Egrifta (Tesamorelin) Side Effects: Potentially Permanent Adverse Events

Does the Egrifta label describe any permanent side effect?

No reaction in the current Egrifta SV or Egrifta WR prescribing information is described as permanent [1][2]. The closest the labels come is the fluid-retention group. Section 5.3 states that edema, arthralgia and carpal tunnel syndrome are either transient or resolve with discontinuation of treatment [1].

The long-term concerns the label raises are the ones it tells prescribers to watch or says have not been worked out: blood sugar, IGF-1, malignancy and cardiovascular safety over years [1].

Glucose intolerance and diabetes

This is the labeled risk with the clearest numbers. In the clinical trials, the proportion of patients with HbA1c of 6.5% or higher from baseline to week 26 was 5% on Egrifta and 1% on placebo, an intent-to-treat hazard ratio of 3.3 (95% CI 1.4 to 9.6) [1]. The label directs prescribers to evaluate glucose before starting, monitor periodically during treatment, consider discontinuing in patients who do not show a clear efficacy response, and monitor people with diabetes at regular intervals for development or worsening of retinopathy [1].

Individual trials reported less of a signal. In the 412-patient Falutz trial, glycemic measures showed no significant differences over 26 weeks [3]. In a 50-patient trial by Stanley and colleagues, fasting glucose was 9 mg/dL higher on tesamorelin versus 2 mg/dL on placebo at two weeks, but the groups did not differ at six months [4].

IGF-1 elevation: high on treatment, lower after stopping

Tesamorelin stimulates the pituitary to release growth hormone, and IGF-1 rises. Across the two 26-week trials, mean IGF-1 increased by 107 and 108 ng/mL on tesamorelin, against a fall of 15 ng/mL and a rise of 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, with the effect seen as early as week 13. Among those who stayed on treatment to 52 weeks, 34% were above 2 SDS and 23% above 3 [1]. The label says the effects of prolonged IGF-1 elevation are unknown and asks prescribers to monitor levels and consider discontinuing in patients with persistent elevations, for example above 3 SDS, particularly when the fat-loss response is not strong [1].

Levels do come down when the drug is withdrawn. In the extension phase, patients switched to placebo for the second 26 weeks had IGF-1 fall by 137 ng/mL in one trial and 135 ng/mL in the other, versus 59 and 25 ng/mL in those who continued tesamorelin [1].

Fluid retention, joint pain and carpal tunnel syndrome

In the combined 26-week trials, arthralgia occurred in 13% on tesamorelin versus 11% on placebo, peripheral edema in 6% versus 2%, myalgia in 6% versus 2%, and carpal tunnel syndrome in 1% versus 0% [1]. The label describes edema, joint pain and carpal tunnel syndrome as fluid-retention reactions that are transient or resolve after treatment stops [1].

Injection-site reactions

Injection-site reactions were reported in 25% of tesamorelin-treated patients and 14% of placebo-treated patients during the first 26 weeks, and include redness, itching, pain, irritation and bruising [1]. Both labels instruct users to rotate injection sites to different areas of the abdomen to reduce them [1][2].

Hypersensitivity reactions

Hypersensitivity reactions occurred in 4% of patients treated with Egrifta in clinical trials and included itching, redness, flushing, hives and rash. The label advises patients to seek prompt medical attention and to stop treatment if a reaction is suspected [1].

Malignancy risk and the cancer warning

Tesamorelin induces release of endogenous growth hormone, which the label calls a known growth factor [1]. Active malignancy is a contraindication, any preexisting malignancy should be inactive with treatment complete before starting, and the label says to discontinue if there is evidence of recurrent malignancy [1][2]. It also asks prescribers to weigh the higher background risk of malignancy in HIV-positive patients when deciding whether to start [1].

Critical illness

Increased mortality has been reported after pharmacologic doses of growth hormone in patients with acute critical illness: complications after open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure. Because Egrifta stimulates growth hormone production, the label says to consider discontinuing it in critically ill patients [1].

What the label says is not established

Long-term cardiovascular safety has not been established, and the label asks prescribers to reconsider continuing in patients who have not had a reduction in visceral fat [1]. There is no information on use in people older than 65, and pharmacokinetics in renal or hepatic impairment are not established [1].

Does the fat come back after stopping?

The visceral fat reduction is not permanent. In the extension phase, patients who had responded and were switched to placebo at week 26 had visceral fat rise by 25 cm2 in one trial and 24 cm2 in the other, mean changes of +22% and +16%. Those who continued tesamorelin stayed flat or fell slightly, at 0% and -5% [1].

Who should not use it

The labels contraindicate tesamorelin in people with disruption of the hypothalamic-pituitary axis from hypophysectomy, hypopituitarism, pituitary tumor or surgery, head irradiation or head trauma; in active malignancy; in known hypersensitivity to tesamorelin or the excipients; and in pregnancy [1][2]. In rat studies, tesamorelin given during organogenesis produced hydrocephaly in offspring at roughly two and four times the clinical exposure [1]. Safety and effectiveness in children are not established, and in children with open growth plates the drug may accelerate linear growth [1].

Bottom line

The Egrifta labels describe fluid retention, joint pain, carpal tunnel syndrome, injection-site reactions and hypersensitivity, and they call the fluid-related ones transient or resolving after the drug is stopped [1]. The open questions concern risk carried during treatment: the glucose signal, IGF-1 elevation, and cardiovascular safety over years [1].