Fedratinib

Fedratinib is a kinase inhibitor with activity against wild-type and mutationally activated Janus kinase 2 (JAK2) and against FMS-like tyrosine kinase 3 (FLT3). It is JAK2-selective: its inhibitory activity is higher for JAK2 than for the related family members JAK1, JAK3 and TYK2. JAK2 signalling is highly active in myeloproliferative neoplasms such as myelofibrosis.

Mechanism of Action

• JAK2 inhibition: fedratinib reduces JAK2-mediated phosphorylation of the signal transducer and activator of transcription proteins STAT3 and STAT5. It inhibited the proliferation of malignant cells in vitro and in vivo; by preventing cell division it also induces apoptosis.
• FLT3 activity: fedratinib also inhibits FMS-like tyrosine kinase 3.
• Pharmacodynamic effect: in whole blood from patients with myelofibrosis, fedratinib inhibits cytokine-induced STAT3 phosphorylation. After a single dose of 300, 400 or 500 mg, inhibition was maximal about 2 hours after dosing and returned to near baseline at 24 hours; similar inhibition was reached at steady state.

Pharmacokinetics

• Absorption: fedratinib is absorbed rapidly. At steady state the peak plasma concentration is reached about 3 hours after a 400 mg dose (range 2–4 hours), and oral absorption is estimated at 63–77%. Exposure rises in proportion to dose between 300 and 500 mg daily; steady state is reached within 15 days, with 3- to 4-fold accumulation. At 400 mg once daily the geometric mean steady-state peak concentration is 1,804 ng/mL and the AUC over the dosing interval is 26,870 ng·h/mL. A low-fat or high-fat meal raised the AUC by up to 24% and the peak concentration by up to 14%, which is not clinically meaningful.
• Distribution: the apparent volume of distribution at steady state is about 1,770 L, indicating extensive tissue distribution. About 95% is bound to plasma proteins, mostly α1-acid glycoprotein.
• Metabolism: several CYP enzymes metabolise fedratinib in vitro, mainly CYP3A4, with smaller contributions from CYP2C19 and flavin-containing monooxygenases. The parent drug accounts for about 80% of plasma radioactivity, and no metabolite contributes more than 10% of the total parent-related exposure.
• Elimination: after a radiolabelled dose, elimination was mainly by metabolism, with about 77% of the radioactivity recovered in faeces (23% of the dose as unchanged drug) and about 5% in urine (3% as unchanged drug). The reported effective half-life is about 41 hours and the terminal half-life about 114 hours.
• Special populations: severe renal impairment calls for a lower dose and moderate renal impairment may increase exposure; the starting dose is not changed for hepatic impairment of any grade or for age (see Administration and Dosage).

• Myelofibrosis: treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis who are Janus kinase (JAK) inhibitor naïve or have been treated with ruxolitinib.

• Hypersensitivity to fedratinib or to any of the excipients.
• Pregnancy.

In 486 patients with myelofibrosis treated with 400 mg daily (pooled data from six studies), the most frequent non-haematological reactions were diarrhoea (55.3%), nausea (49.6%) and vomiting (32.5%), and the most frequent haematological reactions were anaemia (51.4%) and thrombocytopenia (28.8%) by laboratory values. The most frequent serious reactions were anaemia (2.3%) and neutropenia (0.4%). Permanent discontinuation because of an adverse event occurred in 20.2% of patients.

Very common (≥1/10): urinary tract infection; anaemia, thrombocytopenia, bleeding of any type; low thiamine; headache, dizziness; diarrhoea, vomiting, nausea, constipation; increased alanine and aspartate aminotransferase; muscle spasms; increased blood creatinine; fatigue and asthenia.

Common (≥1/100 to <1/10): neutropenia; increased lipase and amylase; hyperkalaemia; peripheral neuropathy; uveitis; hypertension; dyspepsia; bone pain, pain in extremity; dysuria; weight increased.

Uncommon (≥1/1,000 to <1/100): Wernicke’s encephalopathy.

The frequencies of anaemia, thrombocytopenia, lipase, amylase, aminotransferase and creatinine increases are based on laboratory values.

