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TOFACITINIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tofacitinib is a Janus kinase inhibitor used to treat moderate to severe rheumatoid arthritis in adult patients who have had an inadequate response or an intolerance to methotrexate therapy.

Specific Substances

    1) Tofacitinib citrate
    2) CAS 477600-75-2 (tofacitinib)
    3) CAS 540737-29-9 (tofacitinib citrate)
    1.2.1) MOLECULAR FORMULA
    1) C16H20N6O.C6H8O7 (tofacitinib citrate) (Prod Info XELJANZ(R) oral tablets, 2016)

Available Forms Sources

    A) FORMS
    1) Tofacitinib is available as a 5 mg immediate-release film-coated tablet and as an 11 mg extended-release film-coated tablet (Prod Info XELJANZ(R) oral tablets, 2016; Prod Info XELJANZ (R) XR extended release oral tablets, 2016).
    B) USES
    1) Tofacitinib is used to treat moderate to severe rheumatoid arthritis in adult patients who have had an inadequate response or an intolerance to methotrexate therapy. It may be given as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs) (Prod Info XELJANZ(R) oral tablets, 2016; Prod Info XELJANZ (R) XR extended release oral tablets, 2016).

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: Tofacitinib is used to treat moderate to severe rheumatoid arthritis in adult patients who have had an inadequate response or an intolerance to methotrexate therapy. It may be given as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
    B) PHARMACOLOGY: Tofacitinib inhibits Janus kinases (JAK), which are intracellular enzymes, and modulates a signaling pathway that influences the cellular processes of hematopoiesis and immune cell function. Signals in this pathway arise from cytokine or growth factor-receptor interactions on the cellular membrane. Inhibition of JAK prevents the phosphorylation and activation of Signal Transducers and Activators of Transcription (STATs), which modulate gene expression and other intracellular activity.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects (greater than 2%) are diarrhea, nasopharyngitis, headache, and upper respiratory tract infections.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include hypertension, anemia, diverticulitis, insomnia, paresthesia, dyspnea, cough, sinus congestion, nausea, vomiting, dyspepsia, gastritis, abdominal pain, urinary tract infections, hepatic steatosis, rash, pruritus, erythema, musculoskeletal pain, arthralgia, tendonitis, joint swelling, pyrexia, fatigue, and peripheral edema.
    3) RARE: Lymphopenia, neutropenia, and elevated liver enzymes have been rarely reported.
    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.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Pyrexia was reported in patients treated with tofacitinib during clinical trials.
    0.2.20) REPRODUCTIVE
    A) Tofacitinib is classified as FDA pregnancy category C. Although there are no adequate and well-controlled studies in pregnant women, animal studies have reported teratogenicity at doses up to 146 times the maximum recommended human dose. It is unknown whether tofacitinib is excreted in human milk, although it is excreted in the milk of lactating rats.
    0.2.21) CARCINOGENICITY
    A) Lymphomas and solid cancers, including lung, breast, gastric, colorectal, renal cell, and prostate cancers, and malignant melanoma have been observed during controlled rheumatoid arthritis clinical trials and during long-term extension studies in patients treated with tofacitinib. Non-melanoma skin cancers have also occurred in patients treated with tofacitinib.

Laboratory Monitoring

    A) Monitor serial CBC with differential and liver enzymes in symptomatic patients.
    B) Monitor for clinical evidence of infection.
    C) Serum tofacitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

