Farydak (Capsules) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Farmaceutica S.A. (Spain)

ATC Code

L01XH03 (Panobinostat)

Active Substance

Panobinostat (Rec.INN registered by WHO)

Dosage Forms

	Farydak	Capsules 10 mg: 6, 12 or 24 pcs.
		Capsules 15 mg: 6, 12 or 24 pcs.
		Capsules 20 mg: 6, 12 or 24 pcs.

Dosage Form, Packaging, and Composition

Capsules are hard, opaque, size #3, light green in color, with radial marking “LBH 10 mg” on the cap in black ink and two radial bands on the body in black ink; capsule contents: white or almost white powder.

Excipients: mannitol – 46.224 mg, microcrystalline cellulose – 45 mg, corn starch pregelatinized – 15 mg, magnesium stearate – 1.2 mg.

Capsule shell composition: gelatin – q.s. to 100%, titanium dioxide (E171) – 1.1129%, brilliant blue dye (E133) – 0.0134%, iron oxide yellow dye (E172) – 0.3005%, black ink.
Ink composition for all colors: shellac, iron oxide black dye (E172), propylene glycol (E1520).

6 pcs. – blisters (1) – cardboard packs.
6 pcs. – blisters (2) – cardboard packs.
6 pcs. – blisters (4) – cardboard packs.

Capsules are hard, opaque, size #1, orange in color, with radial marking “LBH 15 mg” on the cap in black ink and two radial bands on the body in black ink; capsule contents: white or almost white powder.

Excipients: mannitol – 69.336 mg, microcrystalline cellulose – 67.5 mg, corn starch pregelatinized – 22.5 mg, magnesium stearate – 1.8 mg.

Capsule shell composition: gelatin – q.s. to 100%, titanium dioxide (E171) – 0.7816%, iron oxide yellow dye (E172) – 0.9471%, iron oxide red dye (E172) – 0.3163%, black ink.
Ink composition for all colors: shellac, iron oxide black dye (E172), propylene glycol (E1520).

6 pcs. – blisters (1) – cardboard packs.
6 pcs. – blisters (2) – cardboard packs.
6 pcs. – blisters (4) – cardboard packs.

Capsules are hard, opaque, size #1, red in color, with radial marking “LBH 20 mg” on the cap in black ink and two radial bands on the body in black ink; capsule contents: white or almost white powder.

Excipients: mannitol – 92.448 mg, microcrystalline cellulose – 90 mg, corn starch pregelatinized – 30 mg, magnesium stearate – 2.4 mg.

Capsule shell composition: gelatin – q.s. to 100%, titanium dioxide (E171) – 1.6146%, iron oxide red dye (E172) – 1.6333%, black ink.
Ink composition for all colors: shellac, iron oxide black dye (E172), propylene glycol (E1520).

6 pcs. – blisters (1) – cardboard packs.
6 pcs. – blisters (2) – cardboard packs.
6 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent

Pharmacological Action

Antineoplastic agent, a hydroxamic acid derivative, deacetylase inhibitor (DACi). It has high activity against all classes I, II and IV isoenzymes expressed in the nucleus and cytoplasm. DACi is a new class of antineoplastic drugs that target epigenetic changes in cells through histone and non-histone substrates such as heat shock protein 90 (HSP90) and alpha tubulin. In vitro studies have shown that Panobinostat at low nanomolar concentrations inhibits the proliferation of tumor cell lines. In vivo studies have shown that Panobinostat has antineoplastic activity in patients with multiple myeloma both as monotherapy and in combination with standard therapy drugs.

Panobinostat also inhibits HDAC6, leading to degradation of HSP90 protein, depletion of oncoproteins and reduction of oncogenic signaling. Inhibition of HDAC6 by panobinostat also leads to disruption of aggresomes, suggesting synergy in combination with the proteasome inhibitor bortezomib. Thus, affecting both pathogenetic links has a significant impact on multiple myeloma cells.

The effect of panobinostat on tumor cells leads to a dose-dependent increase in acetylation of histones H3 and H4 in in vitro and in vivo studies, demonstrating high target inhibition. Panobinostat also triggers increased expression of the tumor suppressor gene p21CDKNIA (cyclin-dependent kinase inhibitor 1/p21), a key mediator of G1 arrest and differentiation.

