Pegvisomant

Interactions

Pegvisomant interacts in the following cases:

Hypoglycaemic medicinal products

Patients receiving insulin or oral hypoglycaemic medicinal products may require dose reduction of these active substances due to the effect of pegvisomant on insulin sensitivity.

The study conducted with pegvisomant in diabetic patients treated either by insulin or by oral hypoglycaemic medicinal products revealed the risk of hypoglycaemia in this population. Therefore, in acromegalic patients with diabetes mellitus, doses of insulin or hypoglycaemic medicinal products may need to be decreased.

Growth hormone-secreting tumours

Growth hormone-secreting pituitary tumours may sometimes expand, causing serious complications (for example, visual field defects). Treatment by pegvisomant does not reduce tumour size. All patients with these tumours should be carefully monitored in order to avoid any eventual progression in tumour size under treatment.

Alanine aminotransferase elevations, aspartate transaminase elevations

Prior to the start of pegvisomant, 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)].

Evidence of obstructive biliary tract disease should be ruled out in patients with elevations of ALT and AST or in patients with a prior history of treatment with any somatostatin analogue. Administration of pegvisomant should be discontinued if signs of liver disease persist. For recommendations regarding initiation of pegvisomant, based on baseline liver tests (LTs) and recommendations for monitoring of liver tests while on pegvisomant, refer to Table A.

Table A. Recommendations for initiation of pegvisomant treatment based on baseline LTs and for periodic monitoring of LTs during pegvisomant treatment:

Baseline LT LevelsRecommendations
NormalMay treat with pegvisomant.
• Serum concentrations of ALT and AST should be monitored at 4- to 6-week intervals for the first 6 months of treatment with pegvisomant, or at any time in patients exhibiting symptoms suggestive of hepatitis.
Elevated, but less than or equal to 3 times ULN May treat with pegvisomant; however, monitor LTs monthly for at least 1 year after initiation of therapy and then bi-annually for the next year.
Greater than 3 times ULNDo not treat with pegvisomant until a comprehensive workup establishes the cause of the patient’s liver dysfunction.
Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs.
Based on the workup, consider initiation of therapy with pegvisomant.
If the decision is to treat, LTs and clinical symptoms should be monitored very closely.

Abbreviations: ALT = alanine aminotransferase; AST = aspartate transaminase; LT = liver test; ULN = upper limit of normal.

If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction while receiving pegvisomant, the following patient management is recommended (Table B).

Table B. Clinical recommendations based on abnormal liver test results while on pegvisomant:

LT Levels and Clinical Signs/SymptomsRecommendations
Elevated, but less than or equal to 3 times ULNMay continue therapy with pegvisomant. However, monitor LTs monthly to determine if further increases occur
Greater than 3 but less than 5 times ULN (without signs/symptoms of hepatitis or other liver injury, or increase in serum TBIL) May continue therapy with pegvisomant. However, monitor LTs weekly to determine if further increases occur (see below)
Perform a comprehensive hepatic workup to discern if an alternative cause of liver dysfunction is present
At least 5 times ULN, or transaminase elevations at least 3 times ULN associated with any increase in serum TBIL (with or without signs/symptoms of hepatitis or other liver injury)Discontinue pegvisomant immediately.
Perform a comprehensive hepatic workup, including serial LTs, to determine if and when serum levels return to normal.
If LTs normalize (regardless of whether an alternative cause of the liver dysfunction is discovered), consider cautious reinitiation of therapy with pegvisomant, with frequent LT monitoring
Signs or symptoms suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, right upper quadrant pain, ascites, unexplained edema, easy bruisability) Immediately perform a comprehensive hepatic workup.
If liver injury is confirmed, the drug should be discontinued.

Increased fertility

The therapeutic benefits of a reduction in IGF-I concentration which results in improvement of the patient’s clinical condition could potentially increase fertility in female patients. Patients should be advised to use adequate contraception if necessary. Pegvisomant is not recommended during pregnancy.

Growth hormone

Pegvisomant has significant structural similarity to growth hormone which causes it to cross-react in commercially available growth hormone assays. Since serum concentrations of therapeutically-effective doses of this medicine are generally 100 to 1,000 times higher than the actual serum growth hormone concentrations seen in acromegalics, measurements of serum growth hormone concentrations will be spuriously reported in commercially available growth hormone assays. Pegvisomant treatment should therefore not be monitored or adjusted based on serum growth hormone concentrations reported from these assays.

