Ruxolitinib

Ruxolitinib is a selective inhibitor of the Janus-associated kinases JAK1 and JAK2. These enzymes carry the signals of many cytokines and growth factors that matter for blood formation and immune function. The same active substance is used in two ways. Swallowed as Jakavi, it acts throughout the body on myeloproliferative neoplasms and on graft-versus-host disease, a complication of allogeneic haematopoietic cell transplantation. Applied to the skin as Opzelura, it is a separate product with limited systemic exposure. The pharmacology below is that of Jakavi.

Mechanism of Action

• JAK1 and JAK2 inhibition: IC50 values are 3.3 nM for JAK1 and 2.8 nM for JAK2 enzymes. There is some activity against JAK3 and TYK2 as well.
• Myelofibrosis (MF) and polycythaemia vera (PV): both are myeloproliferative neoplasms linked to dysregulated JAK1 and JAK2 signalling. The basis is thought to include high levels of circulating cytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2 V617F, and silencing of negative regulatory mechanisms. MF patients show dysregulated JAK signalling whether or not they carry JAK2 V617F, and activating JAK2 mutations (V617F or exon 12) are found in more than 95% of PV patients. Ruxolitinib inhibits JAK-STAT signalling and the proliferation of cytokine-dependent cell models of blood cancers.
• Graft-versus-host disease (GvHD): JAK-STAT pathways regulate the development, proliferation and activation of immune cell types that are important in GvHD. By blocking JAK1 and JAK2, ruxolitinib limits the expansion of donor T cells and pro-inflammatory responses.
• Pharmacodynamic effects: ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy subjects, MF patients and PV patients. Inhibition is greatest 2 hours after dosing and returns to near baseline by 8 hours, so neither the parent drug nor its active metabolites accumulate. In MF, raised inflammatory markers linked to constitutional symptoms (TNFα, IL-6 and CRP) fell with treatment.

Pharmacokinetics

• Absorption: ruxolitinib is a class 1 compound in the Biopharmaceutical Classification System (high permeability and solubility, rapid dissolution). It is absorbed rapidly, with peak plasma concentrations about 1 hour after a dose and oral absorption of 95% or more. Peak concentration and total exposure rise in proportion to dose over single doses of 5 to 200 mg. A high-fat meal lowered the peak by 24% and raised total exposure by 4%, which is not clinically relevant, so Jakavi is taken with or without food.
• Distribution: the mean volume of distribution at steady state is about 75 L in MF and PV patients, 67.5 L in adolescent and adult acute GvHD, 60.9 L in adolescent and adult chronic GvHD, and about 30 L in children with a body surface area below 1 m². Plasma protein binding is about 97%, mostly to albumin. Whole-body autoradiography in rats showed no penetration of the blood–brain barrier.
• Metabolism: mainly CYP3A4 (over 50%), with a further contribution from CYP2C9. Unchanged ruxolitinib is the main entity in plasma (about 60% of drug-related material). Two major active metabolites represent 25% and 11% of the parent AUC and have one half to one fifth of its JAK-related activity; together all active metabolites contribute about 18% of the overall pharmacodynamics. At clinically relevant concentrations ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4, and is not a potent inducer of CYP1A2, CYP2B6 or CYP3A4 in vitro. In vitro data indicate that it may inhibit P-glycoprotein and BCRP.
• Elimination: ruxolitinib is eliminated mainly by metabolism. The mean elimination half-life is about 3 hours, and about 5.8 hours for the metabolites. After a radiolabelled dose, about 74% was found in urine and 22% in faeces, mostly as hydroxylated and oxo metabolites, and less than 1% of the radioactivity was unchanged ruxolitinib.
• Special populations: severe renal impairment and hepatic impairment call for lower starting doses (see Administration and Dosage).

Jakavi (tablets and oral solution) and Opzelura (cream) are separate medicinal products with separate SmPCs.

