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  • CLASSES

    Growth Hormones

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic growth hormone releasing factor analogue; given subcutaneously
    Indicated for reducing excess abdominal fat in HIV-infected adult patients with lipodystrophy
    Contraindicated in patients with disruption of hypothalamic-pituitary axis, active malignancy, known hypersensitivity to the drug or mannitol, and in pregnant women

    COMMON BRAND NAMES

    Egrifta

    HOW SUPPLIED

    Egrifta Subcutaneous Inj Pwd F/Sol: 1mg, 2mg

    DOSAGE & INDICATIONS

    For the treatment of excess abdominal fat in patients with HIV-associated lipodystrophy.
    Subcutaneous dosage (Egrifta 1 mg/vial formulation)
    Adults 18 to 65 years of age

    2 mg via subcutaneous injection once daily into the abdomen. There are no data in patients older than 65 years of age.[42405] LIMITS OF USE: Long-term cardiovascular benefit and safety of tesamorelin have not been studied. Tesamorelin is not indicated for weight loss management (weight neutral effect). There are no data to support improved compliance with anti-retroviral therapies in HIV-positive patients taking tesamorelin.

    Subcutaneous dosage (Egrifta SV 2 mg/vial formulation)
    Adults 18 to 65 years

    1.4 mg (0.35 mL) via subcutaneous injection once daily into the abdomen. There are no data in patients older than 65 years of age. LIMITS OF USE: Long-term cardiovascular benefit and safety of tesamorelin have not been studied. Tesamorelin is not indicated for weight loss management (weight neutral effect). There are no data to support improved compliance with anti-retroviral therapies in HIV-positive patients taking tesamorelin.

    MAXIMUM DOSAGE

    Adults

    1.4 mg/day subcutaneous injection for the 2 mg/vial formulation (Egrifta SV); 2 mg/day subcutaneous injection for the 1 mg/vial formulation (Egrifta).

    Geriatric

    65 years: 1.4 mg/day subcutaneous injection for the 2 mg/vial formulation (Egrifta SV); 2 mg/day subcutaneous injection for the 1 mg/vial formulation (Egrifta).
    66 years and older: Data are not available.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Subcutaneous Administration

    Reconstitution of the 1 mg/vial formulation (Egrifta):
    Two 1 mg vials must be reconstituted with the provided diluent (Sterile Water for Injection) as follows to provide the 2-mg once daily subcutaneous dose.
    To reconstitute, inject 2.2 mL of the provided Sterile Water for injection into the first 1 mg tesamorelin vial. To avoid foaming, push the plunger in slowly with the needle on a slight angle so the sterile water goes down the inside wall of the tesamorelin vial. With the needle and syringe attached to the vial, keep the vial upright and gently roll between hands for 30 seconds until mixed. Do not shake the vial.
    Withdraw the entire amount of reconstituted solution from the first vial, and inject into the second 1 mg tesamorelin vial. Keep the vial upright and gently roll between hands for 30 seconds. Do not shake the vial.
    Take the syringe out of the vial, once you have withdrawn all of the reconstituted solution from the second vial. The medicine in the syringe after reconstitution of the 2 vials will be around the 2.2-mL mark on the syringe.
    Place the needle cap on its side against a clean flat surface. Without touching the needle, hold the syringe and slide the needle carefully into the protective cap. Push the cap all the way or until it snaps shut. Do not touch the cap until it covers the needle completely. Remove the needle.
    Place the 1/2-inch 27-gauge safety injection needle onto the syringe.
    Use reconstituted solution immediately. If injection in the syringe is not used immediately, it should be discarded; do not freeze or refrigerate. Throw away any unused tesamorelin and the used Sterile Water for Injection container.
    The reconstituted solution should be clear. Do not use if the solution contains particulates, is cloudy, or is discolored. It is not unusual to have slight foaming of the product upon reconstitution.[42405] [42406]
     
    Reconstitution of the 2 mg/vial formulation (Egrifta SV):
    Add 0.5 mL of the provided diluent (Sterile Water for Injection) to the vial containing lyophilized powder. To avoid foaming, push the plunger in slowly with the needle on a slight angle so the sterile water goes down the inside wall of the tesamorelin vial.
    Mix by gently rolling the vial between hands for 30 seconds. Do not shake the vial.
    The reconstituted solution (concentration: 2 mg/0.5 mL) should be clear, colorless, and without particulate matter. Do not use if the solution contains particulates, is cloudy, or is discolored.
    Place the needle cap on its side against a clean flat surface. Without touching the needle, hold the syringe and slide the needle carefully into the protective cap. Push the cap all the way or until it snaps shut. Do not touch the cap until it covers the needle completely. Remove the needle.
    Place a new 1/2-inch 30-gauge needle onto the syringe.
    Administer dose immediately after reconstitution, and discard any unused solution and diluent. If not used immediately, discard the reconstituted solution. Do not freeze or refrigerate.[64420]
     
