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VORINOSTAT

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2, HDAC3 (Class 1), and HDAC6 (Class II). Its mechanism as an antineoplastic agent is not fully understood.

Specific Substances

    1) SAHA
    2) Suberoylanilide Hydroxamine Acid
    3) Vorinostatum
    4) N-hydroxy-N-phenyl octanediamide
    5) C14-H20-N2-O3
    6) CAS 149647-78-9
    1.2.1) MOLECULAR FORMULA
    1) C14-H20-N2-O3

Available Forms Sources

    A) FORMS
    1) Vorinostat is available as a 100 mg capsules (Prod Info ZOLINZA(R) oral capsules, 2013).
    B) USES
    1) Vorinostat is a histone deacetylase (HDAC) inhibitor used in patients with cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) who develop progressive, persistent or recurrent disease after receiving systemic therapy (Prod Info ZOLINZA(R) oral capsules, 2013).

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: Vorinostat, a histone deacetylase (HDAC) inhibitor, is used in patients with cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) who develop progressive, persistent or recurrent disease after receiving systemic therapy.
    B) PHARMACOLOGY: Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2, HDAC3 (Class 1), and HDAC6 (Class II). Its mechanism as an antineoplastic agent is not fully understood.
    C) EPIDEMIOLOGY: Exposure is uncommon; limited data.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Pulmonary embolism and anemia are the most serious drug-related adverse events reported with vorinostat therapy. Other potentially serious adverse effects are deep vein thrombosis, thrombocytopenia, and QTc prolongation. Nausea, vomiting, diarrhea, anorexia, constipation, muscle spasm and hyperglycemia are common adverse events. Less frequently reported events include: peripheral edema, headache, pruritus, upper respiratory infection, cough and fever.
    E) WITH POISONING/EXPOSURE
    1) No overdose information is available. Overdose effects are likely an extension of adverse events reported with vorinostat therapy.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported during therapeutic use.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) QTc prolongation has been reported with therapeutic use in a small number of patients.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Pulmonary embolism, cough and upper respiratory infection have been reported with therapy.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Minor neurologic events have included dizziness and headache with therapy.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting and diarrhea are frequently reported with vorinostat therapy.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Dehydration is a common Grade 3 or 4 adverse event following oral therapy.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Dose-related thrombocytopenia and anemia have developed with therapy. These events may be potentially serious.
    0.2.16) ENDOCRINE
    A) WITH THERAPEUTIC USE
    1) Hyperglycemia has occurred frequently with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Vorinostat is classified as FDA pregnancy category D.
    B) In animal studies, vorinostat crosses the placenta. Developmental effects have included a decrease in fetal weights, incomplete ossification of the skull, thoracic vertebra, sternebra, and skeletal variations in rats.
    0.2.21) CARCINOGENICITY
    A) Carcinogenicity studies with vorinostat have not been conducted in animals. Vorinostat produced mutagenic and chromosomal aberrations in vitro.

Laboratory Monitoring

    A) Monitor serial CBC with differential and platelet count following a significant exposure.
    B) Monitor serum electrolytes, blood glucose and serum creatinine following a significant exposure.
    C) Monitor fluid status and electrolytes (including potassium and magnesium) in patients with significant vomiting, dehydration, or diarrhea.
    D) Obtain a baseline ECG following a significant overdose or in patients with a history of a prolonged QT interval.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Dose-related thrombocytopenia and anemia have been reported. Monitor serial CBC with differential and platelet count. Severe thrombocytopenia leading to GI bleeding has been reported with concomitant use of vorinostat with other histone deacetylase (HDAC) inhibitors. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Dose-related neutropenia has been infrequently reported. Obtain a baseline ECG following a significant exposure or in patient's with a history of prolonged QT interval; repeat as necessary. Monitor electrolytes and correct as needed.
    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) Endotracheal intubation is unlikely to be necessary following a mild to moderate ingestion, intubate if patient is unable to protect airway.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) It is not known if vorinostat is dialyzable.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with an inadvertent ingestion of 1 or 2 extra doses can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions, any patient who is symptomatic or ingested more than 2 extra doses, 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 evidence of thrombocytopenia, anemia or active bleeding, or severe dehydration that has not responded to therapy 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.
    H) PITFALLS
    1) When managing a suspected vorinostat overdose, the possibility of multi-drug involvement should be considered (ie, evaluate for the use of other histone deacetylase (HDAC) inhibitors; eg, valproic acid).
    I) PHARMACOKINETICS
    1) Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 mcg/mL. The mean terminal half-life was 2 hours for both vorinostat and the O-glucuronide metabolite, while the other metabolite (anilino-4-oxobutanoic acid) was 11 hours. The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by beta-oxidation. It is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in the urine.
    J) DIFFERENTIAL DIAGNOSIS
    1) Vorinostat may be administered with other agents that may cause thrombocytopenia (ie, other histone deacetylase (HDAC) inhibitors).