Jakavi tablets

• Myelofibrosis (MF): treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis.
• Polycythaemia vera (PV): adults with polycythaemia vera who are resistant to or intolerant of hydroxycarbamide.
• Acute graft-versus-host disease (GvHD): adults and paediatric patients aged 28 days and older with acute GvHD who have an inadequate response to corticosteroids or other systemic therapies.
• Chronic GvHD: adults and paediatric patients aged 6 months and older with chronic GvHD who have an inadequate response to corticosteroids or other systemic therapies.

Jakavi 5 mg/mL oral solution

• Acute GvHD (from 28 days of age) and chronic GvHD (from 6 months of age), as above. The oral solution is for GvHD only.

Opzelura cream

• Vitiligo: non-segmental vitiligo with facial involvement in adults and adolescents from 12 years of age.
• Atopic dermatitis: moderate atopic dermatitis in adults for whom topical corticosteroids and topical calcineurin inhibitors are inadequate or inappropriate.

• Jakavi (tablets and oral solution): hypersensitivity to ruxolitinib or to any of the excipients; pregnancy and breastfeeding.
• Opzelura (cream): hypersensitivity to ruxolitinib or to any of the excipients; pregnancy and breastfeeding.

Jakavi (Tablets and Oral Solution)

Changes in blood counts are the most frequent reactions and are dose related. The percentages below are the SmPC figures; the blood-count figures for MF and PV are for any grade on the Common Terminology Criteria for Adverse Events (CTCAE).

• Myelofibrosis: anaemia 83.8%, thrombocytopenia 80.5% and neutropenia 20.8%. The most frequent non-haematological reactions were bruising (33.3%), other bleeding such as nosebleed, post-procedural haemorrhage and blood in the urine (24.3%) and dizziness (21.9%). The most frequent laboratory abnormalities were raised alanine aminotransferase (40.7%), raised aspartate aminotransferase (31.5%) and raised triglycerides (25.2%). Treatment was stopped because of adverse events in 30.0% of patients.
• Polycythaemia vera: anaemia 61.8%, thrombocytopenia 25.0% and neutropenia 5.3%. The most frequent non-haematological reactions were weight gain (20.3%), dizziness (19.4%) and headache (17.9%), and the most frequent laboratory abnormalities were raised alanine aminotransferase (45.3%), raised aspartate aminotransferase (42.6%) and raised cholesterol (34.7%). Treatment was stopped because of adverse events in 19.4% of patients.
• Acute GvHD (study REACH2, adults and adolescents): thrombocytopenia 85.2%, anaemia 75.0% and neutropenia 65.1%; cytomegalovirus (CMV) infection 32.3%, sepsis 25.4%, urinary tract infection 17.9%, nausea 16.4% and hypertension 13.4%; raised alanine aminotransferase 54.9%, aspartate aminotransferase 52.3% and cholesterol 49.2%. Treatment was stopped because of adverse events in 29.4%.
• Chronic GvHD (study REACH3, adults and adolescents): anaemia 68.6%, neutropenia 36.2% and thrombocytopenia 34.4%; hypertension 15.0% and headache 10.2%; raised cholesterol 52.3%, aspartate aminotransferase 52.2% and alanine aminotransferase 43.1%. Treatment was stopped because of adverse events in 18.1%.
• In 106 children and adolescents with GvHD (2 to under 18 years) the safety profile was similar to that in adults, and in GvHD patients over 65 no new safety concerns were found.

Frequency groups for MF and PV (long-term follow-up of the phase 3 studies; where the two diseases differ, this is stated):

Very common (≥1/10): anaemia, thrombocytopenia, urinary tract infections, herpes zoster, bleeding of any kind (including bruising and other bleeding), raised cholesterol, raised triglycerides, weight gain, dizziness, headache, raised lipase, constipation, raised alanine and aspartate aminotransferases, hypertension; also neutropenia and gastrointestinal bleeding in MF.

Common (≥1/100 to <1/10): pancytopenia, flatulence; in MF sepsis and intracranial bleeding; in PV neutropenia, gastrointestinal bleeding and pneumonia.

