Imbruvica Janssen medicine treats lymphoma, chronic lymphocytes (90 tablets)
Dosage form Box of 90 tablets
Specifications Ibrutinib
Ingredient
| Composition information | Content |
| Ibrutinib | 140mg |
Uses
indications
Imbruvica drug indicated in the following cases:
IMBruvica is indicated for treating adult patients with mantle cell lymphoma (MCL) recurrence or resistance.
Imbruvica is indicated for treatment for adult patients with chronic leukemia (CLL) that has not been previously treated.
IMBruvica mono -therapy or in combination with Bendamustine and Rituximab (Br) is indicated for treatment for adult patients with clots that have been treated at least one previous therapy.
Imbruvica mono therapy is indicated to treat adult patients with hyperactive macroglobulin (Waldenström’s MacrogloBulinaemia-WM) has been treated at least one previous therapy, or in the treatment of one (First-line) for patients who are not suitable for exemptional chemotherapy (Chemo-olmunotherapy).
Pharmacokinus
Pharmacological group treatment: Anti -dystrophy, Protein Kinase inhibitors, ATC code: L01XE27.
Mechanism of action
Ibrutinib is a strong, small, small molecular Tyrosine Kinase Bruton (BTK) inhibitor. IBrutinib creates a covalent bond with a cysteine branch (CYS-481) at the operation of BTK, resulting in the sustainable inhibition of BTK enzyme activity. BTK, a member of Kinase Tec group, is an important signal molecule of B -cell antigen receptor (BCR) and cytokine receptor path.The BCR path is related to the pathology of some B -cell malignant diseases, including MCL, large B -Cell B -Cell Lymphoma (DLBCL), cystic lymphoma and CLL. The key role of BTK in signal transmission through B -cell surface receptors leads to the activation of the paths needed for B cells to move, dynamically and adhesive. Precipable studies show that IBRUTINIB effectively inhibits the proliferation and survival of malignant B cells on In Vivo as well as cell migration and adhesion to the substrate on in vitro.
Hypergly hypernipation of blood lymphocytes
When starting to treat, the increased number of lymphocytes with recovery (such as increased> 50% compared to the original value and absolute amount> 5000/MCL), often accompanied by a decrease in lymph nodes, met in about three -quarters of the number of CLL patients treated with Imbruvica. Also observed this effect on about a third of the number of MCL patients recurrent or resistant to treatment with Imbruvica.
This observed blood lymphocytes are a pharmacological effect and is not considered a progressive disease when there are no other clinical signs. In both types of diseases, typical lymphocytes often appear in the first month of treatment with Imbruvica and often recovered within 8 weeks in MCL patients and 14 weeks in CLL patients. Also observed in some patients with large amounts of circulation lymphocytes (e.g.> 400,000/mCL).
No observation shows increased lymphocytes in WM patients treated with Imbruvica.
affect QT/QTC and Heart Crazy
The influence of IBrutinib on QTC is evaluated over 20 men and healthy women
In a double, random QT study with placebo and active ingredients. At a dose on the dose of treatment at 1680 mg, IBrutinib does not extend the QTC range but causes any clinical manifestations. The largest upper limit of the two sides of the 90% CI reliables for the average difference is initially adjusted between Ibrutinib and the placebo is lower than 10 ms. In this study, the short -term QTC was found (-5.3 ms [90% CI: -9,4; -1,1] at CMAX was 719 ng/ml after the dose higher than the dose at 1680 mg).
Pharmacokinetics
absorption
Ibrutinib is quickly absorbed after drinking with TMAX median from 1 to 2 hours. Absolute bioavailability in fasting conditions (n = 8) is 2.9% (90% CI = 2.1 - 3.9) and double when used with food. Ibrurinib's pharmacokinetics does not change significantly in patients with cell tumors B. Ibrutinib concentration increases when the dose is up to 840 mg. AUC has been recorded in a stable state in the patient with a dose of 560 mg of 953 ± 705 ng h/ml (average ± standard deviation). Using ibrutinib in hunger, concentration (Auclast) reached about 60% compared to 30 minutes ago, 30 minutes later (full food) or 2 hours after breakfast rich in fat.
Ibrutinib has a pH dependent solubility, with lower solubility when pH is higher. In healthy people at hunger, only 560 mg of IBRUTINIB after using omeprazole 40 mg once a day for 5 days, compared to the single Ibrutinib, the average geometry ratio (Geometric Mean Ratios) (90% CI) of AUC0-24, AUCLAST, and CMAX corresponding to 83% (68 - 102%), 92%), 92%) 38% (26 - 53%).
