Trabectedin

Registered South African indications:

• Advanced liposarcoma
• Advanced leiomyosarcoma
• Relapsed ovarian cancer

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding
• Concurrent serious or uncontrolled infection
• Coadministration with yellow fever vaccine

Cautions

• Pregnancy
• Men and women of childbearing potential
• Severe renal impairment
• Hepatic impairment
• Elderly
• Risk factors for rhabdomyolysis
  - History of medicinal products associated with rhabdoymyolysis e.g. statins
• Peripheral venous line administration
• Risk factors for cardiac dysfunction
  - Left ventricular ejection fraction less than the lower limit of normal
  - Prior cumulative anthracycline dose of >300mg/m²
  - >65 years
  - History of cardiovascular disease (especially in those with cardiac medication)
• Baseline neutrophil counts <1500 cells/mm3
  Baseline platelets count <100 000 cells/mm3
  Creatine phosphokinase > 2.5 times the upper limit of normal
  Risk factors for cardiomyopathy
  Decreased cardiac function
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Advanced soft tissue sarcoma 
  - After failure of anthracyclines or ifosfamide, or unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients
• Relapsed platinum-sensitive ovarian cancer (additional agent required)
  - In combination with pegylated liposomal doxorubicin

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• No sufficient clinical data on exposed pregnancies are available. However, based on its known mechanism of action, trabectedin may cause serious birth defects when administered during pregnancy
• Trabectedin crossed the placenta when administered to pregnant rats
• Trabectedin should not be used during pregnancy. If pregnancy occurs during treatment, the patient must be informed of the potential risk to the foetus and be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns
• Women of childbearing potential must use effective contraception during treatment and 3 months thereafter, and immediately inform the treating physician if a pregnancy occurs. If pregnancy occurs during treatment the possibility of genetic counselling should be considered

Breastfeeding

• Contraindicated
• It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milk has not been established in animals
• Breastfeeding is contraindicated during treatment and 3 months thereafter

Fertility

• Men of fertile age must use effective contraception during treatment and 5 months after treatment
• Trabectedin can have genotoxic effects. Advice on conservation of ovules or sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with trabectedin
• Genetic counselling is also recommended for patients wishing to have children after therapy

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available
  Studies including patients with renal insufficiency (CrCl <30ml/min for monotherapy, and CrCl <60ml/min for the combination regimen) have not been conducted and therefore trabectedin must not be used in this patient population

Hepatic Impairment

• Caution; dose adjustment recommended
  Special caution is advised and dose adjustments may be necessary since systemic exposure to trabectedin is increased and the risk of hepatotoxicity might be increased. Patients with increased serum bilirubin levels at baseline must not be treated with trabectedin. Liver function tests should be monitored during treatment with trabectedin as dose adjustments may be indicated

Elderly            

• Caution; no dose adjustment recommended 
  No specific studies in older people have been performed. It seems that plasma clearance and distribution volume of trabectedin are not influenced by age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Headache
• Peripheral sensory neuropathy
• Dizziness
• Paraesthesia
• Fatigue
• Syncope (ovarian cancer only)

Cardiovascular Disorders

• Palpitations (ovarian cancer only)
• Left ventricular dysfunction (ovarian cancer only)
• Hypotension
• Flushing
• Capillary leak syndrome (with fatal outcomes)
• Oedema

Respiratory Disorders

• Dyspnoea
• Cough
• Pulmonary embolism (ovarian cancer only)
• Pulmonary oedema

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Diarrhoea
• Stomatitis
• Abdominal pain
• Dyspepsia

Hepatobiliary Disorders

• Hyperbilirubinemia
• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase
• Increased gamma-glutamyltransferase
• Hepatic failure

Genitourinary Disorders

• Increased blood creatinine 

Endocrine and Metabolic Disorders

• Dehydration
• Decreased appetite
• Hypokalaemia
• Decreased weight
• Increased blood creatinine

Musculoskeletal Disorders

• Myalgia
• Arthralgia
• Back pain
• Increased blood creatine phosphokinase
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Palmar-plantar erythrodysaesthesia syndrome (ovarian cancer only)
• Alopecia
• Rash
• Skin hyperpigmentation (ovarian cancer only)
• Injection site reaction
• Mucosal inflammation (ovarian cancer only)
• Extravasation
• Soft tissue necrosis

Immune, Blood and Lymphatic System Disorders

• Neutropenic infection
• Sepsis
• Septic shock
• Neutropenia
• Thrombocytopenia
• Anaemia
• Leukopenia
• Febrile neutropenia
• Hypersensitivity
• Pyrexia
• Decreased blood albumin

Sensory Disorders

• Dysgeusia

• Yellow fever vaccine
• CYP3A4 inhibitors
• Oral ketoconazole
• Fluconazole
• Ritonavir
• Clarithromycin
• Aprepitant
• CYP3A4 inducers
• Rifampicin
• Phenobarbital
• Agents associated with hepatotoxicity 
• Live attenuated vaccines
• Phenytoin 
• P-glycoprotein inhibitors
• Cyclosporin
• Verapamil

Other

• St John's wort
• Alcohol

• Full blood count with differential
• Hepatic function
• Renal function
• Echocardiogram or multigated acquisition scan
• Creatine phosphokinase

Specific cases may require:

• Pregnancy test

Additional observations

• Signs and symptoms of:
  - Capillary leak syndrome
  - Extravasation (infusion site)

Trabectedin binds to the minor groove of deoxyribonucleic acid (DNA), bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the cell cycle.

Injection (per vial) 1mg

• Yondelis 1mg (Key Oncologics) originator