Uncommon (≥1/1,000 to <1/100): in PV intracranial bleeding and sepsis.

Not known: hepatitis B reactivation (reported after marketing).

In GvHD the SmPC gives frequencies for each study. In acute and chronic GvHD, anaemia, thrombocytopenia, neutropenia, raised cholesterol, raised alanine and aspartate aminotransferases and hypertension are very common. In acute GvHD in adults and adolescents, CMV infection, sepsis, urinary tract infection, nausea and pancytopenia are also very common. In chronic GvHD, raised lipase, raised creatine phosphokinase and headache are also very common.

Important serious reactions include serious bacterial, mycobacterial, fungal, viral and other opportunistic infections (including pneumonia, sepsis and tuberculosis), hepatitis B reactivation, progressive multifocal leukoencephalopathy, major adverse cardiac events, thrombosis, lymphoma and other malignancies including non-melanoma skin cancer, and withdrawal effects after stopping. In the acute GvHD study REACH2, fatal (grade 5) sepsis occurred in 20 patients (10%).

Selected reactions:

• Anaemia: in MF, the first grade 2 or higher anaemia appeared after a median of 1.5 months. Haemoglobin fell to a low point of about 10 g/L below baseline after 8 to 12 weeks, then recovered to a new steady state about 5 g/L below baseline. In the COMFORT-I study, 60.6% of Jakavi-treated MF patients and 37.7% of placebo-treated patients received red-cell transfusions.
• Thrombocytopenia: in MF, grade 3 or 4 thrombocytopenia appeared after a median of about 8 weeks and was generally reversible with a lower dose or an interruption. Platelet counts returned above 50,000/mm³ after a median of 14 days.
• Neutropenia: in MF, grade 3 or 4 neutropenia appeared after a median of 12 weeks.
• Bleeding: in the MF phase 3 studies bleeding of any kind was reported in 32.6% of patients on ruxolitinib and 23.2% of controls, with grade 3 to 4 events in 4.7% and 3.1%.
• Blood pressure: in the MF studies a rise in systolic pressure of 20 mmHg or more was recorded at least once in 31.5% of ruxolitinib-treated and 19.5% of control patients.
• On stopping: MF symptoms such as fatigue, bone pain, fever, itching, night sweats, symptomatic splenomegaly and weight loss may return, and the total symptom score returned to baseline within 7 days of stopping.

Opzelura (Cream)

The most common reaction is application site acne (5.8% in vitiligo and 4.4% in atopic dermatitis).

Common (≥1/100 to <1/10): application site acne.

Uncommon (≥1/1,000 to <1/100): herpes zoster.

These apply to Jakavi. Interaction studies have been done only in adults. Ruxolitinib is cleared by CYP3A4 and CYP2C9, so medicines that inhibit these enzymes raise its exposure. For Opzelura, see its own SmPC.

• Strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin and voriconazole): ketoconazole raised the peak concentration of a single 10 mg dose by 33% and the AUC by 91%, and lengthened the half-life from 3.7 to 6.0 hours. The unit dose of ruxolitinib should be reduced by about 50%, given twice daily, with close monitoring for cytopenias (for example twice weekly) and dose titration on safety and efficacy.
• Dual CYP2C9 and CYP3A4 inhibitors (such as fluconazole): fluconazole raised the peak by 47% and the AUC by 232%. A 50% dose reduction should be considered, and fluconazole doses above 200 mg daily should be avoided.
• Cytoreductive therapies: use with Jakavi was associated with manageable cytopenias.
• St John’s wort: this herb induces CYP3A4 and may lower ruxolitinib levels, so take care.
• Grapefruit: grapefruit products inhibit CYP3A4 and should be avoided.
• Food: Jakavi can be taken with or without food.

Jakavi: Who Starts Treatment and How It Is Taken

Jakavi treatment should only be started by a physician experienced in the use of anti-cancer medicinal products. A complete blood count with a white cell differential is done before starting, and repeated every 2 to 4 weeks until the dose is stable and then as clinically indicated. Jakavi is taken by mouth, with or without food.

