INREBIC 100mg capsules medication leaflet

Inrebic 100 mg hard capsules

Each hard capsule contains fedratinib dihydrochloride monohydrate equivalent to 100 mg fedratinib.

For the full list of excipients, see section 6.1.

Hard capsule.

Reddish-brown opaque capsules, 21.4 - 22.0 mm (size 0), printed with “FEDR” on the cap and“100 mg” on the body in white ink.

Inrebic is indicated for the treatment of disease-related splenomegaly or symptoms in adult patientswith primary myelofibrosis, post polycythaemia vera myelofibrosis or post essentialthrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor naïve or have beentreated with ruxolitinib.

Treatment with Inrebic should be initiated and monitored under the supervision of physiciansexperienced in the use of anti-cancer medicinal products.

Patients who are on treatment with ruxolitinib, prior to starting treatment with Inrebic, must taper anddiscontinue ruxolitinib according to the ruxolitinib prescribing information.

Baseline testing of thiamine (vitamin B1) levels, complete blood count, hepatic panel, amylase/lipase,blood urea nitrogen (BUN) and creatinine should be obtained prior to starting treatment with Inrebic,periodically during treatment and as clinically indicated. Inrebic treatment should not be started inpatients with thiamine deficiency, until thiamine levels have been corrected (see section 4.4). Initiatingtreatment with Inrebic is not recommended in patients with a baseline platelet count below 50 x 109/Land ANC < 1.0 x 109/L.

It is recommended that prophylactic anti-emetics be used according to local practice for the first8 weeks of treatment and continued thereafter as clinically indicated (see section 4.4). Administrationof Inrebic with a high fat meal may reduce the incidence of nausea and vomiting.

The recommended dose of Inrebic is 400 mg once daily.

Treatment may be continued for as long as patients derive clinical benefit. Dose modifications shouldbe considered for haematologic and non-haematologic toxicities (Table 1). Inrebic should bediscontinued in patients who are unable to tolerate a dose of 200 mg daily.

If a dose is missed, the next scheduled dose should be taken the following day. Extra capsules shouldnot be taken to make up for the missed dose.

Dose modifications for haematologic toxicities, non-haematologic toxicities and management of

Wernicke’s encephalopathy (WE) are shown in Table 1.

Dose management of thiamine levels

Before treatment initiation and during treatment, thiamine levels should be replenished if they are low.

While on treatment, all patients should receive prophylaxis with daily 100 mg oral thiamine andshould have thiamine levels assessed.

Dose modifications with concomitant use of strong CYP3A4 inhibitors

If concomitant strong CYP3A4 inhibitors cannot be avoided, the dose of Inrebic should be reduced to200 mg. Patients should be carefully monitored (e.g. at least weekly) for safety (see section 4.4and 4.5).

In cases where co-administration with a strong CYP3A4 inhibitor is discontinued, the Inrebic doseshould be increased to 300 mg once daily during the first two weeks after discontinuation of the

CYP3A4 inhibitor and then 400 mg once daily thereafter as tolerated. Additional dose adjustmentsshould be made as needed, based upon monitoring of Inrebic-related safety and efficacy.

Dose re-escalation

If the adverse reaction due to Inrebic that resulted in a dose reduction is controlled with effectivemanagement and the toxicity is resolved for at least 28 days, the dose level may be re-escalated to onedose level higher per month up to the original dose level. Dose re-escalation is not recommended if thedose reduction was due to a Grade 4 non-haematologic toxicity, ≥ Grade 3 alanine aminotransferase(ALT), aspartate aminotransferase (AST), or total bilirubin elevation, or reoccurrence of a Grade 4haematologic toxicity.

Table 1: Dose reductions for haematologic, non-haematologic treatment emergenttoxicities and management of Wernicke’s encephalopathy

Haematologic toxicity Dose reduction

Grade 3 thrombocytopenia with active bleeding Interrupt Inrebic dose until resolved to ≤ Grade 2(platelet count < 50 x 109/L) or Grade 4 (platelet count < 75 x 109/L) or baseline. Restartthrombocytopenia (platelet count < 25 x 109/L) dose at 100 mg daily below the last given dose.

Interrupt Inrebic dose until resolved to ≤ Grade 2

Grade 4 neutropenia (absolute neutrophil count (ANC < 1.5 x 109/L) or baseline. Restart dose at[ANC] < 0.5 x 109/L) 100 mg daily below the last given dose.

Granulocyte growth factors may be used at thephysician’s discretion (see sections 4.4 and 4.5).

Interrupt Inrebic dose until resolved to ≤ Grade 2

Grade 3 and higher anaemia, transfusion (haemoglobin level < 10.0 g/dL) or baseline.indicated (haemoglobin level < 8.0 g/dL) Restart dose at 100 mg daily below the last givendose.

Recurrence of a Grade 4 haematologic toxicity Inrebic discontinuation as per physician’sdiscretion.

Non-haematologic toxicity Dose reduction≥ Grade 3 nausea, vomiting or diarrhoea not Interrupt Inrebic dose until resolved to ≤ Grade 1responding to supportive measures within or baseline. Restart dose at 100 mg daily below48 hours the last given dose.

Interrupt Inrebic dose until resolved to ≤ Grade 1(AST/ALT (> ULN - 3.0 x ULN) or bilirubin(> ULN - 1.5 x ULN)) or baseline. Restart dose≥ Grade 3 ALT/AST (> 5.0 to 20.0 x upper limit at 100 mg daily below the last given dose.of normal [ULN]) or bilirubin (> 3.0 to Monitor ALT, AST and bilirubin (total and10.0 ULN) direct) every 2 weeks for at least 3 monthsfollowing the dose reduction. If re-occurrence ofa Grade 3 or higher elevation, discontinuetreatment with Inrebic.