Range Of Toxicity

    A) In a dose escalation study, the maximum tolerated dose was 300 mg/m(2)/day IV, 5 days a week for 3 weeks in patients with hematologic malignancies.
    B) In clinical trials, a patient with metastatic breast cancer developed hypotension and respiratory distress after a dose of 900 mg/m(2)/day IV 5 days a week for 3 weeks. Two out of 5 patients with hematologic malignancies receiving 600 mg/m(20)/day 5 days a week for 3 weeks developed severe leukopenia and/or thrombocytopenia. No acute overdoses have been reported.
    C) THERAPEUTIC DOSE: ADULT: 400 mg orally once daily. PEDIATRIC: The safety and efficacy of vorinostat in pediatric patients have not been established. In a Phase I pediatric trial, the maximum tolerated dose in children (ages 2.6 to 22 years) with refractory tumors or refractory leukemia was 230 mg/m(2) (equivalent to a 400 mg dose in an adult).

Clinical Effects

Summary Of Exposure

    A) USES: Vorinostat, a histone deacetylase (HDAC) inhibitor, is used in patients with cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) who develop progressive, persistent or recurrent disease after receiving systemic therapy.
    B) PHARMACOLOGY: Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2, HDAC3 (Class 1), and HDAC6 (Class II). Its mechanism as an antineoplastic agent is not fully understood.
    C) EPIDEMIOLOGY: Exposure is uncommon; limited data.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Pulmonary embolism and anemia are the most serious drug-related adverse events reported with vorinostat therapy. Other potentially serious adverse effects are deep vein thrombosis, thrombocytopenia, and QTc prolongation. Nausea, vomiting, diarrhea, anorexia, constipation, muscle spasm and hyperglycemia are common adverse events. Less frequently reported events include: peripheral edema, headache, pruritus, upper respiratory infection, cough and fever.
    E) WITH POISONING/EXPOSURE
    1) No overdose information is available. Overdose effects are likely an extension of adverse events reported with vorinostat therapy.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported during therapeutic use.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever was reported in 10.5% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days. Of the cases reported, 1.2% developed Grade 3 or 4 fever (Prod Info ZOLINZA(R) oral capsules, 2013).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) QTc prolongation has been reported with therapeutic use in a small number of patients.
    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) QTc prolongation has been reported in a small number of patients during therapeutic use, although no definitive study of the effect on QTc has been performed. Grade 1 (greater than 450 to 470 msec) or Grade 2 (greater than 470 to 500 msec or an increase of more than 60 msec above baseline) QTc prolongation occurred in 3 of 86 cutaneous T-cell lymphoma (CTCL) patients administered 400 mg vorinostat once daily (Prod Info ZOLINZA(R) oral capsules, 2013).
    1) In a combined analysis of five Phase 1 and Phase 2 studies, Grade 2 (greater than 470 to 500 msec or increase of greater than 60 msec above baseline) QTc prolongation occurred in 4 of 116 patients and Grade 3 (higher than 500 msec) occurred in 1 of 116 patients. Among 49 patients who did not have CTCL, 2 patients had QTc greater than 500 msec and 1 patient had QTc prolongation of more than 60 msec longer than baseline (Prod Info ZOLINZA(R) oral capsules, 2013).
    b) SINGLE SUPRATHERAPEUTIC DOSE: In a QTc assessment study of patients with advanced cancer a single dose of 800 mg of vorinostat and placebo was given to 25 patients to assess the potential effect on QTc interval. ECG readings were recorded at predetermined points and the change from baseline for vorinostat QTc was less than 10 ms at each point suggesting that a single 800 mg dose is not associated with QTc interval prolongation (Iwamoto et al, 2013).
    c) CASE REPORT: A 49-year-old man with a history of cutaneous T-cell lymphoma (treated with vorinostat 400 mg/day), liver disease, renal insufficiency, hemolytic anemia, and a right hepatic lobe hemangioma was admitted for a brief history of hematemesis, hematochezia and a syncopal episode. Other medications included sertraline and doxepin. Upon admission, an ECG showed normal sinus rhythm with a prolonged QTc interval of 826 ms, T-wave inversions in the precordial and limb leads and a QRS of 60 ms. During the first day, pulseless polymorphic ventricular tachycardia developed that responded to brief cardiac resuscitation measures. Intravenous magnesium and potassium (3.1 mmol/L on admission) were given. No further episodes of torsades de pointes occurred and the patient remained stable. By day 4, the QTc remained prolonged at 559 ms after discontinuation of vorinostat, doxepin and sertraline and a normal potassium concentration. A second-trial of vorinostat had not occurred (Lynch et al, 2012).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Pulmonary embolism, cough and upper respiratory infection have been reported with therapy.
    3.6.2) CLINICAL EFFECTS
    A) PULMONARY EMBOLISM
    1) WITH THERAPEUTIC USE
