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CILOSTAZOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cilostazol, a quinolone derivative, is a selective phosphodiesterase inhibitor (more specific for type III).

Specific Substances

    1) OPC-21
    2) OPC-13013
    3) Pletaal
    4) Pletal(R)
    5) Molecular Formula: C20-H27-N5-O2
    6) CAS 73963-72-1
    7) CAS 89332-50-3

Available Forms Sources

    A) FORMS
    1) Cilostazol is available in the United States as 50 mg and 100 mg tablets for oral dosing (Prod Info PLETAL(R) oral tablets, 2015).
    B) USES
    1) Cilostazol is an antiplatelet agent with vasodilating properties. It is indicated for the treatment of intermittent claudication due to occlusive peripheral arterial disease (Prod Info PLETAL(R) oral tablets, 2015).

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: Cilostazol is used to reduce symptoms of intermittent claudication.
    B) PHARMACOLOGY: Cilostazol and its active metabolites inhibit phosphodiesterase activity and suppress degradation of cyclic adenosine monophosphate (cAMP) resulting in an increase in cAMP in platelets and blood vessels. It reversibly inhibits platelet aggregation induced by various stimuli, including thrombin, adenosine diphosphate (ADP), collagen, arachidonic acid, epinephrine, and shear stress. Cilostazol produces nonhomogenous vasodilation, with greater dilation in femoral beds than in vertebral, carotic, or superior mesenteric arteries, but without effect in renal arteries.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Cilostazol is generally well tolerated by most patients. COMMON: Headache, diarrhea, abnormal stools, palpitations, and dizziness. OTHER EFFECTS: Abdominal pain, dyspepsia, nausea, peripheral edema, pharyngitis, rhinitis, and back pain. RARE: Bleeding, tachycardia, hypotension, atrial fibrillation, ventricular tachycardia, Stevens-Johnson syndrome, dermatitis medicamentosa. There have been rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis was reversible on discontinuation of cilostazol.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Severe headache, diarrhea, hypotension, tachycardia, and possible dysrhythmias may occur with cilostazol overdose.
    0.2.20) REPRODUCTIVE
    A) Cilostazol is classified as FDA pregnancy category C. Oral administration of large doses of cilostazol to rats were associated with increased incidences of anomalies. In animal studies, transfer of cilostazol into milk has been observed.

