Ruxolitinib

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# Overview
Ruxolitinib is a tyrosine Kinase Inhibitor that is FDA approved for the treatment of myelofibrosis and polycythemia vera.   Common adverse reactions include bruising, dizziness, headache, thrombocytopenia and anemia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Myelofibrosis
- For Patients with intermediate or high-risk myelofibrosis, including:
- Primary myelofibrosis
- Post-polycythemia vera myelofibrosis
- Post-essential thrombocythemia myelofibrosis.
The recommended starting dose of ruxolitinib is based on platelet count (TABLE 1).
- Interrupt treatment for platelet counts less than 50 X 109/L or absolute neutrophil count (ANC) less than 0.5 X 109/L.
- If the response is insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every 2 weeks.
Consider dose increases in patients who meet all of the following conditions:
- Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume as measured by computed tomography (CT) or magnetic resonance imaging (MRI);
- Platelet count greater than 125 X 10 9/L at 4 weeks and platelet count never below 100 X 10 9/L;
- ANC Levels greater than 0.75 X 10 9/L.
Based on limited clinical data, long-term maintenance at a 5 mg twice daily dose has not shown responses and continued use at this dose should be limited to patients in whom the benefits outweigh the potential risks. Discontinue ruxolitinib if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Dose Modifications for Hematologic Toxicity for Patients with Myelofibrosis Starting Treatment with Platelet Counts of 50 X 109/L to Less Than 100 X 109/L
This section applies only to patients with platelet counts of 50 X 109/L to less than 100 X 109/L prior to any treatment with ruxolitinib. For dose modifications for hematological toxicity in patients whose platelet counts were 100 X 109/L or more prior to starting treatment with ruxolitinib.
Treatment Interruption and Restarting Dosing
Interrupt treatment for platelet counts less than 25 X 109/L or ANC less than 0.5 X 109/L.
After recovery of platelet counts above 35 X 109/L and ANC above 0.75 X 109/L, dosing may be restarted. Restart dosing at the higher of 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to the decrease in platelet count below 25 X 109/L or ANC below 0.5 X 109/L that led to dose interruption.
Reduce the dose of ruxolitinib for platelet counts less than 35 X 109/L as described in TABLE 4.
Do not increase doses during the first 4 weeks of therapy, and do not increase the dose more frequently than every 2 weeks.
If the response is insufficient, doses may be increased by increments of 5 mg daily to a maximum of 10 mg twice daily if:
- Theplatelet count has remained at least 40 X 10 9/L, and
- The platelet count has not fallen by more than 20% in the prior 4 weeks, and
- The ANC is more than 1 X 10 9/L, and
- The dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks.
Continuation of treatment for more than 6 months should be limited to patients in whom the benefits outweigh the potential risks. Discontinue ruxolitinib if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Interrupt treatment for bleeding requiring intervention regardless of current platelet count. Once the bleeding event has resolved, consider resuming treatment at the prior dose if the underlying cause of bleeding has been controlled. If the bleeding event has resolved but the underlying cause persists, consider resuming treatment with ruxolitinib at a lower dose.

### Polycythemia Vera
- For patients who have had an inadequate response to or are intolerant of hydroxyurea.
- Recommended starting dose of ruxolitinib is 10 mg twice daily. Doses may be titrated based on safety and efficacy.
- Interrupt treatment for hemoglobin less than 8 g/dL, platelet counts less than 50 X 109/L or ANC less than 1.0 X 109/L.
- After recovery of the hematologic parameter(s) to acceptable levels, dosing may be restarted.
Restarting Doses for ruxolitinib after Safety Interruption for Hematologic Parameter(s):
- Use the most severe category of a patients hemoglobin, platelet count, or ANC abnormality to determine the corresponding maximum restarting dose.
Patients who had required dose interruption while receiving a dose of 5 mg twice daily, may restart at a dose of 5 mg twice daily or 5 mg once daily, but not higher, once hemoglobin is greater than or equal to 10 g/dL, platelet count is greater than or equal to 75 X 109/L, and ANC is greater than or equal to 1.5 X 109/L.
After restarting ruxolitinib following treatment interruption, doses may be titrated, but the maximum total daily dose should not exceed 5 mg less than the dose that resulted in the dose interruption. An exception to this is dose interruption following phlebotomy-associated anemia, in which case the maximal total daily dose allowed after restarting ruxolitinib would not be limited.
If the response is insufficient and platelet, hemoglobin, and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every two weeks.
Consider dose increases in patients who meet all of the following conditions:
Inadequate efficacy as demonstrated by one or more of the following:
- Continued need for phlebotomy
- WBC greater than the upper limit of normal range
- Platelet count greater than the upper limit of normal range
- Palpable spleen that is reduced by less than 25% from Baseline
Platelet count greater than or equal to 140 X 109/L
Hemoglobin greater than or equal to 12 g/dL
ANC greater than or equal to 1.5 X 109/L

