Semblix
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEMPLIX (SCEMBLIX)
Composition:
Active substance: asciminib;
1 tablet contains 20 mg or 40 mg of asciminib (as asciminib hydrochloride);
Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, polyvinyl alcohol, titanium dioxide (E 171), magnesium stearate, talc, anhydrous colloidal silicon dioxide, lecithin, xanthan gum, iron oxide red (E172);
tablets of 20 mg: iron oxide yellow (E172);
tablets of 40 mg: iron oxide black (E172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
- 20 mg tablets: pale yellow, round, biconvex, film-coated tablets with beveled edges, approximately 6 mm in diameter, with the company logo imprinted on one side and "20" on the other;
- 40 mg tablets: violet-white, round, biconvex, film-coated tablets with beveled edges, approximately 8 mm in diameter, with the company logo imprinted on one side and "40" on the other.
Pharmacotherapeutic group. Antineoplastic agents, protein kinase inhibitors, BCR-ABL tyrosine kinase inhibitors. Asciminib. ATC code L01E A06.
Pharmacological Properties
Pharmacodynamics
Mechanism of Action
Asciminib is a potent inhibitor of the ABL/BCR::ABL1 tyrosine kinase. It suppresses the kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket.
Pharmacodynamic Effects
In vitro, asciminib inhibits ABL1 tyrosine kinase activity with mean IC50 values below 3 nmol. In patient-derived cancer cells, asciminib specifically inhibited the proliferation of cells harboring BCR::ABL1 with IC50 values ranging from 1 to 25 nmol. In engineered cells expressing the mutant and wild-type T315I in the BCR::ABL1 gene, asciminib inhibited cell growth with mean IC50 values of 0.61 ± 0.21 and 7.64 ± 3.22 nmol, respectively.
In murine xenograft models of chronic myeloid leukemia, asciminib dose-dependently suppressed tumor growth in the presence of both mutant and wild-type T315I in the BCR::ABL1 gene, with tumor regression observed at doses above 7.5 mg/kg or 30 mg/kg twice daily.
Cardiac Electrophysiology
Asciminib treatment is associated with exposure-dependent QT interval prolongation.
The concentration–response relationship between asciminib concentration and the predicted mean change from baseline in QT interval corrected using Fridericia’s formula (ΔQTcF) was evaluated in 239 patients with Philadelphia chromosome-positive chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) who received asciminib at doses ranging from 10 to 280 mg twice daily and 80 to 200 mg once daily. The predicted mean ΔQTcF was 3.35 ms (upper bound of 90% CI [confidence interval]: 4.43 ms) with asciminib 40 mg twice daily (see section "Special Warnings and Precautions for Use").
Clinical Efficacy and Safety
Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase
The clinical efficacy and safety of asciminib in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase who had experienced treatment failure or intolerance to two or more tyrosine kinase inhibitors (TKIs) were evaluated in a multicenter, randomized, active-controlled, open-label Phase III study (ASCEMBL). Resistance to the last TKI was defined as lack of hematologic or cytogenetic response by 3 months; BCR::ABL1 (per International Scale [IS]) > 10% by 6 months or later; > 65% Ph+ metaphases by 6 months or > 35% by 12 months or later; loss of complete hematologic response, partial cytogenetic response, complete cytogenetic response (CCyR), or major molecular response (MMR) at any time; emergence of new BCR::ABL1 mutations potentially conferring resistance to the investigational drug or clonal evolution of Ph+ metaphases at any time. Intolerance to the last TKI was defined as non-hematologic toxicity unresponsive to optimal management or recurrent hematologic toxicity after dose reduction to the lowest recommended dose.
In this study, a total of 233 patients were randomized in a 2:1 ratio and stratified by major cytogenetic response status at baseline to receive either asciminib 40 mg twice daily (N = 157) or bosutinib 500 mg once daily (N = 76). Patients with known T315I and/or V299L mutations at any time prior to study entry were excluded from the ASCEMBL study. Patients continued treatment until unacceptable toxicity or loss of therapeutic effect occurred.
The patient population with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase consisted of 51.5% women and 48.5% men, with a median age of 52 years (range: 19 to 83 years). Of the 233 patients, 18.9% were over 65 years of age and 2.6% were over 75 years. Patients of Caucasian race accounted for 74.7%, Asian race for 14.2%, and Black race for 4.3%. Of these 233 patients, 80.7% and 18% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1, respectively. Patients who had previously received 2, 3, 4, and 5 or more lines of TKI therapy accounted for 48.1%, 31.3%, 14.6%, and 6%, respectively.
