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Ruxolitinib
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The FDA has designated ruxolitinib as an orphan drug for the treatment of polycythemia vera.
Initially, 10 mg orally twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Titrate the ruxolitinib dosage based on response and toxicity. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dosage may be increased in 5 mg twice daily increments. Maximum dosage: 25 mg orally twice daily if the patient meets all of the following criteria: an inadequate response defined as the continued need for phlebotomy, WBC count greater than the upper limit of normal (ULN), platelet count greater than the ULN, and/or a palpable spleen that is reduced by less than 25% from baseline; a platelet count 140 x 109 cells/L or more; hemoglobin 12 grams/dL or more; and ANC 1.5 x 109 cells/L or more.[46782] A significantly higher response rate at week 32 was achieved with ruxolitinib compared with investigator selected best available therapy (20.9% vs. 0.9%; p less than 0.001) in patients with polycythemia vera who had an inadequate response to or unacceptable side effects from hydroxyurea in a multinational, randomized, phase 3 trial (n = 222; the RESPONSE trial); additionally, this response was maintained at week 48 (19.1% vs. 0.9%; p less than 0.001). Eligible patients had a spleen volume of 450 cm3 or more and phlebotomy dependence, defined as 2 or more phlebotomies within 24 weeks before screening and at least 1 phlebotomy within 16 weeks before screening. Best available therapy consisted of single-agent anagrelide (7.1%), low-dose hydroxyurea (58.9%), immunomodulators such as lenalidomide or thalidomide (4.5%), interferon or pegylated interferon (11.6%), pipobroman (1.8%), or no medication (15.2%). All patients received low-dose aspirin unless it was contraindicated. The primary endpoint of response at 32 weeks was defined as a reduction in spleen volume of 35% or more from baseline and hematocrit control (eligible for no more than 1 phlebotomy between randomization and study week 8 and not eligible for a phlebotomy during study weeks 8 to 32). The complete hematologic remission (CHR) rate (defined as hematocrit control, a platelet count of 400 x 109 cells/L or less, and a white blood cell count of 10 x 109 cells/L or less) at week 32 was significantly higher with ruxolitinib compared with best standard therapy (23.6% vs. 8.9%, p = 0.003). Crossover to the ruxolitinib arm occurred in 85.7% of patients in the best standard therapy arm at or after week 32.[58808] In an extended analysis at week 80, 76% of patients who achieved a response at 32 weeks maintained a response, and 58% of patients who achieved a CHR at 32 weeks maintained this response.[46782]
NOTE: Patients experiencing significant decreases in platelet counts may be candidates for abrupt dose reductions and/or treatment interruptions. Consider risk to benefits ratio in patients maintained on 5 mg PO twice daily (minimum dose) as long-term use at this dose has failed to produce clinical response.[46782]
20 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may be increased in 5 mg twice daily increments to a maximum dose of 25 mg PO twice daily if the patient meets all of the following criteria: 1) failure to achieve a reduction from baseline palpable spleen length of 50% or a 35% reduction in spleen volume as measured by CT or MRI; 2) platelet count more than 125 x 109 cells/L at treatment week 4 and platelet counts never less than 100 x 109 cells/L; 3) absolute neutrophil count (ANC) more than 0.75 x 109 cells/L. Discontinue ruxolitinib if spleen size reduction or symptom improvement is not observed after 6 months of therapy. When discontinuing therapy for any reason other than thrombocytopenia, consider gradually tapering dose by 5 mg twice daily each week.[46782]
15 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may be increased in 5 mg twice daily increments to a maximum dose of 25 mg PO twice daily if the patient meets all of the following criteria: 1) failure to achieve a reduction from baseline palpable spleen length of 50% or a 35% reduction in spleen volume as measured by CT or MRI; 2) platelet count more than 125 x 109 cells/L at treatment week 4 and platelet counts never less than 100 x 109 cells/L; 3) absolute neutrophil count (ANC) more than 0.75 x 109 cells/L. Discontinue ruxolitinib if spleen size reduction or symptom improvement is not observed after 6 months of therapy. When discontinuing therapy for any reason other than thrombocytopenia, consider gradually tapering dose by 5 mg twice daily each week.[46782]
5 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After the first 4 weeks of therapy, and no more frequently than every 2 weeks, the dose may be increased in 5 mg daily increments to a maximum dose of 10 mg PO twice daily if the patient meets all of the following criteria: 1) platelet count has remained more than 40 x 109 cells/L and has not fallen by more than 20% in prior 4 weeks; 2) absolute neutrophil count (ANC) more than 1 x 109 cells/L; 3) dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks. Consider risk to benefits ratio in patients continuing treatment for more than 6 months. Discontinue ruxolitinib if spleen size reduction or symptom improvement is not observed after 6 months of therapy.[46782]
NOTE: The FDA has designated ruxolitinib as an orphan drug for the treatment of GVHD.
5 mg PO twice daily, initially. May increase the dose to 10 mg PO twice daily after 3 days if the absolute neutrophil count (ANC) and platelet counts are not decreased by 50% or more. Decrease dose or interrupt therapy for adverse reactions. Consider tapering dose after 6 months in persons who have discontinued therapeutic doses of corticosteroids; taper dose by 1 dose level (i.e., 10 mg PO twice daily to 5 mg twice daily to 5 mg once daily) every 8 weeks. Consider retreatment if GVHD signs or symptoms recur during or after the taper. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[46782]
5 mg PO twice daily, initially. May increase the dose to 10 mg PO twice daily after 3 days if the absolute neutrophil count (ANC) and platelet counts are not decreased by 50% or more. Decrease dose or interrupt therapy for adverse reactions. Consider tapering dose after 6 months in persons who have discontinued therapeutic doses of corticosteroids; taper dose by 1 dose level (i.e., 10 mg PO twice daily to 5 mg twice daily to 5 mg once daily) every 8 weeks. Consider retreatment if GVHD signs or symptoms recur during or after the taper. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[46782]
10 mg PO twice daily. Decrease dose or interrupt therapy for adverse reactions. Consider tapering dose after 6 months in persons who have discontinued therapeutic doses of corticosteroids; taper dose by 1 dose level (i.e., 10 mg PO twice daily to 5 mg twice daily to 5 mg once daily) every 8 weeks. Consider retreatment if GVHD signs or symptoms recur during or after the taper. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[46782]
10 mg PO twice daily. Decrease dose or interrupt therapy for adverse reactions. Consider tapering dose after 6 months in persons who have discontinued therapeutic doses of corticosteroids; taper dose by 1 dose level (i.e., 10 mg PO twice daily to 5 mg twice daily to 5 mg once daily) every 8 weeks. Consider retreatment if GVHD signs or symptoms recur during or after the taper. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[46782]
NOTE: Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants.[66999]
Apply a thin layer topically to the affected skin area(s) of up to 20% of body surface area 2 times daily until symptoms resolve. Do not use more than 60 g/week or 100 g/2 weeks. If no improvement within 8 weeks, re-evaluate use.[66999]
Apply a thin layer topically to the affected skin area(s) of up to 20% of body surface area 2 times daily until symptoms resolve. Do not use more than 60 g/week or 100 g/2 weeks. If no improvement within 8 weeks, re-evaluate use.[66999]
Apply a thin layer topically to the affected skin area(s) of up to 10% of body surface area twice daily. Max: 60 g/week or 100 g/2 weeks. May require treatment for more than 3 months to see initial repigmentation and more than 1 year before maximal repigmentation is achieved. Re-evaluate if repigmentation is not meaningful by Week 24.[66999] [71059]
Apply a thin layer topically to the affected skin area(s) of up to 10% of body surface area twice daily. Max: 60 g/week or 100 g/2 weeks. May require treatment for more than 3 months to see initial repigmentation and more than 1 year before maximal repigmentation is achieved. Re-evaluate if repigmentation is not meaningful by Week 24.[66999] [71059]
Management of Treatment-Related Toxicity
Myelofibrosis:
Thrombocytopenia
NOTE: Hold ruxolitinib regardless of platelet count for bleeding that requires intervention. In this situation, treatment may be resumed once bleeding has resolved; consider a lower dose if the underlying cause of bleeding persists.
Baseline platelet count of 100 X 109 cells/L or higher:
Baseline platelet count of 50 to 99 X 109 cells/L:
Neutropenia
For an absolute neutrophil count (ANC) of less than 0.5 X 109 cells/L: Hold ruxolitinib. When ANC greater than 0.75 X 109 cells/L, may restart treatment at 5 mg twice daily below the largest dose in the week prior to holding therapy, or 5 mg daily (whichever is higher).
Polycythemia Vera:
Hematologic Toxicity
Determining the Maximum Restarting Dosage:
NOTE: Following therapy interruption, the final titrated daily dosage should not exceed 5 mg less than the held dosage. The exception is for dose interruption after phlebotomy-associated anemia; the maximum total daily dose in this case would be 25 mg twice daily.
Graft-Versus-Host Disease (GVHD):
Recommended Dosage Adjustments
Current dosage of 10 mg PO twice daily: Reduce to 5 mg PO twice daily.
Current dosage of 5 mg PO twice daily: Reduce to 5 mg PO once daily.
Current dosage of 5 mg PO once daily: Hold therapy until clinical and/or laboratory parameters recover.
Acute GVHD
Therapy-Related Hematologic Toxicity
Thrombocytopenia
Clinically significant thrombocytopenia after supportive measures: Reduce the ruxolitinib dosage; resume therapy at the prior dosage when the platelet counts recover to previous values.
Neutropenia
ANC less than 1 X 109 cells/L: Hold ruxolitinib for up to 14 days; resume at a reduced dosage upon recovery.
Chronic GVHD
Therapy-Related Hematologic Toxicity
Thrombocytopenia
Platelet count less than 20 X 109 cells/L: Reduce the ruxolitinib dosage. If the toxicity resolves within 7 days, resume therapy at the prior dosage. Maintain the dosage reduction if the toxicity does not resolve within 7 days.
Neutropenia
ANC less than 0.75 X 109 cells/L: Reduce the ruxolitinib dosage; resume therapy at the initial dosage upon recovery.
ANC less than 0.5 X 109 cells/L: Hold ruxolitinib for up to 14 days; resume at a reduced dosage upon recovery. The initial dosage may be resumed when the ANC is greater than 1 X 109 cells/L.
Other Toxicity
Grade 3 toxicity: Reduce the ruxolitinib dosage until recovery.
Grade 4 toxicity: Discontinue ruxolitinib therapy.[46782]
25 mg PO twice daily for myelofibrosis or polycythemia vera; 10 mg PO twice daily for graft-versus-host disease; 60 grams per week or 100 grams every 2 weeks topically for atopic dermatitis or nonsegmental vitiligo.
25 mg PO twice daily for myelofibrosis or polycythemia vera; 10 mg PO twice daily for graft-versus-host disease; 60 grams per week or 100 grams every 2 weeks topically for atopic dermatitis or nonsegmental vitiligo.
10 mg PO twice daily for graft-versus-host disease; 60 grams per week or 100 grams every 2 weeks topically for atopic dermatitis or nonsegmental vitiligo.
12 years: 10 mg PO twice daily for graft-versus-host disease; 60 grams per week or 100 grams every 2 weeks topically for atopic dermatitis or nonsegmental vitiligo.
11 years and younger: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Myelofibrosis
Mild, moderate, or severe (Child-Pugh class A, B, C) hepatic impairment at baseline:
Polycythemia Vera (any platelet count)
Mild, moderate, or severe (Child-Pugh class A, B, C) hepatic impairment at baseline: Initial dosage, 5 mg PO twice daily.
Graft-Versus-Host Disease (GVHD) (any platelet count)
Mild, moderate, or severe (NCI criteria) hepatic impairment at baseline without liver GVHD: No initial dosage adjustment recommended.
Acute GVHD
Stage 1, 2, or 3 liver GVHD: No initial dosage adjustment recommended.
Stage 4 liver GVHD: Initial dosage, 5 mg PO once daily.
Chronic GVHD
Score 1 or 2 liver GVHD: No initial dosage adjustment recommended.
Score 3 liver GVHD: Monitor blood counts more frequently and adjust dosage if treatment-related toxicity occurs.
Management of Treatment-Related Toxicity in Patients with GVHD
Recommended Dosage Adjustments
Current dosage of 10 mg PO twice daily: Reduce to 5 mg PO twice daily.
Current dosage of 5 mg PO twice daily: Reduce to 5 mg PO once daily.
Current dosage of 5 mg PO once daily: Hold therapy until clinical and/or laboratory parameters recover.
Acute GVHD and No Liver GVHD
Total bilirubin level of 3 to 5 times the ULN: Continue therapy at a reduced dosage until toxicity recovery.
Total bilirubin level of greater than 5 to 10 times the ULN: Hold ruxolitinib for up to 14 days; resume therapy at the current dosage when the bilirubin level is 1.5 times the ULN or less.
Total bilirubin level of greater than 10 times the ULN: Hold ruxolitinib for up to 14 days; resume therapy at a reduced dosage when the bilirubin level is 1.5 times the ULN or less.
Acute GVHD with Liver GVHD
Total bilirubin level greater than 3 times the ULN: Continue therapy at a reduced dosage until toxicity recovery.
Chronic GVHD
Total bilirubin level of 3 to 5 times the ULN: Continue therapy at a reduced dosage until toxicity recovery; maintain this dosage if the toxicity does not resolve within 14 days. If the toxicity resolves within 14 days, increase the dosage back to the previous dose level.
Total bilirubin level of greater than 5 to 10 times the ULN: Hold ruxolitinib for up to 14 days until the toxicity resolves; resume therapy at the current dosage. If the toxicity does not resolve within 14 days, resume therapy at a reduced dosage upon recovery.
Total bilirubin level of greater than 10 times the ULN: Hold ruxolitinib for up to 14 days until the toxicity resolves, then resume therapy at a reduced dosage. If the toxicity does not resolve within 14 days, discontinue ruxolitinib therapy.[46782]
NOTE: Modify the initial ruxolitinib dosage based on the severity of renal impairment (moderate: creatinine clearance (CrCl) of 30 to 59 mL/min; severe: CrCl of 15 to 29 mL/min; end-stage renal disease (ESRD): CrCl less than 15 mL/min and on dialysis) and on the initial platelet count in patients with myelofibrosis. Avoid use in patients with ESRD not requiring dialysis.
Myelofibrosis
Mild renal impairment (CrCl of 60 to 89 mL/min): No dosage adjustment recommended.
Moderate or severe renal impairment:
ESRD on dialysis:
Polycythemia Vera
Mild renal impairment: No dosage adjustment recommended.
Moderate or severe renal impairment: Initial dosage, 5 mg PO twice daily.
ESRD on dialysis: Initial dose, 10 mg PO once after each dialysis session.
Graft-Versus-Host Disease (GVHD)
Acute GVHD
Mild renal impairment: No dosage adjustment recommended.
Moderate or severe renal impairment: Initial dosage, 5 mg PO once daily.
ESRD on dialysis: Initial dose, 5 mg PO once after each dialysis session.
Chronic GVHD
Mild renal impairment: No dosage adjustment recommended.
Moderate or severe renal impairment: Initial dosage, 5 mg PO twice daily.
ESRD on dialysis: Initial dose, 10 mg PO once after each dialysis session.[46782]
Ruxolitinib is a kinase inhibitor that inhibits Janus Associated Kinases (JAKs), JAK1 and JAK2. The drug is available as an oral tablet and a topical cream. The oral formulation is indicated for the treatment of adults with intermediate- or high-risk myelofibrosis, adults with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea, and patients 12 years and older with steroid-refractory acute graft-versus-host disease (GVHD) or chronic GVHD after failure of 1 or 2 lines of systemic therapy. The topical formulation is indicated for use in patients 12 years and older to treat nonsegmental vitiligo and for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised patients whose disease is not adequately controlled with topical therapies or when those therapies are not advisable. Hematologic toxicity and infection have been reported with ruxolitinib therapy. In a large, randomized, postmarketing safety study in rheumatoid arthritis patients, an increased risk of all-cause mortality (including sudden cardiovascular death), major adverse cardiovascular events (MACE; defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), thrombosis (including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis), and cancer (e.g., lymphomas, lung cancer) was observed in patients treated with an oral JAK inhibitor as compared to those treated with a tumor necrosis factor (TNF) inhibitor. Current or past tobacco smokers were at increased risk of lung cancer, overall cancers, and major cardiovascular events. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particularly those with risk factors such as tobacco smoking, cardiovascular risk factors, those who develop malignancy, and those with a known malignancy other than successfully treated non-melanoma skin cancer.[46782][66999]
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
Extemporaneous compounding instructions for ruxolitinib oral suspension:
NOTE: The effect of using a nasogastric tube feeding preparation on ruxolitinib exposure has not been evaluated.
Hematologic toxicity including anemia (72% to 96%; grade 3 or 4, 45% or less), neutropenia (3% to 58%; grade 3 or 4, 40% or less), and thrombocytopenia (27% to 75%; grade 3 or 4, 61% or less) occurred in patients who received oral ruxolitinib in clinical trials. Obtain complete blood counts prior to therapy, every 2 to 4 weeks until the dose is stabilized, and then as clinically indicated. Therapy interruption, a dosage adjustment, and/or blood or platelet transfusions may be necessary in patients who develop severe myelosuppression. In a randomized trial, 2.4% of patients with chronic graft-versus-host disease who received oral ruxolitinib (n = 165) died from neutropenia, anemia, and/or thrombocytopenia. Red blood cell and platelet transfusions were administered in 60% and 5% of ruxolitinib-treated patients with myelofibrosis (n = 155), respectively, in another randomized trial.[46782] Thrombocytopenia, anemia, neutropenia (less than 1%), and eosinophilia (1%) were also reported in clinical trials with topical ruxolitinib.[66999]
Bacterial, mycobacterial, fungal, and viral infections have been reported in patients who received oral ruxolitinib in clinical trials. Monitor patients for signs and symptoms of infection, especially for tuberculosis, herpes zoster, and disseminated herpes simplex. Initiate treatment (i.e., antibiotic, antifungal, or antiviral medication) promptly in patients who develop an infection. Herpes zoster infection/post-herpetic neuralgia (2% vs. less than 1%) and urinary tract infection (9% vs. 5%) occurred more often in patients with myelofibrosis who received oral ruxolitinib (n = 155) compared with placebo (n = 151) in a randomized, phase 3 study. Urinary tract infection included the conditions of cystitis, urosepsis, kidney infection, pyuria, bacteria present in urine, and nitrite present in urine. Herpes zoster infection/post-herpetic neuralgia (6%) and urinary tract infection (less than 6%) were reported in patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study; grade 3 and 4 herpes zoster infection occurred in less than 1% of ruxolitinib-treated patients. Infection (55% grade 3 or 4, 41%) including bacterial infections (32% grade 3 or 4, 28%) and viral infections (31% grade 3 or 4, 14%) were reported in patients with acute graft-versus-host disease (GVHD) who received oral ruxolitinib in a single-arm study (n = 71). Infection (45%; grade 3 or 4, 15%) and viral infection (28%; grade 3 or 4, 5%) occurred in patients with chronic GVHD who received oral ruxolitinib (n = 165) in a randomized trial. Herpes simplex virus reactivation and dissemination has been reported in postmarketing surveillance.[46782] Serious lower respiratory tract infections were reported in the clinical development program of topical ruxolitinib. Other adverse events reported by recipients of topical ruxolitinib during the clinical trials included urinary tract infection (2%), otitis media (up to 1%), otitis externa (less than 1%), herpes zoster (less than 1%), staphylococcal infections (less than 1%), hordeolum (less than 1%), and influenza-like illness (less than 1%).[66999]
Bleeding events have been reported in patients who received oral ruxolitinib in clinical trials. In patients with myelofibrosis, hold therapy if bleeding occurs; resume ruxolitinib after the bleeding event has resolved and consider a dose reduction if the underlying cause persists. Bruising or ecchymosis occurred in 23% of patients with myelofibrosis who received oral ruxolitinib (n = 155) compared with 15% of patients who received placebo (n = 151) in a randomized, phase 3 study. Additionally, grade 3 bruising or ecchymosis was reported in less than 1% of ruxolitinib-treated patients. Bruising included the conditions of contusion, hematoma (injection site hematoma, periorbital hematoma, vessel puncture site hematoma), petechiae, and purpura. Epistaxis was reported in 6% of patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study. Bleeding occurred in 49% (grade 3 or 4, 20%) and 12% (grade 3 or 4, 2%) of patients with acute graft-versus-host disease (GVHD) (n = 71) and chronic GVHD (n = 165), respectively, who received oral ruxolitinib in separate clinical trials.[46782]
Dizziness and headache have been reported in patients who received oral ruxolitinib in clinical trials. Dizziness (18% vs. 7%) and headache (15% vs. 5%) occurred more often in patients with myelofibrosis who received oral ruxolitinib (n = 155) compared with placebo (n = 151) in a randomized, phase 3 study; additionally, grade 3 dizziness was reported in less than 1% of ruxolitinib-treated patients. Dizziness included the conditions of balance disorder, labyrinthitis, Meniere's Disease, postural dizziness, and vertigo. Dizziness (15%) and headache (16%) were reported in patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study; additionally, grade 3 and 4 headache occurred in less than 1% of ruxolitinib-treated patients. Headache (21%; grade 3 or 4, 4%) and dizziness (16%) were reported in patients with acute graft-versus-host disease who received oral ruxolitinib in a single-arm study (n = 71).[46782] In 2 clinical studies involving 449 patients with nonsegmental vitiligo, treatment with topical ruxolitinib was associated with the development of headache (4%), anxiety (less than 1%), and insomnia (less than 1%).[66999]
Weight gain occurred in 7% of patients with myelofibrosis who received oral ruxolitinib (n = 155) compared with 1% of patients who received placebo (n = 151) in a randomized, phase 3 study. Additionally, grade 3 weight gain was reported in less than 1% of ruxolitinib-treated patients. Weight gain was reported in less than 6% of patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study.[46782]
Flatulence occurred in 5% of patients with myelofibrosis who received oral ruxolitinib (n = 155) compared with less than 1% of patients who received placebo (n = 151) in a randomized, phase 3 study. Other gastrointestinal toxicity including abdominal pain (all grade, 15%; grade 3 and 4, less than 1%), constipation (8%), diarrhea (15%), and nausea (6%) was reported in patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study. Diarrhea was reported in 24% (grade 3 and 4, 7%) of patients with acute graft-versus-host disease (GVHD) who received oral ruxolitinib in a single-arm study (n = 71). Nausea (12%) and diarrhea (10%; grade 3 or 4, 1%) occurred in patients with chronic GVHD who received oral ruxolitinib (n = 165) in a randomized trial.[46782] Safety data for topical ruxolitinib are available from 2 clinical trials involving 499 patients with atopic dermatitis and 2 clinical trials involving 449 patients with nonsegmental vitiligo. Adverse events reported by recipients of topical ruxolitinib during these trials included diarrhea (up to 1%), gastritis (less than 1%), gastroenteritis (less than 1%), and vomiting (less than 1%).[66999]
Elevated hepatic enzymes including increased ALT (25% to 73%; grade 3 or 4, 11% or less) and AST (17% to 65%; grade 3 or 4, 6% or less) levels occurred in patients who received oral ruxolitinib in clinical trials. Evaluate bilirubin levels prior to therapy, every 2 to 4 weeks until the dose is stabilized, and then as clinically indicated. Avoid ruxolitinib in patients with myelofibrosis who have a platelet count of less than 50 X 109 cells/L and hepatic impairment. Patients with graft-versus-host disease (GVHD) who develop hepatotoxicity may require therapy interruption, a dosage reduction, or drug discontinuation. Increased gamma glutamyltransferase (GGT) level was reported in patients with chronic GVHD who received oral ruxolitinib (n = 165) in a randomized trial.[46782]
Progressive multifocal leukoencephalopathy (PML) has been reported in patients with myelofibrosis who received oral ruxolitinib treatment. Consider PML, an opportunistic viral infection of the brain caused by reactivated latent John Cunningham (JC) virus, in the differential diagnosis of patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. Such symptoms include changes in mood, vision, speech, or gait, abnormal thinking, unusual behavior, confusion, memory impairment, and decreased strength on one side of the body. PML is usually diagnosed by brain imaging, cerebrospinal fluid testing for JC viral DNA by polymerase chain reaction, and/or brain biopsy. If PML is suspected, stop treatment with ruxolitinib and evaluate; consider consultation with a neurologist and/or infectious disease specialist. Unfortunately, PML is usually fatal or leads to severe disability, and there are no known effective treatments.[46782]
There have been reports of patients stopping oral ruxolitinib during an acute illness after which the patient's clinical course continued to worsen. However, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. Some patients have experienced fever, respiratory depression, hypotension, disseminated intravascular coagulation (DIC), or multi-organ failure after ruxolitinib discontinuation. Following abrupt discontinuation of oral ruxolitinib, symptoms of myeloproliferative disease generally return to pretreatment levels in about 1 week. For these reasons, gradual tapering of the dose is recommended except for patients who develop thrombocytopenia or neutropenia. If one or more of these symptoms occur after discontinuation of, or while tapering the dose of oral ruxolitinib, evaluate for and treat any illness and consider restarting or increasing the dose of ruxolitinib. Fever occurred in 16% (grade 3 or 4, 2%) of patients with chronic graft-versus-host disease who received oral ruxolitinib (n = 165) in a randomized trial.[46782] Among the 449 patients who received topical ruxolitinib for nonsegmental vitiligo during clinical trials, fever was reported in 1% of the drug recipients.[66999]
New primary malignancy has been reported with ruxolitinib therapy, specifically non-melanoma skin cancer such as basal cell, squamous cell, and Merkel cell carcinoma. Periodic skin examinations are recommended; advise patients to report any new or changing lesions.[46782] [66999]
Hypercholesterolemia including elevated total cholesterol, elevated low-density lipoprotein (LDL) cholesterol (88% or less; grade 3 or 4, 10% or less) and hypertriglyceridemia (15% or less; grade 3 or 4, 1% or less) have been reported in patients who received oral ruxolitinib in clinical studies. Obtain a lipid panel and assess triglyceride levels about 8 to 12 weeks after starting ruxolitinib; monitor and treat patients with high cholesterol or triglycerides according to clinical guidelines.[46782]
Asthenia (7%) and fatigue (15%) were reported in patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study. Fatigue occurred in 37% (grade 3 or 4, 14%) and 13% (grade 3 or 4, 1%) of patients with acute graft-versus-host disease (GVHD) (n = 71) and chronic GVHD (n = 165), respectively, who received oral ruxolitinib in separate clinical trials.[46782]
Pruritus was reported in 14% of patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study; additionally, grade 3 and 4 pruritus occurred in less than 1% of ruxolitinib-treated patients.[46782] Pooled data from 2 clinical studies involving 449 patients with nonsegmental vitiligo found 5% of patients who received treatment with topical ruxolitinib developed application site pruritus.[66999]
Cough (8%), dyspnea or exertional dyspnea (13%; grade 3 and 4, 3%) and naso-pharyngitis (9%) were reported in patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study. Dyspnea was reported in 32% (grade 3 or 4, 7%) of patients with acute graft-versus-host disease (GVHD) who received oral ruxolitinib in a single-arm study (n = 71). Cough (13%) and dyspnea (11%; grade 3 or 4, 1%) occurred in patients with chronic GVHD who received oral ruxolitinib (n = 165) in a randomized trial.[46782] Safety data for topical ruxolitinib are available from 2 clinical trials involving 499 patients with atopic dermatitis and 2 clinical trials involving 449 patients with nonsegmental vitiligo. Adverse events reported by recipients of topical ruxolitinib during these trials included naso-pharyngitis (3% to 4%), bronchitis (1%), tonsillitis (1%), rhinorrhea (1%), and nasal congestion (less than 1%).[66999]
Arthralgia (7%) and muscle cramps/spasms (12%; grade 3 and 4, less than 1%) were reported in patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized study. Musculoskeletal pain occurred in 18% (grade 3 or 4, 1%) of patients with chronic graft-versus-host disease who received oral ruxolitinib (n = 165) in another randomized trial.[46782]
Edema including peripheral edema was reported in 8% of patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study. Edema occurred in 51% (grade 3 or 4, 13%) and 10% (grade 3 or 4, 1%) of patients with acute graft-versus-host disease (GVHD) (n = 71) and chronic GVHD (n = 165), respectively, who received oral ruxolitinib in separate clinical trials.[46782]
Hypertension was reported in less than 6% of patients with polycythemia vera who received oral ruxolitinib (n = 110) in a randomized, phase 3 study. Hypertension occurred in 20% (grade 3 or 4, 13%) and 16% (grade 3 or 4, 5%) of patients with acute graft-versus-host disease (GVHD) (n = 71) and chronic GVHD (n = 165), respectively, who received oral ruxolitinib in separate clinical trials.[46782] Pooled data from 2 clinical studies involving 449 patients with nonsegmental vitiligo found less than 1% of patients who received treatment with topical ruxolitinib developed hypertension.[66999]
Rash was reported in 23% (grade 3 or 4, 3%) of patients with acute graft-versus-host disease (GVHD) who received oral ruxolitinib in a single-arm study (n = 71). In a randomized trial, 1 patient with chronic GVHD who received oral ruxolitinib (n = 165) died from toxic epidermal necrolysis.[46782] Safety data for topical ruxolitinib are available from 2 clinical trials involving 499 patients with atopic dermatitis and 2 clinical trials involving 449 patients with nonsegmental vitiligo. Adverse events reported by recipients of topical ruxolitinib during these trials included application site acne vulgaris (6%), application site erythema (2%), urticaria (1%), folliculitis (up to 1%), acneiform dermatitis (less than 1%), contact dermatitis (less than 1%), contusion (less than 1%), and application site skin discoloration (less than 1%).[66999]
Thrombosis was reported in 25% of patients with acute graft-versus-host disease who received oral ruxolitinib in a single-arm study (n = 71); grade 3 or 4 thrombosis occurred in 11% of patients.[46782] Additionally, thromboembolic events were observed in clinical trials with topical ruxolitinib; however, there was not a clear relationship between elevated platelet counts and the thrombotic events.[66999]
Safety data for topical ruxolitinib are available from 2 clinical trials involving 499 patients with atopic dermatitis. Adverse events reported by less than 1% of patients treated with topical ruxolitinib during these 8-week trials included allergic conjunctivitis, pyrexia, and seasonal allergies.[66999]
Nephrotoxicity, specifically increased serum creatinine level, was reported in 47% (grade 3 or 4, 1%) of patients with chronic graft-versus-host disease who received oral ruxolitinib (n = 165) in a randomized trial.[46782]
Increased lipase level (38%; grade 3 or 4, 12%) and hyperamylasemia (35%; grade 3 or 4, 8%) occurred in patients with chronic graft-versus-host disease who received oral ruxolitinib (n = 165) in a randomized trial.[46782]
Increased hepatitis B virus (HBV) viral load (hepatitis B exacerbation) with or without elevated transaminase levels has been reported in ruxolitinib-treated patients with chronic HBV infection. Monitor and treat these patients according to clinical guidelines.[46782]
Hematologic toxicities (e.g., anemia, neutropenia, and thrombocytopenia) have been reported with ruxolitinib therapy. The initial oral dose is based on platelet count in patients with myelofibrosis. Obtain complete blood counts prior to therapy, every 2 to 4 weeks until the dose is stabilized, and then as clinically indicated. Therapy interruption, a dosage adjustment, and/or blood or platelet transfusions may be necessary in patients who develop severe myelosuppression. In patients with myelofibrosis, hold oral therapy if bleeding occurs; resume ruxolitinib after the bleeding event has resolved and consider a dose reduction if the underlying cause persists.[46782] Consider the benefits and risk of using topically applied ruxolitinib in patients with a known history of anemia, neutropenia, or thrombocytopenia. Monitor complete blood counts as clinically indicated, and discontinue use of the topical cream if signs or symptoms of a clinically significant hematologic toxicity develops.[66999]
Serious and sometimes fatal infections such as tuberculosis (TB), progressive multifocal leukoencephalopathy (PML), bacterial and mycobacterial infection, fungal infection, and viral infection (e.g., herpes zoster, herpes simplex) have been reported in patients receiving oral ruxolitinib therapy; do not start oral ruxolitinib in patients with an active infection. Screen patients for a history of infections, including TB, herpes zoster, herpes simplex, and hepatitis B virus (HBV). Administer prophylactic antibiotics as appropriate per clinical guidelines. Monitor patients for signs and symptoms of infection during therapy and manage promptly. Discontinue treatment if PML is suspected or diagnosed. Increased hepatitis B virus (HBV) viral load with or without elevated transaminase levels has occurred in patients with chronic HBV infection; monitor and treat these patients according to clinical guidelines. Consider interrupting therapy in patients who develop evidence of dissemination of herpes simplex; treat and monitor these patients according to clinical guidelines. Evaluate patients for risk of TB and test patients at higher risk for latent TB; consult with a physician with expertise in treating TB prior to starting ruxolitinib in patients with active or latent TB. Risk factors include history of residence or travel to countries with a high prevalence of TB, close contact with a person with active TB, and a history of active or latent TB where an adequate course of treatment cannot be confirmed.[46782] Avoid use of topical ruxolitinib in patients with an active, serious infection, including localized infections. Consider the risks and benefits prior to using topical ruxolitinib in patients with chronic or recurrent infections, history of serious or opportunistic infections, exposure to TB, reside or traveled to areas of endemic TB or mycosis, or underlying conditions that may predispose them to an infection. Closely monitor patients for sign and symptoms of an infection during and after treatment. Interrupt topical ruxolitinib therapy in patients who develop a serious infection, opportunistic infection, or sepsis. Do not resume treatment until the infection is controlled. Serious lower respiratory tract infections have been reported during treatment with topical ruxolitinib. Additionally, viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in topical ruxolitinib clinical trials; consider interrupting therapy if a patient develops herpes zoster during treatment with topical ruxolitinib. Treatment with topical ruxolitinib is not recommended in patients with active hepatitis B or C, as the impact of Janus kinase inhibitors on chronic viral hepatitis reactivation is unknown.[66999]
Patients with preexisting hepatic disease may be at increased risk for ruxolitinib-induced adverse events. Evaluate bilirubin levels prior to therapy, every 2 to 4 weeks until the dose is stabilized, and then as clinically indicated. An initial oral ruxolitinib dosage reduction may be necessary in patients with myelofibrosis (MF) or polycythemia vera who have baseline hepatic impairment. Avoid ruxolitinib in patients with MF who have a platelet count of less than 50 X 109 cells/L and hepatic impairment. An initial dosage reduction of oral ruxolitinib may be necessary in patients with graft versus host disease (GVHD) based on the presence of or severity of liver GVHD. Patients with chronic GVHD who have score 3 liver GVHD at baseline should have blood counts monitored more frequently. Patients with GVHD who develop hepatotoxicity may require therapy interruption, a dosage reduction, or drug discontinuation.[46782]
Patients with preexisting renal disease may be at increased risk for ruxolitinib-induced adverse events. An initial oral ruxolitinib dosage reduction may be necessary in patients with baseline moderate (creatinine clearance (CrCl) of 30 to 59 mL/min) or severe (CrCl of 15 to 29 mL/min) renal impairment. Avoid oral ruxolitinib in patients with end-stage renal disease (CrCl less than 15 mL/min) who do not require dialysis and in patients with myelofibrosis who have moderate to severe renal impairment and a platelet count less than 50 X 109 cells/L.[46782]
Avoid abrupt discontinuation of oral ruxolitinib when stopping the drug for reasons other than thrombocytopenia. Following discontinuation of oral ruxolitinib, symptoms of myeloproliferative neoplasms generally return to pretreatment levels in about 1 week. There have been reports of patients stopping ruxolitinib during an acute illness after which the patient's clinical course continued to worsen. However, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. Some patients have experienced fever, respiratory distress, hypotension, DIC, or multi-organ failure after ruxolitinib discontinuation. For these reasons, gradual tapering of the dose is recommended. If one or more of these symptoms occur after discontinuation of, or while tapering the dose of ruxolitinib, evaluate for and treat any illness and consider restarting or increasing the dose of ruxolitinib.[46782]
New primary malignancy, including lymphoma, have been observed in patients receiving Janus kinase (JAK) inhibitors for inflammatory conditions. In a large, randomized, postmarketing safety study in rheumatoid arthritis patients, a higher rate of malignancies (excluding non-melanoma skin cancer) was observed in patients treated with an oral JAK inhibitor as compared to those treated with a tumor necrosis factor (TNF) blocker. This included a higher rate of lymphomas and lung cancers (among current and past smokers) in the JAK inhibitor treated patients. Additionally, patients who were current or past smokers had an additional increased risk of overall malignancies. Consider the benefits and risks of initiating or continuing treatment with ruxolitinib in patients with a known malignancy (other than successfully treated non-melanoma skin cancers), patients who develop a malignancy when on treatment, and patients who are currently or have a history of tobacco smoking. Further, periodic skin examinations are recommended as non-melanoma skin cancer (e.g., basal cell, squamous cell, and Merkel cell carcinoma) have occurred in patients treated with ruxolitinib. Advise patients to report any history of skin cancer or if they develop any new or changing lesions during ruxolitinib therapy. Instruct patients taking topical ruxolitinib to limit exposure to sunlight (UV) exposure by wearing protective clothing and using broad-spectrum sunscreen.[46782] [66999]
Hypercholesterolemia (e.g., elevated total cholesterol, elevated low-density lipoprotein (LDL) cholesterol) and hypertriglyceridemia have been reported with oral ruxolitinib therapy. The effect of ruxolitinib-induced high cholesterol or high triglycerides on cardiovascular morbidity and mortality is not known. Obtain a lipid panel and assess triglyceride levels about 8 to 12 weeks after starting ruxolitinib; monitor and treat patients with high cholesterol or triglycerides according to clinical guidelines.[46782]
In a large, randomized, postmarketing safety study in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, a higher rate of all-cause mortality (including sudden cardiovascular death) was observed with the use of an oral Janus kinase inhibitor as compared to tumor necrosis factor (TNF) blocker treatment. Consider the benefits and risks for individual patients prior to initiating or continuing therapy with ruxolitinib.[46782] [66999]
In a large, randomized, postmarketing safety study in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke was observed with the use of an oral Janus kinase inhibitor as compared to tumor necrosis factor (TNF) blocker treatment. Consider the risks and benefits prior to initiating or continuing therapy with ruxolitinib, particularly in patients who are current or past smokers and patients with cardiovascular risk factors (e.g., hypercholesterolemia or a history of cardiac disease, myocardial infarction, or stroke). Inform patients about the symptoms of serious cardiovascular events and the steps to take if these symptoms occur. Discontinue treatment in patients that have experienced a myocardial infarction or stroke.[46782] [66999]
Thrombosis [i.e., deep venous thrombosis (DVT), pulmonary thromboembolism (PE), and arterial thrombosis] has been reported in patients treated with oral Janus kinase (JAK) inhibitors for inflammatory conditions. Many of these adverse reactions were serious and some resulted in death. In a large, randomized, postmarketing safety study in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed with the use of an oral JAK inhibitor as compared to tumor necrosis factor (TNF) blocker treatment. Avoid use of topical ruxolitinib in patients who may be at increased risk for thrombosis. If symptoms of thrombosis occur, discontinue ruxolitinib and treat patients appropriately.[46782] [66999]
No well-controlled studies have been conducted to evaluate the use of ruxolitinib in pregnant patients. Data are insufficient to determine a drug-associated risk for major birth defects, miscarriages, or other adverse maternal or fetal outcomes. Animal data involving rats and rabbits administered doses of 15, 30, or 60 mg/kg/day and 10, 30, or 60 mg/kg/day, respectively, during organogenesis, revealed no evidence of teratogenicity. However, at doses of 60 mg/kg/day, reductions in fetal weights were observed in both rats and rabbits. Additionally, rabbits experienced an increase in late resorptions when exposed to the 60 mg/kg/day dose. Health care providers are encouraged to report topical ruxolitinib exposures to the pregnancy registry by calling 1-855-463-3463.[46782] [66999]
There are no data regarding the presence of ruxolitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Because there is a potential for adverse reactions in nursing infants, advise women to discontinue breast-feeding during ruxolitinib therapy and for at least 2 weeks after the last oral dose or 4 weeks after the last topical application.[46782] [66999]
Ruxolitinib is a kinase inhibitor that inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2. Normally, JAK1 and JAK2 mediate the signaling of several cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors and activation and subsequent localization of STATs to the nucleus, which leads to gene expression modulation. It is not currently known how inhibiting specific JAK enzymes relates to therapeutic efficacy in atopic dermatitis or nonsegmental vitiligo.[66999]
Dysregulated JAK1 and JAK2 signaling has been noted in myelofibrosis and polycythemia vera, which are myeloproliferative neoplasms. In a mouse model of JAK2V617F-positive myeloproliferative neoplasm, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen, and decreased circulating inflammatory cytokines such as TNF-alpha and IL-6.
