Treatment with the drug Faridak should begin a doctor who has experience in the use of antitumor drugs.
The recommended initial dose of Faridak is 20 mg once a day orally on days 1, 3, 5, 8, 10 and 12 of a 21 day cycle. At the initial stage, patients should receive 8 cycles of treatment. In the case of clinical benefit, the patient is recommended to conduct another 8 treatment cycles. The total duration of treatment is up to 16 cycles (48 weeks).
The drug Faridak should be used inside once a day, every day at the same time, swallowing whole and squeezed with water. The drug Faridak can be taken regardless of the meal.
Capsules of Faridak should not be opened, broken or chewed. If the dose is missed, it can be taken later, but no later than 12 hours after the scheduled time of admission. In case of vomiting, the patient should not take the drug in addition; it is necessary to take the next capsule at the usual time.
The drug Faridak is used in combination with bortezomib and dexamethasone, as indicated in Tables 1 and 2 (before the start of therapy it is recommended to read the instructions for the use of bortezomib and dexamethasone, in particular, to assess the need for dose correction of bortezomib and dexamethasone).
The recommended dose of bortezomib is 1.3 mg / m2 in the form of an injection. The recommended dose of dexamethasone is 20 mg orally, the drug is applied on a full stomach.
Table 1. Recommended doses and method of using Faridak in combination with bortezomib and dexamethasone (cycles 1-8)
| Cycles 1-8 (3-week cycles) | Week 1 Days | Week 2 Days | Week 3 |
| Faridak | 1 | | 3 | | 5 | | | 8 | | 10 | | 12 | | | Period of rest |
| Bortezomib | 1 | | | 4 | | | | 8 | | | 11 | | | | Period of rest |
| Dexamethasone | 1 | 2 | | 4 | 5 | | | 8 | 9 | | 11 | 12 | | | Period of rest |
Table 2. Recommended doses and method of using Faridak in combination with bortezomib and dexamethasone (cycles 9-16)
| Cycles 9-16 (3-week cycles) | Week 1 Days | Week 2 Days | Week 3 |
| Faridak | 1 | | 3 | | 5 | | | 8 | | 10 | | 12 | | | Period of rest |
| Bortezomib | 1 | | | | | | | 8 | | | | | | | Period of rest |
| Dexamethasone | 1 | 2 | | | | | | 8 | 9 | | | | | | Period of rest |
Monitoring Recommendations
Clinical blood count with counting of shaped elements: This study should be conducted prior to the use of the drug Faridak. The initial number of platelets should be ≥100 * 109/ l, and the initial absolute number of neutrophils (AMN) is ≥1.0 * 109/ l. During treatment, hematological indicators should be monitored regularly, especially for the purpose of early detection of thrombocytopenia. Before the start of any treatment cycle with Faridak in combination with bortezomib and dexamethasone, the platelet count should be ≥100 * 109/ l. Blood tests obtained during the "rest period", for example on the 15th and 18th days, especially in patients aged 65 years and older, as well as in patients with an initial platelet count of less than 150 * 10, should be evaluated additionally.9/ l.
Electrocardiogram (ECG): panobinostat can increase the length of the interval QTc; The ECG should be performed prior to treatment and repeated before each treatment cycle. Prior to the use of the drug Faridak, the length of the interval QTcF should be <480 ms.
The level of electrolytes in the blood: the content of electrolytes in the blood, especially the content of potassium, magnesium and phosphorus, should be measured before the start of treatment and periodically measured later, especially in patients with diarrhea. Violations of the water-electrolyte balance should be adjusted according to clinical indications.
Dysfunction of the liver: before the start of treatment and during it is necessary to assess liver function, especially in patients with impaired liver function.
Thyroid function control
One clinical study reported mild hypothyroidism in patients treated with pannobinostat in combination with bortezomib and dexamethasone, with some patients requiring treatment. It is necessary to monitor the function of the thyroid gland and pituitary gland with the determination of the concentration of the corresponding hormones (for example, free T4 and TSH) according to clinical indications.
Dose change
Depending on the individual tolerability, a dose change and / or drug regimen may be required. If the patient has adverse side reactions, the doctor must decide on the regimen for further treatment with the drug.
If the dose of Faridak is required to be reduced, it should be reduced in stages, each time by 5 mg (for example, from 20 mg to 15 mg or 15 mg to 10 mg). The dose should not be lower than 10 mg / day. The drug should always be used according to the same scheme (3-week cycles of treatment).
