Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

RUXOLITINIB

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ruxolitinib is a kinase inhibitor used for the treatment of intermediate or high-risk myelofibrosis.

Specific Substances

    1) Ruxolitinib phosphate
    2) INCB018424
    3) CAS 941678-49-5 (ruxolitinib)

Available Forms Sources

    A) FORMS
    1) Ruxolitinib is available as 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg tablets (Prod Info JAKAFI(TM) oral tablets, 2011).
    B) USES
    1) Ruxolitinib is used for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis (Prod Info JAKAFI(TM) oral tablets, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Indicated for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.
    B) PHARMACOLOGY: Inhibits dysregulated Janus Associated Kinase (JAK) 1 and JAK2 signaling associated with myelofibrosis. JAK1 and JAK2 recruit signal transducers and activators of transcription (STATs) to cytokine receptors leading to modulation of gene expression.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects (greater than 10%) are bruising, dizziness, headache, elevated hepatic enzyme concentrations, anemia, neutropenia, and thrombocytopenia.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include urinary tract infections, elevated serum cholesterol, weight gain, and flatulence.
    3) WITHDRAWAL: A severe withdrawal syndrome, including acute relapse of disease symptoms (splenomegaly, pruritus, fever, fatigue), respiratory distress associated with pleural and/or pericardial effusion and pulmonary edema, coagulopathy, and a septic shock-like syndrome (severe hypoxia, hypotension, fever, and confusion), have been reported after discontinuation of ruxolitinib treatment.
    E) WITH POISONING/EXPOSURE
    1) Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses and may include anemia, neutropenia, and thrombocytopenia.
    0.2.20) REPRODUCTIVE
    A) Ruxolitinib is classified as FDA pregnancy category C. During animal studies, there was no evidence of teratogenicity; however, an increase in late resorptions and reduced fetal weights were observed following administration of maternally toxic doses.