The median duration of randomized treatment was 103 weeks (range: 0.1 to 201 weeks) in patients receiving asciminib and 31 weeks (range: 1 to 188 weeks) in those receiving bosutinib.
Results
The primary endpoint of the study was the rate of MMR at 24 weeks, and a key secondary endpoint was the rate of MMR at 96 weeks. MMR was defined as a BCR::ABL1 ratio ≤ 0.1% on the International Scale (IS). Other secondary endpoints included the rate of CCyR at 24 and 96 weeks, defined as the absence of Ph+ metaphases in bone marrow with a minimum of 20 metaphases analyzed.
Key results from the ASCEMBL study are summarized in the table below.
Efficacy outcomes in patients who received two or more tyrosine kinase inhibitors (ASCEMBL)
| |
Asciminib 40 mg twice daily |
Bosutinib 500 mg once daily |
Difference (95% CI)1 |
p-value |
| MR4.0 rate, % (95% CI) at 24 weeks |
N = 157 25.48 (18.87, 33.04) |
N = 76 13.16 (6.49, 22.87) |
12.24 (2.19, 22.30) |
0.0292 |
| MR4.0 rate, % (95% CI) at 96 weeks |
37.58 (29.99, 45.65) |
15.79 (8.43, 25.96) |
21.74 (10.53, 32.95) |
0.0012 |
| CCyR rate, % (95% CI) at 24 weeks |
N = 1033 40.78 (31.20, 50.90) |
N = 623 24.19 (14.22, 36.74) |
17.30 (3.62, 30.99) |
Not formally assessed |
| CCyR rate, % (95% CI) at 96 weeks |
39.81 (30.29, 49.92) |
16.13 (8.02, 27.67) |
23.87 (10.3, 37.43) |
Not formally assessed |
| 1 Adjusted for baseline major cytogenetic response status. 2 Cochran-Mantel-Haenszel test, two-sided, stratified by baseline major cytogenetic response status. 3 CCyR analysis based on data from patients who did not have CCyR at baseline. |
||||
Primary and key secondary endpoints were the only ones officially assessed for statistical significance according to the protocol.
In the ASCEMBL study, 12.7% of patients receiving asciminib and 13.2% of patients receiving bosutinib had one or more BCR::ABL1 mutations detected at baseline. MMR at 24 weeks was observed in 35.3% and 24.8% of patients receiving asciminib with or without any BCR::ABL1 mutation at baseline. MMR at 24 weeks was observed in 25% and 11.1% of patients receiving bosutinib with or without any mutation at baseline. The frequency of MMR at 24 weeks in patients whose randomized treatment was third, fourth, fifth, or later line of TKI therapy was 29.3%, 25%, and 16.1% in patients receiving asciminib, and 20%, 13.8%, and 0% in patients receiving bosutinib.
The Kaplan–Meier estimated percentage of patients receiving asciminib who maintained MMR for at least 72 weeks was 96.7% (95% CI: 87.4, 99.2).
Pharmacokinetics
Absorption
Asciminib is rapidly absorbed, with median time to maximum plasma concentration (Tmax) reached within 2–3 hours after oral administration regardless of dose. The steady-state geometric mean (geoCV %) values of Cmax and AUCtau are 793 ng/mL (49%) and 5262 ng·h/mL (48%), respectively, after administration of 40 mg twice daily. Physiologically based models predict approximately 100% absorption of asciminib, while bioavailability is approximately 73%.
The bioavailability of asciminib may be reduced when coadministered with oral medicinal products containing the excipient hydroxypropyl-β-cyclodextrin. Coadministration of multiple doses of oral itraconazole solution containing hydroxypropyl-β-cyclodextrin at a total dose of 8 g per dose with a 40 mg dose of asciminib reduced asciminib AUCinf by 40.2% in healthy volunteers.
Effect of food
Food intake reduces the bioavailability of asciminib, with high-fat food having a greater effect on asciminib pharmacokinetics than low-fat food. AUC of asciminib was reduced by 62.3% with high-fat food and by 30% with low-fat food compared to fasting conditions (see section "Posology and method of administration").