Thrombocytopenia
It is necessary to determine the number of platelets before each injection of bortezomib. If a patient develops thrombocytopenia, a temporary withdrawal of Faridak and a subsequent decrease in his dose may be required. In patients with thrombocytopenia of grade 3 (<50 * 109/ l, complicated by bleeding) or degree 4 (<25 * 109/ l) by criteria for the evaluation of adverse events (Common Terminology Criteria - CTC), the drug Faridak should be temporarily canceled and resumed treatment in a reduced dose after the severity of thrombocytopenia decreases to ≤2. In the presence of clinical indications, transfusion of platelet mass may be required. If despite the change in the treatment scheme described above, the severity of thrombocytopenia does not change for the better and / or if the patient needs repeated transfusions of platelet mass, it is recommended to evaluate the possibility of canceling therapy. A dose change of bortezomib may also be required.
Adverse reactions from the digestive tract
Gastrointestinal side reactions with the use of the drug Faridak occur very often. Patients who experience diarrhea, nausea, or vomiting may need to temporarily stop the drug or reduce its dose, see Table 3.
Table 3.Recommendations for dose changes in case of adverse reactions from the gastrointestinal tract
| Unfavorable adverse reaction | Degree of severity on the day of administration of the drug | Change initial dose of pannobinostat | Dose panbinostat with a decrease in the degree of expression to ≤1 | Change initial dose of bortezomib | Dose bortezomib with a decrease in severity to ≤1 |
| Diarrhea | Degree 2 despite the use of antidiarrheal agents | Temporarily cancel a drug | Resume treatment at the same dose | Temporarily cancel a drug | Resume treatment in a reduced dose or replace it with the application once a week |
| Degree 3 despite the use of antidiarrheal agents | Temporarily cancel a drug | Resume treatment in a reduced dose | Temporarily cancel a drug | Resume treatment in a reduced dose or in the same dose, but once a week |
| Degree 4 despite the use of antidiarrheal agents | Finally abolish | | Finally abolish | |
At the first sign of intestinal colic, liquid stools or diarrhea, it is recommended that the patient be prescribed antidiarrhoeic agents. In case of nausea of 3rd degree of severity or vomiting of 3-4 degrees of severity, despite the use of anti-emetics, it is necessary to cancel the treatment with a paninostat.Treatment is resumed at a reduced dose with a decrease in the severity of symptoms to grade 1.
Prophylactic antiemetics (for example, granisetron, prochlorperesin) should be used at the doctor's discretion and in accordance with accepted clinical recommendations.
Neutropenia
Neutropenia may require a temporary or permanent dose reduction. Instructions for the temporary cancellation and reduction of the dose of Faridak are given in Table. 4.
Table 4. Recommendations for dose change in the case of neutropenia
| The degree of neutropenia on the day of application of the drug | Change in the initial dose of the pannobinostat | The dose of panobinostat after a decrease in the degree of neutropenia to 2 (<1,5-1,0*109/ l) | Change initial dose of bortezomib | Dose bortezomib with a decrease in severity to neutropenia 2 |
| Neutropenia of degree 3 (<1.0-0.5 * 109/ l) | Temporarily cancel a drug | Resume treatment at the same dose | Temporarily cancel a drug | Resume treatment at the same dose |
| Neutropenia of degree 4 (<0.5 * 109/ l) or febrile neutropenia (<1.0 * 109/ l and fever ≥38.5 ° C) | Temporarily cancel a drug | Resume treatment in a reduced dose | Temporarily cancel a drug | Resume treatment at the same dose |
In the case of grade 3 or 4 neutropenia, the physician should consider the possibility of using growth factors. The question of definitive drug cancellation should be considered if neutropenia does not improve despite dose changes and / or the addition of colony-stimulating factors and / or in the event of severe secondary infections.
Interval lengthening QTc
If prior to the application of the preparation of Faridak interval QT elongated (initial length of the interval QTcF ≥480 ms), the start of treatment should be postponed until the length of the interval QTcF does not decrease to <480 ms. In addition, prior to the initiation of treatment with Faridak, correction of such water-electrolyte disturbances, such as changes in potassium, magnesium and phosphorus in the serum, should be performed.