Interrupt Inrebic dose until resolved to Grade 1(> ULN - 1.5 x ULN) or baseline. Restart dose at100 mg daily below the last given dose.

≥ Grade 3 amylase/lipase (> 2.0 to 5.0 x ULN) Monitor amylase/lipase every 2 weeks for atleast 3 months following the dose reduction. Ifre-occurrence of a Grade 3 or higher elevation,discontinue treatment with Inrebic.

Interrupt Inrebic dose until resolved to ≤ Grade 1≥ Grade 3 other non-haematologic toxicities or baseline. Restart dose at 100 mg daily belowthe last given dose.

Management of thiamine levels and

Wernicke’s encephalopathy Dose reduction

Interrupt Inrebic treatment. Dose with daily

For thiamine levels < normal range (74 to 100 mg oral thiamine until thiamine levels are222 nmol/L)* but ≥ 30 nmol/L without signs or restored to normal range*. Consider re-startingsymptoms of WE Inrebic treatment when thiamine levels arewithin normal range*.

Interrupt Inrebic treatment. Initiate treatment

For thiamine levels < 30 nmol/L without signs or with parenteral thiamine at therapeutic dosagessymptoms of WE until thiamine levels are restored to normalrange*. Consider re-starting Inrebic treatmentwhen thiamine levels are within normal range*.

For signs or symptoms of WE regardless of Discontinue Inrebic treatment and immediatelythiamine levels administer parenteral thiamine at therapeuticdosages.

*the normal thiamine range may differ depending on the methods used by the laboratory.

For patients with severe renal impairment (creatinine clearance [CLcr] 15 mL/min to 29 mL/min by

Cockcroft-Gault [C-G]), the dose should be reduced to 200 mg. No modification of the starting dose isrecommended for patients with mild to moderate renal impairment (CLcr 30 mL/min to 89 mL/minby C-G). Due to potential increase of exposure, patients with pre-existing moderate renal impairmentmay require at least weekly safety monitoring and if necessary, dose modifications based on adversereactions.

No modification of the starting dose is required for patients with mild, moderate and severe hepaticimpairment, based on the Child-Pugh classification.

No additional dose adjustments are required in elderly patients (> 65 years of age).

The safety and efficacy of Inrebic in children and adolescents aged up to 18 years have not beenestablished. No data are available.

Inrebic is for oral use.

The capsules should not be opened, broken or chewed. They should be swallowed whole, preferablywith water, and may be taken with or without food. Administration with a high fat meal may reducethe incidence of nausea and vomiting, therefore it is recommended to be taken with food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy (see section 4.6).

Encephalopathy, including Wernicke’s encephalopathy

Cases of serious and fatal encephalopathy, including Wernicke’s, were reported in patients taking

Inrebic. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (vitamin B1)deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental statuschanges and ophthalmoplegia (e.g. nystagmus, diplopia). Any change in mental status, confusion ormemory impairment should raise concern for potential encephalopathy, including Wernicke’s andprompt a full evaluation including a neurologic examination, assessment of thiamine levels andimaging (see sections 4.2 and 4.8).

Thiamine levels and nutritional status in patients should be assessed before starting treatment with

Inrebic. Inrebic treatment should not be started in patients with thiamine deficiency. Before treatmentinitiation, thiamine levels should be replenished if they are low. While on treatment, all patients shouldreceive prophylaxis with oral thiamine and should have thiamine levels assessed as clinicallyindicated. If encephalopathy is suspected, Inrebic treatment should be discontinued immediately andparenteral thiamine treatment should be initiated while evaluating for all possible causes. Patientsshould be monitored until symptoms have resolved or improved and thiamine levels have normalised(see sections 4.2 and 4.8).

Anaemia, thrombocytopenia and neutropenia

Treatment with Inrebic may cause anaemia, thrombocytopenia and neutropenia. Complete bloodcounts should be obtained at baseline, periodically during treatment and as clinically indicated (seesections 4.2 and 4.8). Inrebic has not been studied in patients with a baseline plateletcount < 50 x 109/L and ANC < 1.0 x 109/L.

Anaemia generally occurs within the first 3 months of treatment. Patients with a haemoglobin levelbelow 10.0 g/dL at the start of therapy are more likely to develop anaemia of Grade 3 or above duringtreatment and should be carefully monitored (e.g. once weekly for the first month until haemoglobinlevels improve). Patients developing anaemia may require blood transfusions. Consider dose reductionfor patients developing anaemia particularly for those who become red blood cell transfusiondependent (see sections 4.2 and 4.8).

Thrombocytopenia generally occurs within the first 3 months of treatment. Patients with low plateletcounts (< 100 x 109/L) at the start of therapy are more likely to develop thrombocytopenia of Grade 3or above during treatment and should be carefully monitored (e.g. once weekly for the first monthuntil platelet count improves) (see sections 4.2 and 4.8). Thrombocytopenia is generally reversible andis usually managed by supportive treatment such as dose interruptions, dose reduction and/or platelettransfusions if necessary. Patients should be made aware of the increased risk of bleeding associatedwith thrombocytopenia.

Neutropenia was generally reversible and was managed by temporarily withholding Inrebic (seesections 4.2 and 4.8).

Gastrointestinal events

Nausea, vomiting and diarrhoea are among the most frequent adverse reactions in Inrebic-treatedpatients. Most of the adverse reactions are Grade 1 or 2 and typically occur within the first 2 weeks oftreatment. Consider providing appropriate prophylactic anti-emetic therapy (e.g. 5-HT3 receptorantagonists) during Inrebic treatment. Treat diarrhoea with anti-diarrhoeal medicinal productspromptly at the first onset of symptoms. For cases of Grade 3 or higher nausea, vomiting, anddiarrhoea that are not responsive to supportive measures within 48 hours, the dose of Inrebic should beinterrupted until resolved to Grade 1 or less/baseline. The dose should be restarted at 100 mg dailybelow the last given dose. Thiamine levels should be monitored and replenished as needed (seesections 4.2 and 4.8).