    a) Pulmonary embolism was reported in 4.7% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days (Prod Info ZOLINZA(R) oral capsules, 2013).
    b) In several clinical studies, pulmonary embolism was one of the most common serious clinical events reported (Prod Info ZOLINZA(R) oral capsules, 2013).
    B) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Upper respiratory infection and cough each developed in 10.5% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days. No Grade 3 or 4 events were reported (Prod Info ZOLINZA(R) oral capsules, 2013).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Minor neurologic events have included dizziness and headache with therapy.
    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 15.1% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days. Of the cases reported, 1.2% developed Grade 3 or 4 dizziness (Prod Info ZOLINZA(R) oral capsules, 2013).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported in 11.6% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days (Prod Info ZOLINZA(R) oral capsules, 2013).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting and diarrhea are frequently reported with vorinostat therapy.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea was reported in 40.7% and vomiting occurred in 15.1% of 86 patients with cutaneous T-cell lymphoma (CTCL) who received 400 mg vorinostat once daily for a median of 97.5 days (Prod Info ZOLINZA(R) oral capsules, 2013).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is one of the most common adverse events observed and developed in 52.3% of cutaneous T-cell lymphoma patients (n=86) who received 400 mg vorinostat once daily for a median of 97.5 days; no cases were Grade 3 to 5 (Prod Info ZOLINZA(R) oral capsules, 2013). In another study of 33 patients with CTCL, diarrhea was reported in 60% of patients and was one of the most common adverse events reported (Duvic et al, 2007).
    b) In a comparison of Grade 3 or 4 toxicities in patients with hematologic malignancies or solid tumors, hematologic malignancy patients receiving IV or oral suberoylanilide hydroxamic acid (SAHA) had a higher risk of developing diarrhea and dehydration (O'Connor et al, 2006).
    C) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) In 2 clinical trials of 86 patients with CTCL, anorexia, decreased appetite, dysgeusia, xerostomia and constipation were reported frequently (greater than 10%) during oral therapy with vorinostat 400 mg daily (Prod Info ZOLINZA(R) oral capsules, 2013; Duvic et al, 2007; O'Connor et al, 2006).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) An increase in serum creatinine was reported in 16.3% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days; no case was Grade 3 to 5 (Prod Info ZOLINZA(R) oral capsules, 2013).
    B) PROTEINURIA
    1) WITH THERAPEUTIC USE
    a) Proteinuria has been observed with therapeutic use; the clinical significance is unknown (Prod Info ZOLINZA(R) oral capsules, 2013).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dose-related thrombocytopenia and anemia have developed with therapy. These events may be potentially serious.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Dose-related thrombocytopenia has occurred with therapy. In several clinical studies, thrombocytopenia was one of the most common serious events reported (Prod Info ZOLINZA(R) oral capsules, 2013).
    b) Thrombocytopenia developed in 25.6% of 86 cutaneous T-cell lymphoma (CTCL) patients who received 400 mg vorinostat once daily for a median of 97.5 days. Of the cases reported, 5.8% developed Grade 3 or 4 thrombocytopenia (Prod Info ZOLINZA(R) oral capsules, 2013). In another study of 33 patients with CTCL, thrombocytopenia occurred in 54% of patients, and was the most common Grade 3 or 4 adverse event occurring in 19% of patients (Duvic et al, 2007).
    c) In a clinical trial of 35 patients with hematologic malignancies, patients receiving oral suberoylanilide hydroxamic acid (SAHA) had a greater incidence of thrombocytopenia and neutropenia as compared to patients receiving intravenous therapy (O'Connor et al, 2006).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Dose-related anemia has occurred with therapy. In several clinical studies, anemia was one of the most common serious events reported (Prod Info ZOLINZA(R) oral capsules, 2013).
    b) Anemia occurred in 14% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days. Of the cases reported, 2.3% of patients developed Grade 3 or 4 anemia (Prod Info ZOLINZA(R) oral capsules, 2013).
    C) DEEP VENOUS THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Deep vein thrombosis has occurred during treatment (Prod Info ZOLINZA(R) oral capsules, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus has been reported in 11.6% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days (Prod Info ZOLINZA(R) oral capsules, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) SPASM
    1) WITH THERAPEUTIC USE
    a) Muscle spasms were reported in 19.8% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days. Of the cases reported, 2.3% developed Grade 3 or 4 muscle spasms (Prod Info ZOLINZA(R) oral capsules, 2013).