Distribution
In vitro, the recovery of IBRUTINIB with human plasma proteins is 97.3 % and does not depend on the concentration of about 50 to 1000 ng/ml. The apparent distribution volume in a stable state (VD, SS/F) is approximately 10000L.
Metabolism
IBRUTINIB is metabolized mainly by CYP3A4 to form a dihydrodiol metabolism with BTK inhibitor activity about 15 times lower than IBrutinib. The relationship with CYP2D6 in metabolism of IBrutinib seems to be minimal.
Therefore, there is no need to be cautious in patients with other CYP2D6 genotypes.
Elimination
The apparent clearance (Cl/F is about 1000 l/h. The half-life of IBRUTINIB is 4 to 13 hours. After the only dose [14C] -Brutinib is marked with radiation in healthy people, about 90% of the active active ingredient has been excreted within 168 hours, with most (80%) excretion in feces and less than 10% in urine. In feces and not in the urine.
Special population group
Elderly: The pharmacokinetics of the population shows that age does not significantly affect the clearance of iBrutinib from circulation.
Children: Do not conduct pharmacokinetic research of patients under 18 years old.
Sex: Population pharmacokinetics show that gender does not significantly affect the clearance of Ibrutinib from circulation.
Race: There is no enough data to assess the potential effects of racial factors to the pharmacokinetics of IBRUTINIB.
Body: The dynamic data of the population shows the weight (41-146 kg; average [SD]: 83 [19 kg]) has a significant impact on the IBRUTINIB clearance.
Renal failure: IBRUTINIB is minimized in the kidneys; Elimination through urine of metabolites
Hepatic failure: IBRUTINIB is metabolized in the liver. Having conducted a study of liver failure on non -cancer subjects using only 140 mg dose in hunger. The impaired impairment of liver function changes significantly between individuals, but it has recorded the average Ibrutinib level of 2.7; 8.2; and 9.8 times corresponding to the object of mild liver failure (n = 6, child-pgh type A), average (n = 10, child-pug type B) and heavy (n = 8, child pugh type C). The free Ibrutinib part also increases with the level of liver failure, equivalent to 3.0; 3.8 and 4.8% in mild, medium and heavy liver failure subjects compared to 3.3% of plasma achieved in healthy subjects in this study. Increasing the concentration of IBRUTINIB is not linked (Aucunbound, Last) is estimated at 4.1 to 9.8 and 13 times in mild, medium and heavy liver failure objects.
Concentrated with CYP substrate: In vitro research shows that IBRUTINIB is weak inhibited with recovery CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in the digestive tract (but not in the liver) and does not show the inhibitor depends on the time related time related to CYP1A2, CYP2B6, CYP2C8, CYP2C CYP2C19 and CYP2D6. Dihydrodiol metabolites of IBRUTINIB inhibit weak CYP2B6, CYP2C8, CYP2C9, and CYP2D6. Dihydrodiol metabolites are weak, ISOENZE CYP450 on in vitro. Although IBRUTINIB is sensitive to CYP3A4 substrate, it has no clinical effects related to concentration.
Concentrated with the inhibitor/transportation: In vitro studies show that iBrutinib is not the substrate of P-GP, or any other main transportation, except OCT2. Dihydrodiol metabolites and other metabolites are the substrate of P-GP. In vitro, IBRUTINIB inhibit P-GP and BCRP.
Before taking Imbruvica Janssen medicine treats lymphoma, chronic lymphocytes (90 tablets)
How to use
Take Imbruvica once a day with a glass of water at the same time every day. Should swallow the whole capsule with water without opening, breaking or chewing. Do not drink Imbruvica with grapefruit juice or bitter orange juice (Seville Orange).
Dosage
Cell cell lymphocytes (MCL): The recommended dose for MCL treatment is 560 mg (four capsules) once daily.
Chronic leukemia lymphocytes (CLL) and hyperactive disease (Waldenström’s MacrogloBulina-WM):
Dosage recommended for cLL, or single or combined treatment, is 420 mg (three capsules) once a day (see pharmacological learning for details about the combined regimen).
recommended dose for WM treatment is 420 mg (three capsules) once daily.
should be treated continuously until the disease progresses or the patient is intolerant.
Dose adjustment
Average and strong CYP3A4 inhibitors increase the concentration of IBRUTINIB (see warning and interaction).
When combined with medium CYP3A4 inhibitors, low -dose Imbruvica should be used 280 mg once daily (two capsules).
When combined with strong CYP3A4 inhibitors, the Imbruvica dose should be reduced to 140 mg once daily (one capsule) or temporarily suspended up to 7 days.