Elevations of ALT and AST have been reported with Inrebic treatment and one case of hepatic failurewas reported. Patients should have their hepatic function monitored at baseline, at least monthly forthe first 3 months, periodically during treatment and as clinically indicated. After observed toxicity,patients should be monitored at least every 2 weeks until resolution. ALT and AST elevations weregenerally reversible with dose modifications or permanent treatment discontinuation (see sections 4.2and 4.8).

Elevated amylase/lipase

Elevations of amylase and/or lipase have been reported with Inrebic treatment and one case ofpancreatitis was reported. Patients should have their amylase and lipase monitored at baseline, at leastmonthly for the first 3 months, periodically during treatment and as clinically indicated. Afterobserved toxicity, patients should be monitored at least every 2 weeks until resolution. For Grade 3 orhigher amylase and/or lipase, dose modifications are recommended (see sections 4.2 and 4.8).

Elevated creatinine

Elevations of creatinine have been reported with Inrebic treatment (see section 4.8). Patients shouldhave their creatinine levels monitored at baseline, at least monthly for the first 3 months, periodicallyduring treatment and as clinically indicated. For severe renal impairment (CLcr 15 mL/minto 29 mL/min by C-G), dose modifications are recommended (see section 4.2).

Concomitant administration of Inrebic with strong CYP3A4 inhibitors increases Inrebic exposure.

Increased exposure of Inrebic may increase the risk of adverse reactions. In place of strong CYP3A4inhibitors, consider alternative therapies that do not strongly inhibit CYP3A4 activity. If strong

CYP3A4 inhibitors cannot be replaced, the dose of Inrebic should be reduced when administering withstrong CYP3A4 inhibitors, (e.g. ketoconazole, ritonavir). Patients should be carefully monitored (e.g.at least weekly) for safety. Prolonged co-administration of a moderate CYP3A4 inhibitor may requireclose safety monitoring and if necessary, dose modifications based on adverse reactions (seesections 4.2 and 4.5).

Agents that simultaneously inhibit CYP3A4 and CYP2C19 (e.g. fluconazole, fluvoxamine) or thecombination of inhibitors of CYP3A4 and CYP2C19 may increase Inrebic exposure. Therefore,patients taking concomitant dual inhibitors of CYP3A4 and CYP2C19 may require more intensivesafety monitoring and if necessary, dose modifications of Inrebic based on adverse reactions (seesections 4.2 and 4.5).

Agents that strongly or moderately induce CYP3A4 (e.g. phenytoin, rifampicin, efavirenz) maydecrease Inrebic exposure and should be avoided in patients receiving Inrebic (see section 4.5).

If Inrebic is to be co-administered with substrate of CYP3A4 (e.g. midazolam, simvastatin), CYP2C19(e.g. omeprazole, S-mephenytoin) or CYP2D6 (e.g. metoprolol, dextromethorphan), dosemodifications of co-administered medicines should be made as needed with close monitoring of safetyand efficacy (see section 4.5).

If Inrebic is to be co-administered with agents that are renally excreted via organic cation transporter(OCT)2 and multidrug and toxin extrusion (MATE)1/2-K (e.g. metformin), caution should beexercised and dose modifications should be made as needed (see section 4.5).

The concomitant use of haematopoietic growth factors with Inrebic has not been studied. The safetyand efficacy of these co-administrations are not known (see section 4.5 and 4.2).

Major adverse cardiac events (MACE)

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rateof major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatalmyocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNFinhibitors.

Events of MACE have been reported in patients receiving Inrebic. Prior to initiating or continuingtherapy with Inrebic, the benefits and risks for the individual patient should be considered particularlyin patients 65 years of age and older, patients who are current or past long-time smokers, and patientswith history of atherosclerotic cardiovascular disease or other cardiovascular risk factors.

Thrombosis

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dosedependent higher rate of venous thromboembolic events (VTE) including deep venous thrombosis(DVT) and pulmonary embolism (PE) was observed with tofacitinib compared to TNF inhibitors.

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported inpatients receiving Inrebic. Prior to initiating or continuing therapy with Inrebic, the benefits and risksfor the individual patient should be considered particularly in patients with cardiovascular factors (seealso section 4.4 “Major adverse cardiovascular events (MACE)”).

In patients with known VTE risk factors other than cardiovascular or malignancy risk factors, Inrebicshould be used with caution. VTE risk factors other than cardiovascular or malignancy risk factorsinclude previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonalcontraceptives or hormone replacement therapy, and inherited coagulation disorder.

Patients should be re-evaluated periodically during Inrebic treatment to assess for changes in VTErisk.

Promptly evaluate patients with signs and symptoms of VTE and discontinue Inrebic in patients withsuspected VTE, regardless of dose.

Secondary malignancies

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rateof malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) wasobserved with tofacitinib compared to TNF inhibitors.

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including

Inrebic. Prior to initiating or continuing therapy with Inrebic, the benefits and risks for the individualpatient should be considered particularly in patients 65 years of age and older and patients who arecurrent or past long-time smokers.

The experience in the age group 75 years and older is limited. In clinical studies, 13.8% (28/203) ofpatients treated with Inrebic were 75 years and older and serious adverse reactions and adversereactions leading to treatment discontinuation occurred more frequently.

Inrebic capsules contain less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodiumfree’.

Effect of other medicinal products on fedratinib

Fedratinib is metabolised by multiple CYPs in vitro with the predominant contribution from CYP3A4and with a lesser contribution from CYP2C19, and flavin-containing monooxygenases (FMOs).