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ruxolitinib in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ruxolitinib in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ruxolitinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ruxolitinib in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ruxolitinib in pediatric patients.

# Contraindications
- None

# Warnings

### Thrombocytopenia, Anemia and Neutropenia
- Treatment with ruxolitinib can cause thrombocytopenia, anemia and neutropenia.
- Manage thrombocytopenia by reducing the dose or temporarily interrupting ruxolitinib.
- Platelet transfusions may be necessary.
- Patients developing anemia may require blood transfusions and/or dose modifications of ruxolitinib.
- Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding ruxolitinib until recovery.
- Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated.

### Risk of Infection
- Serious bacterial, mycobacterial, fungal and viral infections have occurred.
- Delay starting therapy with ruxolitinib until active serious infections have resolved.
- Observe patients receiving ruxolitinib for signs and symptoms of infection and manage promptly.

### Tuberculosis
- Tuberculosis infection has been reported in patients receiving ruxolitinib.
- Observe patients receiving ruxolitinib for signs and symptoms of active tuberculosis and manage promptly.
- Prior to initiating ruxolitinib, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection.
- Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed.
- For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting ruxolitinib.
- The decision to continue ruxolitinib during treatment of active tuberculosis should be based on the overall risk-benefit determination.

### PML
- Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis.
- If PML is suspected, stop ruxolitinib and evaluate.

### Herpes Zoster
- Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected.

### Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Ruxolitinib
- Following discontinuation of ruxolitinib, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week.
- Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing ruxolitinib: fever, respiratory distress, hypotension, DIC, or multi-organ failure.
- If one or more of these occur after discontinuation of, or while tapering the dose of ruxolitinib, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of ruxolitinib.
- Instruct patients not to interrupt or discontinue ruxolitinib therapy without consulting their physician.
- When discontinuing or interrupting therapy with ruxolitinib for reasons other than thrombocytopenia or neutropenia, consider tapering the dose of ruxolitinib gradually rather than discontinuing abruptly.

### Non-Melanoma Skin Cancer
- Non-melanoma skin cancer including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with ruxolitinib.
- Perform periodic skin examinations.

# Adverse Reactions

## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

### Experience in Myelofibrosis
The safety of ruxolitinib was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies.
In these two Phase 3 studies, patients had a median duration of exposure to ruxolitinib of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy.
In a double-blind, randomized, placebo-controlled study of ruxolitinib, among the 155 patients treated with ruxolitinib, the most frequent adverse drug reactions were thrombocytopenia and anemia . Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache .
Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with ruxolitinib and 11% of patients treated with placebo.
TABLE 10 presents the most common adverse reactions occurring in patients who received ruxolitinib in the double-blind, placebo-controlled study during randomized treatment.
Description of Selected Adverse Drug Reactions
Anemia
In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving ruxolitinib, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy.
In the randomized, placebo-controlled study, 60% of patients treated with ruxolitinib and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with ruxolitinib and 1.7 in placebo treated patients.
Thrombocytopenia
In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving ruxolitinib and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving ruxolitinib and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting ruxolitinib had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%).
Neutropenia
In the two Phase 3 clinical studies, 1% of patients reduced or stopped ruxolitinib because of neutropenia.
TABLE 11 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with ruxolitinib or placebo in the placebo-controlled study.
Additional Data from the Placebo-controlled Study
25% of patients treated with ruxolitinib and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for ruxolitinib with 1% Grade 3 and no Grade 4 ALT elevations.
17% of patients treated with ruxolitinib and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for ruxolitinib with no Grade 3 or 4 AST elevations.
17% of patients treated with ruxolitinib and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for ruxolitinib with no Grade 3 or 4 cholesterol elevations.

