Tesamorelin

GH inhibits 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. tesamorelin stimulates GH production; therefore, patients receiving glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses following initiation of tesamorelin. Patients treated with cortisone acetate and prednisone may be affected more than others because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.

Co-administration of tesamorelin with simvastatin, a CYP3A substrate had no significant impact on the pharmacokinetics profiles of simvastatin in healthy subjects.

Tesamorelin stimulates GH production. Published data indicate that GH may modulate cytochrome P450 (CYP450) mediated antipyrine clearance. 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, and cyclosporine). Monitor patients for potential interactions when administering tesamorelin in combination with other drugs known to be metabolized by CYP450 liver enzymes.

For patients with a history of non-malignant neoplasms, initiate tesamorelin therapy after careful evaluation of the potential benefit of treatment. For patients with a history of treated and stable malignancies, initiate tesamorelin therapy only after careful evaluation of the potential benefit of treatment relative to the risk of re-activation of the underlying malignancy. Discontinue tesamorelin if there is any evidence of recurrent malignancy.

Tesamorelin increases IGF-1, monitor patients with diabetes who are receiving treatment with tesamorelin at regular intervals for potential development or worsening of retinopathy.

Risk Summary

Tesamorelin is contraindicated in pregnant women because modifying visceral adipose tissue offers no benefit in pregnant women and could result in fetal harm. Administration of tesamorelin acetate to rats during organogenesis resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, based on measured drug exposure (AUC). If tesamorelin is used during pregnancy, or if the patient becomes pregnant while taking it, discontinue tesamorelin.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying pregnancy-associated physiologic changes in visceral adipose tissue with tesamorelin offers no known benefit and could result in fetal harm.

Data

Animal Data

Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). Actual animal dose was 1.2 mg/kg. During organogenesis, lower doses approximately 0.1 to 1 times the clinical dose caused delayed skull ossification in rats. Actual animal doses were 0.1 to 0.6 mg/kg. No adverse developmental effects occurred in rabbits using doses up to approximately 500 times the clinical dose.

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. There are no data on the presence of tesamorelin in human milk, the effects on the breastfed child, or the effects on milk production. Because of both the potential for (1) HIV-1 infection transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive patients), and (3) any possible adverse effects of tesamorelin, mothers should not breastfeed if they receive tesamorelin.

Life-time carcinogenicity studies in rodents have not been conducted with tesamorelin acetate. No potential mutagenicity of tesamorelin acetate was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (hamster CHOK1 cells), and chromosomal damage in intact animals (bone marrow cells in mice). There was no effect on fertility in male or female rats following administration of tesamorelin acetate at doses up to 0.6 mg/kg (approximately equal to clinical exposure) for 28 days in males or 14 days in females.

Clinical Trials 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 tesamorelin (2 mg/vial formulation) has been established based on clinical trials conducted with tesamorelin (1 mg/vial formulation). Adverse reactions for the 1.4 mg dose (2 mg/vial formulation) of tesamorelin are expected to be similar to those observed with the 2 mg dose (1 mg/vial formulation) of tesamorelin.

Seven hundred and forty (740) HIV-infected patients with lipodystrophy and excess abdominal fat were treated with tesamorelin in clinical trials; of these, 543 received tesamorelin 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, and carpal tunnel syndrome), hyperglycemia, and injection site reactions (injection site erythema, pruritus, pain, urticaria, irritation, swelling, and hemorrhage).

Adverse reactions that occurred more frequently with tesamorelin 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 tesamorelin–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.

In the tesamorelin clinical trials, mean baseline HbA_1c was 5.3% among patients in both the tesamorelin and placebo groups. Patients receiving tesamorelin 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).

Immunogenicity

As with all therapeutic proteins and peptides, there is a potential for development of anti-tesamorelin 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 tesamorelin with the incidence of antibodies to other products may be misleading.

In the clinical trials with the tesamorelin 1 mg/vial formulation, anti-tesamorelin IgG antibodies were detected in 50% of patients who received tesamorelin for 26 weeks and 47% of patients who received tesamorelin 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 tesamorelin treatment, 18% were still antibody positive.

Neutralizing antibodies to tesamorelin and human GHRH (hGHRH) were detected in vitro at Week 52 in 10% and 5% of tesamorelin-treated patients, respectively. Changes in VAT and IGF-1 levels in patients with or without in vitro neutralizing antibodies were comparable.