Egrifta Wr Drug Information
Generic name: TESAMORELIN
Uses of Egrifta Wr
EGRIFTA WR is indicated for the reduction of excess abdominal fat in HIV-infected adult patients with lipodystrophy. Limitations of Use: Long-term cardiovascular safety of EGRIFTA WR has not been established. Consider risk/benefit of continuation of treatment in patients who have not had a reduction in visceral adipose tissue.
EGRIFTA WR is not indicated for weight loss management as it has a weight neutral effect. There are no data to support improved compliance with anti-retroviral therapies in HIV-positive patients taking EGRIFTA WR. Not indicated for weight loss management.
Dosage & Administration of Egrifta Wr
Recommended Dosage and Administration Instructions There are two EGRIFTA formulations (EGRIFTA WR and EGRIFTA SV) with different recommended dosages. These two formulations and strengths have differences in the dosage, the number of vials required to prepare a dose, reconstitution instructions, and storage requirements. EGRIFTA WR and EGRIFTA SV are not substitutable.
The dosage and administration recommendations in this prescribing information only apply to EGRIFTA WR (tesamorelin) for injection 11.6 mg per vial formulation. For dosage and administration recommendations for tesamorelin for injection 2 mg per vial formulation, see the EGRIFTA SV prescribing information. The recommended dosage of EGRIFTA WR is 1.28 mg subcutaneously once daily.
Inject EGRIFTA WR into the abdomen. Rotate injection sites to different areas of the abdomen. Do not inject into scar tissue, bruises or the navel.
Reconstitution Procedure
Instruct patients to read the Instructions for Use enclosed in the EGRIFTA WR Injection Box. Use only the diluent provided, Bacteriostatic Water for Injection, to reconstitute EGRIFTA WR. Reconstitute 1 vial of EGRIFTA WR lyophilized powder with 1.3 mL of diluent (8 mg per mL).
Move the vial in a circle (swirl) to mix all the powder and liquid. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
EGRIFTA WR is a clear, colorless solution. Do not use if solid particles appear or if the solution is cloudy or colored. One reconstituted EGRIFTA WR vial provides daily doses for 7 consecutive days.
One dose of EGRIFTA WR is 1.28 mg in 0.16 mL of the reconstituted solution. Store reconstituted EGRIFTA WR at room temperature at 20°C to 25°C (68°F to 77°F). Discard unused solution of EGRIFTA WR 7 days after mixing.
Do not freeze.
Side Effects of Egrifta Wr
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. The safety of EGRIFTA WR (11.6 mg/vial formulation) has been established based on clinical trials conducted with EGRIFTA (1 mg/vial formulation). Seven hundred and forty HIV-infected patients with lipodystrophy and excess abdominal fat were treated with EGRIFTA in clinical trials; of these, 543 received EGRIFTA 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 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 Phase (Combined Studies) In the EGRIFTA clinical trials, mean baseline HbA1c was 5.3% among patients in both the EGRIFTA and placebo groups.
| 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. | ||
| Preferred Term | Placebo (N=263) | EGRIFTA (N=543) |
| Injection site reaction* Arthralgia Pain in extremity Myalgia Edema peripheral Paresthesia Hypoesthesia Rash Dyspepsia Musculoskeletal pain Pain Pruritus Vomiting Musculoskeletal stiffness Blood creatine phosphokinase increased Carpal tunnel syndrome Joint swelling Muscle strain Night sweats Palpitations | 6 11 5 2 2 2 2 2 1 1 1 1 0 0 0 0 0 0 0 0 | 17 13 6 6 6 5 4 4 2 2 2 2 3 2 1 1 1 1 1 1 |
Warnings & Cautions for Egrifta Wr
Increased Risk of Neoplasms New Malignancy
Carefully consider the decision to start treatment with EGRIFTA WR based on the increased background risk of malignancies in HIV-positive patients. Active Malignancy EGRIFTA WR induces the release of endogenous growth hormone (GH), a known growth factor. Do not treat patients with active malignancy with EGRIFTA WR.
History of Malignancy For patients with a history of non-malignant neoplasms, initiate EGRIFTA WR therapy after careful evaluation of the potential benefit of treatment. For patients with a history of treated and stable malignancies, initiate EGRIFTA WR therapy only after careful evaluation of the potential benefit of treatment relative to the risk of re-activation of the underlying malignancy. Discontinue EGRIFTA WR if there is any evidence of recurrent malignancy.