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. Monitor for clinical signs of infection and treat as indicated. Neutropenia has been reported with therapeutic use and may occur in overdose. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim).
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect their airway.
    E) ANTIDOTE
    1) None
    F) NEUTROPENIA
    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.
    G) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be effective in overdose.
    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. EXTENDED RELEASE TABLETS: Peak concentrations of extended-release tofacitinib are reached 4 hours after ingestion. Peak concentrations are expected to be delayed after overdose. Patients ingesting overdoses of extended-release tofacitinib should be observed for the development of toxic effects for at least 6 to 12 hours after ingestion.
    3) ADMISSION CRITERIA: Patients with clinical evidence of infection or 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 tofacitinib overdose, the possibility of multi-drug involvement should be considered.
    2) Symptoms of overdose may be similar to reported side effects of the medication.
    3) Prolonged observation may be needed after overdose with the extended-release formulation.
    J) PHARMACOKINETICS
    1) Tmax for immediate-release and extended release tablets are 0.5 to 1 hour and 4 hours, respectively. The absolute oral bioavailability is 74%. Protein binding is approximately 40%, primarily to albumin; volume of distribution following IV administration is 87 L. Hepatic metabolism accounts for approximately 70% of the clearance of tofacitinib. The major enzyme responsible for metabolism is CYP3A4, with minor contribution from CYP2C19. The elimination half-life of tofacitinib is about 3 hours and 6 hours following administration of immediate-release tablets and extended-release tablets, respectively.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause lymphopenia or neutropenia.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose of tofacitinib has not been established. At the time of this review, overdose has not been reported.
    B) THERAPEUTIC DOSE: ADULT: IMMEDIATE-RELEASE: 5 mg orally twice daily. EXTENDED-RELEASE: 11 mg orally once daily. PEDIATRIC: Safety and effectiveness have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Tofacitinib is used to treat moderate to severe rheumatoid arthritis in adult patients who have had an inadequate response or an intolerance to methotrexate therapy. It may be given as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
    B) PHARMACOLOGY: Tofacitinib inhibits Janus kinases (JAK), which are intracellular enzymes, and modulates a signaling pathway that influences the cellular processes of hematopoiesis and immune cell function. Signals in this pathway arise from cytokine or growth factor-receptor interactions on the cellular membrane. Inhibition of JAK prevents the phosphorylation and activation of Signal Transducers and Activators of Transcription (STATs), which modulate gene expression and other intracellular activity.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects (greater than 2%) are diarrhea, nasopharyngitis, headache, and upper respiratory tract infections.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include hypertension, anemia, diverticulitis, insomnia, paresthesia, dyspnea, cough, sinus congestion, nausea, vomiting, dyspepsia, gastritis, abdominal pain, urinary tract infections, hepatic steatosis, rash, pruritus, erythema, musculoskeletal pain, arthralgia, tendonitis, joint swelling, pyrexia, fatigue, and peripheral edema.
    3) RARE: Lymphopenia, neutropenia, and elevated liver enzymes have been rarely reported.
    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.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Pyrexia was reported in patients treated with tofacitinib during clinical trials.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) PYREXIA was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) NASOPHARYNGITIS: In controlled clinical trials, nasopharyngitis was reported in 3.8% and 2.8% of patients treated with tofacitinib 5 mg twice daily (n=1336) or 10 mg twice daily (n=1349), respectively, with or without disease modifying antirheumatic drugs, compared to 2.8% of patients on placebo (n=809), over a 3-month exposure period (Prod Info XELJANZ(R) oral tablets, 2016).
    2) SINUS CONGESTION was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials, hypertension was reported in 1.6% and 2.3% of patients treated with tofacitinib 5 mg twice daily (n=1336) or 10 mg twice daily (n=1349), respectively, with or without disease modifying antirheumatic drugs, compared to 1.1% of patients on placebo (n=809), over a 3-month exposure period (Prod Info XELJANZ(R) oral tablets, 2016).
    B) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials, upper respiratory tract infection was reported in 4.5% and 3.8% of patients treated with tofacitinib 5 mg twice daily (n=1336) or 10 mg twice daily (n=1349), respectively, with or without disease modifying antirheumatic drugs, compared to 3.3% of patients on placebo (n=809), over a 3-month exposure period (Prod Info XELJANZ(R) oral tablets, 2016).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials, headache was reported in 4.3% and 3.4% of patients treated with tofacitinib 5 mg twice daily (n=1336) or 10 mg twice daily (n=1349), respectively, with or without disease modifying antirheumatic drugs, compared to 2.1% of patients on placebo (n=809), over a 3-month exposure period (Prod Info XELJANZ(R) oral tablets, 2016).
    B) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesia was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials, diarrhea was reported in 4% and 2.9% of patients treated with tofacitinib 5 mg twice daily (n=1336) or 10 mg twice daily (n=1349), respectively, with or without disease modifying antirheumatic drugs, compared to 2.3% of patients on placebo (n=809), over a 3-month exposure period (Prod Info XELJANZ(R) oral tablets, 2016).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting were reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain and gastritis were reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    D) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    E) DIVERTICULITIS
    1) WITH THERAPEUTIC USE
    a) Diverticulitis was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    F) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal perforation has been reported in patients treated with tofacitinib during clinical studies (Prod Info XELJANZ(R) oral tablets, 2016).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) In controlled background DMARD trials, elevated ALT concentrations greater than 3 times the upper limit of normal were reported in 1.3% and 1.2% of patients treated with tofacitinib at a dosage regimen of 5 mg twice daily or 10 mg twice daily, respectively, during the first 3 months of exposure, compared to 1% of patients receiving placebo (Prod Info XELJANZ(R) oral tablets, 2016).
    b) One patient developed symptomatic AST and ALT elevations greater than 3 times the upper limit of normal (ULN) and elevated bilirubin concentrations greater than 2 times ULN, necessitating a liver biopsy, following tofacitinib therapy, 10 mg twice daily for approximately 2.5 months (Prod Info XELJANZ(R) oral tablets, 2016).
    B) STEATOSIS OF LIVER
    1) WITH THERAPEUTIC USE
    a) Hepatic steatosis was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) In seven controlled clinical trials, urinary tract infections were reported in 2% of patients treated with tofacitinib, based on the first 3 months of exposure (Prod Info XELJANZ(R) oral tablets, 2016).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    B) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials, absolute lymphocyte counts less then 500 cell/mm(3) were reported in 0.04% of patients in the combined 5 mg twice daily and 10 mg twice daily tofacitinib treatment groups during the first 3 months of exposure (Prod Info XELJANZ(R) oral tablets, 2016).
    C) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials, absolute neutrophil counts less than 1000 cells/mm(3) were reported in 0.07% of patients in the combined 5 mg twice daily and 10 mg twice daily tofacitinib treatment groups during the first 3 months of exposure (Prod Info XELJANZ(R) oral tablets, 2016).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Erythema, rash, and pruritus were reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) Musculoskeletal pain was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia and joint swelling were reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).
    C) TENDINITIS
    1) WITH THERAPEUTIC USE
    a) Tendonitis was reported in patients treated with tofacitinib during controlled and open-label extension studies (Prod Info XELJANZ(R) oral tablets, 2016).

