Jakafi (Oral)

Dosage Forms And Strengths

5 mg tablets -round and white with “INCY” on one side and “5” on the other.

10 mg tablets -round and white with “INCY” on one side and “10” on the other.

15 mg tablets -oval and white with “INCY” on one side and “15” on the other.

20 mg tablets -capsule-shaped and white with “INCY” on one side and “20” on the other.

25 mg tablets -oval and white with “INCY” on one side and “25” on the other.

Storage And Handling

Jakafi (ruxolitinib) Tablets are available as follows:

Jakafi Trade Presentations

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

Manufactured for: Incyte Corporation Wilmington, DE 19803. Revised: Dec 2017

Myelofibrosis

Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF.

Polycythemia Vera

Jakafi is indicated for treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.

Myelofibrosis

The recommended starting dose of Jakafi is based on platelet count (Table 1). A complete blood count (CBC) and platelet count must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Doses may be titrated based on safety and efficacy.

Table 1: Jakafi Starting Doses for Myelofibrosis

Dose Modification Guidelines For Hematologic Toxicity For Patients With Myelofibrosis Starting Treatment With A Platelet Count Of 100 X 10⁹/L Or Greater

Treatment Interruption and Restarting Dosing

Interrupt treatment for platelet counts less than 50 X 10⁹/L or absolute neutrophil count (ANC) less than 0.5 X 10⁹/L.

After recovery of platelet counts above 50 X 10⁹/L and ANC above 0.75 X 10⁹/L, dosing may be restarted. Table 2 illustrates the maximum allowable dose that may be used in restarting Jakafi after a previous interruption.

Table 2: Myelofibrosis: Maximum Restarting Doses for Jakafi after Safety Interruption for Thrombocytopenia for Patients Starting Treatment with a Platelet Count of 100 X 10⁹/L or Greater

Following treatment interruption for ANC below 0.5 X 10⁹/L, after ANC recovers to 0.75 X 10⁹/L or greater, 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 treatment interruption.

Dose Reductions

Dose reductions should be considered if the platelet counts decrease as outlined in Table 3 with the goal of avoiding dose interruptions for thrombocytopenia.

Table 3: Myelofibrosis: Dosing Recommendations for Thrombocytopenia for Patients Starting Treatment with a Platelet Count of 100 X 10⁹/L or Greater

Dose Modification Based On Insufficient Response For Patients With Myelofibrosis Starting Treatment With A Platelet Count Of 100 X 10⁹/L Or Greater

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:

1. 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);
2. Platelet count greater than 125 X 10⁹/L at 4 weeks and platelet count never below 100 X 10⁹/L;
3. ANC Levels greater than 0.75 X 10⁹/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 Jakafi 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 Jakafi. See Section 2.1.1 for dose modifications for hematological toxicity in patients whose platelet counts were 100 X 10⁹/L or more prior to starting treatment with Jakafi.

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.

Dose Reductions

Reduce the dose of Jakafi for platelet counts less than 35 X 10⁹/L as described in Table 4.

Table 4: Myelofibrosis: Dosing Modifications for Thrombocytopenia for Patients with Starting Platelet Count of 50 X 10⁹/L to Less Than 100 X 10⁹/L

Dose Modifications Based On Insufficient Response For Patients With Myelofibrosis And Starting Platelet Count Of 50 X 10⁹/L To Less Than 100 X 10⁹/L

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 as defined in Section 2.1.2, doses may be increased by increments of 5 mg daily to a maximum of 10 mg twice daily if:

1. the platelet count has remained at least 40 X 10⁹/L, and
2. the platelet count has not fallen by more than 20% in the prior 4 weeks, and
3. the ANC is more than 1 X 10⁹/L, and
4. 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 Jakafi if there is no spleen size reduction or symptom improvement after 6 months of therapy.

Dose Modification For Bleeding

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 Jakafi at a lower dose.

Polycythemia Vera

The recommended starting dose of Jakafi is 10 mg twice daily. Doses may be titrated based on safety and efficacy.

Dose Modification Guidelines For Patients With Polycythemia Vera

A complete blood count (CBC) and platelet count must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated.

Dose Reductions

Dose reductions should be considered for hemoglobin and platelet count decreases as described in Table 5.

Table 5: Polycythemia Vera: Dose Reductions

Treatment Interruption and Restarting Dosing

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.

Table 6 illustrates the dose that may be used in restarting Jakafi after a previous interruption.

Table 6: Polycythemia Vera: Restarting Doses for Jakafi after Safety Interruption for Hematologic Parameter(s)

Use the most severe category of a patient’s 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.

Dose Management after Restarting Treatment

After restarting Jakafi 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 Jakafi would not be limited.

Dose Modifications Based On Insufficient Response For Patients With Polycythemia Vera

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:

1. 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
2. Platelet count greater than or equal to 140 X 10⁹/L
3. Hemoglobin greater than or equal to 12 g/dL
4. ANC greater than or equal to 1.5 X 10⁹/L

Dose Modifications For Concomitant Use With Strong CYP3A4 Inhibitors Or Fluconazole

Modify the Jakafi dosage when coadministered with strong CYP3A4 inhibitors and fluconazole doses of less than or equal to 200 mg , according to Table 7.