Strong and moderate CYP3A4 inhibitors

Co-administration of ketoconazole (strong CYP3A4 inhibitor: 200 mg twice daily) with a single doseof fedratinib (300 mg) increased the fedratinib area under the plasma concentration time curve fromtime zero to infinity (AUCinf) by approximately 3-fold. (see section 4.2).

Based on physiologically based pharmacokinetic (PBPK) simulations, co-administration of moderate

CYP3A4 inhibitors, erythromycin (500 mg three times daily) or diltiazem (120 mg twice daily), withfedratinib 400 mg once daily is predicted to increase fedratinib AUC at steady state by 1.1-fold.

Adverse reactions following prolonged co-administration of a moderate CYP3A4 inhibitor cannot beexcluded.

Simultaneous inhibition of CYP3A4 and CYP2C19

Co-administration of fluconazole (dual inhibitor of CYP3A4 and CYP2C19, 200 mg once daily) witha single dose of fedratinib (100 mg) increased AUCinf of fedratinib by 1.7-fold.

Based on PBPK simulations, co-administration of fluconazole (200 mg once daily) with fedratinib400 mg once daily is predicted to increase fedratinib AUC at steady state by 1.5-fold.

Due to potential increase in exposure of fedratinib, patients taking concomitant dual inhibitors of

CYP3A4 and CYP2C19 may require more intensive safety monitoring and if necessary, dosemodifications of Inrebic based on adverse reactions (see section 4.2).

Strong and moderate CYP3A4 inducers

Co-administration of rifampicin (strong CYP3A4 inducer: 600 mg once daily) or efavirenz (moderate

CYP3A4 inducer: 600 mg once daily) with a single dose of fedratinib (500 mg) decreased AUCinf offedratinib by approximately 80% or 50%, respectively.

Co-administration of pantoprazole (proton pump inhibitor: 40 mg daily) with a single dose offedratinib (500 mg) increased fedratinib AUCinf to a clinically insignificant extent (by 1.15-fold).

Therefore, an increase in gastric pH is not expected to have clinically meaningful impact on fedratinibexposure and no dose adjustment is needed for concomitant administration of fedratinib with agentsthat increase gastric pH.

Effect of fedratinib on other medicinal products

Effects on enzymes: CYP3A4, CYP2C19 or CYP2D6 substrates

Concomitant administration of fedratinib with the CYP3A4 substrate, midazolam (2 mg), the

CYP2C19 substrate, omeprazole (20 mg), and the CYP2D6 substrate, metoprolol (100 mg), increasesmidazolam, omeprazole, and metoprolol AUCinf by 3.8-, 2.8-, 1.8- fold and peak concentrations (Cmax)by 1.8-, 1.1- and 1.6-fold, respectively. Therefore, dose modifications of medicinal products that are

CYP3A4, CYP2C19, or CYP2D6 substrates should be made as needed with close monitoring of safetyand efficacy.

Effects on transporters

In in vitro studies, fedratinib inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP),

MATE1, MATE2-K, organic anion transporting polypeptide (OATP)1B1, OATP1B3 and OCT2.

Co-administration of a single dose of fedratinib (600 mg) with a single dose of digoxin (P-gpsubstrate: 0.25 mg), rosuvastatin (OATP1B1/1B3 and BCRP substrate: 10 mg), and metformin (OCT2and MATE1/2-K substrate: 1000 mg) had no clinically meaningful effect on the AUCinf of digoxin,rosuvastatin, and metformin. Renal clearance of metformin was decreased by 36% in the presence offedratinib. The glucose-lowering pharmacodynamic effect of metformin in the presence of fedratinibappears reduced, with the glucose AUC0-3h being 17% higher. Caution should be exercised and dosemodifications should be made as needed for agents that are renally excreted via OCT2 and

MATE1/2-K.

Haematopoietic growth factors

The concurrent use of haematopoietic growth factors and fedratinib has not been studied. It is notknown whether the JAK inhibition by fedratinib reduces the efficacy of haematopoietic growth factorsor whether the haematopoietic growth factors affect the efficacy of fedratinib (see sections 4.2 and4.4).

Females of reproductive potential should be advised to avoid becoming pregnant whilst receiving

Inrebic and should use effective contraception during treatment with Inrebic and for at least 1 monthafter the last dose.

There are no data from the use of Inrebic in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3); exposure in these studies was lower than human exposure at therecommended dose. Based on its mechanism of action, Inrebic may cause foetal harm. Inrebic belongsto a class of drugs, JAK inhibitors, that has been shown in pregnant rats and rabbits to causeembryo-foetal mortality and teratogenicity at clinically-relevant exposures. Inrebic is contraindicatedduring pregnancy (see section 4.3). Women of childbearing potential have to use effectivecontraception during treatment and for at least 1 month after the last dose. If Inrebic is used duringpregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient shouldbe advised of the potential hazard to the foetus.

It is unknown whether fedratinib/metabolites are excreted in human milk. A risk to the breast-fed childcannot be excluded.

Women should not breastfeed during treatment with Inrebic and for at least 1 month after the last doseof Inrebic.

There are no human data on the effect of fedratinib on fertility. There are no data on effects on fertilityin animals at clinically-relevant exposure levels (see section 5.3).

Inrebic has minor influence on the ability to drive and use machines. Patients who experiencedizziness after taking Inrebic should refrain from driving or using machines.

The overall safety information of Inrebic was assessed in 608 patients who received continuous dosesof Inrebic in Phase 1, 2 and 3 clinical studies.

Primary or secondary myelofibrosis (JAKARTA, JAKARTA2, ARD11936)

In clinical studies of patients with primary myelofibrosis (MF), post polycythaemia vera myelofibrosis(post-PV MF), or post essential thrombocythemia myelofibrosis (post-ET MF), treated with Inrebic400 mg (N = 203), including patients previously exposed to ruxolitinib (N = 97; JAKARTA2), themedian exposure was 35.6 weeks (range 0.7 to 114.6 weeks) and the median number of cycles(1 cycle = 28 days) initiated was 9 cycles. Sixty-three percent of 203 patients were exposed for6 months or longer and 38% were exposed for 12 months or longer.