### Clinical Trial Experience in Polycythemia Vera
In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received ruxolitinib and 111 patients received best available therapy. The most frequent adverse drug reaction was anemia. TABLE 12 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32.
Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with ruxolitinib.
Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with ruxolitinib were:
- Weight gain
- Hypertension
- Urinary tract infections
Clinically relevant laboratory abnormalities are shown in TABLE 13.

## Postmarketing Experience
There is limited information regarding Ruxolitinib Postmarketing Experience in the drug label.

# Drug Interactions

### Drugs That Inhibit or Induce Cytochrome P450 Enzymes
- Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.
- The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. *Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention..
- When administering ruxolitinib with strong CYP3A4 inhibitors, consider dose reduction.
- The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively.
- Avoid the concomitant use of ruxolitinib with fluconazole doses of greater than 200 mg daily.
- The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4
inducer rifampin in healthy subjects.
- No dose adjustment is recommended; however, monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of ruxolitinib in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. ruxolitinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

### Animal Data
Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose.
In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ruxolitinib in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Ruxolitinib during labor and delivery.

### Nursing Mothers
It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ruxolitinib, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
The safety and effectiveness of ruxolitinib in pediatric patients have not been established.

### Geriatic Use
Of the total number of myelofibrosis patients in clinical studies with ruxolitinib, 52% were 65 years of age and older. No overall differences in safety or effectiveness of ruxolitinib were observed between these patients and younger patients.

### Gender
There is no FDA guidance on the use of Ruxolitinib with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ruxolitinib with respect to specific racial populations.

### Renal Impairment
The safety and pharmacokinetics of single dose ruxolitinib (25 mg) were evaluated in a study in healthy subjects ] 72-164 mL/min (N=8)] and in subjects with mild , moderate ] 38-57 mL/min (N=8)], or severe renal impairment ] 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled.
The pharmacokinetics of ruxolitinib was 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 end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out.
When administering ruxolitinib to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended.

### Hepatic Impairment
The safety and pharmacokinetics of single dose ruxolitinib (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild, Child-Pugh A (N=8), moderate Child-Pugh B (N=8), or severe hepatic impairment, Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib.
When administering ruxolitinib to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ruxolitinib in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ruxolitinib in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
- Monitor complete blood counts every 2 to 4 weeks until doses are stabilized
- In the concomitant administration with CYP3A4 inducers, monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy

# IV Compatibility
There is limited information regarding the compatibility of Ruxolitinib and IV administrations.

# Overdosage
There is no known antidote for overdoses with ruxolitinib. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given.
Hemodialysis is not expected to enhance the elimination of ruxolitinib.

# Pharmacology

## Mechanism of Action
Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.
Myelofibrosis (MF) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN) known to be associated with dysregulated JAK1 and JAK2 signaling]. In a mouse model of JAK2V617F-positive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-, IL-6).

## Structure
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-pyrrolopyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular weight of 404.36. Ruxolitinib phosphate has the following structural formula:
Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous buffers across a pH range of 1 to 8.

## Pharmacodynamics
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF and PV patients. ruxolitinib administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both healthy subjects and MF and PV patients.

## Pharmacokinetics

### Absorption
In clinical studies, ruxolitinib is rapidly absorbed after oral ruxolitinib administration with maximal plasma concentration (Cmax) achieved within 1 to 2 hours post-dose. Based on a mass balance study in humans, oral absorption of ruxolitinib was estimated to be at least 95%. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. There were no clinically relevant changes in the pharmacokinetics of ruxolitinib upon administration of ruxolitinib with a high-fat meal, with the mean Cmax moderately decreased (24%) and the mean AUC nearly unchanged (4% increase).

### Distribution
The mean volume of distribution at steady-state is 72 L in MF patients with an associated inter-subject variability of 29% and 75 L in PV patients with an associated inter-subject variability of 23%. |Binding to plasma proteins]] in vitro is approximately 97%, mostly to albumin.

### Metabolism
In vitro studies suggest that ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.

### Elimination
Following a single oral dose of -labeled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism with 74% of radioactivity excreted in urine and 22% excretion via feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity. The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of ruxolitinib + metabolites is approximately 5.8 hours.

