Data from FDA - Curated by EPG Health - Last updated 29 August 2018

Indication(s)

1 INDICATIONS AND USAGE 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-I (IGF-I) levels. SOMAVERT is a growth hormone receptor antagonist 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-I (IGF-I) levels.(1)

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other section of the labeling include: Hypoglycemia associated with GH lowering in patients with Diabetes Mellitus [see Warnings and Precautions (5.1)] Liver test elevations [see Warnings and Precautions (5.2)] Cross-reactivity with GH assay [see Warnings and Precautions (5.3)] Lipohypertrophy [see Warnings and Precautions (5.4)] Systemic hypersensitivity [see Warnings and Precautions (5.5)] Elevations of serum concentrations of ALT and AST greater than ten times the ULN were reported in two patients (0.8%) exposed to SOMAVERT in pre-approval clinical studies. One patient was rechallenged with SOMAVERT, and the recurrence of elevated transaminase levels suggested a probable causal relationship between administration of the drug and the elevation in liver enzymes. A liver biopsy performed on the second patient was consistent with chronic hepatitis of unknown etiology. In both patients, the transaminase elevations normalized after discontinuation of the drug. Elevations in ALT and AST levels were not associated with increased levels of TBIL and ALP, with the exception of two patients with minimal associated increases in ALP levels (i.e., less than 3 times ULN). The transaminase elevations did not appear to be related to the dose of SOMAVERT administered, generally occurred within 4 to 12 weeks of initiation of therapy, and were not associated with any identifiable biochemical, phenotypic, or genetic predictors. Most common reported adverse reactions (> 6%) are infection, pain, nausea, diarrhea, abnormal liver tests, flu syndrome, injection site reaction (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at (phone 1-800-438-1985 andwww.pfizer.com) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in clinical trials of a drug cannot be directly compared to rates in 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 [see Clinical Studies (14)]. A total of 108 subjects (30 placebo, 78 Somavert) completed 12 weeks of study treatment. 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 AcromegalyTable includes only those events that were reported in at least 2 patients and at a higher incidence in patients treated with SOMAVERT than in patients treated with placebo. Placebo n=32 SOMAVERT 10 mg/day n=26 15 mg/day n=26 20 mg/day N=28 InfectionThe 6 events coded as "infection" in the group treated with SOMAVERT 10 mg were reported as cold symptoms (3), upper respiratory infection (1), blister (1), and ear infection (1).The 2 events in the placebo group were reported as cold symptoms (1) and chest infection (1). 2 (6%) 6 (23%) 0 0 Pain 2 (6%) 2 (8%) 1 (4%) 4 (14%) Nausea 1 (3%) 0 2 (8%) 4 (14%) Diarrhea 1 (3%) 1 (4%) 0 4 (14%) Abnormal liver function tests 1 (3%) 3 (12%) 1 (4%) 1 (4%) Flu syndrome 0 1 (4%) 3 (12%) 2 (7%) Injection site reaction 0 2 (8%) 1 (4%) 3 (11%) Dizziness 2 (6%) 2 (8%) 1 (4%) 1 (4%) Accidental injury 1 (3%) 2 (8%) 1 (4%) 0 Back pain 1 (3%) 2 (8%) 0 1 (4%) Sinusitis 1 (3%) 2 (8%) 0 1 (4%) Chest pain 0 1 (4%) 2 (8%) 0 Peripheral edema 0 2 (8%) 0 1 (4%) Hypertension 0 0 2 (8%) 0 Paresthesia 2 (6%) 0 0 2 (7%) 6.2 Immunogenicity In pre-marketing clinical studies, approximately 17% of the SOMAVERT-treated patients developed low titer, non-neutralizing anti-GH antibodies. Although the presence of these antibodies did not appear to impact the efficacy of SOMAVERT, the long-term clinical significance of these antibodies is not known. No assay for anti-pegvisomant antibodies is commercially available for patients receiving SOMAVERT. The data above reflect the percentage of patients whose test results were considered positive for antibodies to SOMAVERT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SOMAVERT with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience 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 [see Warnings and Precautions (5.5)]. Registry of Patients with Acromegaly Treated with SOMAVERT ACROSTUDY is an international observational registry that captures long term safety data in patients with acromegaly treated with SOMAVERT, as used in clinical practice. Treatment dose and schedule were at the discretion of each treating physician. 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. In an interim report, there were 1288 patients enrolled (mean duration of treatment 3.7 years). At the start of SOMAVERT treatment 648 patients were on SOMAVERT monotherapy for acromegaly. Of the 454 patients who had a normal AST and ALT at baseline, 4 patients had elevated tests >3 times ULN, two of whom had elevated tests >5 times ULN. Lipohypertrophy was reported in 6 (0.5%) patients. MRIs were compared to any previous ones, and a change in tumor volume was reported as significant locally only if the diameter increased by more than 3 mm for microadenomas or volume increased by more than 20% for macroadenomas. All MRI changes considered significant at the local reading were reanalyzed centrally. Of the 747 patients who had a MRI reported at baseline and at least once during follow up in the study, 51 (7%) were reported to have an increase by local MRI. Of these, 16 patients (2%) had confirmation of this increase, 6 patients had a decrease, 12 had "no change"; there was 1 with insufficient data and 16 patients did not have a central MRI reading.