Among the 203 patients with MF treated with a 400 mg dose of Inrebic in the clinical studies, the mostfrequent non-haematologic adverse reactions were diarrhoea (67.5%), nausea (61.6%), and vomiting(44.8%). The most frequent haematologic adverse reactions were anaemia (99.0%) andthrombocytopenia (68.5%) based on laboratory values (Table 2). The most frequent serious adversereactions in MF patients treated with 400 mg were anaemia (2.5% based on reported adverse eventsand not laboratory values) and diarrhoea (1.5%). Permanent discontinuation due to adverse eventregardless of causality occurred in 24% of patients receiving 400 mg of Inrebic.

Adverse reactions from clinical studies for entire treatment duration (Table 2) are listed by MedDRAsystem organ class. Within each system organ class, the adverse reactions are ranked by frequency,with the most frequent reactions first. Frequencies are defined as: 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); and not known (cannot be estimated from available data).

Table 2: All adverse reactions by system organ class and preferred term

System organ class Adverse reaction All gradesfrequency

Infections and Urinary tract infection Very commoninfestations

Blood and lymphatic Anaemiaa Very commonsystem disorders Thrombocytopeniaa Very common

Neutropeniaa Very common

Bleedingb Very common

Metabolism and nutrition Lipase increaseda Very commondisorders Amylase increaseda Very common

Nervous system disorders Headache Very common

Wernicke's encephalopathy Common

Dizziness Common

Vascular disorders Hypertension Common

Gastrointestinal Diarrhoea Very commondisorders Vomiting Very common

Nausea Very common

Constipation Very common

Dyspepsia Common

Hepatobiliary disorders Alanine aminotransferase Very commonincreaseda

Aspartate aminotransferase Very commonincreaseda

Musculoskeletal and Bone pain Commonconnective tissue Muscle spasms Very commondisorders Pain in extremity Common

Renal and urinary Blood creatinine increaseda Very commondisorders Dysuria Common

General disorders and Fatigue/ Very commonadministration site Astheniaconditions

Investigations Weight increased Common

MedDRA = Medical dictionary of regulatory activities

SMQ = Standardized MedDRA Query (a grouping of several MedDRA preferred terms to capture a medical concept).a Frequency is based on laboratory value.b Bleeding includes any type associated with thrombocytopenia requiring clinical intervention. Bleeding is evaluated using the MedDRA

SMQ haemorrhage terms (broad scope).

Encephalopathy, including Wernicke’s

Serious cases of encephalopathy, including 1 established case of Wernicke’s, were reported in 1.3%(8/608) of patients treated with Inrebic in clinical studies; 7 patients were taking Inrebic at 500 mgdaily prior to the onset of neurologic findings and had predisposing factors such as malnutrition,gastrointestinal adverse events, and other risk factors that could lead to thiamine deficiency. Onepatient treated with Inrebic at 400 mg was determined to have hepatic encephalopathy. Most eventsresolved with some residual neurological symptoms including memory loss, cognitive impairment anddizziness, except for one fatal case (1/608; 0.16%). This was a patient with head and neck cancer,brain metastasis, difficulty eating, and weight loss who received fedratinib 500 mg in a study foranother indication (see sections 4.2 and 4.4 for monitoring and management guidance and section 4.9).

In a randomised controlled post-marketing study (FEDR-MF-002) of Fedratinib vs. best availabletherapy (BAT), the incidence of thiamine levels below the lower limit of normal (< 70 nmol/L) was20.9% for Fedratinib vs 4.5% for BAT. Thiamine levels < 30 nmol/L were not observed in the study.

The median time to the first low thiamine level after initiation of Fedratinib was 29.5 days. Thefrequency of low thiamine levels in participants receiving Fedratinib was 4.8% in those receivingthiamine supplementation 100 mg orally per day vs. 23.9% in those not receiving thiaminesupplementation.

Gastrointestinal toxicity

Nausea, vomiting, and diarrhoea are among the most frequent adverse reactions in Inrebic-treatedpatients. In MF patients treated with 400 mg of Inrebic, diarrhoea occurred in 68% of patients, nauseain 62% of patients, and vomiting in 45% of patients. Grade 3 diarrhoea, nausea, and vomiting occurredin 5%, 0.5% and 2% of patients, respectively. The median time to onset of any grade nausea,vomiting, and diarrhoea was 2 days, with 75% of cases occurring within 3 weeks of starting treatment.

Dose interruptions and reductions due to gastrointestinal toxicity were reported in 11% and 9% ofpatients, respectively. Permanent discontinuation of 400 mg Inrebic occurred due to gastrointestinaltoxicity in 4% of patients (see sections 4.2 and 4.4 for monitoring and management guidance).

In patients with primary or secondary myelofibrosis treated with 400 mg of Inrebic, 52% of patientsdeveloped Grade 3 anaemia. The median time to first onset of Grade 3 anaemia event wasapproximately 60 days with 75% of cases occurring within 4 months of starting treatment. Red bloodcell transfusions were received by 58% of 400 mg Inrebic-treated patients and permanentdiscontinuation of 400 mg Inrebic occurred due to anaemia in 1.5% of patients (see sections 4.2 and4.4 for monitoring and management guidance).

In patients with primary or secondary myelofibrosis treated with 400 mg of Inrebic, 14% and 9% ofpatients developed Grade 3 and Grade 4 thrombocytopenia, respectively. The median time to firstonset of Grade 3 or 4 thrombocytopenia was approximately 70 days with 75% of cases occurringwithin 7 months of starting treatment. Platelet transfusions were received by 9% of 400 mg

Inrebic-treated patients. Bleeding (associated with thrombocytopenia), that required clinicalintervention occurred in 11% of patients. Permanent discontinuation of treatment due tothrombocytopenia occurred in 3% of patients (see sections 4.2 and 4.4 for monitoring andmanagement guidance).