Distribution
The apparent volume of distribution of asciminib at steady state is 111 liters, based on population pharmacokinetic analysis. Asciminib distributes primarily into plasma, with a mean blood-to-plasma ratio of 0.58 independent of dose, based on in vitro data. Asciminib is 97.3% bound to human plasma proteins independent of dose.
Biotransformation
Asciminib is primarily metabolized via CYP3A4-mediated oxidation and glucuronidation mediated by UGT2B7 and UGT2B17. Asciminib is the major circulating component in plasma (92.7% of administered dose).
Elimination
Asciminib is primarily eliminated in feces and to a minor extent in urine. After a single oral dose of 80 mg [14C]-labeled asciminib, 80% and 11% of the dose were recovered in feces and urine, respectively, in healthy volunteers. Unchanged asciminib excreted in feces accounted for 56.7% of the administered dose.
Asciminib is excreted in bile via breast cancer resistance protein (BCRP).
The total oral clearance of asciminib is 6.31 L/h based on population pharmacokinetic analysis. The elimination half-life of asciminib is 5.2 hours when administered at 40 mg twice daily.
Linearity/Non-linearity
Asciminib demonstrated a less-than-dose-proportional increase in steady-state exposure (AUC and Cmax) over the dose range of 10 to 200 mg once or twice daily.
The geometric mean accumulation ratio increases approximately twofold. Steady state is achieved within 3 days with 40 mg twice daily dosing.
Assessment of drug interaction potential in vitro
CYP450 and UGT enzymes
In vitro, asciminib reversibly inhibits CYP3A4/5, CYP2C9, and UGT1A1 at plasma concentrations achieved with 40 mg twice daily dosing.
Transporters
Asciminib is a substrate of BCRP and P-gp.
Asciminib inhibits BCRP and P-gp, with Ki values of 24.3 and 21.7 µmol, respectively.
Multiple pathways
Asciminib is metabolized through multiple pathways, including CYP3A4, UGT2B7, and UGT2B17 enzymes, and is excreted in bile via the BCRP transporter. Medicinal products that inhibit or induce CYP3A4, UGT, and BCRP pathways may alter asciminib exposure.
Special patient populations
Sex, race, body weight
Sex, race, or body weight do not have a clinically significant effect on systemic exposure to asciminib.
Renal impairment
A dedicated renal impairment study was conducted in 6 patients with normal renal function (absolute glomerular filtration rate [aGFR] ≥ 90 mL/min) and 8 patients with severe renal impairment not requiring dialysis (aGFR 15 to < 30 mL/min). AUCinf and Cmax of asciminib increased by 56% and 8%, respectively, in patients with severe renal impairment compared to those with normal renal function after a single 40 mg oral dose of asciminib (see section "Posology and method of administration"). Population pharmacokinetic models showed a 11.5% increase in median steady-state AUC0–24h of asciminib in patients with mild or moderate renal impairment compared to patients with normal renal function.
Hepatic impairment
A dedicated hepatic impairment study was conducted in 8 patients with normal liver function, mild hepatic impairment (Child–Pugh class A, 5–6 points), moderate hepatic impairment (Child–Pugh class B, 7–9 points), or severe hepatic impairment (Child–Pugh class C, 10–15 points). The AUCinf of asciminib increased by 22%, 3%, and 66% in patients with mild, moderate, and severe hepatic impairment, respectively, compared to patients with normal liver function after a single 40 mg oral dose of asciminib (see section "Posology and method of administration").
Clinical characteristics
Indications
For the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML CP), previously treated with two or more tyrosine kinase inhibitors (see section "Pharmacodynamics").
Contraindications
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Interaction with other medicinal products and other forms of interaction
Medicinal products that may induce torsades de pointes
Caution should be exercised when administering asciminib concomitantly with medicinal products that may induce torsades de pointes, including bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin, or pimozide (see section "Pharmacodynamics").
Medicinal products that may reduce plasma concentrations of asciminib
Strong CYP3A4 inducers
Concomitant administration of a strong CYP3A4 inducer (rifampicin) decreased asciminib AUCinf by 15% and increased Cmax by 9% in healthy volunteers receiving a single 40 mg dose of asciminib.
Caution is advised when administering asciminib concomitantly with strong CYP3A4 inducers, including carbamazepine, phenobarbital, phenytoin, or St. John’s wort (Hypericum perforatum), as they may reduce the efficacy of asciminib.