Pharmacokinetics

After oral administration, Panobinostat is rapidly and almost completely absorbed from the gastrointestinal tract; in patients with late-stage malignancies, the time to reach C_max (T_max) in plasma is 2 hours. The absolute bioavailability of panobinostat after oral administration is about 21%. After oral administration, the pharmacokinetics of panobinostat are linear with dose in the dose range of 10-30 mg. However, AUC increases less than proportionally with increasing dose.

The total exposure of panobinostat and interindividual variability of exposure do not depend on whether the drug is taken with food or separately; however, C_max when panobinostat is taken with food (both normal and high fat) decreases by <45%, and T_max increases by 1.5-2.5 hours. Binding to human plasma proteins is about 90%. In vitro, the fraction of panobinostat contained in erythrocytes is 0.60 and is independent of concentration.

According to pharmacokinetic analysis, the V_d of panobinostat at steady state is approximately 1000 L.

Panobinostat undergoes intensive metabolism, a significant portion of the dose is metabolized before reaching the systemic circulation. Metabolism occurs mainly through its reduction, hydrolysis, oxidation and formation of glucuronic acid conjugates. Oxidative metabolism of panobinostat plays a less significant role; it accounts for the elimination of approximately 40% of the administered drug. The isoenzyme CYP3A4 plays the main role in the oxidative metabolism of panobinostat; the role of isoenzymes CYP2D6 and CYP2C19 in its metabolism is potentially insignificant.

Panobinostat accounts for 6-9% of the substance circulating in plasma. The pharmacological activity of panobinostat appears to be due to the unchanged substance.

In patients who took Panobinostat orally once, from 29 to 51% of the administered radioactive label was excreted by the kidneys, and from 44 to 77% through the intestine. In unchanged form, <2.5% of the taken dose of panobinostat was excreted by the kidneys, and <3.5% through the intestine. The remaining label was accounted for by metabolites. The apparent renal clearance (CLr/F) of panobinostat ranged from 2.4 to 5.5 L/h. According to human pharmacokinetic studies, the terminal half-life of panobinostat is about 37 hours.

Based on pooled data from panobinostat monotherapy studies in patients aged 65 years or younger and patients older than 65 years, panobinostat plasma exposure in the dose range of 10-80 mg was approximately the same.

In patients with mild and moderate hepatic impairment, panobinostat plasma exposure increased by 43% and 105%, respectively. The use of panobinostat has not been studied in patients with severe hepatic impairment.

Indications

Relapsed and/or refractory multiple myeloma after at least 2 prior lines of therapy, including bortezomib and an immunomodulatory drug.

ICD codes

Dosage Regimen

Administer Farydak orally in combination with bortezomib and dexamethasone.

Initiate treatment at a starting dose of 20 mg once daily on specified days of each treatment cycle.

Take capsules with a full glass of water; do not crush or chew.

Adhere strictly to the prescribed schedule, typically a 21-day cycle with specific dosing and rest days.

Swallow capsules whole; do not take with grapefruit, grapefruit juice, pomegranate, or star fruit.

Perform complete blood count before initiation and frequently during therapy, particularly prior to each bortezomib dose.

Withhold dose for platelet count ≤100×10⁹/L or absolute neutrophil count ≤1.5×10⁹/L.

Monitor electrolytes and ECG before and during treatment; correct abnormalities prior to dosing.

Adjust dose based on individual tolerance and management of adverse reactions.

Reduce dose to 15 mg or 10 mg for severe hematologic or non-hematologic toxicities as per protocol.

Discontinue permanently for life-threatening adverse reactions or failure to tolerate the 10 mg dose.

For moderate hepatic impairment, initiate at a reduced dose of 15 mg.

Concomitant use with strong CYP3A4 inhibitors requires a dose reduction to 10 mg.

Avoid concomitant use with strong CYP3A4 inducers.

Adverse Reactions

Infections and parasitic diseases very common – upper respiratory tract infections, pneumonia; common – septic shock, urinary tract infections, viral infections, oral herpes, Clostridium difficile colitis, otitis media, cellulitis, sepsis, gastroenteritis, lower respiratory tract infections, candidiasis; uncommon – fungal pneumonia, hepatitis B, aspergillosis.

From the hematopoietic system very common – pancytopenia, thrombocytopenia, anemia, leukopenia, neutropenia, lymphopenia.

From the endocrine system: very common – weight loss; common – hypothyroidism.