Important serious reactions:

• Wernicke’s encephalopathy and low thiamine: Wernicke’s encephalopathy occurred in 1 of 486 patients (0.2%) given thiamine supplementation with clinical monitoring; the risk was higher without supplementation, particularly at doses above 400 mg daily. In a randomised post-marketing study, thiamine levels below 70 nmol/L were found in 20.9% of fedratinib-treated patients (4.5% with best available therapy), and in 4.8% of those taking 100 mg oral thiamine daily against 23.9% of those not taking it.
• Blood counts and bleeding: grade 3 or 4 anaemia in 40.3% of patients, grade 3 or 4 thrombocytopenia in 13.8% and grade 3 or 4 neutropenia in 4.5%. Bleeding of any type occurred in 29.2% (grade 3 or 4 in 6.2%).
• Liver, pancreas and kidney: ALT and AST elevations (all grades) in 8.0% and 5.6%, with one case of hepatic failure; amylase and lipase elevations in 2.5% and 5.1%, with one case of pancreatitis; creatinine elevations in 8.0%.
• Uveitis: in 4.4% of patients in pooled post-approval studies; most patients with uveitis had more than one episode.

Fedratinib is metabolised mainly by CYP3A4, and to a lesser extent by CYP2C19 and flavin-containing monooxygenases. It also inhibits several enzymes and transporters, so both its own exposure and that of other medicines can change.

• Strong CYP3A4 inhibitors (for example ketoconazole, ritonavir): ketoconazole raised fedratinib exposure about 3-fold. Alternatives that do not strongly inhibit CYP3A4 should be considered; if they cannot be avoided, the fedratinib dose is reduced (see Administration and Dosage) and safety is monitored closely.
• Moderate CYP3A4 inhibitors (erythromycin, diltiazem): predicted to raise steady-state exposure by 1.1-fold. Prolonged co-administration may call for close safety monitoring and dose changes based on adverse reactions.
• Dual CYP3A4 and CYP2C19 inhibitors (fluconazole, fluvoxamine): fluconazole raised exposure 1.7-fold after a single dose and is predicted to raise steady-state exposure 1.5-fold. More intensive safety monitoring and, if needed, dose modification may be required.
• CYP3A4 inducers (strong: rifampicin, phenytoin; moderate: efavirenz): rifampicin reduced fedratinib exposure by about 80% and efavirenz by about 50%. These medicines should be avoided.
• Acid-reducing medicines: pantoprazole changed exposure to a clinically insignificant extent (1.15-fold), so no adjustment is needed with agents that raise gastric pH.
• CYP3A4, CYP2C19 and CYP2D6 substrates: fedratinib raised the exposure (AUC) of midazolam 3.8-fold, omeprazole 2.8-fold and metoprolol 1.8-fold. Doses of such medicines (for example simvastatin, S-mephenytoin, dextromethorphan) are adjusted as needed, with close monitoring of safety and efficacy.
• OCT2 and MATE1/2-K substrates (for example metformin): the renal clearance of metformin fell by 36% and its glucose-lowering effect appeared reduced. Caution and dose changes as needed are advised. Fedratinib also inhibits renal transporters and raises serum creatinine, so creatinine should be interpreted with caution as a marker of kidney function.
• Other transporters: fedratinib inhibits P-glycoprotein, BCRP and OATP1B1/1B3 in vitro, but a single dose had no clinically meaningful effect on digoxin or rosuvastatin.
• Haematopoietic growth factors: use together with fedratinib has not been studied.
• Food and herbal products: grapefruit products inhibit CYP3A and should be avoided; St John’s wort induces CYP3A and should also be avoided. The capsules may be taken with or without food.

Treatment is started and monitored by physicians experienced in the use of anti-cancer medicinal products. The capsules are swallowed whole, preferably with water, with or without food; they must not be opened, broken or chewed. Taking them with food is recommended because a high-fat meal may reduce nausea and vomiting.

Recommended Dose

• 400 mg once daily (four 100 mg capsules).
• Treatment may continue for as long as the patient derives clinical benefit.
• Fedratinib is discontinued in patients who cannot tolerate 200 mg daily.