Additional dose modifications should be made with frequent monitoring of safety and efficacy.

Avoid the use of fluconazole doses of greater than 200 mg daily with Jakafi.

Table 7: Dose Modifications for Concomitant Use with Strong CYP3A4 Inhibitors or Fluconazole

Dose Modifications For Organ Impairment

Renal Impairment

Patients with Moderate or Severe Renal Impairment

Modify the Jakafi dosage for patients with moderate or severe renal impairment according to Table 8.

Table 8: Dose Modifications for Renal Impairment

Patients with End Stage Renal Disease on Dialysis

The recommended starting dose for patients with MF with end stage renal disease (ESRD) on dialysis is 15 mg once after a dialysis session for patients with a platelet count between 100 X 10⁹/L and 200 X 10⁹/L or 20 mg once after a dialysis session for patients with a platelet count of greater than 200 X 10⁹/L.

The recommended starting dose for patients with PV with ESRD on dialysis is 10 mg.

Make additional dose modifications with frequent monitoring of safety and efficacy. Avoid use of Jakafi in patients with ESRD (CLcr less than 15 mL/min) not requiring dialysis.

Hepatic Impairment

Modify the Jakafi dosage for patients with hepatic impairment according to Table 9.

Table 9: Dose Modifications for Hepatic Impairment

Method Of Administration

Jakafi is dosed orally and can be administered with or without food.

If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose.

When discontinuing Jakafi therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered, for example by 5 mg twice daily each week.

For patients unable to ingest tablets, Jakafi can be administered through a nasogastric tube (8 French or greater) as follows:

• Suspend one tablet in approximately 40 mL of water with stirring for approximately 10 minutes.
• Within 6 hours 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. The effect of tube feeding preparations on Jakafi exposure during administration through a nasogastric tube has not been evaluated.

None.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Thrombocytopenia, Anemia And Neutropenia

Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia..

Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary.

Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi.

Severe neutropenia (ANC less than 0.5 X 10⁹/L) was generally reversible by withholding Jakafi 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 Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly.

Tuberculosis

Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly.

Prior to initiating Jakafi, 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 Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) has occurred with Jakafi treatment. If PML is suspected, stop Jakafi and evaluate.

Herpes Zoster

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

Hepatitis B

Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines.

Symptom Exacerbation Following Interruption Or Discontinuation Of Treatment With Jakafi

Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with MF have experienced one or more of the following adverse events after discontinuing Jakafi: 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 Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia , consider tapering the dose of Jakafi gradually rather than discontinuing abruptly.

Non-Melanoma Skin Cancer

Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations.

Lipid Elevations

Treatment with Jakafi has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management of hyperlipidemia.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Discuss the following with patients prior to and during treatment with Jakafi:

Thrombocytopenia, Anemia And Neutropenia

Inform patients that Jakafi 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 Jakafi

Inform patients that after discontinuation of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician.

Non-Melanoma Skin Cancer

Inform patients that Jakafi 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.

Lipid Elevations

Inform patients that Jakafi may increase blood cholesterol, and of the need to monitor blood cholesterol levels.

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.

Lactation

Inform women not to breastfeed during treatment with Jakafi and for two weeks after the final dose.

Compliance

Advise patients to continue taking Jakafi 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 Jakafi without first consulting their physician. Patients should be aware that after discontinuation of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return.

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 assay.

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.

Use In Specific Populations

Pregnancy

Risk Summary

When pregnant rats and rabbits were administered ruxolitinib during the period of organogenesis adverse developmental outcomes occurred at doses associated with maternal toxicity (see Data). There are no studies with the use of Jakafi in pregnant women to inform drug-associated risks.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk in the U.S. general population of major birth defects is 2% to 4% and miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

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 were no treatment-related malformations. Adverse developmental outcomes, such as 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).

Lactation

Risk Summary

No data are available regarding the presence of ruxolitinib in human milk, the effects on the breast fed infant, or the effects on milk production. Ruxolitinib and/or its metabolites were present in the milk of lactating rats (see Data). Because many drugs are present in human milk and because of the potential for thrombocytopenia and anemia shown for Jakafi in human studies, discontinue breastfeeding during treatment with Jakafi and for two weeks after the final dose.

Data

Animal Data

Lactating rats were administered a single dose of [¹⁴C]-labeled ruxolitinib (30 mg/kg) on postnatal Day 10, after which plasma and milk samples were collected for up to 24 hours. The AUC for total radioactivity in milk was approximately 13-fold the maternal plasma AUC. Additional analysis showed the presence of ruxolitinib and several of its metabolites in milk, all at levels higher than those in maternal plasma.

Pediatric Use

The safety and effectiveness of Jakafi in pediatric patients have not been established.

Geriatric Use

Of the total number of patients with MF in clinical studies with Jakafi, 52% were 65 years and older, while 15% were 75 years and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients.

Renal Impairment

Reduce the Jakafi dosage when administering Jakafi to patients with MF and moderate (CLcr 30 mL/min to 59 mL/min as estimated using Cockcroft-Gault) or severe renal impairment (CLcr 15 mL/min to 29 mL/min) with a platelet count between 50 X 10⁹/L and 150 X 10⁹/L.