Medicinal products whose plasma concentrations may be altered by asciminib
CYP3A4 substrates with a narrow therapeutic index
Concomitant administration of asciminib with a CYP3A4 substrate (midazolam) increased AUCinf and Cmax of midazolam by 28% and 11%, respectively, in healthy volunteers receiving asciminib 40 mg twice daily.
Caution is advised when administering asciminib concomitantly with CYP3A4 substrates with a narrow therapeutic index, including such CYP3A4 substrates as fentanyl, alfentanil, dihydroergotamine, or ergotamine (see section "Pharmacokinetics"). Dose adjustment of asciminib is not required.
CYP2C9 substrates
Concomitant administration of asciminib with a CYP2C9 substrate (warfarin) increased AUCinf and Cmax of S-warfarin by 41% and 8%, respectively, in healthy volunteers receiving asciminib 40 mg twice daily.
Caution is advised when administering asciminib concomitantly with CYP2C9 substrates with a narrow therapeutic index, including phenytoin or warfarin (see section "Pharmacokinetics"). Dose adjustment of asciminib is not required.
Special Warnings and Precautions for Use
Myelosuppression
Thrombocytopenia, neutropenia, and anemia have been observed in patients treated with asciminib. Severe (Grade III–IV according to NCI CTC [National Cancer Institute Common Terminology Criteria for Toxicity]) thrombocytopenia and neutropenia have been reported during treatment with asciminib (see section "Adverse Reactions"). In most cases, myelosuppression is reversible and managed by temporary discontinuation of the drug. A complete blood count should be performed every two weeks during the first 3 months of treatment and then monthly or as clinically indicated. Patients should be closely monitored for signs and symptoms of myelosuppression.
Depending on the severity of thrombocytopenia and/or neutropenia, the dose of the drug should be reduced or temporarily or permanently discontinued as specified in the table "Recommendations for dose modification of asciminib to manage adverse reactions" (see section "Dosage and Administration").
Pancreatic toxicity
Pancreatitis and asymptomatic elevations in serum lipase and amylase levels, including severe reactions, have occurred in patients receiving asciminib (see section "Adverse Reactions").
Serum lipase and amylase levels should be assessed monthly during treatment with asciminib or as clinically indicated. Patients should be closely monitored for signs and symptoms of pancreatic toxicity. More frequent monitoring is recommended in patients with a history of pancreatitis. If elevated serum lipase and amylase levels are accompanied by abdominal symptoms, treatment should be temporarily interrupted and appropriate diagnostic measures undertaken to exclude pancreatitis (see section "Dosage and Administration").
Depending on the degree of elevation in serum lipase and amylase levels, the dose of the drug should be reduced or temporarily or permanently discontinued as specified in the table "Recommendations for dose modification of asciminib to manage adverse reactions" (see section "Dosage and Administration").
QT interval prolongation
Prolongation of the QT interval has been observed in patients receiving asciminib (see section "Adverse Reactions").
An electrocardiogram (ECG) is recommended before initiating treatment with asciminib, and cardiac monitoring should be performed during treatment as clinically indicated. Hypokalemia and hypomagnesemia should be corrected prior to starting asciminib and monitored during treatment as clinically indicated.
Caution should be exercised when using asciminib concomitantly with medicinal products that may induce torsades de pointes (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Pharmacodynamics").
Arterial hypertension
Arterial hypertension, including severe arterial hypertension, has been observed in patients receiving asciminib (see section "Adverse Reactions").
During treatment with asciminib, arterial hypertension and other cardiovascular risk factors should be regularly monitored and managed with standard antihypertensive therapy.
Hepatitis B virus reactivation
Hepatitis B virus (HBV) reactivation has been reported in patients who are chronic carriers of HBV following treatment with other BCR::ABL1 tyrosine kinase inhibitors (TKIs). Patients should be tested for HBV infection prior to initiating treatment with asciminib. HBV carriers requiring treatment with asciminib should be closely monitored for signs and symptoms of active HBV infection during therapy and for several months after discontinuation of therapy.
Lactose
This medicinal product is contraindicated in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Sodium
This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".
Use during pregnancy or breastfeeding
Females of reproductive potential / Contraception
Pregnancy should be ruled out in females of reproductive potential prior to initiating treatment with asciminib.
Sexually active females of reproductive potential are advised to use effective contraception (methods with a failure rate of less than 1% per year) during treatment with asciminib and for at least 3 days after discontinuation of therapy.