Should suspend treatment with Imbruvica when there is any new onset or evolved of non -hematetical toxicity ≥ 3, neutropeniasis with infection or fever ≥ level 3, or hematetical toxicity of level 4. If recurrent toxicity, one daily dose should be reduced by one tablet (140 mg). If necessary, consider a 140 mg. Stop treatment if the toxicity is persistent or relapse after two dose reduction.
Recommendation recommendations are described below:
Side Effects
Safety records based on gross data from 981 patients treated with Imbruvica in three clinical studies phase 2 and four random study phase 3 and from after -sales experience. MCL patients are treated in clinical studies using Imbruvica at a dose of 560 mg once daily and the CLL or WM patient is treated in clinical studies at a dose of 420 mg once a day. All patients in clinical research use Imbruvica until the disease progresses or is intolerant.
The most common adverse reaction (≥ 20%) is diarrhea, neutrophils, hemorrhage (such as purple patches), musculoskeletal pain, nausea, rash and fever. The most common 3/4 adverse reaction (≥ 5%) is neutropenia, pneumonia, thrombocytopenia and leukopenia with fever.
Table adverse reaction
The adverse reactions in patients with B -cell malignant tumors are treated with IBrutinib and the adverse reaction after the drug is marketed listed in Table 9 by organ and frequency group. The frequency is determined as follows: Very common (≥ 1/10), common (≥ 1/100 to
The adverse reaction of the drug is reported in clinical research or post -commercial studies in malignant patients with B+cells
Warnings
Before using the drug you need to read the instructions carefully and refer to the information below.
contraindicated
IMBruvica drugs contraindicated in the following cases:
Be cautious when using
Ceremony related to bleeding
There has been a report on hemorrhage events in patients with Imbruvica treatment with or without platelets, including small hemorrhage events such as bruising, nose bleeding and hemorrhagic spots; And large hemorrhage events, sometimes death, including gastrointestinal bleeding, intracranial hemorrhage and blood urine.
Patients are eliminated from phase 2 and 3 of Imbruvica if they need warfarin or other vitamin K antagonists. Warfarin should not be used or other vitamin K antagonists along with Imbruvica. Supplementary foods should be avoided such as fish oil and vitamin E. Using Imbruvica in patients who need anticoagulant drugs or platelet function inhibitors can increase the risk of bleeding, need to be careful, especially if used against anticoagulants.
should stop treating Imbruvica at least 3 to 7 days before and after surgery depending on the type of surgery and the risk of bleeding.
Unknown the mechanism of events related to bleeding. Patients with congenital bleeding organs do not participate in research.
leukostasis (Leukostasis)
There was a report on leukemia in patients treated with Imbruvica. A large number of lymph cells in the circulation (> 400,000/mcL) may increase the risk. Consider suspension of Imbruvica. The patient should be closely monitored and supported to support support including rehydration and/or reducing the number of cells.
Infections
Infections (including hemorrhage, neutropenia, bacterial, viral or fungus infections) met in patients treated with Imbruvica. Some of these infections need to be hospitalized and die. Most patients with death infections also have neutropenia. Patients should be monitored with fever, neutropenia and infections and should be treated with appropriate anti -infection if needed. Preventive attention in the standard care for patients increasing the risk of opportunistic infections.
There have been reports on cases of Cases of Progressive Multifocal Leuk whileNencephalopathy (PML) including deaths after using ibrutinib in the context of previous treatment or simultaneously with immunosuppressive therapy. Doctors should think of PML in distinguished diagnosis in patients with new signs or symptoms or worsening of neuropathy, awareness or behavior. If PML is suspected, it is necessary to evaluate appropriate diagnosis and stop treatment until PML excludes. If there is a doubt, it is recommended to see a neurologist and conduct the appropriate PML diagnosis including MRI scan that often prefer to choose MRI with contrast, JC virus DNA test in cerebrospinal fluid and nerve evaluation.
Hemocalus reduction: Reducing blood cells due to treatment of degree 3 or 4 (neutropenia, thrombocytopenia and anemia) have been reported in patients treated with Imbruvica. Monitor the whole blood formula every month.
Interstitial disabling (ILD): ILD reports in patients treated with Imbruvica. Monitor the patient on the ILD point symptoms. If symptoms appear, stop imbruvica and appropriate iLD control. If the symptoms are persistent, consider the risk and benefits of Imbruvica treatment and follow the dose adjustment instructions.
arrhythmia
There have been reports of atrial, atrial and ventricular tachycardia cases in patients treated with Imbruvica. Atrial and atrial fibrillation is reported mainly in patients with risk factors for heart, hypertension, acute infection, and a history of atrial fibrillation. Clinically monitoring the manifestation of arrhythmia in all patients. Patients with symptoms of arrhythmia or new onset of shortness of breath, dizziness or fainting should be clinically evaluated and if necessary, electrocardiogram (ECG).
