Ruxolitinib

Pronunciation: RUX-oh-LI-ti-nib
Class: Kinase inhibitor

Trade Names

Jakafi
- Tablets, oral 5 mg
- Tablets, oral 10 mg
- Tablets, oral 15 mg
- Tablets, oral 20 mg
- Tablets, oral 25 mg

Pharmacology

Inhibits Janus-associated kinases (JAKs) JAK1 and JAK2 that mediate the signaling of a number of 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, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression.

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Pharmacokinetics

Absorption

Rapidly absorbed, with a T max of 1 to 2 h. Bioavailability is at least 95%. Upon administration with a high-fat meal, the mean C max moderately decreased (24%) and the mean AUC was nearly unchanged (4% increase).

Distribution

Vd is 53 to 65 L. Approximately 97% bound to plasma proteins, mostly to albumin.

Metabolism

CYP3A4 is the major enzyme responsible for metabolism. Two major and active metabolites were identified.

Elimination

74% is excreted in the urine and 22% is excreted via the feces. The mean elimination half-life is approximately 3 h and the mean half-life of ruxolitinib plus metabolites is approximately 5.8 h.

Special Populations

Renal Function Impairment

The pharmacokinetics were similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with ESRD requiring hemodialysis.

Hepatic Function Impairment

The mean AUC for ruxolitinib was increased by 87%, 28%, and 65%, in patients with mild, moderate, and severe hepatic impairment, respectively. The terminal elimination half-life was prolonged in patients with hepatic impairment compared with healthy controls (4.1 to 5 h vs 2.8 h).

Elderly

No relationship was apparent between oral Cl and patient age.

Gender

In women Cl was 17.7 L/h and in men Cl was 22.1 L/h with 39% intersubject variability.

Race

No significant difference in ruxolitinib pharmacokinetics were observed.

Indications and Usage

For the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.

Contraindications

None well documented.

Dosage and Administration

Myelofibrosis
Adults

PO Initially, for a platelet count greater than 200 × 10 9 /L, administer 20 mg twice daily; for a platelet count 100 × 10 9 /L to 200 × 10 9 /L, administer 15 mg twice daily. Doses may be increased in 5 mg twice daily increments (max, 25 mg twice daily). Doses should not be increased during the first 4 wk of therapy and not more frequently than every 2 wk.

Dosage interruption for thrombocytopenia
Adults

PO Interrupt treatment for platelet counts less than 50 × 10 9 /L. After recovery of platelet counts, dosing may be restarted or increased. When restarting, begin with a dosage at least 5 mg twice daily below the dose at interruption. Max ruxolitinib dose when restarting treatment is as follows: for a current platelet count 125 × 10 9 /L or more, 20 mg twice daily; for a current platelet count 100 to less than 125 × 10 9 /L, 15 mg twice daily; for a current platelet count 75 to less than 100 × 10 9 /L, 10 mg twice daily for at least 2 wk (if stable, may increase to 15 mg twice daily); for a platelet count 50 to less than 75 × 10 9 /L, 5 mg twice daily for at least 2 wk (if stable, may increase to 10 mg twice daily); for a platelet count less than 50 × 10 9 /L, continue hold.

Dosage reduction for thrombocytopenia
Adults

PO Dose reductions should be considered if the platelet counts decrease, with the goal of avoiding dose interruptions for thrombocytopenia. For patients on ruxolitinib 25 mg twice daily at the time of platelet decline, decrease dosage to 20 mg twice daily, 10 mg twice daily, or 5 mg twice daily for platelet counts 100 to less than 125 × 10 9 /L, 75 to less than 100 × 10 9 /L, or 50 to less than 75 × 10 9 /L, respectively. For patients on ruxolitinib 20 mg twice daily at the time of platelet decline, decrease dose to 15 mg twice daily, 10 mg twice daily or 5 mg twice daily for platelet counts 100 to less than 125 × 10 9 /L, 75 to less than 100 × 10 9 /L, or 50 to less than 75 × 10 9 /L, respectively. For patients on ruxolitinib 15 mg twice daily at the time of platelet decline, decrease dosage to 10 or 5 mg twice daily for platelet counts 75 to less than 100 × 10 9 /L or 50 to less than 75 × 10 9 /L, respectively. For patients on ruxolitinib 10 mg twice daily at the time of platelet decline, decrease dosage to 5 mg twice daily for platelet counts 50 to less than 75 × 10 9 /L.

Concomitant CYP3A4 therapy
Adults

PO When administering ruxolitinib with strong CYP3A4 inhibitors, the recommended starting dosage is 10 mg twice daily for patients with a platelet count greater than or equal to 100 × 10 9 /L. Additional dose modifications should be made with careful monitoring of safety and efficacy. Coadministration of ruxolitinib with strong CYP3A4 inhibitors should be avoided in patients with platelet counts less than 100 × 10 9 /L.