Grade 4 neutropenia occurred in 3.5% of patients and dose interruption due to neutropenia werereported in 0.5% of patients (see sections 4.2 and 4.4 for monitoring and management guidance).

Elevations of ALT and AST (all Grades) occurred in 52% and 59%, respectively, with Grade 3 or 4 in3% and 2%, respectively, of 400 mg Inrebic-treated patients. The median time to onset of any Gradetransaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months ofstarting treatment (see sections 4.2 and 4.4 for monitoring and management guidance).

Elevated amylase/lipase

Elevations of amylase and/or lipase (all Grades) occurred in 24% and 40%, respectively, of

Inrebic-treated MF patients. Most of these events were Grade 1 or 2, with Grade 3/4 in 2.5% and 12%,respectively (see section 4.2). The median time to onset of any Grade amylase or lipase elevation was16 days, with 75% of cases occurring within 3 months of starting treatment. Permanentdiscontinuation of treatment due to elevated amylase and/or lipase occurred in 1.0% of patientsreceiving 400 mg of Inrebic (see sections 4.2 and 4.4 for monitoring and management guidance).

Elevated creatinine

Elevations of creatinine (all Grades), occurred in 74% of MF patients taking 400 mg of Inrebic. Theseelevations were generally asymptomatic Grade 1 or 2 events, with Grade 3 elevations observed in 3%of patients. The median time to onset of any Grade creatinine elevation was 27 days, with 75% ofcases occurring within 3 months of starting treatment. Dose interruptions and reductions due toelevated creatinine were reported in 1% and 0.5% of patients, respectively. Permanent discontinuationof treatment due to elevated creatinine occurred in 1.5% of 400 mg Inrebic-treated patients (seesections 4.2 and 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Experience with overdose of Inrebic is limited. During clinical studies of Inrebic in myelofibrosispatients, doses were escalated up to 600 mg per day including 1 accidental overdose at 800 mg. Atdoses above 400 mg, gastrointestinal toxicity, fatigue and dizziness aswell as anaemia andthrombocytopenia tended to occur more commonly. In pooled clinical studies data encephalopathyincluding Wernicke’s encephalopathy was associated with doses of 500 mg. In the event of anoverdose, no further Inrebic should be administered; the individual should be monitored clinically andsupportive measures should be undertaken as clinically indicated.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EJ02

Fedratinib is a kinase inhibitor with activity against wild type and mutationally activated Janus

Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selectiveinhibitor with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and TYK2.

Fedratinib reduced JAK2-mediated phosphorylation of signal transducer and activator of transcription(STAT3/5) proteins, inhibited malignant cell proliferation in vitro and in vivo.

Fedratinib inhibits cytokine induced signal transducer and activator of transcription (STAT)3phosphorylation in whole blood from myelofibrosis patients. A single dose administration of 300, 400,or 500 mg of fedratinib resulted in maximal inhibition of STAT3 phosphorylation approximately2 hours after dosing, with values returning to near baseline at 24 hours. Similar levels of inhibitionwere achieved at steady state PK on cycle 1 day 15, after administration of 300, 400 or 500 mg offedratinib per day.

Two key clinical studies (JAKARTA and JAKARTA2) were conducted in patients with myelofibrosis.

JAKARTA was a randomised placebo-controlled Phase 3 study in patients who are JAK inhibitornaïve. JAKARTA2 was a single-arm study in patients who have been treated with ruxolitinib.

JAKARTA: Myelofibrosis patients who are JAK inhibitor naive

JAKARTA was a double-blind, randomised, placebo-controlled Phase 3 study in patients withintermediate-2 or high-risk myelofibrosis, post-polycythaemia vera myelofibrosis or post-essentialthrombocythemia myelofibrosis with splenomegaly and platelet count ≥ 50 x 109/L. A total of289 patients were randomised to receive either Inrebic 500 mg (N = 97), 400 mg (n = 96) or placebo(n = 96) once daily for at least 24 weeks (6 x 28 day cycles). Placebo patients could cross-over after24 weeks to active treatment. The 400 mg dose appeared to be better tolerated than the 500 mg dosewith fewer patients in the 400 mg arm reporting Grade 3 or 4 treatment emergent adverse events(TEAEs), TEAEs leading to dose reduction or dose interruption, and TEAEs leading to permanenttreatment discontinuation. Fifty-nine percent (59%) of patients were male and the median age was65 years (range 27 to 86 years), with 40% of patients between 65 and 74 years and 11% of patientsat least 75 years. Sixty-four percent (64%) of patients had primary MF, 26% hadpost-polycythaemia vera MF, and 10% had post-essential thrombocythemia MF. Fifty-two percent(52%) of patients had intermediate-2 risk, and 48% had high-risk disease. The median haemoglobincount at baseline was 10.2 g/dL (range 4.5 to 17.4 g/dL). The median platelet count was213.5 x 109/L (range 23.0 to 1155.0 x 109/L); 16.3% of patients had a platelet count < 100 x 109/Land 83.7% of patients had a platelet count ≥ 100 x 109/L. Patients had a median palpable spleenlength of 15 cm (range 4 to 40 cm) at baseline and a median spleen volume as measured bymagnetic resonance imaging (MRI) or computed tomography (CT) of 2568.0 mL (range of 316 to8244 mL) at baseline. (The median normal spleen volume is approximately 215 mL).

The primary efficacy endpoint was the proportion of patients achieving ≥ 35% reduction frombaseline in spleen volume at week 24 (end of cycle 6) as measured by MRI or CT confirmed4 weeks later.

The key secondary endpoint was the proportion of patients with a ≥ 50% reduction in Total

Symptom Score (TSS) from baseline to the end of cycle 6 as measured by the modified

Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary.