    Subcutaneous injection:
    Subcutaneously inject the reconstituted solution into the abdomen. Avoid injection into scar tissue, bruises or the navel. Injection sites should be rotated to different areas of the abdomen.
    Slowly push the plunger all the way down until all of the medicine in the syringe has been injected under the skin.
    After removing the injection from the skin, flip back the needle shield until it snaps, covering the injection needle completely. Keep pressing until a click is heard, which means the injection needle is protected.
    Using a piece of sterile gauze to rub the injection site clean. If there is bleeding, apply pressure to the injection site with gauze for 30 seconds. If bleeding continues, apply a bandage to the site.
    Properly dispose of used syringes and needles in a sharps container.[42405] [42406] [64420]

    STORAGE

    Egrifta:
    - Discard unused portion. Do not store for later use.
    - Do not freeze reconstituted product
    - Do not refrigerate reconstituted product
    - Protect from light
    - Store unreconstituted product at 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Coronary artery bypass graft surgery (CABG), respiratory insufficiency, surgery, trauma

    The use of tesamorelin has not been studied in critically ill patients; however, increased mortality has been reported in patients administered growth hormone (GH) following abdominal surgery, coronary artery bypass graft surgery (CABG), multiple accidental trauma, and in patients with acute respiratory failure (respiratory insufficiency). Since tesamorelin stimulates GH production, consider withholding therapy in the critically ill population.

    Head trauma, hypopituitarism, hypothalamic-pituitary-adrenal (HPA) suppression, radiation therapy

    Tesamorelin is contraindicated in patients with disruption of the hypothalamic-pituitary axis (e.g. hypothalamic-pituitary-adrenal (HPA) suppression) due to hypophysectomy, hypopituitarism, pituitary tumor/surgery, radiation therapy of the head or head trauma.

    Neoplastic disease

    Tesamorelin is contraindicated in patients with active neoplastic disease (either newly diagnosed or recurrent); any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy. Tesamorelin induces the release of endogenous growth hormone (GH), a known growth factor. 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. Carefully consider the decision to start treatment with tesamorelin based on the increased background risk of malignancies in HIV-positive patients.

    Mannitol hypersensitivity

    Tesamorelin is contraindicated in patients with known tesamorelin hypersensitivity and/or mannitol hypersensitivity.

    Diabetes mellitus, diabetic retinopathy

    Diabetes mellitus and diabetic retinopathy may result from treatment with tesamorelin. In clinical trials, reports of elevated HbA1c (6.5% or more) occurred more frequently in patients treated with tesamorelin (4.5%) than with placebo (1.3%). Based on data from these trials, it was determined that tesamorelin therapy is associated with an increased risk of developing diabetes mellitus (intent-to-treat odds ratio = 3.3). The manufacturer recommends monitoring serum glucose status in all tesamorelin-treated patients. Additionally, health care providers are encouraged to monitor diabetic patients treated with the drug for signs of developing or worsening retinopathy. Consider the risk to benefit ratio of continuing therapy in patients who develop glucose intolerance or diabetes.

    Edema

    Fluid retention, theorized to result from increased growth hormone secretion, may occur in patients treated with tesamorelin; thus, use caution when administering to patients with a history of edema. Symptoms associated with fluid retention and reported during clinical trials with tesamorelin include edema, peripheral edema, arthralgia, joint swelling, stiffness, myalgia, and carpal tunnel syndrome. According to the manufacturer, these symptoms are either transient or resolve following discontinuation of tesamorelin.

    Intramuscular administration, intravenous administration

    Tesamorelin is only administered subcutaneously; take measures to prevent accidental intramuscular administration or intravenous administration.

    Geriatric

    Tesamorelin is only indicated for use in adults aged 18 to 65 years. No information is available on the use of tesamorelin in geriatric patients older than 65 years of age with HIV and lipodystrophy.

    Children, infants, neonates

    Tesamorelin is only indicated for use in adults age 18 to 65 years. Safety and efficacy have not been established in adolescents, children, infants, or neonates.

    Pregnancy

    Tesamorelin is contraindicated for use during pregnancy. During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying this physiologic change of pregnancy with tesamorelin offers no benefit and could result in fetal harm; administration to rats during organogenesis and lactation resulted in hydrocephalus in offspring at a dose approximately 2- and 4-times the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue tesamorelin therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, notify the patient of the potential hazard to the fetus.