Jakavi: Starting Doses

• Myelofibrosis (by platelet count): above 200,000/mm³, 20 mg twice daily; 100,000 to 200,000/mm³, 15 mg twice daily; 75,000 to under 100,000/mm³, 10 mg twice daily; 50,000 to under 75,000/mm³, 5 mg twice daily.
• Polycythaemia vera: 10 mg twice daily.
• GvHD, acute and chronic (by age): 12 years and over, 10 mg twice daily; 6 years to under 12 years, 5 mg twice daily; for acute GvHD from 28 days to under 6 years, and for chronic GvHD from 6 months to under 6 years, 8 mg/m² twice daily. The tablet can be used by patients who can swallow it whole; otherwise the oral solution is used. Jakavi can be added to corticosteroids and calcineurin inhibitors.

Jakavi: Oral Solution (5 mg/mL)

• Used for GvHD only. The starting doses are 10 mg (2 mL) twice daily from 12 years, 5 mg (1 mL) twice daily from 6 to under 12 years, and 8 mg/m² twice daily below 6 years. Below 6 years the volume is set from the child’s body surface area using the SmPC table, from 0.3 mL (0.16 to 0.21 m²) to 1.8 mL (1.10 to 1.15 m²).
• A healthcare professional should discuss with the carer how to give the prescribed daily dose before the first dose. The dose is taken at a similar time every day using the re-usable oral syringe supplied.

Jakavi: Dose Adjustments

• MF and PV: doses are titrated for efficacy and safety. If efficacy is insufficient and blood counts allow, the dose can be raised by at most 5 mg twice daily, to a maximum of 25 mg twice daily. The starting dose is not raised in the first four weeks, and later no more often than every 2 weeks. Treatment is stopped if platelets fall below 50,000/mm³ or neutrophils below 500/mm³; in PV it is also interrupted if haemoglobin is below 8 g/dL. The SmPC gives the detailed dose-reduction schedules.
• GvHD: dose reductions or interruptions may be needed for thrombocytopenia, neutropenia or raised total bilirubin after standard supportive care (growth factors, anti-infective therapy, transfusion). The starting dose is reduced by about 50% twice daily, and treatment is interrupted if that dose is not tolerated.
• With strong CYP3A4 inhibitors or dual CYP2C9/CYP3A4 inhibitors: reduce the unit dose by about 50%, twice daily (see Drug Interactions).

Jakavi: Stopping and Tapering

• GvHD: in patients who have responded and stopped corticosteroids, tapering can be considered, with a 50% dose reduction every two months. If signs or symptoms of GvHD return during or after tapering, escalating again should be considered.
• MF: symptoms may return over about a week after treatment is interrupted or stopped. Unless abrupt stopping is required, gradual tapering may be considered, although its benefit is unproven.

Jakavi: Special Populations

• Renal impairment: no adjustment in mild or moderate impairment. In severe impairment (creatinine clearance below 30 mL/min), reduce the starting dose, based on platelet count for MF, PV and GvHD, by about 50%, given twice daily, with careful monitoring.
• End-stage renal disease on haemodialysis: data are limited. For MF the SmPC gives single post-dialysis doses of 15 to 20 mg, or two 10 mg doses 12 hours apart, given only on haemodialysis days: a single 15 mg dose if platelets are 100,000 to 200,000/mm³, and a single 20 mg dose or two 10 mg doses if platelets are above 200,000/mm³. For PV the starting dose is a single 10 mg dose, or two 5 mg doses 12 hours apart, only on haemodialysis days. These recommendations rest on simulations and need careful monitoring. There are no data for GvHD patients with end-stage renal disease.
• Hepatic impairment: in MF and PV, reduce the starting dose by about 50%. In GvHD with hepatic impairment not related to GvHD, reduce it by 50%. In GvHD with liver involvement and total bilirubin above 3 times the upper limit of normal, monitor blood counts more often and reduce the dose by one dose level. Patients found to have hepatic impairment during treatment need blood counts at least every one to two weeks for the first 6 weeks, and then as indicated.
• Elderly: no additional adjustment in GvHD.
• Children: GvHD doses as above; for MF and PV, see the SmPC.