Analyses of reduction in spleen volume are presented in Table 3.

Table 3: Percentage of patients achieving spleen volume reduction from baseline to theend of cycle 6 in the Phase 3 study, JAKARTA (intent-to-treat (ITT) Population)

Spleen volume and spleen size at the end of Inrebic 400 mg Placebocycle 6 N = 96 N = 96n (%) n (%)

Spleen volume

Number (%) of patients with spleen volume 45 (46.9) 1 (1.0)reduction by 35% or more at the end ofcycle 695% confidence interval 36.9, 56.9 0.0, 3.1p-value p < 0.0001

Number (%) of patients with spleen volume 35 (36.5) 1 (1.0)reduction by 35% or more at the end ofcycle 6 (with a follow-up scan 4 weeks later)95% confidence interval 26.8, 46.1 0.0, 3.1p-value p < 0.0001

A higher proportion of patients in Inrebic 400 mg group achieved a ≥ 35% reduction from baseline inspleen volume regardless of the presence or absence of the JAKV617F mutation.

Based on Kaplan-Meier estimates, the median duration of spleen response was 18.2 months for the

Inrebic 400 mg group.

The modified MFSAF included 6 key MF associated symptoms: night sweats, itching, abdominaldiscomfort, early satiety, pain under ribs on left side, and bone or muscle pain. The symptoms weremeasured on a scale from 0 (absent) to 10 (worst imaginable).

The percentage of patients (95% confidence interval) with a ≥ 50% reduction in TSS at the end ofcycle 6 was 40.4% (36/89, 95% CI:30.3%, 50.6%) in the Inrebic 400 mg arm and 8.6% (7/81, 95% CI:2.5%, 14.8%) in the placebo arm.

JAKARTA2: Myelofibrosis patients who have been treated with ruxolitinib

JAKARTA2, was a multicentre, open-label, single-arm study in patients previously exposed toruxolitinib with a diagnosis of intermediate-1 with symptoms, intermediate-2 or high-risk primarymyelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemiamyelofibrosis with splenomegaly and platelet count ≥ 50 x 109/L. A total of 97 patients who wereheavily pre-treated (79% of patients had received ≥ 2 prior therapies and 13% had received ≥ 4 priortherapies) were enrolled and started treatment with Inrebic 400 mg once daily with dose escalation upto 600 mg permitted. Fifty-five percent (55%) of patients were male and the median age was 67 years(range 38 to 83 years) with 46% of patients between 65 and 74 years and 17% of patients at least75 years. Fifty-five percent (55%) of patients had primary MF, 26% had post-polycythaemia vera MF,and 19% had post-essential thrombocythemia MF. Sixteen percent (16%) of patients hadintermediate-1 with symptoms, 49% had intermediate-2, and 35% had high-risk disease. The medianhaemoglobin count was 9.8 g/dL (range 6.8 to 15.3 g/dL) at baseline. The median platelet count was147.0 x 109/L (range 48.0 to 929.0 x 109/L) at baseline; 34.0% of patients had a platelet count< 100 x 109/L, and 66.0% of patients had a platelet count ≥ 100 x 109/L. Patients had a medianpalpable spleen length of 18 cm (range 5 to 36 cm) at baseline and a median spleen volume asmeasured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2893.5 mL (rangeof 737 to 7815 mL) at baseline.

The median duration of prior exposure to ruxolitinib was 10.7 months (range 0.1 to 62.4 months).

Seventy-one percent (71%) of patients had received a dose of either 30 mg or 40 mg daily ofruxolitinib prior to study entry.

The primary efficacy endpoint was the proportion of patients achieving a ≥ 35% reduction in spleenvolume from baseline to the end of cycle 6 as measured by MRI or CT.

For the primary endpoint, the percentage of patients (95% confidence interval) who achieved a ≥ 35%reduction in spleen volume by MRI or CT at the 400 mg dose at the end of cycle 6 was 22.7% (22/97,95% CI: 14.8%, 32.3%)

The European Medicines Agency has waived the obligation to submit the results of studies with

Inrebic in all subsets of the paediatric population for the treatment of myelofibrosis (MF) (seesection 4.2 for information on paediatric use).

Fedratinib at 300 mg to 500 mg once daily (0.75 to 1.25 times the recommended dose of 400 mg)results in a dose proportional increase in geometric mean fedratinib Cmax and the area under the plasmaconcentration time curve over the dosing interval (AUCtau). The mean steady state levels are achievedwithin 15 days of daily dosing. The mean accumulation ratios are similar in adult patients withprimary MF, post-PV MF or post-ET MF, ranging from 3- to 4-fold.

At the dose of 400 mg once daily, the geometric mean (coefficient of variation, %CV) fedratinib

Cmax,ss is 1 804 ng/mL (49%) and AUCtau,ss is 26 870 ng.hr/mL (43%) in patients with myelofibrosis.

Following 400 mg once daily oral administration, fedratinib is rapidly absorbed, achieving Cmax atsteady-state in 3 hours (range: 2 to 4 hours). Based on a mass balance study in humans, oral absorptionof fedratinib is estimated to be approximately 63-77%.

A low-fat, low-calorie (total 162 calories: 6% from fat, 78% from carbohydrate and 16% from protein)or a high-fat, high-calorie (total 815 calories: 52% from fat, 33% from carbohydrate and 15% fromprotein) meal increased AUCinf up to 24% and Cmax up to 14% of a single 500 mg dose of fedratinib.

Thus, fedratinib can be taken with or without food since no clinically meaningful effect on thepharmacokinetics of fedratinib was observed with food. Administration with a high fat meal mayreduce the incidence of nausea and vomiting and thus fedratinib is recommended to be taken withfood.