From metabolism very common – decreased appetite, hypophosphatemia, hypokalemia, hyponatremia; common – dehydration, fluid retention, hyperglycemia, hypoalbuminemia, hyperuricemia, hypocalcemia, hypomagnesemia

Mental disorders very common – insomnia.

From the nervous system very common – dizziness, headache; common – intracranial hemorrhage, syncope, tremor, dysgeusia.

From the organ of vision common – conjunctival hemorrhage.

From the cardiovascular system very common – decreased blood pressure; common – increased blood pressure, hematoma, orthostatic hypotension, bradycardia, atrial fibrillation, sinus tachycardia, tachycardia, palpitations, QT interval prolongation on ECG; uncommon – hemorrhagic shock, myocardial infarction.

From the respiratory system very common – cough, dyspnea; common – respiratory failure, pulmonary wheezing, stridor, epistaxis; uncommon – pulmonary hemorrhage, hemoptysis.

From the digestive system very common – diarrhea, nausea, vomiting, abdominal pain, dyspepsia; common – gastrointestinal bleeding, blood in stool, gastritis, cheilitis, abdominal distension, dry mouth, flatulence; uncommon – colitis, hematemesis, stomach and intestinal pain.

From the liver and biliary tract common – impaired liver function, hyperbilirubinemia, increased ALT, AST activity in blood serum, increased ALP activity in blood serum.

From the skin and subcutaneous tissues common – skin lesions, rash, erythema; uncommon – petechiae.

From the musculoskeletal system common – joint swelling.

From the urinary system common – renal failure, hematuria, urinary incontinence, increased serum creatinine concentration, increased serum urea concentration, decreased GFR.

General reactions very common – fatigue, peripheral edema, fever, asthenia; common – chills, malaise.

Contraindications

Hypersensitivity to panobinostat, active infectious process, severe hepatic impairment, end-stage chronic renal failure, including in patients on hemodialysis or undergoing hemodialysis; pregnancy, breastfeeding period; children under 18 years of age.

With caution patients with bleeding disorders receiving long-term anticoagulant therapy, with severe gastrointestinal adverse reactions, with prolonged QT_c interval, or patients with a high probability of QT interval prolongation; with simultaneous use of antiemetics such as dolasetron, ondansetron and tropisetron; patients over 65 years of age, moderate hepatic impairment.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindication: severe hepatic impairment.

With caution: moderate hepatic impairment.

Use in Renal Impairment

Use with caution in patients with end-stage chronic renal failure, including patients on hemodialysis.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Geriatric Use

Use with caution in elderly patients to avoid the risk of exacerbation of chronic diseases.

Special Precautions

Panobinostat is used as part of combination therapy, therefore, before starting therapy, it is necessary to read the instructions for medical use of bortezomib and dexamethasone.

Patients treated with panobinostat experienced adverse blood reactions, in particular severe thrombocytopenia, neutropenia and anemia (grades 3 and 4 by CTC), therefore, before starting Farydak and frequently during its use, a complete blood count should be performed (especially before each bortezomib injection).

Before starting treatment, the platelet count should be ≥100×10⁹/L, and ANC ≥1.0×10⁹/L. Before the start of each treatment cycle, the platelet count should be >100×10⁹/L. In patients with CTC grade 3 thrombocytopenia (platelet count <50×10⁹/L, with bleeding), temporary discontinuation of panobinostat and/or subsequent dose reduction may be required. Platelet transfusion may be required if clinically indicated.

Increased risk of thrombocytopenia and possible bleeding should be considered, especially in patients with bleeding disorders receiving long-term anticoagulant therapy.

Treatment with panobinostat should not be initiated in patients with active infections. Existing patient infections must be treated before starting use. During treatment, patients should be monitored for signs and symptoms of infections; if an infectious disease is diagnosed, appropriate treatment should be initiated immediately and discontinuation of panobinostat should be considered.

If an invasive fungal infectious disease is diagnosed, Panobinostat should be discontinued and appropriate treatment initiated.

Nausea, diarrhea, constipation and vomiting observed during treatment sometimes required the use of antiemetic and antidiarrheal drugs. During treatment, water and electrolyte balance should be periodically monitored, especially the content of potassium, magnesium and phosphorus in the blood serum; if clinically necessary, these indicators should be corrected to avoid the development of dehydration and water-electrolyte imbalance.

Prophylactic antiemetics should be used as prescribed by a doctor in accordance with clinical guidelines. Antiemetics that can prolong the QT interval, such as dolasetron, ondansetron and tropisetron, should be used with caution.