Jakavi: Missed Dose

Do not take an extra dose. Take the next usual dose.

Opzelura Cream: Dose

Opzelura is started and supervised by physicians experienced in diagnosing and treating the conditions it is used for. A thin layer is applied twice daily, at least 8 hours apart, to the smallest skin area necessary.

• Vitiligo: apply to depigmented skin up to a maximum of 10% of body surface area (an area as large as 10 times the palm of one hand with the 5 fingers). Use no more than two 100 g tubes a month. Satisfactory repigmentation may need more than 24 weeks; consider stopping if repigmentation in treated areas is below 25% at week 52. Treatment in an area can stop once repigmentation is satisfactory and can restart if depigmentation returns. No tapering is needed.
• Atopic dermatitis: apply to affected skin up to a maximum of 20% of body surface area until the lesions clear. Use no more than four 100 g tubes a month. If signs and symptoms return, restart treatment of the affected areas. Stop if there is no improvement after 8 weeks of twice-daily use.
• Hepatic and renal impairment: no studies were done, but because systemic exposure is limited no dose adjustment is needed. As a precaution, the cream should not be used in end-stage renal disease because of lack of safety data.

Jakavi: Myelosuppression and Blood Counts

• Jakavi can cause thrombocytopenia, anaemia and neutropenia. A full blood count with a white cell differential is needed before treatment, and treatment is stopped in MF patients with platelets below 50,000/mm³ or neutrophils below 500/mm³.
• MF patients whose platelets are below 200,000/mm³ at the start are more likely to develop thrombocytopenia. It is usually reversible with a lower dose or a short interruption; platelet transfusions may be needed.
• Anaemia may call for transfusion, a dose change or an interruption. Patients with haemoglobin below 10.0 g/dL at the start are more likely to fall below 8.0 g/dL (79.3% versus 30.1%) and need more frequent monitoring. Neutropenia below 500 is generally reversible when Jakavi is withheld.

Jakavi: Infections, Tuberculosis and Hepatitis B Screening

• Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred. The risk is assessed before treatment, patients are observed for signs of infection and treated promptly, and Jakavi is not started until an active serious infection has resolved.
• Tuberculosis: before starting, patients are evaluated for active and latent tuberculosis according to local recommendations (history, contact, lung X-ray, tuberculin test or interferon-gamma release assay as applicable). Tuberculin skin tests can be falsely negative in severely ill or immunocompromised patients.
• Hepatitis B: increases in hepatitis B viral load, with or without raised liver enzymes, have been reported in chronic infection. Screening for hepatitis B is recommended before treatment, and patients with chronic infection are treated and monitored according to clinical guidelines.
• Herpes zoster: patients should know the early signs and seek treatment as early as possible.

Jakavi: Progressive Multifocal Leukoencephalopathy

• PML has been reported. Physicians should watch for cognitive, neurological or psychiatric symptoms that patients may not notice and consider a neurologist for new or worsening signs. If PML is suspected, dosing is suspended until it is excluded.

Jakavi: Cardiovascular Events, Thrombosis and Malignancy

• Major adverse cardiac events (MACE): a large study of another JAK inhibitor, tofacitinib, in rheumatoid arthritis patients aged 50 and over with a cardiovascular risk factor found more MACE than with TNF inhibitors, and MACE have been reported with Jakavi. Benefits and risks are weighed before starting or continuing, especially in patients 65 and over, current or past long-time smokers, and patients with atherosclerotic cardiovascular disease or other cardiovascular risk factors.
• Thrombosis: deep vein thrombosis and pulmonary embolism have been reported. In the MF and PV studies the rates of thromboembolic events were similar with Jakavi and with control treatment. Benefits and risks are weighed, especially with cardiovascular risk factors, and symptoms of thrombosis are evaluated and treated promptly.
• Second primary malignancies: lymphoma and other malignancies have been reported with JAK inhibitors including Jakavi. Non-melanoma skin cancers (basal cell, squamous cell and Merkel cell carcinoma) have been reported with ruxolitinib; most MF and PV patients had long prior hydroxycarbamide treatment and earlier non-melanoma skin cancer or pre-malignant skin lesions. Periodic skin examination is recommended for patients at increased risk of skin cancer.