Patients with signs and/or symptoms of ventricular tachycardia should temporarily suspend Imbruvica and need clinical assessments full benefits/risk before re -treatment.
Patients who have had atrial fibrillation before that they need anticoagulant treatment should consider choosing another therapy instead of Imbruvica. If the patient appears atrial fibrillation when treated with Imbruvica, it is advisable to assess the entire risk of thrombosis. If the patient is at high risk and when not suitable for other Imbruvica replacement therapy, consider strict control with anticoagulant drugs.
Tumor solving syndrome: Tumor solving syndrome is reported when treated with Imbruvica. Patients with the risk of tumor syndrome are people with high tumor burden before treatment. Need to monitor patients closely and carefully.
Non -melanoma skin cancer: Non -melan skin cancer is reported on a regular basis in patients treated with Imbruvica rather than patients treated with drugs in gross comparative studies random phase 3. Monitoring of non -melan skin cancer manifestations in patients using imbruvica.
Virus activity: There has been a report on hepatitis B regeneration in patients using Imbruvica. Hepatitis B virus (HBV) should be determined before starting treatment with Imbruvica. Recommended advice from doctors who have experience in treating hepatitis B in patients with positive HBV tests. If the patient has a positive hepatitis B serum, it is necessary to advise liver disease experts before starting treatment and the patient should be monitored and controlled according to the local medical standards to prevent hepatitis B.
Medicine - Drug interaction: Using medium or strong CYP3A4 inhibitors simultaneously with Imbruvica can cause increased IBRUTINIB levels and the result is a higher risk of toxicity. In contrast, the use of CYP3A4 induction drugs can cause Imbruvica levels and the consequence is the risk of ineffective treatment. Therefore, if possible, avoid using Imbruvica simultaneously with CYP3A4 inhibitors and strong or medium CYP3A4 induction drugs and should consider treating simultaneously only when the benefits are clear compared to the potential risk. The patient should closely monitor the toxic signs of IMBRUVICA if the CYP3A4 inhibitors must be used (see the dose and usage and interaction). If you have to take CYP3A4 induction drug, monitor patients closely signs of lack of treatment with Imbruvica.
Women have the ability to reproduce
Women who have the ability to reproduce must use highly effective contraceptive methods during the time of using imbruvica (see used in pregnant and lactating women).
The effect of the drug on the ability to drive and operate machinery
has a fatigue, dizziness and fainting report in some patients using Imbruvica and need to consider when assessing the ability to drive or operate the patient's machines.
Using drugs for women during pregnancy and lactation
Pregnancy:
Do not use Imbruvica for women during pregnancy. There is no data on the use of Imbruvica for pregnant women. Animal research shows that toxicity on fertility (see Pre -clinical safety).
Women have the ability to reproduce/contraceptive in women:
Based on animal findings, Imbruvica can be harmful to the embryo when used for pregnant women. Women should avoid pregnancy when using Imbruvica and until 3 months after the end of treatment. Therefore, women have the ability to reproduce must use highly effective contraception when using Imbruvica and up to 3 months after the end of treatment. So far, it is unclear whether IBRUTINIB has reduced the effectiveness of hormonal contraceptives, and therefore women use hormonal contraceptives, so they use additional diaphragm methods.
Reproduction:
Do not observe the impact on fertility in male or female rats when using a maximum research dose of up to 100 mg/kg/day (equivalent dose in people 16 mg/kg/day) (see preclinical safety). There is no data on the fertility of IBrutinib on humans.
Breastfeeding period:
It is unclear whether IBRUTINIB or its metabolites will excrete in the mother's milk. It is not possible to rule out the risk of babies/emulsion. Should stop breastfeeding during treatment with Imbruvica.
Drug interaction
IBRUTINIB is metabolized mainly by the enzyme 3A4 of Cytochrome P450 (CYP3A4).
Medications increase the level of ibrutinib in plasma
Use Ibrutinib along with strong or medium CYP3A4 inhibitors that can cause increased IBRUTINIB levels and should avoid using the same strong CYP3A4 inhibitors.
