Pegvisomant - Dosage, Uses, and Side Effects

Overview

Pegvisomant is a growth hormone receptor antagonist used in the treatment of a condition known as acromegaly (a rare hormonal disorder). It is indicated for patients for whom surgery or radiation therapy is not appropriate or has provided an inadequate response. The treatment's main aim is to normalize serum insulin-like growth factor- I (IGF-I) (growth hormone). Pegvisomant was approved by the United States Food and Drug Administration (USFDA) on March 25, 2003, and by the European Medicines Agency (EMA) in 2002. This treatment must be taken under the supervision of a healthcare specialist experienced in treating acromegaly.

How Does Pegvisomant Work?

Acromegaly occurs when there is excess production of growth hormone by the pituitary gland. It is usually due to a benign (non-cancerous) tumor and is mostly seen in middle-aged adults. Pegvisomant is genetically engineered and similar to the growth hormone. It is used when acromegaly cannot be managed by surgery, radiation therapy, or other medications. It works by blocking the peripheral receptors to which the growth hormone attaches itself and reducing the concentrations of insulin-like growth factor-1. This leads to inhibiting the unwanted growth of the tissues and correcting the other metabolic defects associated with acromegaly. Pegvisomant is a mutated derivative of the growth hormone; studies have shown that it is significantly effective against acromegaly as it normalizes the IGF-1 levels in most patients.

Indications of Pegvisomant

Pegvisomant is indicated in patients with acromegaly, especially for whom surgery, radiation treatment, and other medications are proven ineffective.

Contraindications of Pegvisomant

• Pegvisomant is not recommended for pregnant and nursing mothers.

• It is also not used in children, elderly people over 65 years old, or individuals with renal impairment.

Available Doses and Dose Forms

Pegvisomant is available as lyophilized powder in 10 mg (milligrams), 15 mg, and 20 mg in single-dose vials. It must be reconstituted for injection with the sterile water supplied with the medicine. The recommended dose of the drug varies among patients and can be around 10 to 30 mg administered subcutaneously once a day. The maximum daily dosage is 30 mg, and it is given subcutaneously once daily.

Considerations for Pegvisomant Administration:

• Loading Dose: The medicine must be removed from the refrigerator 10 minutes before injecting it. One vial of lyophilized powder of Pegvisomant containing 20 mg of the drug is reconstituted with the supplied diluent (sterile water). The diluent must be withdrawn slowly onto the sides of the vial containing the powder. It must not be inverted or shaken, as the solution can cause denaturation of the proteins. The solution must be swirled slowly to ensure all the powder is mixed. Before administration, it must be clear and inspected for discoloration or particulate matter. It must be administered within six hours of reconstitution.

• Administration: One milliliter (ml) of the reconstituted solution of Pegvisomant (20 mg/ml) is withdrawn and injected subcutaneously into the upper arm, upper thigh, buttocks, or abdomen at a 90-degree angle. The same steps are repeated to reconstitute the second dose, but a different area must be selected other than the first injection site.

Warnings and Precautions

• Pegvisomant can decrease insulin sensitivity (the cells' response to insulin) and improve glucose tolerance in some patients; hence, patients must be frequently monitored, and the dose of antidiabetic drugs must be reduced to avoid hypoglycemia (low blood sugar), especially in patients with diabetic mellitus (increased blood sugar).

• Liver enzymes must be monitored, and the levels should be determined before starting the treatment with Pegvisomant.

• Pegvisomant is structurally similar to growth hormone and can cross-react with commercially available assays.

• Clinical studies have shown that Pegvisomant has the potential to cause lipohypertrophy (accumulation of extra fat under the skin) in some patients; therefore, injection sites must be rotated to prevent lipohypertrophy during treatment with Pegvisomant.

• Close monitoring is essential before re-initiating treatment in patients with systemic hypersensitivity reactions (severe allergic reactions) to Pegvisomant.

Adverse Effects of Pegvisomant

Adverse effects of Pegvisomant include the following:

• Nausea and vomiting.

• Diarrhea.

• Injection site reactions.

• Flu syndrome (fever, headache, chills, sore throat, etc).

• Back pain.

• Chest pain.

• Dizziness.

• Hypertension (increased blood pressure).

• Edema (swelling).

• Paraesthesia (tingling or pricking sensation).

• Sinusitis (inflammation of the sinus).

For Patients

What Is Acromegaly?

