SOMAVERT (pegvisomant) for injection

SOMAVERT (pegvisomant) for injection

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SOMAVERT (pegvisomant) for injection

Pegvisomant is an analog of human growth hormone (GH) of recombinant DNA origin that acts as a GH receptor antagonist.

It contains 191 amino acid residues. The molecular weight of pegvisomant is 22 kDa. The molecular weight of the PEG portion of pegvisomant is approximately 5 kDa. The predominant molecular weights of pegvisomant are thus approximately 42, 47, and 52 kDa. Pegvisomant is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist.

Shown below are the amino acid substitutions in pegvisomant, relative to human GH.

hGHPegvisomant
His18Asp18
Ala 21Asn 21
Gly120Lys120
Arg167Asn 167
Lys168Ala 168
Asp171Ser 171
Lys172Arg172
Glu 174Ser 174
Ile179Thr 179

SOMAVERT is available in single-dose sterile vials containing 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of pegvisomant. SOMAVERT 10 mg, 15 mg, and 20 mg vials also contain glycine (1.36 mg), mannitol (36 mg), sodium dihydrogen phosphate monohydrate (0.36 mg), and sodium phosphate dibasic anhydrous (1.04 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 10 mg/mL, 15 mg/mL and 20 mg/mL, respectively, with a pH of 7.1 – 7.7.

SOMAVERT 25 mg vials also contain glycine (1.7 mg), mannitol (45 mg), sodium dihydrogen phosphate monohydrate (0.45 mg), and sodium phosphate dibasic anhydrous (1.3 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 25 mg/mL with a pH of 7.1 – 7.7.

SOMAVERT 30 mg vials also contain glycine (2.04 mg), mannitol (54 mg), sodium dihydrogen phosphate monohydrate (0.54 mg), and sodium phosphate dibasic anhydrous (1.56 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 30 mg/mL with a pH of 7.1 – 7.7.

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.

Mechanism of Action

Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction.

Inhibition of GH action results in decreased serum concentrations of IGF-I, as well as other GH-responsive serum proteins such as free IGF-I, the acid-labile subunit of IGF-I (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3).

Dosage and administration

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

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.

Contraindications

None

Warnings and precautions

Hypoglycemia Associated With GH Lowering in Patients With Diabetes Mellitus: GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may improve in some patients treated with SOMAVERT. Patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary to avoid hypoglycemia in patients with diabetes mellitus.

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Liver Toxicity: Baseline serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP) levels should be obtained prior to initiating therapy with SOMAVERT.

Cross-Reactivity With GH Assays: SOMAVERT has significant structural similarity to growth hormone (GH) which causes it to cross-react in commercially available GH assays. Since serum concentrations of therapeutically effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum GH concentrations seen in patients with acromegaly, measurements of serum GH concentrations will appear falsely elevated.

Lipohypertrophy: There have been cases of lipohypertrophy in patients treated with SOMAVERT. Injection sites should be rotated daily to help prevent lipohypertrophy (different area than the last injection).

Systemic Hypersensitivity: In patients with systemic hypersensitivity reactions, caution and close monitoring should be exercised when re-initiating SOMAVERT therapy

Drug interactions

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-I concentrations compared with patients not receiving opioids. The mechanism of this interaction is not known.

Use in specific populations

Pregnancy: 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.

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.

Lactation: Limited information from a case report in published literature reported that the level of pegvisomant in human milk was below the level of detection. There is no information available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SOMAVERT and any potential adverse effects on the breastfed child from SOMAVERT or from the underlying maternal condition.

Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in growth hormone (GH) levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with pegvisomant may lead to improved fertility.

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

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.

Renal Impairment: SOMAVERT was not studied in patients with renal impairment and the safety and efficacy in these patients is not known.

Overdosage

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-I levels return to within or above the normal range.

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