Endocrine

    3.16.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hyperglycemia has occurred frequently with therapeutic use.
    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia was reported in 5% of 86 cutaneous T-cell lymphoma patients who received 400 mg vorinostat once daily for a median of 97.5 days (Prod Info ZOLINZA(R) oral capsules, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) In a comparison of Grade 3 or 4 toxicities in patients with hematologic malignancies or solid tumors, hematologic malignancy patients receiving intravenous or oral suberoylanilide hydroxamic acid (SAHA) had a higher risk of developing infection (O'Connor et al, 2006).

Reproductive

    3.20.1) SUMMARY
    A) Vorinostat is classified as FDA pregnancy category D.
    B) In animal studies, vorinostat crosses the placenta. Developmental effects have included a decrease in fetal weights, incomplete ossification of the skull, thoracic vertebra, sternebra, and skeletal variations in rats.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Vorinostat is classified as FDA pregnancy category D (Prod Info ZOLINZA(TM) oral capsules, 2006).
    2) Developmental effects have included a decrease in fetal weights, incomplete ossification of the skull, thoracic vertebra, sternebra, and skeletal variations in rats. In rabbits, a decrease in fetal weights was also reported, along with incomplete ossification of the metacarpals at doses of 150 mg/kg/day (Prod Info ZOLINZA(TM) oral capsules, 2006).
    3) A dose-related increase in malformation of the gallbladder was observed in all drug treatment groups in rabbits (Prod Info ZOLINZA(TM) oral capsules, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, it is not known if vorinostat is excreted in human milk (Prod Info ZOLINZA(TM) oral capsules, 2006).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Carcinogenicity studies with vorinostat have not been conducted in animals. Vorinostat produced mutagenic and chromosomal aberrations in vitro.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Carcinogenicity studies with vorinostat have not been conducted (Prod Info ZOLINZA(TM) oral capsules, 2006).

