Oral RET fusion-positive metastatic non-small cell lung cancer
Adult: 400 mg once daily. Continue treatment until disease progression or unacceptable toxicity occurs. Dose reduction, dosing interruption, or discontinuation may be required according to the type and severity of adverse reactions (refer to detailed product guidelines).
Oral RET-mutant metastatic medullary thyroid cancer
Adult: In patients who require systemic therapy: 400 mg once daily. Continue treatment until disease progression or unacceptable toxicity occurs. Dose reduction, dosing interruption, or discontinuation may be required according to the type and severity of adverse reactions (refer to detailed product guidelines). Child: ≥12 years Same as adult dose.
Oral RET fusion-positive metastatic thyroid cancer
Adult: In patients who require systemic therapy and who are refractory to radioactive iodine therapy (if such therapy is appropriate): 400 mg once daily. Continue treatment until disease progression or unacceptable toxicity occurs. Dose reduction, dosing interruption, or discontinuation may be required according to the type and severity of adverse reactions (refer to detailed product guidelines). Child: ≥12 years Same as adult dose.
Special Patient Group
Patients taking strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors: If the current pralsetinib dose is 300 mg or 400 mg once daily, decrease the dose to 200 mg once daily. If the current pralsetinib dose is 200 mg once daily, decrease the dose to 100 mg once daily. After discontinuing treatment with the inhibitor, resume the previous pralsetinib dose after 3-5 elimination half-lives of the inhibitor have passed.
Patients taking strong CYP3A4 inducers: Double the current pralsetinib dosage starting on Day 7 of concomitant treatment with the strong CYP3A4 inducer. After discontinuing treatment with the strong CYP3A4 inducer, resume the previous pralsetinib dose after at least 14 days.
Hepatic Impairment
Moderate or severe: Not recommended.
Administration
Should be taken on an empty stomach.
Contraindications
Uncontrolled hypertension. Lactation.
Special Precautions
Patient with history of cardiac arrhythmias or QT interval prolongation; risk factors for tumour lysis syndrome (e.g. rapidly growing tumours, high tumour burden, renal dysfunction, dehydration). Patients taking strong CYP3A4 inhibitors, combined P-gp and strong CYP3A4 inhibitors, or strong CYP3A4 inducers. Withhold treatment for ≥5 days before elective surgery; defer administration for ≥2 weeks after major surgery and until adequate wound healing. Moderate or severe hepatic impairment. Children. Pregnancy.
Adverse Reactions
Significant: Hypertension; tumour lysis syndrome (particularly in patients with medullary thyroid cancer); hepatotoxicity (e.g. severe transaminase elevations); increased risk of impaired wound healing, prolongation of QT interval. Blood and lymphatic system disorders: Anaemia, neutropenia, leucopenia, lymphopenia, thrombocytopenia. Gastrointestinal disorders: Taste disorder, dry mouth, nausea, vomiting, diarrhoea, constipation, abdominal pain, stomatitis. General disorders and administration site conditions: Pyrexia, oedema, fatigue. Hepatobiliary disorders: Hyperbilirubinaemia. Investigations: Increased blood creatine phosphokinase, blood creatinine, blood alkaline phosphatase. Metabolism and nutrition disorders: Hyperphosphataemia, hypophosphataemia, hypocalcaemia, hypoalbuminaemia, hyponatraemia. Musculoskeletal and connective tissue disorders: Musculoskeletal pain. Nervous system disorders: Headache. Renal and urinary disorders: UTI. Respiratory, thoracic and mediastinal disorders: Cough, pneumonia. Skin and subcutaneous tissue disorders: Rash. Potentially Fatal: Haemorrhagic events, ILD/pneumonitis.
Patient Counseling Information
This drug may cause fatigue, if affected, do not drive or operate machinery. Women of childbearing potential must use a highly effective non-hormonal method of birth control during treatment and for ≥2 weeks after stopping treatment. If the use of a hormonal birth control method is unavoidable, a condom must be used in combination with the hormonal method. Men with partners of childbearing potential should use effective birth control method during treatment and for ≥1 week after stopping treatment. Discontinue breastfeeding during treatment and for 1 week after the last dose.
Monitoring Parameters
Before treatment initiation, screen for the presence of rearranged during transfection (RET) gene fusion (for non-small cell lung cancer or thyroid cancer) or RET gene mutation (for medullary thyroid cancer); evaluate pregnancy status in women of childbearing potential; and perform HBV screening. Monitor ALT and AST (at baseline, every 2 weeks during the 1st 3 months, then monthly thereafter, and as necessary); blood pressure (at baseline, after 1 week, at least monthly thereafter, and as necessary); ECG and serum electrolytes (at the end of the 1st week and 1st month of treatment, then periodically as necessary). Correct hypokalaemia, hypomagnesaemia, and hypocalcaemia before initiation and during treatment. Assess for signs and symptoms of ILD/pneumonitis (e.g. fever, cough, dyspnoea), haemorrhage, impaired wound healing; tumour lysis syndrome (particularly in patients with medullary thyroid cancer). Observe growth plates in adolescents with open growth plates.
Drug Interactions
May increase plasma concentration with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors (e.g. ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, nefazodone). May decrease plasma concentration with strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifabutin, rifampicin). May diminish the therapeutic effect of hormonal contraceptives.
Food Interaction
May increase plasma concentration with grapefruit or Seville oranges. May decrease plasma concentration with St. John's wort. Delayed time to peak plasma concentration with high-fat meal.
Action
Description: Mechanism of Action: Pralsetinib, an antineoplastic agent, is an inhibitor of multiple receptor tyrosine kinases, including wild-type and mutated rearranged during transfection (RET) isoforms. It has shown antitumour activity in cultured cells and animal models harbouring oncogenic RET fusions or mutations including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L, and RET V804M. Pharmacokinetics: Absorption: Time to peak plasma concentration: 2-4 hours; delayed from 4-8.5 hours with high-fat meal (compared to fasted state). Distribution: Volume of distribution: 303 L. Plasma protein binding: Approx 97%. Metabolism: Metabolised mainly by CYP3A4 and UGT1A4, minimally by CYP2D6 and CYP1A2. Excretion: Via faeces (approx 73%; 66% as unchanged drug); urine (approx 6%; approx 5% as unchanged drug). Elimination half-life: Approx 16 hours (single dose); approx 20 hours (multiple doses).
Chemical Structure
Pralsetinib Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 129073603, Pralsetinib. https://pubchem.ncbi.nlm.nih.gov/compound/Pralsetinib. Accessed Mar. 29, 2023.
Storage
Store between 15-30°C. Protect from moisture. Follow applicable procedures for receiving, handling, administration, and disposal.
L01EX23 - pralsetinib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.
References
Anon. Pralsetinib. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 03/02/2023.Anon. Pralsetinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 03/02/2023.Gavreto 100 mg Hard Capsules (Roche Products Limited). MHRA. https://products.mhra.gov.uk. Accessed 03/02/2023.Gavreto 100 mg Hard Capsules (Roche Thailand Ltd.). MIMS Thailand. http://www.mims.com/thailand. Accessed 03/02/2023.Gavreto Capsule (Genentech, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 03/02/2023.Joint Formulary Committee. Pralsetinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/02/2023.
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