeks?

The trials continued into a 26-week extension in which patients who had received tesamorelin were re-randomized: in the first trial, 154 continued and 50 switched to placebo; in the second, 92 continued and 85 switched [1]. The report of that extension described the prevalence of adverse events and serious adverse events in the extension phase as comparable to the initial phase, with glucose changes over 52 weeks similar to those at 26 weeks [7].

The fat loss, however, did not hold once the drug stopped. From week 26 to week 52, visceral fat rose 16% to 22% among patients switched to placebo, versus a change of 0% to -5% in those who continued [1].

What these numbers do not tell you

Long-term cardiovascular safety has not been established [1]. Reports filed with FDA's adverse-event system do not fill that gap: FDA states that the reports cannot be used to estimate how often an event occurs and that a report does not establish that the drug caused the event [9].