Genotoxicity

    A) Chromosomal aberrations occurred in vitro in Chinese hamster ovary cells. An increase in the incidence of micro-nucleated erythrocytes was also observed when vorinostat was given to mice (Prod Info ZOLINZA(TM) oral capsules, 2006).
    B) Mutagenicity from vorinostat has been demonstrated in bacterial reverse mutation assays (Ames test) (Prod Info ZOLINZA(TM) oral capsules, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC with differential and platelet count following a significant exposure.
    B) Monitor serum electrolytes, blood glucose and serum creatinine following a significant exposure.
    C) Monitor fluid status and electrolytes (including potassium and magnesium) in patients with significant vomiting, dehydration, or diarrhea.
    D) Obtain a baseline ECG following a significant overdose or in patients with a history of a prolonged QT interval.
    4.1.2) SERUM/BLOOD
    A) Monitor serial CBC with differential and platelet count following a significant exposure.
    B) Monitor serum electrolytes, blood glucose and serum creatinine following a significant exposure.
    C) Monitor fluid status and electrolytes (including potassium and magnesium) in patients with significant vomiting, dehydration, or diarrhea.
    4.1.3) URINE
    A) Proteinuria has been observed with therapeutic use; the clinical significance is unknown.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain a baseline ECG following a significant overdose or in patients with a history of a prolonged QT interval; repeat as indicated.

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 evidence of thrombocytopenia, anemia or active bleeding, or severe dehydration that has not responded to therapy should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with an inadvertent ingestion of 1 or 2 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, any patient who is symptomatic or ingested more than 2 extra doses, 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 serial CBC with differential and platelet count following a significant exposure.
    B) Monitor serum electrolytes, blood glucose and serum creatinine following a significant exposure.
    C) Monitor fluid status and electrolytes (including potassium and magnesium) in patients with significant vomiting, dehydration, or diarrhea.
    D) Obtain a baseline ECG following a significant overdose or in patients with a history of a prolonged QT interval.

Oral Exposure

    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 specific antidote.
    B) MONITORING OF PATIENT
    1) Monitor serial CBC with differential and platelet count after significant overdose. Thrombocytopenia, anemia and infrequently neutropenia have developed in patients treated with vorinostat.
    2) Monitor serum electrolytes, blood glucose and serum creatinine following a significant exposure.
    3) Monitor vital signs, obtain a baseline ECG repeat as indicated.
    C) FLUID BALANCE MONITORING
    1) Monitor fluid status and electrolytes including potassium and magnesium in patients with significant dehydration, vomiting or diarrhea.
    2) Replace fluids and electrolytes as indicated.
    D) PROLONGED QT INTERVAL
    1) Monitor ECG carefully for dysrhythmias or QTc interval prolongation.
    2) Monitor electrolytes including calcium, magnesium and potassium. Correct any underlying electrolyte imbalances.
    E) MYELOSUPPRESSION
    1) THROMBOCYTOPENIA and ANEMIA: Dose-related thrombocytopenia and anemia have been reported. Monitor serial CBC with differential and platelets. Severe thrombocytopenia leading to GI bleeding has been reported with concomitant use of vorinostat with other histone deacetylase (HDAC) inhibitors (Prod Info ZOLINZA(R) oral capsules, 2013).
    a) Transfusion may be necessary in patients with severe thrombocytopenia or bleeding.
    2) NEUTROPENIA: There have been infrequent reports of neutropenia requiring dose-modification during therapeutic use. Monitor CBC with differential until patient recovery.
    a) Administer colony stimulating factors (filgrastim or sargramostim) as these patients may be at risk for neutropenia.
    b) 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.
    1) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    2) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    3) Monitor CBC with differential.

Enhanced Elimination

    A) SUMMARY
    1) In the event of overdose, it is not known if vorinostat is dialyzable (Prod Info ZOLINZA(R) oral capsules, 2013).

Range Of Toxicity

Summary

    A) In a dose escalation study, the maximum tolerated dose was 300 mg/m(2)/day IV, 5 days a week for 3 weeks in patients with hematologic malignancies.
    B) In clinical trials, a patient with metastatic breast cancer developed hypotension and respiratory distress after a dose of 900 mg/m(2)/day IV 5 days a week for 3 weeks. Two out of 5 patients with hematologic malignancies receiving 600 mg/m(20)/day 5 days a week for 3 weeks developed severe leukopenia and/or thrombocytopenia. No acute overdoses have been reported.
    C) THERAPEUTIC DOSE: ADULT: 400 mg orally once daily. PEDIATRIC: The safety and efficacy of vorinostat in pediatric patients have not been established. In a Phase I pediatric trial, the maximum tolerated dose in children (ages 2.6 to 22 years) with refractory tumors or refractory leukemia was 230 mg/m(2) (equivalent to a 400 mg dose in an adult).