### Effects of Age, Gender, or Race
In healthy subjects, no significant differences in ruxolitinib pharmacokinetics were observed with regard to gender and race. In a population pharmacokinetic evaluation in MF patients, no relationship was apparent between oral clearance and patient age or race, and in women, clearance was 17.7 L/h and in men, 22.1 L/h with 39% inter-subject variability. Clearance was 12.7 L/h in PV patients, with a 42% inter-subject variability, and no relationship was apparent between oral clearance and gender, patient age or race in this patient population.

### Drug Interactions
Strong CYP3A4 inhibitors
In a trial of 16 healthy volunteers, a single dose of 10 mg of ruxolitinib was administered alone on Day 1 and a single dose of 10 mg of ruxolitinib was administered on Day 5 in combination with 200 mg of ketoconazole (a strong CYP3A4 inhibitor' given twice daily on Days 2 to 5). Ketoconazole increased ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ketoconazole also prolonged ruxolitinib half-life from 3.7 to 6.0 hours.
Fluconazole
Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that fluconazole (a dual CYP3A4 and CYP2C9 inhibitor) increases steady state ruxolitinib AUC by approximately 100% to 300% following concomitant administration of 10 mg of ruxolitinib twice daily with 100 mg to 400 mg of fluconazole once daily, respectively.
Mild or moderate CYP3A4 inhibitors
In a trial of 15 healthy volunteers, a single dose of 10 mg of ruxolitinib was administered alone on Day 1 and a single dose of 10 mg of ruxolitinib was administered on Day 5 in combination with 400 mg of erythromycin (a moderate CYP3A4 inhibitor, given twice daily on Days 2 to 5). Erythromycin increased ruxolitinib Cmax and AUC by 8% and 27%, respectively.
CYP3A4 inducers
In a trial of 12 healthy volunteers, a single dose of 50 mg of ruxolitinib was administered alone on Day 1 and a single dose of 50 mg of ruxolitinib was administered on Day 13 in combination with 600 mg of rifampin (a strong CYP3A4 inducer, given once daily on Days 3 to 13). Rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. In addition, the relative exposure to ruxolitinibs active metabolites increased approximately 100%
In vitro studies 
In vitro, ruxolitinib and its M18 metabolite do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Ruxolitinib is not an inducer of CYP1A2, CYP2B6 or CYP3A4 at clinically relevant concentrations.
In vitro, ruxolitinib and its M18 metabolite do not inhibit the P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1 or OAT3 transport systems at clinically relevant concentrations. Ruxolitinib is not a substrate for the P-gp transporter.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
Ruxolitinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model or in a 2-year carcinogenicity study in the rat.
Ruxolitinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (cultured human peripheral blood lymphocytes) or in vivo in a rat bone marrow micronucleus test.
In a fertility study, ruxolitinib was administered to male rats prior to and throughout mating and to female rats prior to mating and up to the implantation day (gestation day 7). Ruxolitinib had no effect on fertility or reproductive function in male or female rats at doses of 10, 30 or 60 mg/kg/day. However, in female rats doses of greater than or equal to 30 mg/kg/day resulted in increased post-implantation loss. The exposure (AUC) at the dose of 30 mg/kg/day is approximately 34% the clinical exposure at the maximum recommended dose of 25 mg twice daily.

# Clinical Studies

### Myelofibrosis
Two randomized Phase 3 studies (Studies 1 and 2) were conducted in patients with myelofibrosis (either primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia-myelofibrosis). In both studies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate 2 (2 prognostic factors) or high risk (3 or more prognostic factors) based on the International Working Group Consensus Criteria (IWG).
The starting dose of ruxolitinib was based on platelet counts. Patients with a platelet count between 100 and 200 X 109/L were started on ruxolitinib 15 mg twice daily and patients with a platelet count greater than 200 X 109/L were started on ruxolitinib 20 mg twice daily. Doses were then individualized based upon tolerability and efficacy with maximum doses of 20 mg twice daily for patients with platelet counts between 100 to less than or equal to 125 X 109/L, of 10 mg twice daily for patients with platelet counts between 75 to less than or equal to 100 X 109/L, and of 5 mg twice daily for patients with platelet counts between 50 to less than or equal to 75 X 109/L.

