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Ayvakyt is a brand name for Avapritinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Unresectable or metastatic gastrointestinal stromal tumour (GIST) AYVAKYT is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) harbouring the platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation. Advanced systemic…
Verbatim from this product's EMA label. Tap a section to expand.
1). Posology Unresectable or metastatic GIST For GIST, the recommended starting dose of avapritinib is 300 mg orally once daily, on an empty stomach (see Method of administration). Treatment should be continued until disease progression or unacceptable toxicity occurs.
Patient selection for treatment of unresectable or metastatic GIST harbouring the PDGFRA D842V mutation should be based on a validated test method. Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided.
5). Advanced systemic mastocytosis For AdvSM, the recommended starting dose of avapritinib is 200 mg orally once daily, on an empty stomach (see Method of administration). This once daily 200 mg dose is also the maximum recommended dose that must not be exceeded by patients with AdvSM.
Treatment should be continued until disease progression or unacceptable toxicity occurs. 4). Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. 5). Indolent systemic mastocytosis For ISM, the recommended dose of avapritinib is 25 mg orally once daily, on an empty stomach (see Method of administration).
This once daily 25 mg dose is also the maximum recommended dose that must not be exceeded in patients with ISM. Treatment of ISM should be continued until disease progression or unacceptable toxicity occurs. 5). Dose modifications for adverse reactions Irrespective of indication, interruption of treatment with or without dose reduction may be considered to manage adverse reactions based on severity and clinical presentation.
The dose should be adjusted as recommended, based on safety and tolerability. Dose reductions and modifications for adverse reactions are recommended in patients with GIST, AdvSM or ISM and are provided in Tables 1 and 2. Table 1. Recommended dose reductions for AYVAKYT for adverse reactions Dose reduction GIST (starting dose 300 mg) AdvSM (starting dose 200 mg) ISM (starting dose 25 mg)* First 200 mg once daily 100 mg once daily 25 mg once every other day Second 100 mg once daily 50 mg once daily - Third - 25 mg once daily - * ISM patients requiring dose reduction below 25 mg once every other day must discontinue treatment.
Table 2. 4) All Grades Permanently discontinue AYVAKYT. 4) Grade 1 Continue at the same dose, reduce dose or interrupt until improvement to baseline or resolution. Resume at the same dose or at a reduced dose. Grade 2 or Grade 3 Interrupt therapy until improved to baseline, Grade 1, or resolution.
8. 8). Liver function (transaminases and bilirubin) should be monitored regularly in patients with GIST or AdvSM receiving avapritinib. 5). 5). Photosensitivity reaction Exposure to direct sunlight must be avoided or minimised due to the risk of phototoxicity associated with avapritinib.
Patients must be instructed to use measures such as protective clothing and sunscreen with high sun protection factor (SPF). Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.
5 Interaction with other medicinal products and other forms of interaction Active substances that may have an effect on avapritinib Strong and moderate CYP3A inhibitors Co-administration of avapritinib with a strong CYP3A inhibitor increased avapritinib plasma concentrations and may result in increased adverse reactions.
2-fold, relative to a 200 mg dose of avapritinib administered alone. Concomitant use of avapritinib with strong or moderate CYP3A inhibitors (such as antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin; active substances to treat human immunodeficiency virus infections/acquired immunodeficiency syndrome (HIV/AIDS) such as cobicistat, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir; as well as conivaptan for hyponatremia and boceprevir to treat hepatitis) including grapefruit or grapefruit juice should be avoided.
If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dose of avapritinib should be reduced from 300 mg to 100 mg orally once daily for patients with GIST, and from 200 mg to 50 mg orally once daily for patients with AdvSM.
4). Strong and moderate CYP3A inducers Co-administration of avapritinib with a strong CYP3A inducer decreased avapritinib plasma concentrations and may result in decreased efficacy of avapritinib. Co-administration of rifampicin (600 mg once daily for 18 days) with a single 400 mg dose of avapritinib on Day 9 in healthy subjects decreased avapritinib Cmax by 74% and AUC0-inf by 92%, relative to a 400 mg dose of avapritinib administered alone.
Haemorrhages Avapritinib has been associated with an increased incidence of haemorrhagic adverse reactions, including serious and severe adverse reactions, like gastrointestinal haemorrhage and intracranial haemorrhage, in patients with unresectable or metastatic GIST and AdvSM.
8). Routine surveillance of haemorrhagic adverse reactions in patients with GIST or AdvSM must include physical examination. g. warfarin and phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding. Intracranial haemorrhages Adverse reactions of intracranial haemorrhage occurred in GIST and AdvSM patients who received avapritinib.
Before initiating avapritinib at any dose the risk for intracranial haemorrhage should be carefully considered in patients with potential increased risk including those with a history of vascular aneurysm, intracranial haemorrhage, cerebrovascular accident within the prior year, concomitant use of anticoagulants or thrombocytopenia.
g. severe headache, vision problems, somnolence, and/or focal weakness) during treatment with avapritinib must interrupt dosing of avapritinib and inform their healthcare professional immediately. Brain imaging by magnetic resonance imaging (MRI) or computed tomography (CT) may be performed at the discretion of the physician based on severity and the clinical presentation.
2). 8). The exact mechanism is unknown. There is no clinical study experience using avapritinib in patients with brain metastases. 8). The exact mechanism is unknown. The incidence of intracranial haemorrhage was higher in patients with platelet counts <50 x 109/L and in patients with a starting dose of ≥300 mg.