Therapeutic Dose

    7.2.1) ADULT
    A) CUTANEOUS T-CELL LYMPHOMA
    1) The recommended dose is 400 mg/day orally with food (Prod Info ZOLINZA(R) oral capsules, 2013).
    7.2.2) PEDIATRIC
    A) CUTANEOUS T-CELL LYMPHOMA
    1) The safety and efficacy of vorinostat in pediatric patients have not been established (Prod Info ZOLINZA(R) oral capsules, 2013).
    2) In a Phase l pediatric trial, vorinostat was given alone or in combination with isotretinoin in children from ages 2.6 to 22 years with refractory tumors or refractory leukemia. The initial dose was 180 mg/m(2) daily (approximately 80% of the adult dose of 400 mg) that was escalated in 30% increments to 230 and 300 mg/m(2). The maximum tolerated dose was 230 mg/m(2) (approximately equivalent to the 400 mg adult dose) and the median AUC and Cmax values at 230 mg/m(2) appeared to be higher than an adult dose at 400 mg. In addition, lower AUC and Cmax for the metabolite were observed for the 230 mg/m(2) doses relative to adult (400 mg dose) pharmacokinetics. Although further study is suggested, pediatric patients may have higher exposure at equivalent doses to vorinostat compared to adults (Iwamoto et al, 2013).
    3) In a Phase l pediatric trial of vorinostat and bortezomib with refractory or recurrent solid tumors, a maximum tolerated dose of 230 mg/m(2) was also observed (Muscal et al, 2013).

Maximum Tolerated Exposure

    A) In a dose escalation study, the maximum tolerated dose was 300 mg/m(2)/day IV, 5 days a week for 3 weeks in patients with hematologic malignancies. Two out of 5 patients with hematologic malignancies receiving 600 mg/m(20)/day 5 days a week for 3 weeks developed severe leukopenia and/or thrombocytopenia. (Kelly et al, 2003).
    1) In the same study, a patient with a solid tumor developed acute respiratory distress and Grade 3 hypotension following 900 mg/m(2)/day IV, times 5 days for 3 weeks. Following drug cessation and steroid therapy, the patient returned to her baseline respiratory function. The authors suggested that the effects were possibly related to vorinostat administration (Kelly et al, 2003).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Suberoylanidide hydroxamic acid (SAHA), is an inhibitor of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class 1) and HDAC6 (Class ll), which catalyze the removal of acetyl groups from the lysine residues of proteins, including histones, and transcription factors. By blocking deacetylation of histones, SAHA promotes an open chromatin structure and can alter the expression of genes regulating cell survival, proliferation, differentiation, and apoptosis. Based on in vitro and in vivo studies, SAHA has demonstrated the induction of cell growth arrest and apoptosis in various cells. However, the exact mechanism has not been fully described in cutaneous T-cell lymphoma (CTCL) patients (Prod Info ZOLINZA(TM) oral capsules, 2006; Zhang et al, 2005).
    1) In an in vitro study, SAHA was found to selectively cause apoptosis of CTCL cells lines in peripheral blood lymphocytes (PBL) as compared to healthy donors' PBL. It also induced an accumulation of acetylated histones and induces cell cycle arrest. SAHA is able to induce tumor cell apoptosis at concentrations to which normal cells are relatively resistant (Zhang et al, 2005).

Physicochemical

Physical Characteristics

    A) a white to light orange powder (Prod Info ZOLINZA(TM) oral capsules, 2006)

Molecular Weight

    A) 264.32 (Prod Info ZOLINZA(TM) oral capsules, 2006)

References

General Bibliography

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    12) Lynch DR Jr, Washam JB, & Newby LK: QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature. Cardiol J 2012; 19(4):434-438.
    13) Muscal JA, Thompson PA, Horton TM, et al: A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (ADVL0916). Pediatr Blood Cancer 2013; 60(3):390-395.
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    20) Product Information: ZOLINZA(TM) oral capsules, vorinostat oral capsules. Merck & Co,Inc, Whitehouse Station, NJ, 2006.
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