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Administer a 40 mg loading dose subcutaneously under physician supervision (2.1) After proper injection instruction, on day after loading dose, patients or caregivers begin daily subcutaneous injections of 10 mg (2.1) Adjust dosage in 5 mg increments or decrements until serum IGF-I concentrations are maintained within age-adjusted normal range. Do not adjust dosage based on growth hormone (GH) levels or signs or symptoms of acromegaly (2.1) Dosage range is 10 to 30 mg once daily (2.1) Perform liver tests prior to first dosage and if greater than 3 time upper limit of normal should work-up prior to SOMAVERT administration (2.2) Follow reconstitution and injection procedures (2.3, 2.4) 2.1 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-I concentrations (serum IGF-I 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-I concentrations would benefit from increased SOMAVERT dosage. Increase the dosage by 5 mg increments every 4–6 weeks if IGF-I concentrations are elevated. Decrease the dosage by 5 mg decrements every 4–6 weeks if IGF-I concentrations are below the normal range. IGF-I levels should also be monitored when a Somavert dose given in multiple injections is converted to a single daily injection [see CLINICAL PHARMACOLOGY (12)]. The recommended dosage range is between 10 to 30 mg given subcutaneously once daily and the maximum daily dosage is 30 mg given subcutaneously once daily. 2.2 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 [serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP)]. 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 (5.2). 2.3 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 [two vials of lyophilized powder and two 2.25 mL syringes containing diluent (Sterile Water for Injection) will be needed for the 40 mg loading dose]. 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 the first package (1 vial of lyophilized powder of SOMAVERT containing 20 mg of pegvisomant and one 2.25 mL syringe containing the diluent) from the refrigerator 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 2.25 mL 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 within 6 hours of 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). 2.4 Maintenance Dose Injection Procedure For patient or caregiver instructions for reconstitution and administration of daily doses (10 to 30 mg), see the Patient's Instructions for Use. a)Before administering the dose, remove one package (1 vial of lyophilized powder of SOMAVERT containing 10, 15, 20, 25 or 30 mg of pegvisomant and one 2.25 mL syringe (containing the diluent) from the refrigerator about 10 minutes prior to the planned injection time. b)Reconstitute the lyophilized powder of SOMAVERT with diluent. When using the diluent in the 2.25 mL 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 10, 15, 20, 25 or 30 mg of pegvisomant in 1 mL of solution. e)Withdraw the 1 mL reconstituted SOMAVERT solution. The solution must be administered within 6 hours of reconstitution. f)Inject the reconstituted SOMAVERT solution subcutaneously into the upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Early embryonic development and teratology studies 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 treatment during organogenesis. At the 10-mg/kg/day dose (10 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies. Because animal reproduction studies are not always predictive of human responses, SOMAVERT should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether pegvisomant is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when SOMAVERT is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of SOMAVERT in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of SOMAVERT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment SOMAVERT was not studied in patients with renal impairment and the safety and efficacy in these patients is not known.
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether pegvisomant is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when SOMAVERT is administered to a nursing woman.

Interactions

7 DRUG INTERACTIONS Insulin and/or Oral hypoglycemic Agents: Patients with acromegaly and with diabetes mellitus may require careful monitoring and dose reductions of insulin and/or oral hypoglycemic agents. (5.2, 7.1) Opioids: Patients on opioids may need higher SOMAVERT doses to achieve appropriate IGF-I suppression. (7.2) 7.1 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 [see Warnings and Precautions (5.1)]. 7.2 Opioids In clinical studies, patients taking opioids often needed higher SOMAVERT doses to normalize IGF-I concentrations compared with patients not receiving opioids. The mechanism of this interaction is not known.

More information

Category Value
Authorisation number NDA021106
Orphan designation No
Product NDC 0009-7199,0009-7166,0009-7200,0009-7168,0009-7188
Date Last Revised 27-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1549452
Storage and handling Storage Prior to reconstitution, SOMAVERT should be stored in a refrigerator at 2 to 8°C (36 to 46°F). Do not freeze.
Marketing authorisation holder Pharmacia and Upjohn Company LLC