Jakavi: Lipids

• Treatment is linked to rises in total, HDL and LDL cholesterol and triglycerides. Lipids are monitored and dyslipidaemia is treated following clinical guidelines.

Jakavi: Stopping Treatment

• After interruption or discontinuation, MF symptoms may return over about a week. Patients who stopped Jakavi have had severe adverse events, particularly during an acute intercurrent illness, and it is not established whether abrupt stopping contributed. Unless abrupt stopping is required, gradual tapering may be considered, although its usefulness is unproven.

Opzelura: Use Limits

• Apply only to the skin, as a thin layer, within the body surface area and monthly tube limits above. Herpes zoster has been reported uncommonly. The cream is not to be used in pregnancy or breastfeeding, and not in end-stage renal disease. The SmPC of Opzelura holds its full warnings.

Pregnancy, Breastfeeding and Fertility

• Jakavi: pregnancy: contraindicated. There are no data in pregnant women. Animal studies showed embryotoxicity and foetotoxicity but no teratogenicity in rats or rabbits; the exposure margins were low, so the risk to humans is unknown. Women of childbearing potential should use effective contraception during treatment. If pregnancy occurs, the risk and benefit are evaluated for the individual, with careful counselling on the risk to the foetus.
• Jakavi: breastfeeding: contraindicated, and breastfeeding must stop when treatment starts. It is not known whether ruxolitinib or its metabolites pass into human milk, but animal data show excretion in milk.
• Jakavi: fertility: there are no human data, and no effect on fertility was seen in animals.
• Opzelura: contraindicated in pregnancy and breastfeeding.

Excipients: Lactose, Propylene Glycol and Parabens

• Jakavi tablets contain lactose monohydrate (71.45 mg in the 5 mg tablet up to 285.80 mg in the 20 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. They contain less than 1 mmol (23 mg) sodium per tablet, so are essentially sodium-free.
• Jakavi oral solution contains propylene glycol (150 mg/mL), methyl parahydroxybenzoate (1.2 mg/mL) and propyl parahydroxybenzoate (0.4 mg/mL), excipients with known effect; see its SmPC for the related warnings.

Effect on Driving

Jakavi has no or negligible sedating effect. Patients who feel dizzy after taking it should not drive or use machines.

Jakavi tablets, Jakavi oral solution and Opzelura cream are all stored at no more than 30 °C. None needs refrigeration, so no cold chain is required. Keep the products out of the sight and reach of children. Jakavi oral solution must be used within 60 days of opening, and Opzelura within 6 months of first opening. Tablets are supplied in PVC/PE/PVDC/aluminium blister packs of 14 or 56 tablets, or multipacks of 168 tablets (3 packs of 56); the oral solution comes in a 60 mL bottle (300 mg); not all pack sizes may be marketed.

• Jakavi tablets: 3 years.
• Jakavi oral solution: 2 years; after opening, use within 60 days.
• Opzelura cream: 21 months; after first opening, 6 months.

Prescription only (Rx). Jakavi is subject to restricted medical prescription (Annex II B), and treatment is started by a physician experienced in anti-cancer medicinal products. Jakavi tablets and oral solution are taken at home, so they are supplied to the patient or to the treating clinic on prescription; no cold-chain delivery is needed. Opzelura is also prescription only, started and supervised by physicians experienced in the conditions it treats, and applied by the patient; it is supplied to the patient or the treating clinic on prescription.