Laboratory Monitoring

    A) Monitor CBC with differential and platelets.
    B) Monitor liver enzymes and renal function after significant overdose.
    C) Serum ruxolitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    D) Monitor for evidence of withdrawal (fever, shortness of breath, anemia, rapidly increasing splenomegaly). It is not known if this syndrome can develop after acute overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Myelosuppression has been reported with therapeutic doses. Monitor serial CBC with differential and platelets. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in patients who are awake and able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain their airway or if the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect their airway.
    E) ANTIDOTE
    1) None
    F) MYELOSUPPRESSION
    1) Severe neutropenia: filgrastim 5 mcg/kg/day IV or SubQ or sargramostim 250 mcg/m(2)/day IV infused over 4 hours. Monitor serial CBC with differential and platelets. Transfusions as needed for severe thrombocytopenia, bleeding.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be effective due to high protein binding (97%).
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions of one or two extra doses can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients with severe neutropenia should be admitted to the hospital.
    4) CONSULT CRITERIA: Consult with a medical toxicologist and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) When managing a suspected ruxolitinib overdose, the possibility of multi-drug involvement should be considered.
    J) PHARMACOKINETICS
    1) Oral absorption is at least 95%. Protein binding is 97% and volume of distribution is 53 to 65 liters. Metabolized primarily by cytochrome P450 3A4 enzymes. Following a single oral dose of radiolabeled ruxolitinib in healthy adults, 74% of the total dose was excreted in the urine, mostly as metabolites, with less than 1% of the total dose as unchanged drug. The mean elimination half-life is approximately 3 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Single doses up to 200 mg have been well-tolerated.
    B) THERAPEUTIC DOSE: ADULTS: The recommended starting dose of ruxolitinib is based on platelet counts. If platelet counts are greater than 200 x 10(9)/L, the starting dose is 20 mg orally twice daily. For platelet counts between 100 x 10(9)/L and 200 x 10(9)/L, the starting dose is 15 mg orally twice daily; May be increased by 5 mg twice daily increments, up to a MAX of 25 mg orally twice daily. CHILDREN: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Indicated for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.
    B) PHARMACOLOGY: Inhibits dysregulated Janus Associated Kinase (JAK) 1 and JAK2 signaling associated with myelofibrosis. JAK1 and JAK2 recruit signal transducers and activators of transcription (STATs) to cytokine receptors leading to modulation of gene expression.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects (greater than 10%) are bruising, dizziness, headache, elevated hepatic enzyme concentrations, anemia, neutropenia, and thrombocytopenia.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include urinary tract infections, elevated serum cholesterol, weight gain, and flatulence.
    3) WITHDRAWAL: A severe withdrawal syndrome, including acute relapse of disease symptoms (splenomegaly, pruritus, fever, fatigue), respiratory distress associated with pleural and/or pericardial effusion and pulmonary edema, coagulopathy, and a septic shock-like syndrome (severe hypoxia, hypotension, fever, and confusion), have been reported after discontinuation of ruxolitinib treatment.
    E) WITH POISONING/EXPOSURE
    1) Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses and may include anemia, neutropenia, and thrombocytopenia.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, dizziness was reported in 18.1% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 7.3% of patients who received placebo (n=151). Dizziness was classified as grade 3 in 0.6% of ruxolitinib-treated patients and 0% of placebo-treated patients. Dizziness included dizziness, postural dizziness, vertigo, balance disorder, Meniere disease, and labyrinthitis (Prod Info JAKAFI(TM) oral tablets, 2011).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, headache was reported in 14.8% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 5.3% of patients who received placebo (n=151) (Prod Info JAKAFI(TM) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, flatulence was reported in 5.2% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 0.7% of patients who received placebo (n=151) (Prod Info JAKAFI(TM) oral tablets, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, new or worsening grade 1 ALT abnormalities were reported in 25.2% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 7.3% of patients who received placebo (n=151). Grade 2 or higher ALT elevations were reported in 1.9% of ruxolitinib-treated patients (grade 3, 1.3%; grade 4, 0%) (Prod Info JAKAFI(TM) oral tablets, 2011).
    b) In a double-blind, randomized controlled trial, new or worsening grade 1 AST abnormalities were reported in 17.4% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 6% of patients who received placebo (n=151). Grade 2 AST elevations were reported in 0.6% of ruxolitinib-treated patients (Prod Info JAKAFI(TM) oral tablets, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, UTI was reported in 9% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 5.3% of patients who received placebo (n=151). UTI included cystitis, urosepsis, bacterial UTI, kidney infection, pyuria, bacteria in the urine, and the presence of nitrite in urine (Prod Info JAKAFI(TM) oral tablets, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, dose-related anemia was reported in 96.1% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 86.8% of patients who received placebo (n=151). RBC transfusions were administered to 60% of ruxolitinib-treated patients (median, 1.2 units/month) and 38% of placebo-treated patients (median, 1.7 units/month) (Prod Info JAKAFI(TM) oral tablets, 2011).
    b) In a double-blind, randomized controlled trial, grade 3 and 4 dose-related anemia were reported in 34.2% and 11%, respectively, of patients with myelofibrosis who received ruxolitinib (n=155) compared with 15.9% and 3.3%, respectively, of patients who received placebo (n=151) (Prod Info JAKAFI(TM) oral tablets, 2011).