    Breast-feeding

    Breast-feeding is not recommended by the Centers for Disease Control and Prevention by HIV-infected mothers in order to minimize the risk of postnatal transmission of HIV. Thus, in the US, HIV-infected mothers should be instructed not to breast-feed, even if they are receiving tesamorelin. It is not known if tesamorelin is excreted in human breast milk.

    ADVERSE REACTIONS

    Severe

    retinopathy / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    edema / Delayed / 1.0-10.0
    peripheral edema / Delayed / 2.0-6.1
    depression / Delayed / 1.6-2.0
    hematoma / Early / 1.7-1.7
    hypertension / Early / 1.3-1.6
    chest pain (unspecified) / Early / 1.1-1.1
    palpitations / Early / 1.1-1.1
    antibody formation / Delayed / 10.0
    erythema / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 6.1-24.5
    arthralgia / Delayed / 13.3-13.3
    diarrhea / Early / 2.6-7.4
    headache / Early / 5.6-5.6
    myalgia / Early / 1.2-5.5
    paresthesias / Delayed / 1.6-4.8
    nausea / Early / 4.4-4.4
    hypoesthesia / Delayed / 1.6-4.2
    rash / Early / 3.7-3.7
    skin irritation / Early / 2.9-2.9
    vomiting / Early / 2.0-2.6
    pruritus / Rapid / 1.2-2.4
    musculoskeletal pain / Early / 1.8-1.8
    dyspepsia / Early / 1.7-1.7
    carpal tunnel syndrome / Delayed / 1.5-1.5
    urticaria / Rapid / 1.2-1.2
    flushing / Rapid / 1.2-1.2
    night sweats / Early / 1.1-1.2
    insomnia / Early / 1.2-1.2
    abdominal pain / Early / 1.1-1.1

    DRUG INTERACTIONS

    Cortisone: (Moderate) Use caution when coadministering tesamorelin with cortisone as their concurrent use may decrease the effectiveness of the steroids. Tesamorelin stimulates the production of growth hormone, which is known to inhibit the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD-1); cortisone and prednisone require the 11-beta-HSD-1 enzyme for conversion to their active metabolites. Patients with hypoadrenalism receiving treatment with cortisone or prednisone may required increased maintenance or stress doses after initiation of tesamorelin.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Minor) Use caution when coadministering tesamorelin with ritonavir as their concurrent use may alter ritonavir plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with ritonavir resulted in a 9% decrease in ritonavir AUC and an 11% decrease in ritonavir Cmax. The clinical impact of these pharmacokinetic changes is unknown; however, patients should be monitored for decreased ritonavir efficacy.
    Ezetimibe; Simvastatin: (Moderate) Use caution when coadministering tesamorelin with simvastatin as their concurrent use may alter simvastatin plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with simvastatin resulted in an 8% decrease in simvastatin AUC and a 5% increase in simvastatin Cmax. The clinical impact of these pharmacokinetic changes are unknown; however, patients should be monitored for decreased simvastatin efficacy. Further, since simvastatin is a substrate for CYP3A4, it may be theorized that tesamorelin has little impact on CYP3A activity.
    Lopinavir; Ritonavir: (Minor) Use caution when coadministering tesamorelin with ritonavir as their concurrent use may alter ritonavir plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with ritonavir resulted in a 9% decrease in ritonavir AUC and an 11% decrease in ritonavir Cmax. The clinical impact of these pharmacokinetic changes is unknown; however, patients should be monitored for decreased ritonavir efficacy.
    Niacin; Simvastatin: (Moderate) Use caution when coadministering tesamorelin with simvastatin as their concurrent use may alter simvastatin plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with simvastatin resulted in an 8% decrease in simvastatin AUC and a 5% increase in simvastatin Cmax. The clinical impact of these pharmacokinetic changes are unknown; however, patients should be monitored for decreased simvastatin efficacy. Further, since simvastatin is a substrate for CYP3A4, it may be theorized that tesamorelin has little impact on CYP3A activity.
    Ombitasvir; Paritaprevir; Ritonavir: (Minor) Use caution when coadministering tesamorelin with ritonavir as their concurrent use may alter ritonavir plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with ritonavir resulted in a 9% decrease in ritonavir AUC and an 11% decrease in ritonavir Cmax. The clinical impact of these pharmacokinetic changes is unknown; however, patients should be monitored for decreased ritonavir efficacy.
    Prednisone: (Moderate) Use caution when coadministering tesamorelin with prednisone as their concurrent use may decrease the effectiveness of the steroids. Tesamorelin stimulates the production of growth hormone, which is known to inhibit the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD-1); cortisone and prednisone require the 11-beta-HSD-1 enzyme for conversion to their active metabolites. Patients with hypoadrenalism receiving treatment with cortisone or prednisone may required increased maintenance or stress doses after initiation of tesamorelin.
    Ritonavir: (Minor) Use caution when coadministering tesamorelin with ritonavir as their concurrent use may alter ritonavir plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with ritonavir resulted in a 9% decrease in ritonavir AUC and an 11% decrease in ritonavir Cmax. The clinical impact of these pharmacokinetic changes is unknown; however, patients should be monitored for decreased ritonavir efficacy.
    Simvastatin: (Moderate) Use caution when coadministering tesamorelin with simvastatin as their concurrent use may alter simvastatin plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with simvastatin resulted in an 8% decrease in simvastatin AUC and a 5% increase in simvastatin Cmax. The clinical impact of these pharmacokinetic changes are unknown; however, patients should be monitored for decreased simvastatin efficacy. Further, since simvastatin is a substrate for CYP3A4, it may be theorized that tesamorelin has little impact on CYP3A activity.
    Simvastatin; Sitagliptin: (Moderate) Use caution when coadministering tesamorelin with simvastatin as their concurrent use may alter simvastatin plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with simvastatin resulted in an 8% decrease in simvastatin AUC and a 5% increase in simvastatin Cmax. The clinical impact of these pharmacokinetic changes are unknown; however, patients should be monitored for decreased simvastatin efficacy. Further, since simvastatin is a substrate for CYP3A4, it may be theorized that tesamorelin has little impact on CYP3A activity.