Elevated IGF-1 Levels EGRIFTA
WR stimulates GH production and increases serum IGF-1, a growth factor. The effects of prolonged elevations in IGF-1 levels are unknown. Monitor IGF-1 levels during EGRIFTA WR therapy.
Consider discontinuing EGRIFTA WR in patients with persistent elevations of IGF-1 levels (e.g., >3 SDS), particularly if the efficacy response is not robust. Among those patients who remained on EGRIFTA for a total of 52 weeks, at the end of treatment, 34% had IGF-1 SDS >2 and 23% had IGF-1 SDS >3.
Fluid Retention
Fluid retention may occur during EGRIFTA WR therapy and is thought to be related to the induction of GH secretion. This manifests as increased tissue turgor and musculoskeletal discomfort resulting in adverse reactions (e.g. edema, arthralgia, and carpal tunnel syndrome) which are either transient or resolve with discontinuation of treatment.
Glucose Intolerance or Diabetes Mellitus EGRIFTA
WR treatment can result in glucose intolerance. An increased risk of developing diabetes with EGRIFTA (HbA 1c level ≥ 6.5%) relative to placebo was observed. Evaluate glucose status prior to initiating EGRIFTA WR.
Monitor all patients treated with EGRIFTA WR periodically to diagnose those who develop impaired glucose tolerance or diabetes. If patients treated with EGRIFTA WR develop glucose intolerance or diabetes, consider discontinuing EGRIFTA WR in patients who do not show a clear efficacy response. EGRIFTA WR increases IGF-1, monitor patients with diabetes who are receiving treatment with TESAMORELIN for injection at regular intervals for potential development or worsening of retinopathy.
Hypersensitivity Reactions
Hypersensitivity reactions occurred in 4% of patients treated with EGRIFTA in clinical trials. Reactions included pruritus, erythema, flushing, urticaria, and rash. In cases of suspected hypersensitivity reactions, advise patients to seek prompt medical attention and immediately discontinue treatment with EGRIFTA WR.
Injection Site Reactions EGRIFTA
WR treatment may cause injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. The incidence of injection site reactions was 25% in EGRIFTA treated patients and 14% in placebo-treated patients during the first 26 weeks of treatment in clinical trials. Rotate injection sites to different areas of the abdomen to decrease injection site reactions.
Increased Mortality in Patients with Acute Critical Illness
Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of growth hormone. EGRIFTA WR is a growth hormone-releasing hormone (GHRH) and since it stimulates growth hormone production, consider discontinuing EGRIFTA WR in critically ill patients.
Drug Interactions with Egrifta Wr
Cytochrome P450-Metabolized Drugs Co-administration of tesamorelin with simvastatin, a CYP3A substrate had no significant impact on the pharmacokinetics profiles of simvastatin in healthy subjects. EGRIFTA WR 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 EGRIFTA WR in combination with other drugs known to be metabolized by CYP450 liver enzymes.
Glucocorticoids
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. EGRIFTA WR stimulates GH production; therefore, patients receiving glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses following initiation of EGRIFTA WR. 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.
Pregnancy Safety for Egrifta Wr
Pregnancy Risk Summary EGRIFTA WR 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 EGRIFTA WR is used during pregnancy, or if the patient becomes pregnant while taking it, discontinue EGRIFTA WR.
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 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 EGRIFTA WR offers no known benefit and could result in fetal harm. 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.
Pediatric Use of Egrifta Wr
Pediatric Use The safety and effectiveness of EGRIFTA WR in pediatric patients have not been established. In pediatric patients with open epiphyses, treatment with EGRIFTA WR may result in linear growth acceleration and excessive growth. EGRIFTA WR is not indicated for use in pediatric patients with open or closed epiphyses.
Contraindications for Egrifta Wr
- EGRIFTA WR is contraindicated in: Patients with disruption of the hypothalamic-pituitary axis Patients with active malignancy Patients with known hypersensitivity to tesamorelin or excipients in EGRIFTA WR Pregnancy EGRIFTA WR is contraindicated in: Patients with disruption of the hypothalamic-pituitary axis due to hypophysectomy, hypopituitarism, pituitary tumor/surgery, head irradiation or head trauma. Patients with active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy. Pregnant women because modifying visceral adipose tissue offers no benefit in a pregnant woman and could result in fetal harm.