Strong CYP3A4 inhibitors: simultaneously used with ketoconazole, is a strong CYP3A4 inhibitor, over 18 healthy people who see the concentration of IBRUTINIB (CMAX and AUC) increased, respectively 29 and 24 times. Simulation of hunger conditions shows strong CYP3A4 inhibitors, Clarithromycin, which can cause an increase in Ibrutinib's AUC by factor 14. Patients with B -cell malignant tumors are using Ibrutinib with food, using strong CYP3A4 inhibitors Voriconzole causing CMAX increase 6.7 times and AUC 5.7 times. Strong CYP3A4 inhibitors should be avoided (such as ketoconazole, indinavir, nelfinavir, ritonavir, saqinavir, clarithromycin, telithromycin, iTraconazole, nefazodon, cobicistat, voriconazole and posaconazole). If the benefits are superior and need to use a powerful CYP3A4 inhibitor, the IBRUTINIB dose reduces 140 mg (a capsule) during the use of inhibitors or temporary suspension of treatment (7 days or less). Monitor patients closely on toxicity and comply with the recommendation of adjusting dose if needed.
Average CYP3A4 inhibitors: In patients with B -cell malignant tumors that are taking ibrutinib with the same food, when used with the same erythromycin, CYP3A4 inhibitors cause CMAX increasing 3.4 times and AUC 3.0 times. If the medium CYP3A4 inhibitors are prescribed (e.g. fluconazole, erythromycin, amprenavir, aprepitant, Atazanavir, Ciprofloxacin, Crizotinib, Diltiazem, Fosamprenavir, Imatinib, Verapamil, Amiodarone and DroneDarone) follicles) During the use of inhibitors. Monitor patients closely on toxicity and follow the dose adjustment guidelines if necessary.
Mild CYP3A4 inhibitors: Simulation using hunger conditions shows that light CYP3A4 inhibitors, Azithromycin and Fluvoxamine, can cause AUC's increase in Ibrutinib
Drugs can reduce the level of ibrutinib in plasma
Use Ibrutinib along with CYP3A4 induction can reduce the level of ibrutinib in plasma.
Concomitance Rifampicin, a powerful CYP3A4 induction drug, over 18 healthy people who see the concentration (CMAX and AUC) of IBRUTINIB decreased by 92 and 90%respectively. Avoid simultaneous use of strong or medium CYP3A4 induction drugs (such as carbamazepine, rifampicin, phenytoin). Contraindicated use of st. John during treatment with IBrutinib due to its effectiveness. Consider replacement drugs with less CYP3A4 touch. If the benefits are superior and need to use strong or medium CYP3A4 induction drugs, it is necessary to monitor patients closely on reducing treatment effectiveness (see contraindications and warnings). Mild CYP3A4 induction drugs can be used with IBRUTINIB but should monitor patients closely on the risk of effective reduction.
Ibrutinib has a pH dependent solubility, with lower solubility when pH is higher. It was observed that CMAX was lower in healthy objects when hungry when using the only Ibrutinib dose of 560 mg after using omeprazole 40 mg once a day for 5 days (see pharmacokinetics). There is no evidence of lower CMAX will have significant clinical changes, and drugs that increase the gastric pH (such as proton pump inhibitors) are used unlimited in key clinical studies.
Drugs may be changed in plasma concentrations due to Ibrutinib
IBRUTINIB is a P-GP and is a breast cancer protein inhibitor (BCRP) on in vitro. Because there is no clinical data on this interaction, IBRUTINIB cannot be excluded inhibiting P-GP and BCRP in the intestine after taking a dose of treatment. To minimize the ability to interact in the gastrointestinal tract, with oral narrow treatment, P-GP or BCRP substrates such as digoxin or methotrexate should be used at least 6 hours before or after ibrutinib. IBRUTINIB can inhibit the BCRP in the liver and increase the concentration of drugs that are metabolized in the liver through BCRP intermediaries like rosuvastatin.
Based on in vitro data, at IBRUTINIB intestinal concentration is a weak CYP3A4 inhibitor who recovers and therefore can increase the concentration of CYP3A4 substrate sensitive to the intestinal metabolites in the intestine. There is no clinical data on this interaction. Caution should be careful when using IBRUTINIB with oral CYP3A4 substrate with narrow treatment (such as dihydroergotamine, ergotamine, fentanyl, cyclosporine, syrolimus and tacrolimus).
Based on in vitro data, IBRUTINIB is a weak CYP2B6 induction and may have the ability to influence other enzymes and shipping enzymes and shipping substances that are air -conditioning through the Andrancan structural receptor (Constitutive Androstan Receptor - CAR) such as CYP2C9, CYP2C19, UGT1A1 and MRP2. It is unknown clinical links but the substrate concentration of CYP2B6 (such as Efavirenz and Bupropion) and of air -conditioning substrates can be reduced when used with IBRUTINIB.
Storage
Leave a cool place, avoid light, temperature below 30⁰C.
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