The mean apparent volume of distribution of fedratinib at steady-state is 1770 L in patients withmyelofibrosis at 400 mg once daily dose suggesting extensive tissue distribution. The human plasmaprotein binding of fedratinib is approximately 95%, mostly to α1-acid glycoprotein.

Fedratinib is metabolised by multiple CYPs in vitro, with the predominant contribution from

CYP3A4, and with a lesser contribution from CYP2C19 and FMOs.

Fedratinib was the predominant entity (approximately 80% of plasma radioactivity) in systemiccirculation after oral administration of radiolabelled fedratinib. None of the metabolites contributegreater than 10% of total parent substance-related exposure in plasma.

Following a single oral dose of radiolabelled fedratinib, elimination was primarily through metabolismwith approximately 77% of radioactivity excreted in faeces and only approximately 5% of the excretedin urine. Unchanged parent substance was the major component in excreta, accounting on average forapproximately 23% and 3% of the dose in faeces and urine, respectively.

Fedratinib pharmacokinetics is characterised by a biphasic disposition with an effective half-life of41 hours, a terminal half-life of approximately 114 hours, and apparent clearance (CL/F) (%CV) of13 L/hr (51%) in patients with myelofibrosis.

Age, body weight, gender and race

In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinicallymeaningful effect on the pharmacokinetics of fedratinib was observed with regard to age (analysisincluding 170 patients with age 65-74 years, 54 with age 75-84 years and 4 with age 85+ years), bodyweight (40 to 135 kg), gender (analysis including 249 males and 203 females) and race (analysisincluding 399 White, 7 Black, 44 Asian and 2 other).

Following a single 300 mg dose of fedratinib, the AUCinf of fedratinib increased by 1.5-fold insubjects with moderate renal impairment (CLcr 30 mL/min to 59 mL/min by C-G) and 1.9-fold insubjects with severe renal impairment (CLcr 15 mL/min to 29 mL/min by C-G), compared to that insubjects with normal renal function (CLcr ≥ 90 mL/min by C-G).

In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinicallymeaningful effect on the pharmacokinetics of fedratinib was observed with regard to mild renalimpairment (defined as 60 ≤ CLcr < 90 mL/min).

The safety and pharmacokinetics of a single oral dose of fedratinib were evaluated in subjects withnormal hepatic function and with mild to moderate hepatic impairment (Child-Pugh class A, B) at300 mg; in subjects with normal hepatic function and with severe hepatic impairment (Child-Pugh C)at 200 mg. No clinically meaningful effect on the pharmacokinetics of fedratinib was observed insubjects with mild, moderate and severe hepatic impairment compared to that in subjects with normalhepatic function (see section 4.2).

In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinicallymeaningful effect on the pharmacokinetics of fedratinib was observed with regard to mild (defined astotal bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST increase;n = 115) or moderate (defined as total bilirubin > 1.5 to 3 times ULN and any AST; n = 17) hepaticimpairment.

Fedratinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity andreproductive toxicity studies and in a carcinogenicity study. Fedratinib was not genotoxic and notcarcinogenic in the 6-month Tg.rasH2 transgenic mouse model. Preclinical studies have demonstratedthat at clinically-relevant doses, fedratinib does not inhibit thiamine transport in the gastrointestinaltract or the brain (see sections 4.2 and 4.8)

In repeat-dose toxicity studies of up to 9 months in length, in mice, rats and dogs, the main toxicitiesobserved included bone marrow hypoplasia; bile duct hypertrophy, necrosis and proliferation;lymphoid atrophy/depletion; renal tubular degeneration/necrosis; gastrointestinal tract inflammation;degeneration/necrosis of skeletal and cardiac muscle; histiocytic infiltration of the lung; and evidenceof immunosuppression including pneumonia and/or abscesses. The highest plasma exposures achievedin the repeat-dose toxicology studies were associated with significant toxicity, including mortality, andwere below the tolerated plasma exposures in patients at the highest recommended dose of 400 mg,suggesting humans are less sensitive than preclinical species to the toxicities of fedratinib.

Clinically-relevant exposures were not attained in the species used in the toxicology studies, thereforethese studies have a limited value in producing clinically relevant safety data on fedratinib.

Fertility and early embryonic development

Fedratinib had no effect on the oestrous cycle parameters, mating performance, fertility, pregnancyrate or reproductive parameters in male or female rats. The exposure (AUC) was approximately 0.10to 0.13 times the clinical exposure at the recommended dose of 400 mg once daily. In a repeat-dosetoxicity study, at exposures approximately equivalent to human clinical exposure, fedratinib causedaspermia, oligospermia and seminiferous tubule degeneration in male dogs (see section 4.6).

Embryo-foetal development

Fedratinib administered to pregnant rats during organogenesis (gestation days 6 to 17) was associatedwith adverse embryo-foetal effects including post-implantation loss, lower foetal body weights, andskeletal variations. These effects occurred in rats at approximately 0.1 times the clinical exposure atthe recommended human daily dose of 400 mg/day. In rabbits, fedratinib did not producedevelopmental toxicity at the highest dose level tested (exposure approximately 0.08 times the clinicalexposure at the recommended human daily dose).

Silicified microcrystalline cellulose (contains microcrystalline cellulose (E460) and silica colloidalanhydrous (E551)).

Sodium stearyl fumarate

Gelatin (E441)

Titanium dioxide (E171)

Red iron oxide (E172)

Shellac (E904)

Titanium dioxide (E171)

Propylene glycol (E1520)

Not applicable.

4 years.

Keep the bottle tightly closed in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

High-density polyethylene (HDPE) bottle with polypropylene child resistant cap and heat inductionseal.

Each bottle contains 120 hard capsules and is packed in a cardboard carton.

Any unused product or waste material should be returned to the pharmacist for safe disposal inaccordance with local requirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/20/1514/001

Date of first authorisation: 8 February 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.