Reproductive

    3.20.1) SUMMARY
    A) Tofacitinib is classified as FDA pregnancy category C. Although there are no adequate and well-controlled studies in pregnant women, animal studies have reported teratogenicity at doses up to 146 times the maximum recommended human dose. It is unknown whether tofacitinib is excreted in human milk, although it is excreted in the milk of lactating rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) During animal studies, administration of tofacitinib at doses up to approximately 146 times the maximum recommended human dose resulted in teratogenic effects including external and soft tissue malformations, thoracogastroschisis, omphalocele, midline and tail defects, membranous ventricular septal defects, and cranial and skeletal malformations (Prod Info XELJANZ(R) oral tablets, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Tofacitinib is classified as FDA pregnancy category C (Prod Info XELJANZ(R) oral tablets, 2016).
    B) PREGNANCY REGISTRY
    1) Healthcare providers may enroll patients with tofacitinib exposure during pregnancy, or pregnant patients may enroll themselves, by calling 1-877-311-8972 (Prod Info XELJANZ(R) oral tablets, 2016).
    C) ANIMAL STUDIES
    1) Reductions in live litter size, postnatal survival and pup body weight were in animals administered tofacitinib at doses approximately 73 times the maximum recommended human dose (MRHD). An increase in post-implantation loss associated with late resorptions occurred at doses approximately 13 times the MRHD (Prod Info XELJANZ(R) oral tablets, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether tofacitinib is excreted in human milk. Advise the nursing mother to either discontinue nursing or discontinue tofacitinib therapy, considering the mother's clinical need and the benefits of breastfeeding to the infant (Prod Info XELJANZ(R) oral tablets, 2016).
    B) ANIMAL STUDIES
    1) Tofacitinib is excreted in rat milk (Prod Info XELJANZ(R) oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In animals, there was no female fertility impairment at tofacitinib exposure levels equal to the maximum recommended human dose (MRHD); however, reduced female fertility due to increased post-implantation loss was reported at tofacitinib exposure levels approximately 17 times the MRHD (Prod Info XELJANZ(R) oral tablets, 2016).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Lymphomas and solid cancers, including lung, breast, gastric, colorectal, renal cell, and prostate cancers, and malignant melanoma have been observed during controlled rheumatoid arthritis clinical trials and during long-term extension studies in patients treated with tofacitinib. Non-melanoma skin cancers have also occurred in patients treated with tofacitinib.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) In seven controlled clinical trials, during a 0 to 12-month exposure period, malignancies, including lymphoma, solid cancers (ie, lung, breast, gastric, colorectal, renal cell, and prostate cancers), and malignant melanoma were reported in 5 and 7 patients who received tofacitinib at a dose of 5 mg orally twice daily and 10 mg orally twice daily, respectively (Prod Info XELJANZ(R) oral tablets, 2016).
    B) NON-MELANOMA SKIN CANCER
    1) Non-melanoma skin cancers have been reported in patients treated with tofacitinib during clinical trials (Prod Info XELJANZ(R) oral tablets, 2016).
    C) LYMPHOPROLIFERATIVE DISORDER
    1) During Phase 2B controlled clinical trials, involving de-novo renal transplant patients who received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid, 5 of 218 patients (2.3%) treated with tofacitinib developed an Epstein Barr Virus-associated post-transplant lymphoproliferative disorder compared to 0 of 111 patients treated with cyclosporine (Prod Info XELJANZ(R) oral tablets, 2016).
    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) During a 39-week animal carcinogenicity study, lymphomas were reported following tofacitinib administration at exposure levels approximately 6 times the maximum recommended human dose (Prod Info XELJANZ(R) oral tablets, 2016).
    2) During a 24-month animal carcinogenicity study, benign Leydig cell tumors, hibernomas, and benign thymomas were reported following tofacitinib administration at doses approximately 42 times the maximum recommended human dose (Prod Info XELJANZ(R) oral tablets, 2016).