Considering the above, a platelet count must be performed prior to initiating therapy. Avapritinib is not recommended in patients with platelet counts <50 x 109/L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks regardless of baseline platelet count.
1.
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Resume at the same dose or at a reduced dose. Grade 4 Permanently discontinue AYVAKYT. 8) Grade 3 or Grade 4 Interrupt therapy until less than or equal to Grade 2. Resume at the same dose or at a reduced dose, if warranted. 4) count is ≥ 50 x 109/L, then resume at reduced dose (see Table 1).
If platelet count does not recover above 50 x 109/L, consider platelet support. 0 ** Adverse reactions with impact on Activities of Daily Living (ADLs) for Grade 2 or higher adverse reactions Missed doses If a dose of avapritinib is missed, the patient should make up for the missed dose unless the next scheduled dose is within 8 hours (see Method of administration).
If the dose has not been taken at least 8 hours prior to the next dose, then that dose must be omitted and the patient should resume treatment with the next scheduled dose. If vomiting occurs after taking a dose of avapritinib, the patient must not take an additional dose but continue with the next scheduled dose.
2). 1). 0 times ULN and any AST). A modified starting dose of avapritinib is recommended for patients with severe hepatic impairment (Child-Pugh Class C). 2). Renal impairment No dose adjustment is recommended for patients with mild and moderate renal impairment (creatinine clearance [CLcr] 30-89 mL/min estimated by Cockcroft-Gault).
Avapritinib has not been studied in patients with severe renal impairment (CLcr 15-29 mL/min) or end-stage renal disease […]
g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone, bosentan, efavirenz, etravirine, modafinil, dabrafenib, nafcillin or Hypericum perforatum, also known as St. John’s wort) should be avoided.
Effect of avapritinib on other active substances Co-administration of avapritinib 300 mg once daily with oral midazolam increased the midazolam AUC and Cmax by 51% and 20%, respectively. These results indicate that avapritinib 300 mg once daily is a weak inhibitor of CYP3A.
Physiologically based pharmacokinetic simulations predict that avapritinib is not an inhibitor of CYP3A at doses of 200 mg once daily and below. Therefore, caution must be exercised with co-administration of avapritinib 300 mg once daily with narrow therapeutic index CYP3A substrates as their plasma concentrations may be increased.
Avapritinib is an inhibitor of P-gp, BCRP, MATE1, MATE2-K, and BSEP in vitro. Therefore, avapritinib has the potential to alter concentrations of co-administered substrates of these transporters. 3). The pregnancy status of women of reproductive potential must be verified prior to initiating AYVAKYT treatment.
10 Women of childbearing potential must use effective contraception during treatment and for 6 weeks after the last dose of AYVAKYT. Males with female partners of childbearing potential must use effective contraception during treatment and for 2 weeks after the last dose of AYVAKYT.
Patients must be advised to contact their healthcare professional immediately if they become pregnant, or if pregnancy is suspected, while taking AYVAKYT. Pregnancy There are no data from the use of avapritinib in pregnant women. 3).
AYVAKYT is not recommended during pregnancy and in women of childbearing potential not using contraception. If AYVAKYT is used during pregnancy or if the patient becomes pregnant while taking AYVAKYT, the patient must be advised of the potential risk to the foetus.
Breast-feeding It is unknown whether avapritinib/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding must be discontinued during treatment with AYVAKYT and for 2 weeks following the final dose.
Fertility There are no data on the effect of AYVAKYT on human fertility. 3). 7 Effects on ability to drive and use machines AYVAKYT may cause adverse reactions such as cognitive effects that may influence the ability to drive and […]
After 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently as clinically 7 indicated) if values are less than 75 x 109/L, every 4 weeks if values are between 75 and 100 x 109/L, and as clinically indicated if values are greater than 100 x 109/L.
Manage platelet counts of <50 x 109/L by temporarily interrupting avapritinib. 2). Thrombocytopenia was generally reversible by reducing or interrupting avapritinib in clinical studies. The maximum dose for patients with AdvSM must not exceed 200 mg once daily.
8). The mechanism of the cognitive effects is not known. It is recommended that patients with GIST or AdvSM are clinically monitored for signs and symptoms of cognitive events such as new or increased forgetfulness, confusion, and/or difficulty with cognitive functioning.
Patients with GIST or AdvSM must notify their healthcare professional immediately if they experience new or worsening cognitive symptoms. 2). In clinical studies conducted in patients with GIST and AdvSM, dose reductions or interruptions improved Grade ≥2 cognitive effects compared to no action.
In patients with ISM, cognitive effects can be one of the disease symptoms. Patients with ISM must notify their healthcare professional if they experience new or worsening cognitive symptoms. Fluid retention Occurrences of fluid retention, including severe cases of localised oedema (facial, periorbital, peripheral oedema and/or pleural effusion) or generalised oedemas, have been reported with a frequency category of at least common in patients with unresectable or metastatic GIST taking avapritinib.
8). 8). Other localised oedemas (laryngeal oedema) have been reported uncommonly. Therefore, it is recommended that patients with GIST or AdvSM be evaluated for these adverse reactions including regular assessment of weight and respiratory symptoms.
An unexpected rapid weight gain or respiratory symptoms indicating fluid retention must be carefully investigated and appropriate supportive care and therapeutic measures, such as diuretics, should be undertaken. For […]