Somavert Drug Information

SOMAVERT is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery or radiation therapy, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum insulin-like growth factor-1 (IGF-1) levels.

Dosage Information

The recommended loading dose of SOMAVERT is 40 mg given subcutaneously, under healthcare provider supervision. Provide proper training in subcutaneous injection technique to patients or their caregivers so they can receive once daily subcutaneous injections. On the next day following the loading dose, instruct patients or their caregivers to begin daily subcutaneous injections of 10 mg of SOMAVERT.

Titrate the dosage to normalize serum IGF-1 concentrations (serum IGF-1 concentrations should be measured every four to six weeks). The dosage should not be based on growth hormone (GH) concentrations or signs and symptoms of acromegaly. It is unknown whether patients who remain symptomatic while achieving normalized IGF-1 concentrations would benefit from increased SOMAVERT dosage. • Increase the dosage by 5 mg increments every 4–6 weeks if IGF-1 concentrations are elevated. • Decrease the dosage by 5 mg decrements every 4–6 weeks if IGF-1 concentrations are below the normal range. • IGF-1 levels should also be monitored when a SOMAVERT dose given in multiple injections is converted to a single daily injection.

The recommended dosage range is between 10 mg to 30 mg given subcutaneously once daily and the maximum daily dosage is 30 mg given subcutaneously once daily.

Assess Liver Tests Prior to Initiation of SOMAVERT Prior to the start of SOMAVERT, patients should have an assessment of baseline levels of liver tests. For recommendations regarding initiation of SOMAVERT based on baseline liver tests and recommendations for monitoring of liver tests while on SOMAVERT, refer to Table 1 in Warning and Precautions.

Loading Dose Injection Procedure

The following instructions are for the healthcare provider to reconstitute and prepare the 40 mg loading dose. The healthcare provider will need to reconstitute 2 vials of lyophilized powder of SOMAVERT each containing 20 mg of pegvisomant with supplied diluent. The healthcare provider will also need to inject the reconstituted SOMAVERT solution twice into the patient's upper arm, upper thigh, abdomen, or buttocks (each injection in a different area). a Before administering the loading dose, remove 1 vial of lyophilized powder of SOMAVERT containing 20 mg of pegvisomant and one syringe containing 1 mL of diluent from the refrigerator, if refrigerated, about 10 minutes prior to the planned injection time. b Reconstitute the first 20 mg vial of lyophilized powder of SOMAVERT containing 20 mg of pegvisomant with diluent.

When using the diluent in the syringe, inject the contents of the syringe slowly onto the sides of the vial containing lyophilized powder of SOMAVERT. Do not inject the diluent directly on the powder. c Do not invert the vial or shake the solution as this may cause denaturation of the pegvisomant protein. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution.

If foaming of the reconstituted SOMAVERT solution is seen, the solution is likely damaged and therefore inappropriate to inject. d Visually inspect the reconstituted SOMAVERT solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear. If the solution is cloudy, do not use it.

Once reconstituted, the solution will contain 20 mg of pegvisomant in 1 mL of solution. e Withdraw the 1 mL reconstituted SOMAVERT solution. The solution must be administered immediately after reconstitution. f Inject the first reconstituted SOMAVERT solution (20 mg/mL) subcutaneously into the patient's upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle. g Repeat steps (a) to (e) to reconstitute the second SOMAVERT dose of 20mg. h Finally, inject the second reconstituted SOMAVERT solution (20 mg/mL) subcutaneously into the patient's upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle (different area than the first injection).

Maintenance Dose Injection Procedure

For patient or caregiver instructions for reconstitution and administration of daily doses (10 mg to 30 mg), see the Patient's Instructions for Use. a Before administering the dose, remove 1 vial of lyophilized powder of SOMAVERT containing mg or 30 mg of pegvisomant and one syringe containing 1 mL of diluent from the refrigerator, if refrigerated, about 10 minutes prior to the planned injection time. b Reconstitute the lyophilized powder of SOMAVERT with diluent.