Acromegaly is a rare hormonal disorder that occurs when there is excess production of growth hormone (GH) by the pituitary gland. It causes an increase in the size of the bones, cartilage, and other tissues of the body. It is estimated that approximately 3 to 14 individuals in every 100,000 people have been diagnosed with acromegaly. It is mostly seen in middle-aged adults, and this condition is known as gigantism in children. It can be associated with other health conditions such as hypertension (increased blood pressure), type 2 diabetes (increased blood glucose), arthritis (inflammation of the joints), heart diseases, and certain conditions affecting the bones and muscles. Acromegaly can be treated in most patients, but as the symptoms develop slowly or gradually over time, health problems may occur before the condition is diagnosed or treated. Medications, radiation therapy, and surgery usually manage Acromegaly.

Some of the common symptoms of acromegaly include:

• Large and swollen lips, tongue, nose, hands, and feet.

• Thick, oily skin or flesh-colored growths of skin with a raised surface.

• Increased sweating and skin odor.

• Headache.

• Joint pain.

• Vision problems.

What Is Pegvisomant?

Pegvisomant is a prescription medicine used to treat acromegaly in patients for whom surgery, radiation therapy, and other medications are proven ineffective. It works by binding to the growth hormone receptors and preventing the effects of excess hormone levels in the body. It can be administered in a hospital or clinic by a healthcare provider or by the patient or caregiver after exactly learning the preparation of the medicine and the proper technique of injection.

How Effective Is Pegvisomant?

Pegvisomant is a genetically engineered medicine with a unique mechanism of action as it lowers insulin-like growth factor I (a growth hormone). Several clinical trials have demonstrated that Pegvisomant is effective in around 60 to 90 percent of patients with acromegaly. It also exhibits a favorable effect on blood glucose levels (glycemic profile) and can benefit acromegalic patients with diabetes. It is known to be safe and tolerant in patients, reduces clinical symptoms, and prevents systemic complications. Therefore, Pegvisomant is considered the most powerful tool to control acromegaly and improve patients' quality of life.

How Should Pegvisomant Be Taken?

A healthcare provider administers Pegvisomant under the skin (subcutaneously) once a day. Some patients may even require two injections per day as their dose. A healthcare professional always administers the first dose; after learning the proper administration technique from them, the subsequent doses may be taken by the patient or provided by a caregiver. However, the instructions for reconstituting and preparing the dose and administration must be followed exactly as directed by the healthcare provider.

What Are the Side Effects of Pegvisomant?

Some of the side effects of Pegvisomant include:

• Nausea and vomiting.

• Headache.

• Fever.

• Itching.

• Skin rash.

• Loss of appetite.

• Unusual tiredness.

• Yellowish discoloration of the skin.

• Abdominal pain.

• Swelling of the lower legs or feet.

• Injection site reactions.

• Clay-colored stools.

• Dark urine.

What Must the Patient Inform the Doctor Before Taking Pegvisomant?

• Before starting treatment, patients must tell the doctor if they are allergic to Pegvisomant, its components, or any other medications.

• Patients must inform the doctor if they are suffering from diabetes, liver problems, or any other medical conditions before taking Pegvisomant.

• Female patients must inform the doctor if they are pregnant, planning pregnancy, or breastfeeding before starting the treatment.

• Before beginning treatment, patients must inform the doctor if they are taking any medications, vitamins, herbal supplements, or over-the-counter drugs.

What Are the Precautionary Measures to Be Followed While Taking Pegvisomant?

• Pegvisomant can interfere with certain drugs, including insulin, opioid medicines, etc.; hence, patients must inform the doctor about all prescription and non-prescription medications taken regularly.

• Instructions for using Pegvisomant must be followed exactly as instructed by the healthcare provider if injected by the patient or caregiver.

• Pegvisomant must be injected only under the skin, and the needles or syringes must not be shared with others as they may cause infections.

• Blood tests are performed before and during treatment with Pegvisomant to check certain hormones and the functioning of the liver.

• Patients must inform the doctor immediately if they notice any liver problems, adverse effects, or allergic reactions during the treatment.

• The doctor may modify the dose of diabetes medicine during the treatment with Pegvisomant.

• Skin thickening can occur at the injection site, leading to lumps.

• Pegvisomant must not be given to other people without the doctor’s consultation, even if they experience similar symptoms, as it may harm them.

Dietary Considerations

The prescribing doctor’s instructions regarding any food or beverage restrictions must be followed.

Missed Dose

If a dose is missed, the next dose of Pegvisomant must be taken at the regularly scheduled time. Two doses must not be taken simultaneously to compensate for the missed dose, and the prescribing doctor must be consulted for any doubts.

Overdose

In cases of overdose or if serious adverse effects are observed during the treatment, the prescribing doctor must be consulted immediately.