Genotoxicity

    A) Tofacitinib was not mutagenic in the bacterial reverse mutation assay, the in vivo rat micronucleus assay, in the in vitro CHO-HGPRT assay, and in the in vivo rat hepatocyte unscheduled DNA synthesis assay; however, it was positive for clastogenicity according to the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but not in the absence of metabolic enzymes (Prod Info XELJANZ(R) oral tablets, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC with differential and liver enzymes in symptomatic patients.
    B) Monitor for clinical evidence of infection.
    C) Serum tofacitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

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 clinical evidence of infection or 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.
    B) EXTENDED RELEASE TABLETS: Peak concentrations of extended-release tofacitinib are reached 4 hours after ingestion. Peak concentrations are expected to be delayed after overdose. Patients ingesting overdoses of extended-release tofacitinib should be observed for the development of toxic effects for at least 6 to 12 hours after ingestion.

Monitoring

    A) Monitor serial CBC with differential and liver enzymes in symptomatic patients.
    B) Monitor for clinical evidence of infection.
    C) Serum tofacitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor for clinical signs of infection and treat as indicated. Neutropenia has been reported with therapeutic use and may occur in overdose. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim).
    B) MONITORING OF PATIENT
    1) Monitor serial CBC with differential and liver enzymes in symptomatic patients.
    2) Monitor for clinical evidence of infection.
    3) Serum tofacitinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    C) NEUTROPENIA
    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.
    D) INFECTIOUS DISEASE
    1) Monitor CBC following a significant exposure; serial testing may be indicated. Confirmed lymphocyte counts of less than 500 cells/mm(3) have been associated with an increased incidence of serious infections (Prod Info XELJANZ(R) oral tablets, 2016). Monitor for signs of infection and treat as necessary.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose of tofacitinib has not been established. At the time of this review, overdose has not been reported.
    B) THERAPEUTIC DOSE: ADULT: IMMEDIATE-RELEASE: 5 mg orally twice daily. EXTENDED-RELEASE: 11 mg orally once daily. PEDIATRIC: Safety and effectiveness have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) IMMEDIATE-RELEASE: The recommended dose is 5 mg orally twice daily (Prod Info XELJANZ(R) oral tablets, 2016).
    B) EXTENDED-RELEASE: The recommended dose is 11 mg orally once daily (Prod Info XELJANZ (R) XR extended release oral tablets, 2016).
    7.2.2) PEDIATRIC
    A) Safety and effectiveness in pediatric patients have not been established (Prod Info XELJANZ(R) oral tablets, 2016; Prod Info XELJANZ (R) XR extended release oral tablets, 2016).

Maximum Tolerated Exposure

    A) A specific toxic dose of tofacitinib has not been established. At the time of this review, overdose has not been reported (Prod Info XELJANZ (R) XR extended release oral tablets, 2016).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Tofacitinib inhibits Janus kinases (JAK), which are intracellular enzymes, and modulates a signaling pathway that influences the cellular processes of hematopoiesis and immune cell function. Signals in this pathway arise from cytokine or growth factor-receptor interactions on the cellular membrane. Inhibition of JAK prevents the phosphorylation and activation of Signal Transducers and Activators of Transcription (STATs), which modulate gene expression and other intracellular activity (Prod Info XELJANZ(R) oral tablets, 2016; Prod Info XELJANZ (R) XR extended release oral tablets, 2016).

Physicochemical

Physical Characteristics

    A) Tofacitinib citrate is a white to off-white powder (Prod Info XELJANZ(R) oral tablets, 2016).

Molecular Weight

    A) 312.4 Daltons as the tofacitinib free base (504.5 Daltons tofacitinib citrate) (Prod Info XELJANZ(R) oral tablets, 2016)

References

General Bibliography

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    2) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    8) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    9) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    10) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    11) 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.
    12) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    13) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    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) Product Information: XELJANZ (R) XR extended release oral tablets, tofacitinib extended release oral tablets. Pfizer Labs (per manufacturer), New York, NY, 2016.
    17) Product Information: XELJANZ(R) oral tablets, tofacitinib oral tablets. Pfizer Labs (per manufacturer), New York, NY, 2016.
    18) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    19) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    20) 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.
    21) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.