Egrifta (Tesamorelin) Side Effects: Withdrawal and Discontinuation Syndrome

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What does tesamorelin do, and what are its labeled risks?

Tesamorelin is a synthetic analog of human growth hormone-releasing factor. It binds growth hormone-releasing factor receptors on pituitary somatotroph cells and increases the pituitary's own output of growth hormone, which in turn raises IGF-1 [1]. It is a peptide, not growth hormone, and it is injected once daily under the skin: 1.4 mg for Egrifta SV, 1.28 mg for Egrifta WR [1][2].

The labeled warnings for both products are increased risk of neoplasms, elevated IGF-1, fluid retention, glucose intolerance or diabetes, hypersensitivity reactions, injection-site reactions, and increased mortality in patients with acute critical illness. Neither label carries a boxed warning [1][2].

Tesamorelin has a short half-life. The mean elimination half-life was 8 minutes after a 1.4 mg dose of Egrifta SV and 11 minutes after a 1.28 mg dose of Egrifta WR in healthy subjects [1][2].

How fast does visceral fat return after stopping?

The approved use is reduction of excess abdominal fat in HIV-infected adults with lipodystrophy. The label says tesamorelin is not indicated for weight loss management because its effect on body weight is neutral [1].

Visceral fat fell 15.2% over 26 weeks on tesamorelin and rose 5.0% on placebo in the 412-patient trial that corresponds to label Study 1 [3]. In Study 2, with 404 patients, visceral fat fell 10.9% (about 21 cm2) versus 0.6% (about 1 cm2) on placebo [4]. On the label's own tables, the week-26 change was -27 cm2 in Study 1 and -21 cm2 in Study 2 [1].

Both trials then re-randomized tesamorelin-treated patients at week 26 to continue the drug or switch to placebo. In Study 1, 154 continued and 50 switched; in Study 2, 92 continued and 85 switched [1]. In patients switched to placebo after week 26, visceral fat increased by 25 cm2 in Study 1 and 24 cm2 in Study 2 over the next 26 weeks, mean increases of 22% and 16%. Patients who continued tesamorelin had little change or a further decrease: +3 cm2 (0%) in Study 1 and -11 cm2 (-5%) in Study 2 [1].

A pooled analysis of the same two trials reported that continuous tesamorelin through week 52 kept visceral fat 35 cm2 down, a 17.5% reduction [5].

What happens to IGF-1 after the last injection?

In the two trials, IGF-1 rose 107 ng/mL and 108 ng/mL over 26 weeks on tesamorelin, against -15 ng/mL and +3 ng/mL on placebo [1]. Among patients treated for 26 weeks, 47% had IGF-1 above 2 standard deviation scores and 36% above 3 [1].

From week 26 to week 52, IGF-1 fell 137 ng/mL in Study 1 and 135 ng/mL in Study 2 among patients switched to placebo, compared with 59 ng/mL and 25 ng/mL among patients who continued tesamorelin [1]. These figures are the change from the week-26 level across 26 weeks.

The label's own instruction on IGF-1 is about treatment, not withdrawal: monitor IGF-1 during therapy and consider discontinuing in patients with persistent elevations, for example above 3 SDS, particularly if the efficacy response is not robust [1].

Do fluid retention, joint pain and injection-site reactions resolve after stopping?

The label states that fluid retention during tesamorelin treatment appears as edema, joint pain or carpal tunnel syndrome, and that these reactions are either transient or resolve with discontinuation of treatment [1][2].

In the combined 26-week data, peripheral edema occurred in 6% of tesamorelin patients versus 2% on placebo, arthralgia in 13% versus 11%, myalgia in 6% versus 2%, and carpal tunnel syndrome in 1% versus 0% [1]. Injection-site reactions (redness, itching, pain, irritation, bruising) occurred in 25% versus 14% during the first 26 weeks [1].

Hypersensitivity reactions occurred in 4% of tesamorelin-treated patients in clinical trials and included itching, redness, flushing, hives and rash. For a suspected hypersensitivity reaction, the label says to advise patients to seek prompt medical attention and to discontinue treatment immediately [1].

Does blood sugar change after stopping?

Mean baseline HbA1c was 5.3% in both groups. By week 26, an HbA1c of 6.5% or higher had developed in 5% of tesamorelin patients versus 1% on placebo, a hazard ratio of 3.3 (95% CI 1.4 to 9.6) [1]. The label says to evaluate glucose before starting and monitor during treatment, to consider discontinuing in patients who develop glucose intolerance or diabetes without a clear efficacy response, and to monitor patients with diabetes for worsening retinopathy [1].

An analysis of 402 tesamorelin-treated patients from the two trials compared people whose visceral fat fell at least 8% with those who responded less: responders had smaller rises in fasting glucose and HbA1c over 52 weeks (at 52 weeks, fasting glucose -1 versus +8 mg/dL) [6]. The analysis grouped patients by their visceral-fat response, so its glucose results do not establish whether blood sugar improves after stopping tesamorelin [6].

Do you need to taper tesamorelin?

Nothing in the labeled warnings calls for a gradual dose reduction. The stop instructions are tied to specific events instead. The labels say to discontinue for a suspected hypersensitivity reaction, for evidence of recurrent malignancy, and if pregnancy occurs. They say to consider discontinuation for persistent IGF-1 elevation (for example above 3 SDS), for glucose intolerance or diabetes without a clear efficacy response, and in critically ill patients. They also say to consider the risk/benefit of continuing in patients who have not had a reduction in visceral adipose tissue [1][2].