Clinical Studies of Egrifta Wr
The safety and effectiveness of EGRIFTA WR (11.6 mg/vial formulation) has been established based on adequate and well controlled studies with EGRIFTA (1 mg/vial formulation), as well as a demonstration of comparable bioavailability between the 1.28 mg EGRIFTA WR dose (11.6 mg/vial formulation) and the 2 mg EGRIFTA dose (1 mg/vial formulation). Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in HIV-infected patients with lipodystrophy and excess abdominal fat (abdominal lipohypertrophy). Study 1 and Study 2 consisted of a 26-week Main Phase and a 26-week Extension Phase, respectively.
Main exclusion criteria included BMI ≤ 20 kg/m 2, type 1 diabetes mellitus, type 2 diabetes mellitus, previous treatment with insulin or with oral hypoglycemic or insulin-sensitizing agents, history of malignancy, and hypopituitarism. Patients were on a stable anti-retroviral regimen for at least 8 weeks prior to randomization. The primary efficacy assessment for each of these studies was the percent change from baseline to Week 26 in visceral adipose tissue (VAT), as assessed by computed tomography (CT) scan at L4-L5 vertebral level.
Secondary endpoints included changes from baseline in patient-reported outcomes related to body image, triglycerides, ratio of total cholesterol to HDL cholesterol, IGF-1 levels, and safety parameters. Other endpoints included changes from baseline in waist circumference, abdominal subcutaneous tissue (SAT), trunk fat, and lean body mass. In both studies, EGRIFTA-treated patients completing the 26-week treatment period were re-randomized to blinded therapy with either daily placebo or a 2 mg dose of EGRIFTA (1 mg/vial formulation) for an additional 26-week treatment period (Extension Phase) in order to assess maintenance of VAT reduction and to gather long-term safety data.
For inclusion in the Extension Phase studies, subjects must have completed the Main Phase with FBG ≤ 150 mg/dL. The twenty-six week completion rate in Study 1 was 80%. The twenty-six week completion rate in Study 2 was 74%.
Patient Reported Outcomes Patients rated the degree of distress associated with their belly appearance on a 9-point rating scale that was then transformed to a score from 0 (extremely upsetting and distressing) to 100 (extremely encouraging). A score of 50 indicated neutral (no feeling either way). A positive change from baseline score indicated improvement, i.e., less distress.
The cumulative distribution of response (change from baseline to 26 weeks) is shown in Figure 1 for both treatment groups. A curve shifted to the right on this scale indicates a greater percentage of patients reporting improvement. Figure 1.
The completion rate for patients randomized into the extension phase of Study 1 was 83%. The completion rate for patients randomized into the extension phase of Study 2 was 81%. Figure 2.
Percent Change from Baseline in VAT over Time Data in Figure 2 are expressed as mean values. T-T (tesamorelin to tesamorelin) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to tesamorelin for Weeks 26-52. P-T (placebo to tesamorelin) refers to the group of patients who received placebo for Weeks 0-26 and were switched to tesamorelin (treated open label) for Weeks 26-52.
Figure 2
| Baseline data are expressed as mean (SD); Change refers to least-squares mean (LSM); CI: confidence interval. | |||||
| 1 Results derived from the statistical model: Ln(VAT Week 26/VAT Baseline) = Ln(VAT Baseline) + treatment group | |||||
| MAIN PHASE (Baseline-Week 26) | |||||
| Study 1 | Study 2 | ||||