Laboratory Monitoring

    A) Monitor vital signs, CBC with differential and platelet count following an overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    D) Monitor serial hemoglobin and hematocrit in patients with suspected bleeding.
    E) Obtain an ECG in symptomatic patients, and institute continuous cardiac monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat hypotension with IV fluids, dopamine, or norepinephrine.
    C) DECONTAMINATION
    1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with serious toxicity or life-threatening cardiac dysrhythmias, severe bleeding (eg, intracranial bleeding or severe hemoptysis or upper GI bleeding).
    E) ANTIDOTE
    1) None
    F) HYPOTENSION
    1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine.
    G) MYELOSUPPRESSION
    1) There have been rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis was reversible on discontinuation of cilostazol. 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. Transfusions as needed for severe thrombocytopenia, bleeding.
    H) VENTRICULAR DYSRHYTHMIAS
    1) Ventricular tachycardia has rarely been reported in patients receiving cilostazol. However, a causal relationship could not be established. Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    I) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Any patient with deliberate ingestions, a significant ingestion, or patients with comorbidities, should be referred to a healthcare facility for observation. All symptomatic patients should be sent to a healthcare facility for observation. Patients who are asymptomatic and who have normal bleeding time can be followed as an outpatient or on a psychiatric ward with twice daily check of their bleeding time.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with bleeding should be admitted. Patients with hypotension, or significant hemorrhage, should be admitted to an intensive care unit.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. A hematology consult should also be considered. If significant hemorrhage develops, surgical consultation may be warranted.
    K) PITFALLS
    1) When managing a suspected cilostazol overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative.
    L) PHARMACOKINETICS
    1) Cilostazol is absorbed from the GI tract following oral administration. Absolute bioavailability is unknown. Protein binding: 95% to 98%; Cilostazol is extensively metabolized in the liver via the cytochrome P450 enzymes, primarily CYP3A4, and to a lesser extent, CYP2C19. Excretion (renal): approximately 74% excreted in the urine; (feces): approximately 20%. Elimination half-life: 11 to 13 hours.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypotension or myelosuppression.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: 100 mg orally twice a day. CHILDREN: safety and efficacy in children have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Cilostazol is used to reduce symptoms of intermittent claudication.
    B) PHARMACOLOGY: Cilostazol and its active metabolites inhibit phosphodiesterase activity and suppress degradation of cyclic adenosine monophosphate (cAMP) resulting in an increase in cAMP in platelets and blood vessels. It reversibly inhibits platelet aggregation induced by various stimuli, including thrombin, adenosine diphosphate (ADP), collagen, arachidonic acid, epinephrine, and shear stress. Cilostazol produces nonhomogenous vasodilation, with greater dilation in femoral beds than in vertebral, carotic, or superior mesenteric arteries, but without effect in renal arteries.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Cilostazol is generally well tolerated by most patients. COMMON: Headache, diarrhea, abnormal stools, palpitations, and dizziness. OTHER EFFECTS: Abdominal pain, dyspepsia, nausea, peripheral edema, pharyngitis, rhinitis, and back pain. RARE: Bleeding, tachycardia, hypotension, atrial fibrillation, ventricular tachycardia, Stevens-Johnson syndrome, dermatitis medicamentosa. There have been rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis was reversible on discontinuation of cilostazol.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Severe headache, diarrhea, hypotension, tachycardia, and possible dysrhythmias may occur with cilostazol overdose.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Cilostazol has vasodilating properties. Hypotension was reported in less than 2% of patients receiving cilostazol in 8 placebo-controlled clinical trials of 2274 patients receiving cilostazol 50 mg or 100 mg twice daily (n=1301) for a median of 127 days, or placebo (n=973) for a median of 134 days (Prod Info PLETAL oral tablets, 2007).
    2) WITH POISONING/EXPOSURE
    a) Hypotension may occur with cilostazol overdose (Prod Info PLETAL oral tablets, 2007).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Ventricular tachycardia was reported in less than 2% of patients receiving cilostazol in 8 placebo-controlled clinical trials of 2274 patients receiving cilostazol 50 mg or 100 mg twice daily (n=1301) for a median of 127 days, or placebo (n=973) for a median of 134 days (Prod Info PLETAL oral tablets, 2007). However, a causal relationship could not be established.
    b) Atrial fibrillation was reported in less than 2% of patients receiving cilostazol in 8 placebo-controlled clinical trials of 2274 patients receiving cilostazol 50 mg or 100 mg twice daily (n=1301) for a median of 127 days, or placebo (n=973) for a median of 134 days (Prod Info PLETAL oral tablets, 2007). However, a causal relationship could not be established.
    c) CASE REPORT: A 92-year-old woman with a history of well-controlled hypertension and chronic atrial fibrillation developed lower-extremity pain after taking cilostazol for several days. On admission, her heart rate was irregular (60 bpm) without an S3 gallop. ECG revealed atrial fibrillation and intraventricular conduction delay. Two-dimensional echocardiography showed an ejection fraction of 55% to 60% and a dilated right atrium. She developed several runs of ventricular tachycardia 2 days after admission. Cilostazol was discontinued and ventricular tachycardia did not recur. The authors speculated that cilostazol contributed to the development of ventricular dysrhythmia in this patient by increasing cAMP levels (Gamssari et al, 2002).
    2) WITH POISONING/EXPOSURE
    a) Dysrhythmias may occur with cilostazol overdose (Prod Info PLETAL oral tablets, 2007).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, tachycardia has been reported in 4% of patients receiving cilostazol (50 mg or 100 mg twice daily) (Kozuma et al, 2001).
    b) In premarketing clinical studies, tachycardia a occurred in 4%, 4%, and 1% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007)
    2) WITH POISONING/EXPOSURE
    a) Tachycardia may occur with cilostazol overdose (Prod Info PLETAL oral tablets, 2007).
    D) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, palpitations occurred in 5%, 10%, and 1% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007)
    E) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, peripheral edema occurred in 9%, 7%, and 4% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007; Elam et al, 1998).
    F) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In one study, unstable angina occurred in a patient on cilostazol 100 mg twice daily (Dawson et al, 1998).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, cough occurred in 3%, 4%, and 3% of patients treated with cilostazol 50 or 100 mg twice daily or placebo, respectively (Prod Info PLETAL(R) oral tablet, 2007).
    B) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, pharyngitis occurred in 7%, 10%, and 7% of patients treated with cilostazol 50 or 100 mg twice daily or placebo, respectively (Prod Info PLETAL(R) oral tablet, 2007).
    C) RHINITIS
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, rhinitis occurred in 12%, 7%, and 5% of patients treated with cilostazol 50 or 100 mg twice daily or placebo, respectively (Prod Info PLETAL(R) oral tablet, 2007).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, headache occurred in 27%, 34%, and 14% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007; Bramer et al, 1999; