Lukedx (Ruxolitinib) 80mg

Generic Name: Ruxolitinib

Brand name: Lukedx (Ruxolitinib) 5mg

Dosage form: 5mg*56tablets/box.

Medication management

Oral administration

• with or without food
• If a dose is missed, the patient does not need an additional dose, but takes the next commonly prescribed dose
• When discontinuing for reasons other than thrombocytopenia, consider tapering the dose (eg, by 5 mg q12hr weekly)

NG tube administration

• If tablets cannot be ingested, they can be given through a nasogastric tube
  • Suspend 1 tablet in 40 mL of water and stir for about 10 minutes
  • Administer within 6 hours of dispersing the tablet into a suspension using a suitable syringe
  • Rinse the NG tube with 75 mL of water
  • The effect on Ruxolitinib exposure during administration via NG tube has not been evaluated

storage

• Tablets: Store at room temperature 20-25°C (68-77°F); excursions 15-30°C (59-86°F)
• Suspension in NG tubes: Store at room temperature 20-25°C (68-77°F) for up to 6 hours

Adults

dosage form

tablet

• 5mg/10mg/15mg/20mg/25mg

myelofibrosis

Kinase inhibitors are indicated for the treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, postpolycythemia MF and essential thrombocythemia MF

initial dose

• Platelet count > 200 x 10^9/L: 20 mg PO BID
• Platelet count 100-200 x 10^9/L: 15mg PO BID
• Platelet count 50 to <100 x 10^9/L: 5 mg PO BID

Insufficient response to initiation of therapy in patients with platelet counts ≥100 x 10^9/L

• If response is inadequate and platelet count and ANC are adequate, dose may be increased in 5 mg BID increments; not to exceed 25 mg PO BID
• Do not increase dose during first 4 weeks of treatment and do not exceed q2Weeks
• Consider dose escalation in patients who meet all of the following criteria:
  • Failure to decrease from pre-treatment baseline at 50% reduction in palpable spleen length or 35% reduction in spleen volume as measured by CT or MRI
  • Platelet count > 125 x10^9/L at 4 weeks, never <100 x10^9/L.
  • ANC level > 0.75 x10^9/L.
  • Long-term maintenance of 5 mg BID has shown no response and limit continued use of this dose for patients whose benefits outweigh potential risks
  • Discontinue if there is no reduction in spleen size or improvement in symptoms after 6 months of treatment

Insufficient response to initiation of therapy in patients with platelet counts of 50 x 10^9/L to <100 x 10^9/L

• If response is inadequate and platelet count and ANC are adequate, dose may be increased by 5 mg qDay up to a maximum of 10 mg BID
• Do not increase dose during first 4 weeks of treatment and do not exceed q2Weeks
• Consider dose escalation in patients who meet all of the following criteria:
  • Platelet counts remain at least 40 x 10^9/L.
  • Platelet count has not decreased >20% in the previous 4 weeks
  • ANC > 1 x 10^9/L.
  • No dose reduction or interruption adverse events or hematologic toxicities in the previous 4 weeks
• Continuation of treatment for > 6 months should be limited to patients where the benefits outweigh the potential risks
• Discontinue treatment if there is no reduction in spleen size or improvement in symptoms after 6 months of treatment

polycythemia vera

Polycythemia vera in patients with an inadequate response or intolerance to hydroxyurea

Initial: 10 mg PO BID

Increase the dose to deal with deficiencies

• If the response is insufficient and platelet, hemoglobin, and neutrophil counts are adequate, the dose can be increased in 5 mg BID increments to a maximum of 25 mg BID
• The dose should not be increased during the first 4 weeks of treatment and should not exceed q2Week
• Consider dose escalation for patients who meet all of the following criteria:
  • Insufficient effect, ≥1 as follows: persistent need for phlebotomy, WBC > ULN, platelet count > ULN, palpable spleen <25% reduction from baseline
  • Platelet count ≥140×10^9/L.
  • Hemoglobin≥2g/dL
  • ANC≥1.5×10^9/L.

acute graft-versus-host disease

For the treatment of steroid-refractory acute graft-versus-host disease (GVHD)

Initial dose: 5 mg PO BID; if ANC and platelet counts do not decrease ≥50% from baseline, increase to 10 mg BID after at least 3 days

Consider tapering after 6 months for responsive patients who have discontinued therapeutic doses of corticosteroids

tapering

• Taper for 1 dose ~q8 weeks (eg, 10 mg BID to 5 mg BID to 5 mg qDay)
• Patients unable to tolerate 5 mg qDay: Interrupt treatment until clinical and/or laboratory parameters have recovered
• Consider retreatment if acute GVHD signs or symptoms recur during or after tapering

Dose Modification (MF)

Changes in bleeding dose (regardless of platelet count)

• Interrupt treatment until bleeding resolves; consider resuming at previous dose if underlying cause of bleeding has resolved, or if underlying cause of bleeding persists

Treatment discontinuation initiated in patients with platelet count ≥100 x 10^9/L

• Interruption of treatment for platelet count <50 x 10^9/L or ANC <0.5 x 10^9/L
• After recovery of platelet count > 50 x 10^9/L and ANC > 0.75 x 10^9/L, restart dosing
• Restart the dose after interruption as follows
  • Restart dose at least 5 mg BID below dose at interruption; maximum dose listed below
  • Platelet count ≥125 x 10^9/L: 20 mg BID
  • Platelet count 100 to <125 x 10^9/L: 15 mg BID
  • Platelet count 75 to <100 x 10^9/L: 10 mg BID for at least 2 weeks; increase to 15 mg BID if stable
  • Platelet count 50 to <75 x 10^9/L: 5 mg BID for at least 2 weeks; may increase to 10 mg BID if stable
  • Platelet count <50 x10^9/L: continue to maintain dose
  • After recovery of ANC to ≥0.75X10^9/L, restart at the higher of the maximum dose of 5 mg qDay or 5 mg BID within the week prior to treatment discontinuation.
• Dose Modification for Thrombocytopenia
  • Platelet count 100 to <125 x10^9/L: If taking 25 mg BID, reduce to 20 mg BID; if taking 20 mg BID, reduce to 15 mg BID; if taking lower dose, do not change dose
  • Platelet count 75 to <100 x 10^9/L: 10 mg BID; do not change dose while taking 5 mg BID
  • Platelet count 50 to <75 x 10^9/L: 5 mg BID
  • Platelet count <50 x10^9/L: maintain dose
  • Long-term maintenance at the 5 mg BID dose has shown no response, and continued use of this dose should be limited to patients where the benefits outweigh the potential risks

Treatment interruption in patients who started treatment with platelet counts of 50 to <75 x 10^9/L.

• Interrupt therapy for platelet count <25 x 10^9/L or ANC less than 0.5 x 10^9/L
• Dosing can be restarted after platelet count recovery >35 X 10^9/L and ANC >0.75 X 10^9/L
• Restart at a submaximal dose of 5 mg qDay or 5 mg BID within one week prior to treatment interruption
• Dose Modification for Thrombocytopenia
  • Platelet count <25 x 10^9/L: Interrupt dose
  • Platelet count of 25 x 10^9/L to <35 X 10^9/L with <20% reduction in platelet count in first 4 weeks: dose decrease by 5 mg qDay; for patients on 5 mg qDay, maintain current dose
  • Platelet count 25 x 10^9/L to <35 X 10^9/L with ≥20% decrease in platelet count in first 4 weeks: dose reduction by 5 mg BID; for patients with 5 mg BID, reduce dose to 5 mg qDay ; For patients on 5 mg qDay, maintain current dose

renal insufficiency

• Moderate to severe (CrCl 15-59 mL/min)
  • Platelet count > 150 x 10^9/L: No dose adjustment required
  • Platelet count 100-150 x 10^9/L: starting dose of 10 mg BID
  • Platelet count 50 to <100 x 10^9/L: starting dose of 5 mg qDay
  • Platelet count <50 x10^9/L: avoid use
• ESRD (CrCl < 15 mL/min)
  • Dialysis and platelet count 100-200 x 10^9/L: 15 mg once after dialysis
  • Dialysis and platelet count > 200 x 10^9/L: 20 mg once after dialysis
  • Without Dialysis: Avoid Use

liver damage (severity)

• Platelet count > 150 x 10^9/L: No dose adjustment required
• Platelet count 100-150 x 10^9/L: starting dose of 10 mg BID
• Platelet count 50 to <100 x 10^9/L: starting dose of 5 mg qDay
• Platelet count <50 x10^9/L: avoid use

Coadministration with strong CYP3A4 inhibitors or fluconazole

• Dose reduction when coadministered with strong CYP3A4 inhibitors or fluconazole (≤200 mg/day)
• Avoid fluconazole doses > 200 mg/day with ruxolitinib
• Closely monitor blood counts for toxicity and adjust ruxolitinib dose in combination with itraconazole if necessary
• Starting dose in patients with myelofibrosis based on platelet count
  • Platelet count ≥100 x 10^9/L: 10 mg BID
  • Platelet count 50 to <100 x 10^9/L: 5 mg BID
• If stabilized at 10 mg BID, reduce by 50% (round to closest available tablet strength)
• If stable at 5 mg BID, reduce qDay by 5 mg
• If stable at 5 mg qDay, avoid strong CYP3A4 inhibitor or fluconazole therapy or interrupt ruxolitinib during strong CYP3A4 inhibitor or fluconazole use

Coadministration with CYP3A4 inducers

• No dose adjustment is recommended; however, closely monitor and titrate dose based on safety and efficacy

Dose adjustment (PV)

dose reduction

• Hgb ≥ 12 g/dL, platelet count ≥ 100 x 10^9/L: no changes required
• Hgb 10 to <12 g/dL and platelet count 75 to <100 x 10^9/L: Consider dose reduction to avoid dose interruption for anemia and thrombocytopenia
• Hgb 8 to <10 g/dL OR platelet count 50 to <75 x10^9/L: Reduce dose by 5 mg BID; if already taking 5 mg BID, reduce dose to 5 mg qDay
• Hgb <8 g/dL OR platelet count <50 x10^9/L: Interrupt dose

Treatment interrupted and dosing restarted

• Interrupt therapy for hgb <8 g/dL, platelet count <50 x 10^9/L, or ANC <1 x10^9/L
• After recovery to acceptable levels, dosing can be restarted
• Use the most severe category for each parameter
  • Hgb <8 g/dL OR platelet count <50 x10^9/L OR ANC <1 x10^9/L: continue to maintain dose
  • Hgb 8 to <10 g/dL or platelet count 50 to <75 x 10^9/L OR ANC 1 to <1.5 x10^9/L: 5 mg BID, or no more than 5 mg BID less than the resulting dose dose interruption
  • Hgb 10 to <12 g/dL OR platelet count 75 to <100 x10^9/L OR ANC 1.5 to <2 x10^9/L: 10 mg BID or no more than 5 mg BID less than the dose leading to dose interruption
  • Hgb ≥ 12 g/dL OR platelet count ≥ 100 x 10^9/L ORANC ≥ 2 x 10^9/L: 15 mg BID or no more than 5 mg BID less than the dose that resulted in dose interruption
  • Re-vaccination dose: Continue for at least 2 weeks; if stable, increase dose by 5 mg BID
  • Patients receiving the 5 mg BID dose and required dose interruption may restart at 5 mg BID or 5 mg qDay, but not once hemoglobin ≥ 10 g/dL, platelet count ≥ 75 x 10^9/L, ANC ≥ would be 1.5 x 10^9/L higher.

renal insufficiency

• Moderate to severe (CrCl 15-59 mL/min), any platelet count: starting dose of 5 mg BID
• ESRD on dialysis (CrCl <15mL/min): 10 mg once after dialysis
• ESRD (CrCl <15 mL/min) without dialysis: avoid use

liver damage

• Mild, moderate or severe (Child-Pugh A, B, C), any platelet count: starting dose of 5 mg BID

Concomitant use of potent CYP3A4 inhibitors

• Dose reduction in PV patients with concomitant strong CYP3A4 inhibitors or fluconazole doses ≤200 mg
• Avoid fluconazole doses > 200 mg/day with ruxolitinib
• Closely monitor blood counts for toxicity and adjust ruxolitinib dose in combination with itraconazole if necessary
• Starting dose for PV patients
  • Stable ≥ 10 mg BID: Reduce dose by 50% (rounded to the nearest tablet strength)
  • 5 mg BID stable: qDay reduced to 5 mg
  • Stable at 5 mg PO qDay: Avoid coadministration with strong CYP3A4 inhibitor or fluconazole therapy or interrupt ruxolitinib therapy during strong CYP3A4 inhibitor or fluconazole use

Coadministration with CYP3A4 inducers

• No dose adjustment is recommended; however, closely monitor and titrate dose based on safety and efficacy

Dose adjustment (acute GVHD)

Taper to 1 dose level (eg, 10 mg BID to 5 mg BID to 5 mg qDay)

Clinically significant thrombocytopenia after supportive measures: reduce dose by 1 dose; when platelets return to previous values, restart dose to previous dose level

ANC < 1 x 10^9/L (dose related): maintain dose for up to 14 days; resume 1 dose level on recovery

Elevated total bilirubin without hepatic GVHD

• Total Bilirubin 3-5x ULN: Continue to reduce 1 dose level until recovery
• Total bilirubin > 5-10x ULN: maintain dose for up to 14 days until bilirubin ≤ 1.5x ULN; resume at current dose upon recovery
• Total bilirubin > 10x ULN: Hold dose for up to 14 days until bilirubin ≤ 1.5x ULN; resume 1 dose level on recovery

Elevated total bilirubin in liver GVHD

• Total bilirubin >3x ULN: Continue to reduce 1 dose level until recovery

renal insufficiency

• Moderate or severe (CrCl 15-59 mL/min): Reduce dose to 5 mg qDay
• ESRD on dialysis (CrCl <15mL/min): 5 mg once after dialysis

liver damage

• Mild, moderate, or severe (Child-Pugh A, B, C), any platelet count: No dose adjustment required
• Stage 3 or 4 GvHD: Monitor blood counts more frequently for toxicity and consider 5 mg qDay

Concomitant use of potent CYP3A4 inhibitors

• Dose reduction in patients with acute GvHD concomitantly using strong CYP3A4 inhibitors or fluconazole doses ≥200 mg
• Avoid fluconazole doses > 200 mg/day with ruxolitinib
• Coadministration with ketoconazole: Reduce dose by 5 mg PO qDay
• Coadministration with other CYP3A4 inhibitors: No dose adjustment required
• Closely monitor blood counts for toxicity and adjust ruxolitinib dose in combination with itraconazole if necessary

Coadministration with CYP3A4 inducers

• No dose adjustment is recommended; however, closely monitor and titrate dose based on safety and efficacy

Dosage Considerations

Perform complete blood count (CBC) and platelet count before starting treatment, q2-4 weeks until dose is stabilized, then as clinically indicated

Orphan Drug Designation: Pancreatic Cancer

Pediatrics

dosage form

tablet

• 5mg/10mg/15mg/20mg/25mg

acute graft-versus-host disease

Indicated for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adults and children (≥12 years)

<12 years : Safety and efficacy not established

≥12 years

• Initial dose: 5 mg PO BID; if ANC and platelet counts do not decrease ≥50% from baseline, increase to 10 mg BID after at least 3 days
• Consider tapering after 6 months of treatment in patients who respond to corticosteroids who have discontinued therapeutic doses
• tapering
  • Taper for 1 dose ~q8 weeks (eg, 10 mg BID to 5 mg BID to 5 mg qDay)
  • Patients unable to tolerate 5 mg qDay: Interrupt treatment until clinical and/or laboratory parameters have recovered
  • Consider retreatment if acute GVHD signs or symptoms recur during or after tapering

Dose adjustment (acute GVHD)

Clinically significant thrombocytopenia after supportive measures: reduce dose by 1 dose; when platelets return to previous values, restart dose to previous dose level

ANC < 1 x 10^9/L (dose related): maintain dose for up to 14 days; resume 1 dose level on recovery

Elevated total bilirubin without hepatic GVHD

• Total Bilirubin 3-5x ULN: Continue to reduce 1 dose level until recovery
• Total bilirubin > 5-10x ULN: maintain dose for up to 14 days until bilirubin ≤ 1.5x ULN; resume at current dose upon recovery
• Total bilirubin > 10x ULN: Hold dose for up to 14 days until bilirubin ≤ 1.5x ULN; resume 1 dose level on recovery

Elevated total bilirubin in liver GVHD

• Total bilirubin >3x ULN: Continue to reduce 1 dose level until recovery

renal insufficiency

• Moderate or severe (CrCl 15-59 mL/min): Reduce dose to 5 mg qDay
• ESRD on dialysis (CrCl <15mL/min): 5 mg once after dialysis

liver damage

• Mild, moderate, or severe (Child-Pugh A, B, C), any platelet count: No dose adjustment required
• Stage 3 or 4 GvHD: Monitor blood counts more frequently for toxicity and consider 5 mg qDay

Concomitant use of potent CYP3A4 inhibitors

• Dose reduction in patients with acute GvHD concomitantly using strong CYP3A4 inhibitors or fluconazole doses ≥200 mg
• Avoid fluconazole doses > 200 mg/day with ruxolitinib
• Coadministration with ketoconazole: Reduce dose by 5 mg PO qDay
• Coadministration with other CYP3A4 inhibitors: No dose adjustment required
• Closely monitor blood counts for toxicity and adjust ruxolitinib dose in combination with itraconazole if necessary

Coadministration with CYP3A4 inducers

• No dose adjustment is recommended; however, closely monitor and titrate dose based on safety and efficacy

Adverse reactions

> 10% (MF and PV)

• Anemia (96.1%)
• Thrombocytopenia (69.7%)
• ALT increase, grade 1 (25.2%)
• Contusions (23.2%)
• Neutropenia (18.7%)
• Dizziness (18.1%)
• AST upgrade, level 1 (17.1%)
• Increased cholesterol, grade 1 (16.8%)
• Headache (14.8%)

> 10% (GvHD)

• Anemia (75%)
• Thrombocytopenia (75%)
• Thrombocytopenia, grade 3-4 (61%)
• Neutropenia (58%)
• Infection (55%)
• Edema (51%)
• Bleeding (49%)
• Anemia, grades 3-4 (45%)
• Infection, grade 3-4 (41%)
• Neutropenia (40%)
• Elevated ALT/AST (48%)
• Fatigue (37%)
• Bacterial infection (32%)
• Grade 3-4 bacterial infections (28%)
• Bleeding, Grade 3-4 (20%)
• Fatigue, grades 3-4 (14%)
• Grade 3-4 edema (13%)
• Hypertriglyceridemia (11%)

1-10% (MF and PV)

• Urinary tract infection (9%)
• Weight gain (7.1%)
• Flatulence (5.2%)
• Shingles (1.9%)
• ALT increase, grade 2 (1.9%)
• ALT increase, grade 3 (1.3%)

1-10% (GvHD)

• Elevated ALT/AST, grades 3-4 (6-8%)
• Hypertriglyceridemia, Grade 3-4 (1%)

<1%

• AST, grade 2 increase (0.6%)
• Increased cholesterol, grade 2 (0.6%)

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Precautions

Non-melanoma skin cancer relocalization assay, including basal, squamous, and Merkel cell carcinomas

Thrombocytopenia, anemia, and neutropenia

• Perform CBC and monitor as clinically indicated before initiating treatment and adjust dose as needed
• Patients with platelet counts <200 x10^9/L at the start of treatment were more likely to develop thrombocytopenia during treatment
• Thrombocytopenia is usually reversible and usually controlled by dose reduction or temporary dose withholding (see Adult Dosage); platelet transfusions may be given if clinically indicated
• Anemia may require blood transfusion; dose modification may also be considered
• Neutropenia (ANC < 0.5 x 10^9/L) is usually reversible and managed by temporarily discontinuing dosing

Infect

• Assess the risk of developing serious bacterial, mycobacterial, fungal and viral infections
• Positive serious feelings should have resolved before starting treatment
• Tuberculosis (TB) infection has been reported; prior to initiation, assess patients for TB risk factors and test those at higher risk for latent infection
• Carefully observe patients for signs and symptoms of infection and initiate appropriate treatment immediately
• Shingles: Inform patients of early signs and symptoms of shingles and advise to seek early treatment
• Progressive multifocal leukoencephalopathy (PML): Treat myelofibrosis with ruxolitinib; if suspected, discontinue drug and evaluate
• Increased hepatitis B viral load (HBV-DNA titer), with or without associated elevations in alanine aminotransferase and aspartate aminotransferase reported in patients with chronic HBV infection; effect of ruxolitinib on viral replication unknown; based on Clinical guidelines for the treatment and monitoring of patients with chronic HBV infection

Symptoms of dose interruption, dose tapering, or discontinuation

• After discontinuation/interruption, myelofibrosis symptoms may worsen and return to pre-treatment levels after 1 week
• Other adverse reactions reported include fever, respiratory distress, hypotension, DIC or multiple organ failure
• If these symptoms develop after discontinuation or dose tapering, evaluate and treat any comorbidities and consider restarting ruxolitinib or increasing dose
• Instruct patients not to interrupt or discontinue ruxolitinib without consulting their physician
• When stopping or interrupting treatment for reasons other than thrombocytopenia or neutropenia, consider tapering the dose rather than abruptly

Hyperlipidemia

• Treatment is associated with increases in lipid parameters, including total cholesterol, LDL, and triglycerides; assess lipid parameters approximately 8-12 weeks after initiation of therapy; monitor according to clinical guidelines for hyperlipidemia

Overview of Drug Interactions

• CYP3A4 inhibitors
  • Ruxolitinib is primarily metabolized by CYP3A4
  • Strong CYP3A4 inhibitors increase ruxolitinib Cmax and AUC by 33% and 91%, respectively
  • with strong CYP3A4 inhibitors (such as but not limited to boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone , nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole recommended dose adjustment when co-administered)
• CYP3A4 inducers
  • Coadministration with strong CYP3A4 inducers reduces ruxolitinib exposure