The JAK-STAT signaling pathway regulates the development, proliferation, and activation of many types of immune cells required for graft-versus-host disease (GVHD) pathogenesis. Decreased expression of inflammatory cytokines in colon homogenates and reduced immune-cell infiltration in the colon were observed in a mouse model of acute GVHD.[46782]
Revision Date: 09/11/2024, 01:56:00 AMRuxolitinib is administered orally and topically. The mean steady-state Vd in patients with myelofibrosis (MF) and polycythemia vera (PV) is 72 L (coefficient of variation (CV), 29%) and 75 L (CV, 23%), respectively. In vitro, it is approximately 97% bound to plasma proteins, mostly to albumin. Ruxolitinib is metabolized primarily by CYP3A4 forming active metabolites (e.g., M18 metabolite). After a single oral radiolabeled dose to healthy adults, elimination was predominately through metabolism with 74% of radioactivity excreted in urine and 22% excreted in feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity. Ruxolitinib clearance was 22.1 L/hour (CV, 39%) in men and 17.7 L/hour in women with MF, 12.7 L/hour (CV, 42%) in patients with PV, 11.8 L/hour (CV, 63%) in patients with acute graft-versus-host disease (GVHD), and 9.7 L/hour (CV, 51%) in patients with chronic GVHD.[46782][66999]
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9
Ruxolitinib is a substrate of the hepatic isoenzymes CYP3A4 (major) and CYP2C9. Inhibitors and inducers of CYP3A4 may alter the pharmacokinetic parameters of ruxolitinib. In vitro, ruxolitinib and its M18 metabolite are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. At clinically relevant concentrations, ruxolitinib is not an inducer of CYP1A2, CYP2B6, or CYP3A4, and ruxolitinib and its M18 metabolite are not inhibitors of the P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1 or OAT3 transport systems. Ruxolitinib is not a substrate for the P-gp transporter.[46782][66999]
Ruxolitinib appears to be well absorbed; oral absorption was estimated to be at least 95%. Administration with a high-fat, high-calorie meal does not cause clinically relevant changes in absorption. Maximal ruxolitinib plasma concentrations are achieved within 1 to 2 hours after oral administration. Mean maximum plasma concentration (Cmax) and systemic exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. Over this ruxolitinib dosage range, the mean Cmax values ranged from 205 to 7,100 nanoMolar (nM) and the AUC values ranged from 862 to 30,700 nM x hour. The mean elimination half-life of oral ruxolitinib is approximately 3 hours, and the mean half-life of ruxolitinib plus metabolites is approximately 5.8 hours.[46782]
Following topical administration of approximately 1.5 mg/cm2 (dose range: 1.2 to 37.6 grams per application) twice daily for 28 days (study included both adults and adolescents), the mean maximum plasma concentration (Cmax) and systemic exposure (AUC) for ruxolitinib on Day 1 in adults with atopic dermatitis were 449 +/- 883 nanoMolar (nM) and 3,215 +/- 6,184 nM x hour, respectively. There was no evidence of drug accumulation after daily application for 28 days. The mean terminal half-life of topically applied ruxolitinib is approximately 116 hours.[66999]
The mean ruxolitinib systemic exposure was increased by 1.9-fold in patients with mild hepatic impairment (Child-Pugh class A), by 1.3-fold in patients with moderate hepatic impairment (Child-Pugh class B), and by 1.7-fold in subjects with severe hepatic impairment (Child-Pugh class C) compared with data from subjects with normal hepatic function. Any degree of baseline hepatic impairment (total bilirubin level greater than the ULN and any AST level) does not clinically impact the pharmacokinetic (PK) parameters of oral ruxolitinib in patients with acute or chronic graft-versus-host disease (GVHD). Patient with stage 4 liver acute GVHD have a lower apparent clearance of ruxolitinib compared with patient who have no liver acute GVHD. It is not known if score 3 liver chronic GVHD has a significant impact on the PK parameters of oral ruxolitinib.[46782]
The total systemic exposure of ruxolitinib and its active metabolites was increased by 1.3-fold in subjects with mild renal impairment (creatinine clearance (CrCl) of 60 to 89 mL/min), by 1.5-fold in subjects with moderate renal impairment (CrCl of 30 to 59 mL/min), by 1.9-fold in subjects with severe renal impairment (CrCl of 15 to 29 mL/min), and by 1.6-fold in subjects with end-stage renal disease after dialysis compared with data from subjects with normal renal function (CrCl of 90 mL/min or greater). Ruxolitinib is not removed by dialysis; however, it is not known if some active metabolites are removed by dialysis.[46782]
Age (pediatrics 12 to less than 18 years compared with adults 18 to 73 years) does not clinically impact the pharmacokinetic parameters of oral ruxolitinib.[46782] Following topical administration of approximately 1.5 mg/cm2 (dose range: 1.2 to 37.6 grams per application) twice daily for 28 days (study included both adults and adolescents), the mean maximum plasma concentration (Cmax) and systemic exposure (AUC) for ruxolitinib on Day 1 in adolescents (13 to 17 years of age) with atopic dermatitis, the mean Cmax and AUC on Day 1 were 110 +/- 255 nM and 801 +/- 2,019 nM x hour, respectively.[66999]
Age (up to 73 years) does not clinically impact the pharmacokinetic parameters of oral ruxolitinib.[46782]
Sex does not clinically impact the pharmacokinetic parameters of oral ruxolitinib.[46782]
Ethnicity (White or Asian) does not clinically impact the pharmacokinetic parameters of oral ruxolitinib.[46782]
Weight (range, 29 to 139 kg) does not clinically impact the pharmacokinetic parameters of oral ruxolitinib.[46782]
No well-controlled studies have been conducted to evaluate the use of ruxolitinib in pregnant patients. Data are insufficient to determine a drug-associated risk for major birth defects, miscarriages, or other adverse maternal or fetal outcomes. Animal data involving rats and rabbits administered doses of 15, 30, or 60 mg/kg/day and 10, 30, or 60 mg/kg/day, respectively, during organogenesis, revealed no evidence of teratogenicity. However, at doses of 60 mg/kg/day, reductions in fetal weights were observed in both rats and rabbits. Additionally, rabbits experienced an increase in late resorptions when exposed to the 60 mg/kg/day dose. Health care providers are encouraged to report topical ruxolitinib exposures to the pregnancy registry by calling 1-855-463-3463.[46782] [66999]
There are no data regarding the presence of ruxolitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Because there is a potential for adverse reactions in nursing infants, advise women to discontinue breast-feeding during ruxolitinib therapy and for at least 2 weeks after the last oral dose or 4 weeks after the last topical application.[46782] [66999]
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