### Study 1
Study 1 was a double-blind, randomized, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy. The median age was 68 years (range 40 to 91 years) with 61% of patients older than 65 years and 54% were male. Fifty percent (50%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 18% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.5 g/dL and the median platelet count was 251 X 109/L. Patients had a median palpable spleen length of 16 cm below the costal margin, with 81% having a spleen length 10 cm or greater below the costal margin. Patients had a median spleen volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2595 cm3 (range 478 cm3 to 8881 cm3). (The upper limit of normal is approximately 300 cm3).
Patients were dosed with ruxolitinib or matching placebo. The primary efficacy endpoint was the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at Week 24 as measured by MRI or CT.
Secondary endpoints included duration of a 35% or greater reduction in spleen volume and proportion of patients with a 50% or greater reduction in Total Symptom Score from baseline to Week 24 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.

### Study 2
Study 2 was an open-label, randomized study in 219 patients. Patients were randomized 2:1 to ruxolitinib versus best available therapy. Best available therapy was selected by the investigator on a patient-by-patient basis. In the best available therapy arm, the medications received by more than 10% of patients were hydroxyurea (47%) and glucocorticoids (16%). The median age was 66 years (range 35 to 85 years) with 52% of patients older than 65 years and 57% were male. Fifty-three percent (53%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 16% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.4 g/dL and the median platelet count was 236 X 109/L. Patients had a median palpable spleen length of 15 cm below the costal margin, with 70% having a spleen length 10 cm or greater below the costal margin. Patients had a median spleen volume as measured by MRI or CT of 2381 cm3 (range 451 cm3 to 7765 cm3).
The primary efficacy endpoint was the proportion of patients achieving 35% or greater reduction from baseline in spleen volume at Week 48 as measured by MRI or CT.
A secondary endpoint in Study 2 was the proportion of patients achieving a 35% or greater reduction of spleen volume as measured by MRI or CT from baseline to Week 24.

### Study 1 and 2 Efficacy Results
Efficacy analyses of the primary endpoint in Studies 1 and 2 are presented in TABLE 14 below. A significantly larger proportion of patients in the ruxolitinib group achieved a 35% or greater reduction in spleen volume from baseline in both studies compared to placebo in Study 1 and best available therapy in Study 2. A similar proportion of patients in the ruxolitinib group achieved a 50% or greater reduction in palpable spleen length.
FIGURE 1 shows the percent change from baseline in spleen volume for each patient at Week 24 (ruxolitinib N=139, placebo N=106) or the last evaluation prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (ruxolitinib N=16, placebo N=47). One (1) patient (placebo) with a missing baseline spleen volume is not included.
In Study 1, myelofibrosis symptoms were a secondary endpoint and were measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary. The modified MFSAF is a daily diary capturing the core symptoms of myelofibrosis (abdominal discomfort, pain under left ribs, night sweats, itching, bone/muscle pain and early satiety). Symptom scores ranged from 0 to 10 with 0 representing symptoms "absent" and 10 representing "worst imaginable" symptoms. These scores were added to create the daily total score, which has a maximum of 60.
TABLE 15 presents assessments of Total Symptom Score from baseline to Week 24 in Study 1 including the proportion of patients with at least a 50% reduction (ie, improvement in symptoms). At baseline, the mean Total Symptom Score was 18.0 in the ruxolitinib group and 16.5 in the placebo group. A higher proportion of patients in the ruxolitinib group had a 50% or greater reduction in Total Symptom Score than in the placebo group, with a median time to response of less than 4 weeks.
FIGURE 2 shows the percent change from baseline in Total Symptom Score for each patient at Week 24 (ruxolitinib N=129, placebo N=103) or the last evaluation on randomized therapy prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (ruxolitinib N=16, placebo N=42). Results are excluded for 5 patients with a baseline Total Symptom Score of zero, 8 patients with missing baseline and 6 patients with insufficient post-baseline data.
FIGURE 3 displays the proportion of patients with at least a 50% improvement in each of the individual symptoms that comprise the Total Symptom Score indicating that all 6 of the symptoms contributed to the higher Total Symptom Score response rate in the group treated with ruxolitinib.
Overall survival was a secondary endpoint in both Study 1 and Study 2. Patients in the control groups were eligible for crossover in both studies, and the median times to crossover were 9 months in Study 1 and 17 months in Study 2.
FIGURE 4 and FIGURE 5 show Kaplan-Meier curves of overall survival at prospectively planned analyses after all patients remaining on study had completed 144 weeks on study.