| 2 mg EGRIFTA (1 mg/vial) (N=273) | Placebo (N=137) | 2 mg EGRIFTA (1 mg/vial) (N=270) | Placebo (N=126) | ||
| Baseline (cm 2 ) | 178 (77) | 171 (77) | 186 (87) | 195 (95) | |
| Change (cm 2 ) | -27 | 4 | -21 | -0 | |
| Mean treatment difference (95% CI) | -31 (-39,-24) | -21 (-29,-12) | |||
| Mean change (%) 1 | -18 | 2 | -14 | -2 | |
| Mean treatment difference (95% CI) 1 | -20 (-24, -15) | -12 (-16, -7) | |||
| Baseline data are expressed as mean (SD); Change refers to least-squares mean (LSM); CI: confidence interval. | |||||
| MAIN PHASE (Baseline-Week 26) | |||||
| Study 1 | Study 2 | ||||
| 2 mg EGRIFTA (1 mg/vial) (N=273) | Placebo (N=137) | 2 mg EGRIFTA (1 mg/vial) (N=270) | Placebo (N=126) | ||
| IGF-1 (ng/mL) | Baseline | 161 (59) | 168 (75) | 146 (66) | 149 (59) |
| Change | 107 | -15 | 108 | 3 | |
| Mean treatment difference (95% CI) | 122 (101, 141) | 105 (85, 126) | |||
| IGFBP-3 (mg/L) | Baseline | 3 (1) | 3 (1) | 3 (1) | 3 (1) |
| Change | 0.4 | -0.2 | 0.8 | -0.0 | |
| Mean treatment difference (95% CI) | 0.6 (0.5, 0.8) | 0.8 (0.5, 1.0) | |||
| Weight (kg) | Baseline | 90 (14) | 90 (14) | 89 (14) | 87 (16) |
| Change | -0.4 | 0.0 | 0.5 | 0.3 | |
| Mean treatment difference (95% CI) | -0.4 (-1.3, 0.5) | 0.2 (-0.7, 1.3) | |||
| Waist circumference (cm) | Baseline | 104 (10) | 105 (9) | 105 (9) | 105 (9) |
| Change | -3 (5) | -1 (4) | -2 (5) | -1 (5) | |
| Mean treatment difference (95% CI) | -2 (-2.8, -0.9) | -1 (-2.5, -0.3) | |||
| Week 26 baseline data are expressed as mean (SD). Change refers to least-squares mean (LSM); CI: confidence interval. | ||||
| 1 T-T = tesamorelin for Weeks 0-26 and tesamorelin for Weeks 26-52 | ||||
| 2 T-P = tesamorelin for Weeks 0-26 and placebo for Weeks 26-52 | ||||
| 3 Results derived from the statistical model: Ln(VAT Week 52/Week 26) = Ln(Week 26 VAT) + treatment group | ||||
| EXTENSION PHASE (Week 26-52) | ||||
| Study 1 | Study 2 | |||
| T-T 1 (Week 26-52) (N=154) | T-P 2 (Week 26-52) (N=50) | T-T 1 (Week 26-52) (N=92) | T-P 2 (Week 26-52) (N=85) | |
| Week 26 (cm 2 ) | 145 (72) | 144 (72) | 166 (89) | 177 (88) |
| Change (cm 2 ) | 3 | 25 | -11 | 24 |
| Mean treatment difference (95% CI) | -22 (-34, -10) | -35 (-48, -22) | ||
| Mean change (%) 3 | 0 | 22 | -5 | 16 |
| Mean treatment difference (95% CI) 3 | -17 (-24, -10) | -18 (-24, -11) | ||
| Week 26 baseline data are expressed as mean (SD); Change refers to least-squares mean (LSM); CI: confidence interval. | |||||
| 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 | |||||
| EXTENSION PHASE (Weeks 26-52) | |||||
| Study 1 | Study 2 | ||||
| T-T 1 (Week 26-52) (N=154) | T-P 2 (Week 26-52) (N=50) | T-T 1 (Week 26-52) (N=92) | T-P 2 (Week 26-52) (N=85) | ||
| IGF-1 (ng/mL) | Week 26 | 291 (124) | 281 (105) | 280 (134) | 269 (110) |
| Change | -59 | -137 | -25 | -135 | |
| Mean treatment difference (95% CI) | 78 (50, 106) | 110 (87, 134) | |||
| IGFBP-3 (mg/L) | Week 26 | 3 (1) | 3 (1) | 3 (1) | 3 (1) |
| Change | -0.2 | -0.5 | -0.3 | -0.9 | |
| Mean treatment difference (95% CI) | 0.3 (-0.0, 0.6) | 0.6 (0.3, 0.9) | |||
| Weight (kg) | Week 26 | 89 (14) | 92 (17) | 89 (13) | 90 (14) |
| Change | 0.2 | 0.6 | -0.5 | 0.1 | |
| Mean treatment difference (95% CI) | -0.4 (-2, 1) | -0.6 (-2, 1) | |||
| Waist circumference (cm) | Week 26 | 101 (10) | 102 (12) | 101 (9) | 103 (11) |
| Change | -0.2 | 2.4 | -1.1 | 0.2 | |
| Mean treatment difference (95% CI) | -2.6 (-4, -1) | -1.3 (-2, 0) | |||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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