In the case of an extension of the interval QT on the background of treatment should be the following activities:
- should temporarily stop taking the drug if the length of the interval QTcF ≥480 ms or greater than the original value by more than 60 ms;
- if within 7 days the length of the interval QT the treatment is resumed either at the same dose (if the phenomenon occurred for the first time), or in a reduced dose (if the interval QT elongated repeatedly);
- if within 7 days the length of the interval QT not normalized, the drug should be canceled;
- if the length of the interval QTcF exceeded 500 ms, the drug Faridak should be finally abolished.
Other Adverse Reactions
For patients who have severe adverse adverse reactions other than thrombocytopenia, neutropenia, lengthening of the interval QTc or disorders of the gastrointestinal tract, it is recommended:
- In case of repeated adverse reactions of degree 2 according to ITS or reactions of degree 3-4 according to ITS, temporarily discontinue the drug until the degree of CTC decreases to ≤1 and resumes treatment at a reduced dose;
- In case of repeated adverse reactions of degree 3-4 according to ITS, the possibility of further dose reduction should be considered before reducing the degree of adverse events to ≤1 in CTC.
Patients of special categories
Patients with impaired renal function
In patients with cancer and impaired renal function from mild to severe degrees of exposure, the exposure to pannobinostat in the blood plasma does not change, so there is no need for correction of the initial dose of the drug. In patients with end-stage CRF and patients on hemodialysis, the use of pannobinostat was not studied.
Patients with hepatic impairment
A clinical study in patients with impaired hepatic function showed that the exposure of pannobinostat in patients with impaired hepatic and mild liver function increases by 43% (1.4-fold increase) and 105% (2-fold increase), respectively. In patients with impaired liver function of mild severity, dose adjustment is not required. The drug Faridak in patients with violations of liver function of moderate severity should be used at a dose of 10 mg during the first cycle. Increasing the dose from 10 mg to 15 mg should be based on the patient's condition, and be accompanied by monitoring of liver function. It should be more often monitored liver function in patients of this category, especially with increasing doses. Consideration should be given to changing the dose of bortezomib.
The use of the drug in patients with impaired liver function is severely contraindicated.
Table 5. Recommended change in the initial dose for patients with impaired hepatic function
| Degree of severity of liver dysfunction | Bilirubin | Glutamate-oxaloacetate-transaminase (aspartateaminotransferase) | Change in the initial dose of the pannobinostat | Change in the initial dose of bortezomib |
| Lightweight | ≤1,0 * upper limit of the norm (VGN) | > VGN | No | |
| > 1.0 * VGN and ≤1.5 * VGN | Any value |
| Average | > 1.5 * VGN and ≤3,0 * VGN | Any value | Reduction of the dose of pannobinostat to 10 mg during the first cycle. Increasing the dose from 10 mg to 15 mg should be based on patient tolerability | Reduction of the dose of bortezomib to 0.7 mg / m2 during the first cycle. Increasing the dose to 1.0 mg / m2 or decrease to 0.5 mg / m2 should be based on patient tolerability |
Strong inhibitors of isoenzyme CYP3A4
It should reduce the dose of the drug to 10 mg in patients receiving concomitant therapy with drugs that are potent inhibitors of the isoenzyme CYP3A4 and / or P-glycoprotein (Pgp), incl. ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone. If long-term therapy with these drugs is necessary, the dose of Faridak may be increased based on the tolerability of the therapy.
It should avoid the use of Faridak in patients with impaired liver function who are receiving concomitant therapy with drugs - potent inhibitors of the isoenzyme CYP3A4.
Do not start therapy with strong inhibitors of isoenzyme CYP3A4 in patients treated with Faridak in a reduced dose due to manifesting undesirable effects. If it is not possible to avoid simultaneous use, the patient should be monitored carefully, taking into account the possibility of further dose reduction or complete discontinuation of therapy according to clinical indications.
Use in children and adolescents under the age of 18 years
The use of the drug in patients of this category is contraindicated due to the lack of data on safety and efficacy.
Use in patients over 65 years of age
Patients over 65 years of age were more likely to develop certain adverse events, and the frequency of withdrawal was higher. Particular care should be taken to monitor the condition of these patients, particularly for the purpose of early diagnosis of thrombocytopenia and gastrointestinal disturbances. For patients over the age of 75 years, depending on the general condition and associated diseases, it is possible to change the initial dose or regimen of concomitant medications.The initial dose of pannobinostat can be 15 mg, with good tolerability in the first cycle of therapy can be increased to 20 mg. The initial dose of bortezomib can be 1.3 mg / m2once a week on days 1 and 8, dexamethasone 20 mg per day 1 and 8.