Storage

Before mixing, Pegvisomant powder and liquid must be stored in a refrigerator between 2 and 8 degrees Celsius (36 and 46 degrees Fahrenheit). After mixing, it must be stored at room temperature between 15 and 25 degrees Celsius (59 and 77 degrees Fahrenheit). The drug must be inside the vial or syringe until the patient is ready for injection. The mixture must be used within six hours; if not, it must be safely discarded.

For Doctors

Pharmacological Aspects of Pegvisomant

Mechanism of Action

Pegvisomant acts by selectively binding to the growth hormone receptor located on the cell surfaces, inhibiting endogenous growth hormone binding, thus interfering with signal transduction. This inhibition reduces the serum concentrations of insulin-like growth factor-1 and other growth hormone serum proteins like free IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) of IGF-1.

Pharmacodynamics

Pegvisomant selectively attaches to the growth hormone receptor but does not cross-react with other cytokine receptors, including prolactin. This causes a reduction in the serum concentrations of IGF-1, free IGF-1, IGFBP-3, and ALS.

Pharmacokinetics

• Absorption: After a subcutaneous administration of Pegvisomant, the peak serum concentrations are not usually attained until 33 to 77 hours after administration. However, the mean absorption of a 20-mg dose of Pegvisomant was approximately 57 percent, relative to a 10-mg intravenous (IV) dose.

• Distribution: Following the administration of a single subcutaneous dose of Pegvisomant, the drug was not distributed extensively into tissues, and the maximum concentration of the drug increased disproportionately with the increase in dose. The mean apparent volume of distribution is about 7 L (liters).

• Metabolism and Elimination: Pegvisomant molecules consist of covalently bound polyethylene glycol polymers to decrease the clearance rate. The clearance of the drug after multiple doses is lower compared to a single dose and is known to increase with body weight. The mean total systemic clearance after multiple doses of Pegvisomant is between 36 and 28 mL/h (milliliters per hour) for subcutaneous doses ranging between 10 to 20 mg/day (milligrams per day). The half-life of Pegvisomant is around 74 to 172 hours after single or multiple doses, and less than one percent of the drug was recovered in urine over 96 hours.

Drug Interactions

Some of the drugs known to interact with Pegvisomant include the following:

• Insulin and other hypoglycemic drugs

• Morphine.

• Codeine.

• Macimorelin.

• Meperidine.

• Liraglutide.

• Methadone.

• Hydrocodone.

• Opium tincture.

• Nalbuphine.

• Oxycodone.

• Tramadol.

• Pentazocine.

Clinical Studies

A 12-week, double-blind, randomized, multi-center study involving 112 patients with acromegaly was conducted to compare Pegvisomant with a placebo. Around 93 patients had undergone pituitary surgery, of which 57 were also treated with radiation therapy. Six patients had irradiation without surgery, nine had obtained drug therapy, and four patients had not received any previous treatments.

The subjects were qualified after the serum IF-1 level was more than 1.3 times the upper limit of the age-appropriate normal range. Subjects were randomly assigned to treatment groups such as placebo and groups receiving doses of Pegvisomant at 10, 15, or 20 mg/day (milligrams per day). All three groups that received Pegvisomant demonstrated statistically significant reductions in serum IGF-1 levels compared to the placebo group. Reductions in IGF-1, ALS, and IGFBP-3 levels were also observed in these subjects compared to the placebo group.

Nonclinical Toxicology

• Carcinogenesis: Long-term treatment withPegvisomant at doses of 8 and 20 mg/kg (milligram per kilogram) injected into male rats demonstrated an increase in malignant fibrous histiocytoma at the injection sites, probably due to irritation or high sensitivity to repeated doses of the drug.

• Mutagenesis: Pegvisomant did not exhibit any genetic damage in the in vitro assays, including bacterial mutation and human lymphocyte chromosome aberration.

• Impairment of Fertility: Animal studies have reported that Pegvisomant did not affect fertility or reproductive performance at subcutaneous doses of about 10 mg/kg/day (milligrams per kilogram per day).

Specific Considerations

• Pregnancy: Adequate and well-controlled studies of Pegvisomant have not been conducted in pregnant women; hence, this drug must be avoided in pregnancy.

• Lactation: It is not understood whether Pegvisomant is excreted in breast milk. However, as many drugs are excreted in breast milk, care must be taken if Pegvisomant is administered to lactating women.

• Pediatric Use: Clinical studies have not determined the safety and effectiveness of Pegvisomant in children.

• Geriatric Use: Not enough patients over 65 were included in clinical studies of Pegvisomant to determine the difference in response compared to younger patients.

• Renal Impairment: The safety and efficacy of Pegvisomant in patients with renal disorders still need to be completely understood.