### Polycythemia Vera
Study 3 was a randomized, open-label, active-controlled Phase 3 study conducted in 222 patients with polycythemia vera. Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy and exhibited splenomegaly. All patients were required to demonstrate hematocrit control between 40-45% prior to randomization. The age ranged from 33 to 90 years with 30% of patients over 65 years of age and 66% were male. Patients had a median spleen volume as measured by MRI or CT of 1272 cm3 (range 254 cm3 to 5147 cm3) and median palpable spleen length below the costal margin was 7 cm.
Patients were randomized to ruxolitinib or best available therapy. The starting dose of ruxolitinib was 10 mg twice daily. Doses were then individualized based upon tolerability and efficacy with a maximum dose of 25 mg twice daily. At Week 32, 98 patients were still on ruxolitinib with 8% receiving greater than 20 mg twice daily, 15% receiving 20 mg twice daily, 33% receiving 15 mg twice daily, 34% receiving 10 mg twice daily, and 10% receiving less than 10 mg twice daily. Best available therapy (BAT) was selected by the investigator on a patient-by-patient basis and included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%).
The primary endpoint was the proportion of subjects achieving a response at Week 32, with response defined as having achieved both hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and spleen volume reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32). Phlebotomy eligibility was defined as a confirmed hematocrit greater than 45% that is at least 3 percentage points higher than the hematocrit obtained at baseline or a confirmed hematocrit greater than 48%, whichever was lower. Secondary endpoints included the proportion of all randomized subjects who achieved the primary endpoint and who maintained their response 48 weeks after randomization, and the proportion of subjects achieving complete hematological remission at Week 32 with complete hematological remission defined as achieving hematocrit control, platelet count less than or equal to 400 X 109/L, and white blood cell count less than or equal to 10 X 109/L.
Results of the primary and secondary endpoints are presented in TABLE 16. A significantly larger proportion of patients in the ruxolitinib group achieved a response for the primary endpoint compared to best available therapy at Week 32 and maintained their response 48 weeks after randomization. A significantly larger proportion of patients in the ruxolitinib group compared to best available therapy also achieved complete hematological remission at Week 32.
For the proportion of patients achieving each of the individual components that make up the primary endpoint at Week 32, there were 60% of the patients with hematocrit control in the ruxolitinib group vs. 20% of the patients in the best available therapy group. There were 38% of the patients with spleen volume reduction from baseline greater than or equal to 35% at Week 32 in the ruxolitinib group vs. less than 1% of the patients in the best available therapy group.

# How Supplied
- Ruxolitinib Tablets are available as follows:

## Storage
- Store at room temperature 20C to 25C (68F to 77F); excursions permitted between 15C and
30C (59F and 86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Discuss the following with patients prior to and during treatment with ruxolitinib:

### Thrombocytopenia, Anemia and Neutropenia
Inform patients that ruxolitinib is associated with thrombocytopenia, anemia and neutropenia, and of the need to monitor complete blood counts before and during treatment. Advise patients to observe for and report bleeding.

### Infections
Inform patients of the signs and symptoms of infection and to report any such signs and symptoms promptly.
Inform patients regarding the early signs and symptoms of herpes zoster and of progressive multifocal leukoencephalopathy, and advise patients to seek advice of a clinician if such symptoms are observed.
Symptom Exacerbation Following Interruption or Discontinuation of Treatment with ruxolitinib
Inform patients that after discontinuation of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return. Instruct patients not to interrupt or discontinue ruxolitinib therapy without consulting their physician.

### Non-Melanoma Skin Cancer
Inform patients that ruxolitinib may increase their risk of certain non-melanoma skin cancers. Advise patients to inform their healthcare provider if they have ever had any type of skin cancer or if they observe any new or changing skin lesions.

### Drug-drug Interactions
Advise patients to inform their healthcare providers of all medications they are taking, including over-the-counter medications, herbal products and dietary supplements.

### Dialysis
Inform patients on dialysis that their dose should not be taken before dialysis but only following dialysis.

### Compliance
Advise patients to continue taking ruxolitinib every day for as long as their physician tells them and that this is a long-term treatment. Patients should not change dose or stop taking ruxolitinib without first consulting their physician. Patients should be aware that after discontinuation of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return.

# Precautions with Alcohol
Alcohol-Ruxolitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- JAKAFI

# Look-Alike Drug Names
There is limited information regarding Ruxolitinib Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price