Renal function impairment
Adults

PO The recommended starting dosage is 10 mg twice daily for patients with a platelet count between 100 × 10 9 /L and 150 × 10 9 /L and moderate (CrCl 30 to 59 mL/min) or severe renal impairment (CrCl 15 to 29 mL/min). The recommended starting dose for patients with ESRD on dialysis is 15 mg for patients with a platelet count between 100 × 10 9 /L and 200 × 10 9 /L or 20 mg for patients with a platelet count of greater than 200 × 10 9 /L. Subsequent doses should be administered on dialysis days following each dialysis session. Additional dose modifications should be made with careful monitoring of safety and efficacy.

Hepatic function impairment
Adults

PO The recommended starting dosage is 10 mg twice daily for patients with a platelet count between 100 × 10 9 /L and 150 × 10 9 /L. Additional dose modifications should be made with careful monitoring of safety and efficacy.

General Advice

  • Administer with or without food.
  • For nasogastric tube (8 French or greater) administration, suspend 1 tablet in approximately 40 mL of water and stir for approximately 10 min; within 6 h after the tablet has dispersed, the suspension can be administered through a nasogastric tube using an appropriate syringe. The tube should be rinsed with approximately 75 mL of water.
  • Discontinue treatment after 6 mo if there is no spleen size reduction or symptom improvement since initiation of therapy with ruxolitinib.
  • When discontinuing for reasons other than thrombocytopenia, gradual tapering of the dose may be considered (eg, by 5 mg twice daily each week).
  • If a dose is missed, an additional dose should not be taken, but the next usual prescribed dose should be taken.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

CYP3A4 inducers (eg, rifampin)

Ruxolitinib plasma concentrations may be reduced, decreasing the pharmacologic effects. No dosage adjustment is recommended when ruxolitinib is coadministered with a CYP3A4 inducer. However, patients should be monitored and the ruxolitinib dose adjusted based on safety and efficacy.

CYP3A4 mild or moderate inhibitors (eg, erythromycin)

Ruxolitinib plasma concentrations may be increased. However, no dose adjustment is recommended when ruxolitinib is coadministered with mild or moderate CYP3A4 inhibitors.

CYP3A4 strong inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole)

Ruxolitinib plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. The recommended starting dosage of ruxolitinib is 10 mg twice daily for patients with a platelet count greater than or equal to 100 × 10 9 /L. Monitor for safety and efficacy and adjust the ruxolitinib dose as needed. Avoid coadministration with strong CYP3A4 inhibitors in patients with platelet counts below 100 × 10 9 /L.

Grapefruit juice

Ruxolitinib plasma concentrations may be elevated when administered with grapefruit juice, increasing the pharmacologic effects and risk of adverse reactions. Patients taking ruxolitinib should not drink grapefruit juice.

Adverse Reactions

CNS

Dizziness (18%); headache (15%).

GI

Weight gain (7%); flatulence (5%).

Hematologic

Anemia (96%); thrombocytopenia (70%); neutropenia (19%).

Lab Tests

Elevated ALT (25%); elevated AST, elevated cholesterol (17%).

Miscellaneous

Bruising (23%); UTI (9%); herpes zoster (2%).

Precautions

Monitor

A CBC and platelet count must be preformed before initiating therapy and every 2 to 4 wk until doses are stabilized, and then as clinically indicated. Carefully observe patients for signs and symptoms of infection.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Renal Function

Avoid use in patients with ESRD (CrCl less than 15 mL/min) not requiring dialysis and in patients with moderate or severe renal impairment with platelet counts less than 100 × 10 9 /L.

Hepatic Function

Avoid use in patients with hepatic impairment with platelet counts less than 100 × 10 9 /L.

Hematologic effects

Thrombocytopenia, anemia, and neutropenia may occur.

Infections

Active serious infections should be resolved before starting therapy with ruxolitinib.

Overdosage

Symptoms

Increased myelosuppression including leukopenia, anemia, and thrombocytopenia.

Patient Information

  • Inform patients that ruxolitinib is associated with thrombocytopenia, anemia, and neutropenia, and of the need to monitor CBC before and during treatment.
  • Inform patients of the signs and symptoms of infection and to report any such signs and symptoms promptly to their health care provider.
  • Inform patients of the early signs and symptoms of herpes zoster; advise them to seek treatment as early as possible.
  • Advise patients to inform their health care providers of all medications they are taking, including OTC medications, herbal products, and dietary supplements.
  • Inform patients on dialysis that their dose should not be taken before dialysis but only following dialysis.
  • Advise patients to continue taking ruxolitinib every day for as long as their health care provider tells them to and that this is a long-term treatment. Patients should not change their dose or stop taking ruxolitinib without first consulting their health care provider. Patients should be aware that after discontinuation of treatment, myelofibrosis signs and symptoms are expected to return.

Copyright © 2009 Wolters Kluwer Health.

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