Before and During Treatment

• Ruxolitinib: patients taking ruxolitinib taper and stop it, following its prescribing information, before starting fedratinib.
• Baseline tests: thiamine (vitamin B1) level, complete blood count, hepatic panel, amylase and lipase, blood urea nitrogen and creatinine, repeated periodically during treatment and as clinically indicated. Treatment is not started in patients with thiamine deficiency until their levels have been corrected. Starting is not recommended with a baseline platelet count below 50 × 10⁹/L and an absolute neutrophil count below 1.0 × 10⁹/L.
• Thiamine: low levels are replenished before and during treatment. All patients take 100 mg oral thiamine daily as prophylaxis and have thiamine levels assessed.
• Anti-emetics: prophylactic anti-emetics are used according to local practice for the first 8 weeks and continued as clinically indicated.

Dose Adjustments

• Toxicity: dose modifications should be considered for haematological and non-haematological toxicity and for the management of Wernicke’s encephalopathy. The thresholds and steps are set out in Table 1 of the SmPC.
• Gastrointestinal toxicity: for grade 3 or higher nausea, vomiting or diarrhoea that does not respond to supportive measures within 48 hours, the dose is interrupted until the event resolves to grade 1 or less (or baseline) and then restarted at 100 mg daily below the last given dose.
• Anaemia: dose reduction is considered, particularly in patients who become dependent on red blood cell transfusion.
• Amylase and lipase: dose modification is recommended for grade 3 or higher increases.
• Strong CYP3A4 inhibitors: if they cannot be avoided, the dose is reduced to 200 mg and the patient is monitored carefully (for example at least weekly).

Special Populations

• Renal impairment: for severe impairment (creatinine clearance 15–29 mL/min) the dose is reduced to 200 mg. No change to the starting dose for mild or moderate impairment (30–89 mL/min); in moderate impairment, exposure may rise and at least weekly safety monitoring and dose changes based on adverse reactions may be needed.
• Hepatic impairment: no change to the starting dose in mild, moderate or severe impairment (Child-Pugh).
• Elderly: no additional dose adjustment above 65 years of age, although all safety parameters were more frequent in patients over 65.
• Children and adolescents: safety and efficacy up to 18 years of age have not been established; no data are available.

Missed Dose

If a dose is missed, the next scheduled dose is taken the following day. Extra capsules are not taken to make up for the missed dose.

Thiamine Testing and Wernicke’s Encephalopathy

• Warning: in the absence of thiamine supplementation, cases of serious and fatal encephalopathy, including Wernicke’s, were reported in patients taking Inrebic. Wernicke’s encephalopathy is a neurological emergency resulting from thiamine (vitamin B1) deficiency.
• Signs: ataxia, mental status changes and ophthalmoplegia (for example nystagmus, diplopia). Any change in mental status, confusion or memory impairment should raise concern for encephalopathy, including Wernicke’s, and prompt a full evaluation: neurological examination, assessment of thiamine levels and imaging.
• Before treatment: thiamine levels and nutritional status are assessed before starting. Treatment is not started in patients with thiamine deficiency, and low levels are replenished first.
• During treatment: all patients receive prophylaxis with oral thiamine and have thiamine levels assessed as clinically indicated.
• If encephalopathy is suspected: Inrebic is discontinued immediately and parenteral thiamine is started while all possible causes are evaluated. Patients are monitored until symptoms have resolved or improved and thiamine levels have normalised.

Anaemia, Thrombocytopenia and Neutropenia

• Complete blood counts are taken at baseline, periodically during treatment and as clinically indicated.
• Anaemia generally occurs within the first 3 months. Patients with haemoglobin below 10.0 g/dL at the start are more likely to develop grade 3 or higher anaemia and should be monitored carefully (for example weekly for the first month); transfusions may be needed.
• Thrombocytopenia generally occurs within the first 3 months. Patients with platelet counts below 100 × 10⁹/L at the start are more likely to develop grade 3 or higher thrombocytopenia and should be monitored carefully. It is usually reversible with dose interruption, dose reduction and, if necessary, platelet transfusion. Patients should know about the increased risk of bleeding.
• Neutropenia was generally reversible and was managed by temporarily withholding fedratinib.
• Fedratinib has not been studied in patients with a baseline platelet count below 50 × 10⁹/L and an absolute neutrophil count below 1.0 × 10⁹/L.