Pregnancy
There are no or limited data on the use of asciminib in pregnant women. Animal studies have shown reproductive toxicity. Asciminib is not recommended during pregnancy and should not be administered to females of reproductive potential who are not using effective contraception. The patient should be informed of the potential risk to the fetus if asciminib is used during pregnancy or if pregnancy occurs while taking asciminib.
Breastfeeding
It is unknown whether asciminib/metabolites are excreted in human breast milk. There are no data on the effect of asciminib on breastfed newborns/infants or on milk production. Because of the potential for serious adverse reactions in breastfed newborns/infants, women should not breastfeed during treatment with asciminib and for at least 3 days after therapy has ended.
Fertility
There are no data on the effect of asciminib on human fertility. In rat fertility studies, asciminib did not affect male or female reproductive function in rats. However, adverse effects on sperm motility and sperm count were observed in rats administered doses of 200 mg/kg/day. The relevance of these findings to humans is unknown.
Ability to affect the speed of reaction when driving or operating machinery. Asciminib has no or negligible effect on the ability to drive or operate machinery. However, patients experiencing dizziness, fatigue, or other adverse effects (see section "Adverse Reactions") that could potentially impair their ability to drive safely or operate machinery are advised to refrain from such activities.
Administration and Dosage
Treatment should be prescribed by a physician experienced in the diagnosis and treatment of patients with leukemia.
Dosage
The recommended dose is 40 mg twice daily, approximately 12 hours apart.
Missed Dose
If a dose is missed by less than 6 hours, it should be taken as soon as remembered, and the next dose should be taken according to the regular schedule.
If a dose is missed by more than approximately 6 hours, it should be skipped, and the next dose should be taken according to the regular schedule.
Duration of Treatment
Treatment with asciminib should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
Dose Modifications Due to Adverse Reactions
The initial dose is 40 mg twice daily; the reduced dose is 20 mg twice daily. Dose adjustments may be made based on individual safety and tolerability, according to the table below. Asciminib treatment should be permanently discontinued if the patient is unable to tolerate the 20 mg twice-daily dose.
Recommendations for dose modification of asciminib to manage adverse reactions
Adverse reactions |
Dose modification |
| Thrombocytopenia and/or neutropenia |
|
| ANC < 1.0 × 109/L and/or platelets < 50 × 109/L |
Discontinue asciminib until ANC recovers to ≥ 1 × 109/L and/or platelets recover to ≥ 50 × 109/L. If symptoms resolve:
In case of recurrent severe thrombocytopenia and/or neutropenia, discontinue asciminib until ANC recovers to ≥ 1 × 109/L and platelets recover to ≥ 50 × 109/L, then resume at a reduced dose. |
| Asymptomatic elevation of amylase and/or lipase |
|
| Elevation > 2.0 × ULN |
Discontinue asciminib until levels return to < 1.5 × ULN.
|
| Non-hematologic adverse reactions |
|
| Grade 3 or higher adverse reactions1 |
Discontinue asciminib until improvement to Grade 1 or lower.
|
| ANC — absolute neutrophil count. Platelets — platelet count. ULN — upper limit of normal 1According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. |
|
Special patient groups
Elderly patients. Dose adjustment is not required for patients aged 65 years and older.
Renal impairment. Patients with mild, moderate or severe renal impairment do not require dose adjustment (see section "Pharmacokinetics").
Hepatic impairment. Patients with mild, moderate or severe hepatic impairment do not require dose adjustment (see section "Pharmacokinetics").
Method of administration
Sembricx is intended for oral use. The film-coated tablets should be swallowed whole with a glass of water. The tablets must not be split, crushed or chewed.
The tablets should be taken orally. The medicinal product should not be taken during meals. Food should be avoided for at least 2 hours before and for at least 1 hour after administration of asciminib (see section "Pharmacokinetics").
Children
Safety and efficacy of Sembricx in children (under 18 years of age) have not been established. Data are lacking.
Overdose
In clinical studies, asciminib was administered at doses up to 280 mg twice daily without signs of increased toxicity.
In all cases of overdose, general supportive measures and symptomatic therapy should be initiated.
Adverse Reactions
Summary of safety profile
The most common adverse reactions of any grade (frequency ≥ 20%) in patients receiving asciminib were musculoskeletal pain (37.1%), upper respiratory tract infections (28.1%), thrombocytopenia (27.5%), fatigue (27.2%), headache (24.2%), arthralgia (21.6%), increased pancreatic enzyme levels (21.3%), abdominal pain (21.3%), diarrhea (20.5%), and nausea (20.2%).