At the first signs of intestinal colic, loose stools or diarrhea, it is recommended to start treatment with antidiarrheal drugs or additional treatment in accordance with clinical guidelines. If correction of water and electrolyte disturbances is necessary, replacement infusion therapy should be performed. Medicines with laxative properties should be used with caution due to possible worsening of diarrhea. Patients should consult their doctor regarding the use of any laxatives.

Before starting treatment and during treatment, electrolyte levels (e.g., potassium, magnesium and phosphorus) should be monitored and ECG performed, especially in patients with severe gastrointestinal adverse reactions.

Panobinostat should be used with caution in patients with QT interval prolongation or at high risk of QT interval prolongation, in particular in patients: with long QT syndrome; with uncontrolled or serious heart disease, including recently suffered myocardial infarction, chronic heart failure, unstable angina or clinically significant bradycardia. Concurrent use of drugs that can prolong the QTc interval is not recommended.

Liver function should be monitored before starting treatment and regularly during treatment. If a patient has impaired liver function biochemical parameters, dose adjustment may be considered; in this case, the patient’s condition should be carefully monitored until serum aminotransferase activity and total bilirubin concentration normalize or return to baseline values. The use of panobinostat is contraindicated in patients with severe hepatic impairment due to insufficient clinical data. Consideration should be given to adjusting the dose of bortezomib.

Thyroid and pituitary function should be monitored by determining the concentration of appropriate hormones (e.g., free T4 and TSH) as clinically indicated.

Effect on ability to drive vehicles and mechanisms

Panobinostat may have a minor effect on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, due to the possibility of developing dizziness and other side effects that may affect these abilities.

Drug Interactions

Panobinostat is metabolized mainly by CYP isoenzymes and other proteins. Approximately 40% of panobinostat is metabolized by the CYP3A4 isoenzyme. The role of CYP2D6 and 2C19 isoenzymes in the metabolism of panobinostat, therefore drugs that can affect the activity of the CYP3A4 isoenzyme may affect the pharmacokinetics of panobinostat. Panobinostat is a substrate of P-glycoprotein.

When a single 20 mg dose of panobinostat was administered concomitantly with ketoconazole, a strong CYP3A isoenzyme inhibitor, the C_max and AUC values of panobinostat were 1.6 and 1.8 times higher, respectively, compared to panobinostat monotherapy. In patients receiving concomitant therapy with medicinal products that are strong inhibitors of the CYP3A4 isoenzyme and/or Pgp (including ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole, and nefazodone), the dose of panobinostat must be reduced to 10 mg.

In patients with hepatic impairment who are receiving concomitant therapy with medicinal products that are strong inhibitors of the CYP3A4 isoenzyme, the use of panobinostat should be avoided due to insufficient clinical data.

Patients should be advised to avoid consuming star fruit, pomegranates or pomegranate juice, grapefruits or grapefruit juice, as these can inhibit CYP3A isoenzymes and may increase the bioavailability of panobinostat.

In clinical studies in patients with multiple myeloma, the exposure to panobinostat when used concomitantly with dexamethasone (a dose-dependent weak/moderate inducer of the CYP3A4 isoenzyme) was decreased by approximately 20%. The pronounced effect of strong inducers can reduce the efficacy of panobinostat; for this reason, it should not be used concomitantly with strong inducers of the CYP3A4 isoenzyme (including avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John’s wort).

Panobinostat increased the C_max and AUC of dextromethorphan (a substrate of the CYP2D6 isoenzyme) by 1.8 and 1.6 times, respectively.

The use of panobinostat concomitantly with sensitive substrates of the CYP2D6 isoenzyme (e.g., atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and venlafaxine) or with substrates of the CYP2D6 isoenzyme that have a narrow therapeutic range (e.g., thioridazine, pimozide) should be avoided. If concomitant use with substrates of the CYP2D6 isoenzyme cannot be avoided, patients should be monitored regularly to prevent the occurrence of adverse events.

According to preclinical and clinical studies, Panobinostat may prolong the QT interval. Its use concomitantly with antiarrhythmic drugs (including amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that can prolong the QT interval (including chloroquine, halofantrine, clarithromycin, methadone, moxifloxacin, bepridil, and pimozide) is not recommended. Antiemetic agents that can prolong the QT interval, such as dolasetron, ondansetron, and tropisetron, should be used with caution.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.