    c) In 2 phase 3 studies, grade 2 or higher anemia occurred a median of approximately 6 weeks after ruxolitinib initiation. After 8 to 12 weeks of ruxolitinib therapy, hemoglobin mean decreases reached a nadir of approximately 1.5 to 2 g/dL below baseline, which gradually recovered to approximately 1 g/dL below baseline. Anemia resulted in drug discontinuation in 1 patient (0.3%) who received ruxolitinib (n=301) (Prod Info JAKAFI(TM) oral tablets, 2011).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, dose-related thrombocytopenia was reported in 69.7% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 30.5% of patients who received placebo (n=151). Risk of thrombocytopenia was increased in patients with a baseline platelet count of less than 200 x 10(9)/L. Thrombocytopenia generally resolved with dose reduction or temporary interruption of ruxolitinib (Prod Info JAKAFI(TM) oral tablets, 2011).
    b) In a double-blind, randomized controlled trial, grade 3 and 4 thrombocytopenia were reported in 9% and 3.9%, respectively, of patients with myelofibrosis who received ruxolitinib (n=155) compared with 1.3% and 0%, respectively, of patients who received placebo (n=151) (Prod Info JAKAFI(TM) oral tablets, 2011).
    c) In 2 phase 3 studies, grade 3 or 4 thrombocytopenia occurred a median of approximately 8 weeks after ruxolitinib initiation. Platelet counts returned to above 50 x 10(9)/L after a median of 14 days. Grade 3 or 4 thrombocytopenia was reported in 16.5% of patients with a baseline platelet count between 100 and 200 x 10(9)/L compared with 7.2% of patients with a baseline platelet count greater than 200 x 10(9)/L. Platelet transfusions were administered to 4.7% of patients who received ruxolitinib compared with 4% of patients who received placebo or best available treatment (Prod Info JAKAFI(TM) oral tablets, 2011).
    C) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, dose-related neutropenia was reported in 18.7% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 4% of patients who received placebo (n=151). In 2 phase 3 studies, neutropenia led to dose reduction or drug discontinuation in 1% of ruxolitinib-treated patients (n=301). Neutropenia (absolute neutrophil count less than 0.5 x 10(9)/L) was generally reversible and resolved with temporary drug discontinuation (Prod Info JAKAFI(TM) oral tablets, 2011).
    b) In a double-blind, randomized controlled trial, grade 3 and 4 dose-related neutropenia were reported in 5.2% and 1.9%, respectively, of patients with myelofibrosis who received ruxolitinib (n=155) compared with 0.7% and 1.3%, respectively, of patients who received placebo (n=151) (Prod Info JAKAFI(TM) oral tablets, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTUSION
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, bruising was reported in 23.2% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 14.6% of patients who received placebo (n=151). Bruising was classified as grade 3 in 0.6% of ruxolitinib-treated patients and 0% of placebo-treated patients. Bruising included contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, and purpura (Prod Info JAKAFI(TM) oral tablets, 2011).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) SERUM CHOLESTEROL RAISED
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized controlled trial, new or worsening grade 1 cholesterol elevations were reported in 16.8% of patients with myelofibrosis who received ruxolitinib (n=155) compared with 0.7% of patients who received placebo (n=151). Grade 2 cholesterol elevations were reported in 0.6% of ruxolitinib-treated patients (Prod Info JAKAFI(TM) oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Ruxolitinib is classified as FDA pregnancy category C. During animal studies, there was no evidence of teratogenicity; however, an increase in late resorptions and reduced fetal weights were observed following administration of maternally toxic doses.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS, RATS: There was no evidence of teratogenicity in rabbits or rats administered oral doses up to 60 mg/kg/day during organogenesis (Prod Info JAKAFI(R) oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ruxolitinib is classified as pregnancy category C (Prod Info JAKAFI(R) oral tablets, 2014).
    2) This drug should only be used during pregnancy if the potential maternal benefit outweighs the fetal risk (Prod Info JAKAFI(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: No effects on maternal or embryofetal survival, growth, and development were observed in rats administered doses up to 30 mg/kg/day (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily) from implantation though lactation. In a separate study, increased post-implantation loss was observed in female rats administered doses of 30 mg/kg/day (approximately 34% the clinical exposure at the maximum recommended dose of 25 mg twice daily, based on AUC) or greater doses prior to mating and up to gestation day 7 (Prod Info JAKAFI(R) oral tablets, 2014).
    2) RATS: Decreased fetal weights was observed in 9% of rats and 8% of rabbits at oral 60 mg/kg/day doses (approximately 2 times and 7% the clinical exposure at the maximum recommended dose of 25 mg twice daily, based on AUC, respectively) during organogenesis. Increased late resorptions were also observed in rabbits (Prod Info JAKAFI(R) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) If ruxolitinib is administered to a nursing woman, either breastfeeding or this drug should be discontinued, taking into account the importance of this drug to the mother (Prod Info JAKAFI(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats at a concentration 13 times that in the maternal plasma (Prod Info JAKAFI(R) oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: No effects on fertility or reproductive function were observed in male or female rats administered doses up to 60 mg/kg/day prior to and throughout mating in mating in males and prior to mating and up to gestation day 7 in females. However, female rats administered doses up to 30 mg/kg/day or greater (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily) resulted in increased post-implantation loss (Prod Info JAKAFI(R) oral tablets, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Ruxolitinib was not carcinogenic in a 6-month Tg.rasH2 transgenic mouse model or in a 2-year rat carcinogenicity study (Prod Info JAKAFI(TM) oral tablets, 2011a).