The most common adverse reactions of grade ≥ 3 (frequency ≥ 5%) in patients receiving asciminib were thrombocytopenia (18.5%), neutropenia (15.7%), increased pancreatic enzyme levels (12.4%), arterial hypertension (8.7%), and anemia (5.3%).
Serious adverse reactions occurred in 12.4% of patients receiving asciminib. The most frequent serious adverse reactions (frequency ≥ 1%) were pleural effusion (2.5%), lower respiratory tract infections (2.2%), thrombocytopenia (1.7%), pyrexia (1.4%), pancreatitis (1.1%), non-cardiac chest pain (1.1%), and vomiting (1.1%).
List of adverse reactions
The overall safety profile of asciminib was evaluated in 356 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic and accelerated phases from the phase III A2301 (ASCEMBL) pivotal study and the phase I X2101 study. In the ASCEMBL study, patients received asciminib as monotherapy at a dose of 40 mg twice daily. In the X2101 study, patients received asciminib as monotherapy at doses ranging from 10 to 200 mg twice daily and from 80 to 200 mg once daily. Based on pooled data, the median exposure to asciminib was 116 weeks (range: 0.1 to 342 weeks).
Adverse reactions observed during clinical studies (table below) are listed by system organ class according to the Medical Dictionary for Regulatory Activities (MedDRA), with frequency of occurrence indicated, the most frequent listed first. Within each frequency group, adverse reactions are listed in order of decreasing severity. The following frequency categories were used: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Adverse reactions observed during clinical studies with asciminib
| Body systems |
Frequency |
Adverse reactions |
| Infections and infestations |
Very common |
Upper respiratory tract infection1 |
| Common |
Lower respiratory tract infection2, influenza |
|
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia3, neutropenia4, anemia5 |
| Uncommon |
Febrile neutropenia |
|
| Immune system disorders |
Uncommon |
Increased sensitivity |
| Metabolism and nutrition disorders |
Very common |
Dyslipidemia6 |
| Common |
Decreased appetite, hyperglycemia |
|
| Nervous system disorders |
Very common |
Headache, dizziness |
| Eye disorders |
Common |
Dry eyes, blurred vision |
| Cardiac disorders |
Common |
Increased heart rate |
| Vascular disorders |
Very common |
Arterial hypertension7 |
| Respiratory, thoracic and mediastinal disorders |
Very common |
Cough |
| Common |
Pleural effusion, dyspnea, non-cardiac chest pain |
|
| Gastrointestinal disorders |
Very common |
Increased pancreatic enzyme activity8, vomiting, diarrhea, nausea, abdominal pain9 |
| Common |
Pancreatitis10 |
|
| Hepatobiliary disorders |
Very common |
Elevated liver enzymes11 |
| Common |
Elevated blood bilirubin12 |
|
| Skin and subcutaneous tissue disorders |
Very common |
Rash13 |
| Common |
Urticaria |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Musculoskeletal pain14, arthralgia |
| General disorders |
Very common |
Fatigue15, pruritus |
| Common |
Pyrexia16, edema17 |
|
| Investigations |
Common |
Elevated creatine phosphokinase |
| Uncommon |
QT interval prolongation on electrocardiogram |
|
| 1 Upper respiratory tract infection includes: upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. 2 Lower respiratory tract infections include: pneumonia, bronchitis, and tracheobronchitis. 3 Thrombocytopenia includes: thrombocytopenia and decreased platelet count. 4 Neutropenia includes: neutropenia and decreased neutrophil count. 5 Anemia includes: anemia, decreased hemoglobin level, and normocytic anemia. 6 Dyslipidemia includes: hypertriglyceridemia, elevated blood cholesterol, hypercholesterolemia, elevated blood triglycerides, hyperlipidemia, and dyslipidemia. 7 Arterial hypertension includes: arterial hypertension and elevated blood pressure. 8 Increased pancreatic enzyme activity includes: elevated lipase levels, elevated amylase levels, and hyperlipasemia. 9 Abdominal pain includes: abdominal pain and upper abdominal pain. 10 Pancreatitis includes: pancreatitis and acute pancreatitis. 11 Elevated liver enzymes includes: elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated gamma-glutamyl transferase, and elevated transaminases. 12 Elevated blood bilirubin includes: elevated blood bilirubin, elevated conjugated bilirubin, and hyperbilirubinemia. 13 Rash includes: rash and maculopapular rash. 14 Musculoskeletal pain includes: limb pain, back pain, myalgia, bone pain, musculoskeletal pain, neck pain, chest musculoskeletal pain, and musculoskeletal discomfort. 15 Fatigue includes: fatigue and asthenia. 16 Pyrexia includes: pyrexia and increased body temperature. 17 Edema includes: edema and peripheral edema. |
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Description of individual adverse reactions
Myelosuppression
Thrombocytopenia was observed in 27.5% of patients receiving asciminib; grade 3 and grade 4 reactions were observed in 6.7% and 11.8% of patients, respectively. Among patients with thrombocytopenia of grade ≥3, the median time to first occurrence of reactions was 6 weeks (range: 0.14 to 64 weeks), and the median duration of any reaction was 1.71 weeks (95% CI: 1.43–2). Thrombocytopenia led to permanent discontinuation of treatment in 2% of patients receiving asciminib, while temporary discontinuation of asciminib due to this adverse reaction occurred in 12.6% of patients.