Pregnancy

For pegvisomant no clinical data on exposed pregnancies are available. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development. The potential risk for humans is unknown. Pegvisomant should not be used during pregnancy unless clearly necessary.

Nursing mothers

The excretion of pegvisomant in breast milk has not been studied in animals. Clinical data are too limited (one reported case) to draw any conclusion on the excretion of pegvisomant in human breast milk. Therefore, pegvisomant should not be used in breast-feeding women. However, breast-feeding may be continued if this medicine is discontinued: this decision should take into account the benefit of pegvisomant therapy to the mother and the benefit of breast-feeding to the child.

Carcinogenesis, mutagenesis and fertility

Fertility

For pegvisomant no data on fertility are available.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

Adverse reactions


Summary of the safety profile

The list below contains adverse reactions seen in clinical trials with pegvisomant.

In clinical studies, for patients treated with pegvisomant (n=550), the majority of adverse reactions to pegvisomant were of mild to moderate intensity, of limited duration and did not require discontinuation of treatment.

The most commonly reported adverse reactions occurring in 10% of patients with acromegaly treated with pegvisomant during the clinical trials were headache 25%, arthralgia 16% and diarrhoea 13%.

List of adverse reactions

The list below contains adverse reactions seen in clinical trials or that were spontaneously reported, classified by system organ class and frequency.

Adverse reactions are listed according to the following categories: Very common: ≥1/10, Common: ≥1/100 to <1/10, Uncommon: ≥1/1,000 to <1/100, Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Uncommon: thrombocytopenia, leukopenia, leukocytosis, haemorrhagic diathesis

Immune system disorders

Uncommon: hypersensitivity reactionsb

Not known: anaphylactic reactionb, anaphylactoid reactionb

Metabolism and nutrition disorders

Common: hypercholesterol aemia, hyperglycaemia, hypoglycaemia, weight increased

Uncommon: hypertriglyceridemia

Psychiatric disorders

Common: abnormal dreams

Uncommon: panic attack, short term memory loss, apathy, confusion, sleep disorder, libido increased

Not known: anger

Nervous system disorders

Very common: headache

Common: somnolence, tremor, dizziness, hypoaesthesia

Uncommon: narcolepsy, migraine, dysgeusia

Eye disorders

Common: eye pain

Uncommon: asthenopia

Ear and labyrinth disorders

Uncommon: Meniere’s disease

Cardiac disorders

Common: oedema peripheral

Vascular disorders

Common: hypertension

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea

Not known: laryngospasmb

Gastrointestinal disorders

Very common: diarrhoea

Common: vomiting, constipation, nausea, abdominal distension, dyspepsia, flatulence

Uncommon: haemorrhoids, salivary hypersecretion, dry mouth, tooth disorder

Hepatobiliary disorders

Common: abnormal liver function tests (e.g. transaminase elevation)

Skin and subcutaneous tissue disorders

Common: hyperhidrosis, contusion, pruritusb, rashb

Uncommon: face oedema, dry skin, increased tendency to bruise, night sweats, erythemab, urticariab

Not known: angioedemab

Musculoskeletal and connective tissue disorders

Very common: arthralgia

Common: myalgia, arthritis

Renal and urinary disorders

Common: haematuria

Uncommon: proteinuria, polyuria, renal impairment

General disorders and administration site conditions

Common: injection site reaction (including injection site hypersensitivity), injection site bruising or bleeding, injection site hypertrophy (e.g. lipohypertro phy)a, influenza-like illness, fatigue, asthenia, pyrexia

Uncommon: feeling abnormal, impaired healing, hunger

a see Description of selected adverse reactions below
b ADR related to hypersensitivity reaction

Description of selected adverse reactions

Most injection site reactions characterised as localised erythemas and soreness, spontaneously resolved with local symptomatic treatment, while pegvisomant therapy continued. Occurrence of injection site hypertrophy has been observed, including lipohypertrophy.

The development of isolated low-titre anti-growth hormone antibodies was observed in 16.9% of patients treated with pegvisomant. The clinical significance of these antibodies is unknown.

Systemic hypersensitivity reactions including anaphylactic/anaphylactoid reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria).have been reported in post marketing use. Some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients.

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