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. In a 12-week randomized, placebo-controlled, double-blind, fixed-dose study of SOMAVERT in subjects with acromegaly, 32 subjects received placebo and 80 subjects received SOMAVERT once daily. Overall, eight patients with acromegaly (5.3%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations, one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain.

Most adverse events did not appear to be dose-dependent. Table 3 shows the incidence of adverse events that were reported in at least two patients treated with SOMAVERT and at frequencies greater than placebo during the 12-week, placebo-controlled study. Table 3.

Adverse Reactions in a 12-week Placebo-Controlled Study in Patients with Acromegaly Table includes only those events that were reported in at least 2 patients and at a higher incidence in patients treated with Infection The 6 events coded as "infection" in the group treated with SOMAVERT 10 mg were reported as cold symptoms, upper respiratory infection, blister, and ear infection.

Postmarketing Experience Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of SOMAVERT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Systemic hypersensitivity reactions including anaphylactic reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria) have been reported in post-marketing use.

Some patients required hospitalization. Symptoms did not re-occur in all patients after re-challenge. Adverse Reactions from an Observational Study ACROSTUDY was an international observational registry that captured long term safety data in 2221 patients with acromegaly treated with SOMAVERT for a mean treatment duration of 8.5 years.

Patients could also receive other therapy for acromegaly during the registry period. Treatment dose and schedule were at the discretion of each treating healthcare provider. Although safety monitoring as per the recommended schedule was mandatory, not all assessments were performed at all time points for every patient.

Because of this, comparison of rates of adverse events to those in the original clinical trial is not appropriate. Lipohypertrophy was reported in 35 (1.6%) patients.

Insulin and/or Oral Hypoglycemic Agents

After initiation of SOMAVERT, patients with acromegaly and diabetes mellitus treated with insulin and/or oral hypoglycemic agents may require dose reductions of insulin and/or oral hypoglycemic agents.

Opioids

In clinical studies, patients taking opioids often needed higher SOMAVERT doses to normalize IGF-1 concentrations compared with patients not receiving opioids. The mechanism of this interaction is not known.

Pregnancy Risk Summary Postmarketing reports of SOMAVERT use in pregnant women are insufficient to establish a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Acromegaly may improve during pregnancy (see Clinical Considerations ). In animal reproduction studies, fetotoxicity was observed at a dose that was 6 times the maximum recommended human dose based on body surface area following subcutaneous administration of pegvisomant during organogenesis or during the preimplantation period (see Data ).

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 embryofetal risk Published data from case reports, case series, and a small interventional study in pregnant women with acromegaly have demonstrated that acromegaly may improve or stabilize without treatment during pregnancy, particularly if acromegaly is treated before pregnancy.

In rare cases, acromegaly may worsen during pregnancy. Since IGF-1 levels may change physiologically during pregnancy and interpreting IGF-1 and growth hormone levels in pregnant women with acromegaly may be unreliable, clinical monitoring is recommended. Data Animal Data The effects of pegvisomant on early embryonic development and embryo-fetal development were evaluated in two separate studies, which were conducted in pregnant rabbits with pegvisomant at subcutaneous doses of 1, 3, and 10 mg/kg/day.

There was no evidence of teratogenic effects associated with pegvisomant administration during organogenesis. At the 10-mg/kg/day dose (6 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies.

Pediatric Use The safety and effectiveness of SOMAVERT in pediatric patients have not been established.

In one reported incident of acute overdose with SOMAVERT during pre-marketing clinical studies, a patient self-administered 80 mg/day (2.7 times the maximum recommended maintenance dosage) for seven days. The patient experienced a slight increase in fatigue, had no other complaints, and demonstrated no significant clinical laboratory abnormalities. In cases of overdose, administration of SOMAVERT should be discontinued and not resumed until IGF-1 levels return to within or above the normal range.