Neutropenia was observed in 19.4% of patients receiving asciminib; grade 3 and grade 4 reactions were observed in 7.3% and 8.4% of patients, respectively. Among patients with neutropenia of grade ≥3, the median time to first occurrence of reactions was 6 weeks (range: 0.14 to 180 weeks), and the median duration of any reaction was 1.79 weeks (95% CI: 1.29–2). Neutropenia led to permanent discontinuation of treatment in 1.1% of patients receiving asciminib, while temporary discontinuation of asciminib due to this adverse reaction occurred in 9.6% of patients.
Anemia was observed in 12.9% of patients receiving asciminib; grade 3 reactions were observed in 5.3% of patients. Among patients with anemia of grade ≥3, the median time to first occurrence of reactions was 30 weeks (range: 0.4 to 207 weeks), and the median duration of any reaction was 0.9 weeks (95% CI: 0.43–2.14). Temporary discontinuation of asciminib due to this adverse reaction occurred in 0.6% of patients.
Toxic effects on the pancreas
Pancreatitis was observed in 2.5% of patients receiving asciminib; grade 3 reactions were observed in 1.1% of patients. All such reactions occurred in the phase I study (X2101). Pancreatitis led to permanent discontinuation of treatment in 0.6% of patients receiving asciminib, while temporary discontinuation of asciminib due to this adverse reaction occurred in 1.1% of patients. Asymptomatic elevations in serum lipase and amylase levels were observed in 21.3% of patients receiving asciminib; grade 3 and grade 4 reactions were observed in 10.1% and 2.2% of patients, respectively. Among patients with elevated pancreatic enzyme activity, temporary discontinuation of asciminib due to this adverse reaction occurred in 2.2% of patients.
QT interval prolongation
QT interval prolongation on electrocardiogram was observed in 0.8% of patients receiving asciminib. In the ASCEMBL clinical trial, one patient experienced QTcF interval prolongation exceeding 500 milliseconds (ms), with an increase in QTcF interval of more than 60 ms from baseline. Additionally, one patient experienced QTcF interval prolongation, with an increase in QTcF interval of more than 60 ms from baseline.
Arterial hypertension
Arterial hypertension was observed in 18.5% of patients receiving asciminib; grade 3 and grade 4 reactions were observed in 8.4% and 0.3% of patients, respectively. Among patients with arterial hypertension of grade ≥3, the median time to first occurrence of reactions was 14 weeks (range: 0.1 to 156 weeks). Temporary discontinuation of asciminib due to this adverse reaction occurred in 0.8% of patients.
Laboratory abnormalities
Decreased phosphate levels were observed as a laboratory abnormality in 17.9% (all grades) and 6.4% (grades 3/4) of 156 patients receiving asciminib at a dose of 40 mg twice daily.
Reporting suspected adverse reactions
Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store at temperatures not exceeding 25 °C. Keep in the original packaging to protect from moisture. Store out of reach of children.
Packaging. 10 tablets in a blister; 2 or 6 blisters per carton.
Prescription status. Prescription only.
Manufacturer. Novartis Pharma Stein AG.
Manufacturer's address and location of business operations. Schaffhauserstrasse, 4332 Stein, Switzerland.