Genotoxicity

    A) Ruxolitinib was not mutagenic in the Ames test (a bacterial mutagenicity assay) or clastogenic in the in vitro chromosomal aberration assay (cultured human peripheral blood lymphocytes) or in an in vivo rat bone marrow micronucleus assay (Prod Info JAKAFI(TM) oral tablets, 2011a).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC with differential and platelets.
    B) Monitor liver enzymes and renal function after significant overdose.
    C) Serum ruxolitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    D) Monitor for evidence of withdrawal (fever, shortness of breath, anemia, rapidly increasing splenomegaly). It is not known if this syndrome can develop after acute overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe neutropenia should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestions of one or two extra doses can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult with a medical toxicologist and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

Monitoring

    A) Monitor CBC with differential and platelets.
    B) Monitor liver enzymes and renal function after significant overdose.
    C) Serum ruxolitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    D) Monitor for evidence of withdrawal (fever, shortness of breath, anemia, rapidly increasing splenomegaly). It is not known if this syndrome can develop after acute overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no known antidote.
    B) MONITORING OF PATIENT
    1) Monitor CBC with differential and platelets.
    2) Monitor liver enzymes after significant overdose.
    3) Serum ruxolitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4) Monitor for evidence of withdrawal (fever, shortness of breath, anemia, rapidly increasing splenomegaly). It is not known if this syndrome can develop after acute overdose.
    C) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be effective due to high protein binding (97%).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Single doses up to 200 mg have been well-tolerated.
    B) THERAPEUTIC DOSE: ADULTS: The recommended starting dose of ruxolitinib is based on platelet counts. If platelet counts are greater than 200 x 10(9)/L, the starting dose is 20 mg orally twice daily. For platelet counts between 100 x 10(9)/L and 200 x 10(9)/L, the starting dose is 15 mg orally twice daily; May be increased by 5 mg twice daily increments, up to a MAX of 25 mg orally twice daily. CHILDREN: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) MYELOFIBROSIS: The recommended starting dose is based on platelet count (Prod Info JAKAFI(R) oral tablets, 2014):
    1) Greater than 200 x 10(9)/L: 20 mg orally twice daily (Prod Info JAKAFI(R) oral tablets, 2014);
    2) Platelet count between 100 x 10(9)/L to 200 x 10(9)/L: 15 mg orally twice daily (Prod Info JAKAFI(R) oral tablets, 2014);
    3) Platelet count between 50 x 10(9)/L to less than 100 x 10(9)/L: 5 mg orally twice daily (Prod Info JAKAFI(R) oral tablets, 2014).
    B) Therapy should be interrupted for bleeding requiring intervention regardless of the platelet count. Treatment can resume once bleeding has resolved (Prod Info JAKAFI(R) oral tablets, 2014).
    C) After the first 4 weeks of therapy, if platelet and neutrophil counts are adequate, doses may be increased by 5 mg twice daily increments, every 2 weeks, to a maximum of 25 mg orally twice daily (Prod Info JAKAFI(R) oral tablets, 2014).
    D) POLYCYTHEMIA VERA: The recommended starting dose is 10 mg orally twice daily. Dose reductions should be considered for hemoglobin and platelet count decreases (Prod Info JAKAFI(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric population have not been established (Prod Info JAKAFI(R) oral tablets, 2014).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established. Single doses up to 200 mg have been well-tolerated (Prod Info JAKAFI(TM) oral tablets, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ruxolitinib inhibits dysregulated Janus Associated Kinase (JAK) 1 and JAK2 signaling associated with myelofibrosis. JAK1 and JAK2 recruit signal transducers and activators of transcription (STATs) to cytokine receptors leading to modulation of gene expression (Prod Info JAKAFI(TM) oral tablets, 2011).

Physicochemical

Physical Characteristics

    A) Ruxolitinib phosphate is a white to off-white to light pink powder. It is soluble in aqueous buffers across a pH range of 1 to 8 (Prod Info JAKAFI(TM) oral tablets, 2011).

Molecular Weight

    A) 404.36 (Prod Info JAKAFI(TM) oral tablets, 2011)

References

General Bibliography

    1) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    4) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    5) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    6) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    7) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    8) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    9) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    10) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    11) Product Information: JAKAFI(R) oral tablets, ruxolitinib oral tablets. Incyte Corporation (per FDA), Wilmington, DE, 2014.
    12) Product Information: JAKAFI(TM) oral tablets, ruxolitinib oral tablets. Incyte Corporation (per FDA), Wilmington, DE, 2011.
    13) Product Information: JAKAFI(TM) oral tablets, ruxolitinib oral tablets. Incyte Corporation (per FDA), Wilmington, DE, 2011a.
    14) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    15) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    16) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    17) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    18) Tefferi A & Pardanani A : Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86(12):1188-1191.