Reduce the Jakafi dosage for patients with PV and moderate (CLcr 30 to 59 mL/min) or severe renal impairment (CLcr 15 to 29 mL/min).

Reduce the Jakafi dosage for all patients with ESRD on dialysis.

Hepatic Impairment

Reduce the Jakafi dosage when administering Jakafi to patients with MF and any degree of hepatic impairment (Child-Pugh Class A, B and C) and with a platelet count between 50 X 10⁹/L and 150 X 10⁹/L.

Reduce the Jakafi dosage for patients with PV and hepatic impairment (Child-Pugh Class A, B and C).

Fluconazole

Simulations suggest 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 Jakafi twice daily with 100 mg to 400 mg of fluconazole once daily.

Strong CYP3A4 Inhibitors

Ketoconazole (a strong CYP3A4 inhibitor) increased ruxolitinib Cmax by 33% and AUC by 91%. Ketoconazole also prolonged ruxolitinib half-life from 3.7 hours to 6 hours.

Moderate CYP3A4 Inhibitors

Erythromycin (a moderate CYP3A4 inhibitor) increased ruxolitinib Cmax by 8% and AUC by 27%.

Strong CYP3A4 Inducers

Rifampin (a strong CYP3A4 inducer) decreased ruxolitinib Cmax by 32% and AUC by 61%. The relative exposure to ruxolitinib’s active metabolites increased approximately 100%.

In Vitro Studies

Ruxolitinib and its M18 metabolite did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Ruxolitinib did not induce CYP1A2, CYP2B6 or CYP3A4 at clinically relevant concentrations.

Ruxolitinib and its M18 metabolite did 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.

Risk Summary

When pregnant rats and rabbits were administered ruxolitinib during the period of organogenesis adverse developmental outcomes occurred at doses associated with maternal toxicity (see Data). There are no studies with the use of Jakafi in pregnant women to inform drug-associated risks.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk in the U.S. general population of major birth defects is 2% to 4% and miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

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 were no treatment-related malformations. Adverse developmental outcomes, such as 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).

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Thrombocytopenia, Anemia and Neutropenia
• Risk of Infection
• Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi
• Non-Melanoma Skin Cancer

Clinical Trials Experience In Myelofibrosis

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.

The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in two Phase 3 studies.

In these two Phase 3 studies, patients had a median duration of exposure to Jakafi 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 Jakafi, among the 155 patients treated with Jakafi, 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 Jakafi and 11% of patients treated with placebo.

Table 10 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

Table 10: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi 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 Jakafi, 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 Jakafi 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 Jakafi 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 Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 10⁹/L to 200 X 10⁹/L before starting Jakafi 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 Jakafi because of neutropenia.

Table 11 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Table 11: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study^a

Additional Data from the Placebo-controlled Study

25% of patients treated with Jakafi 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 Jakafi with 1% Grade 3 and no Grade 4 ALT elevations.

17% of patients treated with Jakafi 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 Jakafi with no Grade 3 or 4 AST elevations.

17% of patients treated with Jakafi 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 Jakafi 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 PV resistant to or intolerant of hydroxyurea received Jakafi 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 Jakafi.

Table 12: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment

Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were:

Weight gain, hypertension, and urinary tract infections

Clinically relevant laboratory abnormalities are shown in Table 13.

Table 13: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment^a

There is no known antidote for overdoses with Jakafi. 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 Jakafi.

Jakafi inhibits cytokine induced STAT3 phosphorylation in whole blood from patients with MF and PV. Jakafi administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in patients with MF and PV.

Cardiac Electrophysiology

At a dose of 1.25 to 10 times the highest recommended starting dosage, Jakafi does not prolong the QT interval to any clinically relevant extent.

Mean ruxolitinib maximal plasma concentration (Cmax) and AUC increased proportionally over a single dose range of 5 mg to 200 mg. Mean ruxolitinib Cmax ranged from 205 nM to 7100 nM and AUC ranged from 862 nM*hr to 30700 nM*hr over a single dose range of 5 mg to 200 mg.

Absorption

Ruxolitinib achieves Cmax within 1 hour to 2 hours post-dose. Oral absorption of ruxolitinib is estimated to be at least 95%.

Food Effect

No clinically relevant changes in the pharmacokinetics of ruxolitinib were observed upon administration of Jakafi with a high-fat, high-calorie meal (approximately 800 to 1000 calories of which 50% were derived from fat).

Distribution

The mean volume of distribution at steady-state is 72 L (coefficient of variation [CV] 29%) in patients with MF and 75 L (23%) in patients with PV.

Binding to plasma proteins is approximately 97%, mostly to albumin.

Elimination

The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of ruxolitinib + metabolites is approximately 5.8 hours.

Ruxolitinib clearance was 17.7 L/h in women and 22.1 L/h in men with MF (39% inter-subject variability).

Ruxolitinib clearance was 12.7 L/h in patients with PV (42% inter-subject variability).

Metabolism

Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.

Excretion

Following a single oral dose of radiolabeled ruxolitinib, 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.