    PREGNANCY AND LACTATION

    Pregnancy

    Tesamorelin is contraindicated for use during pregnancy. During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying this physiologic change of pregnancy with tesamorelin offers no benefit and could result in fetal harm; administration to rats during organogenesis and lactation resulted in hydrocephalus in offspring at a dose approximately 2- and 4-times the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue tesamorelin therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, notify the patient of the potential hazard to the fetus.

    Breast-feeding is not recommended by the Centers for Disease Control and Prevention by HIV-infected mothers in order to minimize the risk of postnatal transmission of HIV. Thus, in the US, HIV-infected mothers should be instructed not to breast-feed, even if they are receiving tesamorelin. It is not known if tesamorelin is excreted in human breast milk.

    MECHANISM OF ACTION

    Tesamorelin is a synthetic analog of the hypothalamic produced peptide known as growth hormone releasing factor (GRF). It binds to growth hormone releasing factor receptors on the pituitary somatotroph cells. This binding stimulates the production and pulsatile release of endogenous growth hormone (GH). Growth hormone interacts with a number of target cells including chondrocytes, osteoblasts, myocytes, hepatocytes, and adipocytes to produce both anabolic and lipolytic pharmacologic effects. The lipolytic (lipid and carbohydrate metabolizing) effects are directly related to GH; however, the anabolic effects result from GH induced production of other hormones known as insulin-like growth factors, specifically insulin-like growth factor 1 (IGF-1). Administration of tesamorelin increases the release of both GH and IGF-1, thus producing both lipolytic and anabolic pharmacologic effects.

    PHARMACOKINETICS

    Tesamorelin is administered subcutaneously; do not give by intramuscular or intravenous injection.
    Following single subcutaneous injections of the 2 mg/vial (Egrifta SV) and 1 mg/vial (Egrifta) formulations to healthy volunteers, the mean volume of distributions were 4.8 L/kg (+/- 1.9 L/kg) and 9.4 L/kg (+/- 3.1 L/kg), respectively. No formal metabolism studies have been performed. A single dose of the 2 mg/vial (Egrifta SV) formulation in healthy volunteers has a mean elimination half-life of 8 minutes. The mean elimination half-life of the 1 mg/vial (Egrifta) formulation in healthy volunteers is 26 minutes after 14 consecutive days of treatment.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None

    Subcutaneous Route

    The absolute bioavailability of tesamorelin is less than 4% following subcutaneous administration. In a pharmacokinetic study involving healthy volunteers, a single subcutaneous 2 mg dose using the 1 mg/vial (Egrifta) formulation resulted in a mean exposure (AUC) of 634.6 pg x h/mL and a mean peak plasma concentration (Cmax) of 2,874.6 pg/mL. In another study involving healthy volunteers, a single subcutaneous 1.4 mg dose using the 2 mg/vial (Egrifta SV) formulation resulted in a mean AUC of 889.1 pg x h/mL and a mean peak plasma concentration (Cmax) of 2,956.1 pg/mL. The time to reach the peak plasma concentration (Tmax) was 0.15 hours for both formulations.[42405] [64420]