Gastrointestinal Events

Nausea, vomiting and diarrhoea are among the most frequent reactions. Most are grade 1 or 2 and typically occur within the first 2 weeks. Prophylactic anti-emetic therapy (for example 5-HT3 receptor antagonists) is given throughout treatment, and diarrhoea is treated with anti-diarrhoeal medicines at the first symptoms. Thiamine levels are monitored and replenished as needed.

Liver, Pancreas and Kidney Monitoring

• Liver: ALT and AST elevations and one case of hepatic failure have been reported. Hepatic function is monitored at baseline, at least monthly for the first 3 months, periodically thereafter and as clinically indicated; after a toxic event, at least every 2 weeks until resolution.
• Pancreas: amylase and lipase elevations and one case of pancreatitis have been reported, with the same monitoring schedule; dose modification is recommended for grade 3 or higher increases.
• Kidney: serum creatinine rose by about 30% in the first cycle and then stayed stable. It is monitored at baseline, at least monthly for the first 3 months, and thereafter as clinically indicated. Because fedratinib inhibits renal transporters, other markers of renal function may be considered.

Uveitis

Uveitis has been seen in post-approval studies as a late-onset event (first episode at a median of 14 months, range 8–22 months). Patients are told about the risk before starting. Symptoms include eye pain, redness, photophobia, floaters and decreased vision; prompt ophthalmological evaluation is recommended. Most cases are anterior uveitis. No dose change is needed while topical corticosteroid treatment controls the inflammation; if uveitis does not respond to local therapy, systemic treatment may be indicated and fedratinib is withheld until the inflammation resolves.

Cardiovascular Events, Thrombosis and Secondary Malignancies

• A large study of another JAK inhibitor (tofacitinib) in rheumatoid arthritis showed higher rates of major adverse cardiovascular events, venous thromboembolism and malignancies than TNF inhibitors. Major adverse cardiac events, deep vein thrombosis, pulmonary embolism, lymphoma and other malignancies have been reported with Inrebic.
• Before starting or continuing treatment, the benefits and risks are weighed for each patient, particularly in patients aged 65 or over, current or past long-time smokers, and patients with atherosclerotic cardiovascular disease or other cardiovascular risk factors.
• Use with caution in patients with other risk factors for venous thromboembolism (previous thromboembolism, major surgery, immobilisation, combined hormonal contraceptives or hormone replacement therapy, inherited coagulation disorder). Patients with signs of thromboembolism are evaluated promptly and fedratinib is stopped if it is suspected.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of reproductive potential avoid becoming pregnant and use effective contraception during treatment and for at least 1 month after the last dose.
• Pregnancy: contraindicated. There are no data in pregnant women; animal studies showed reproductive toxicity, and JAK inhibitors as a class caused embryo-foetal mortality and teratogenicity in pregnant rats and rabbits at clinically relevant exposures. Fedratinib may cause foetal harm.
• Breastfeeding: it is unknown whether fedratinib or its metabolites pass into human milk and a risk to the breast-fed child cannot be excluded. Women should not breastfeed during treatment and for at least 1 month after the last dose.
• Fertility: there are no human data and no animal data on fertility at clinically relevant exposure levels.

Sodium

The capsules contain less than 1 mmol sodium (23 mg) per dose, that is, they are essentially ‘sodium-free’.

Effect on Driving

Fedratinib has a minor influence on the ability to drive and use machines. Patients who experience dizziness after taking it should not drive or use machines.

Inrebic does not require any special temperature storage conditions. Keep the bottle tightly closed to protect the capsules from moisture, and keep it out of the sight and reach of children. Each bottle holds 120 capsules and has a child-resistant cap.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx): a medicinal product subject to restricted medical prescription, started and monitored by physicians experienced in anti-cancer therapy. Testing of thiamine levels before treatment is a condition of use (see Special Instructions). Fedratinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.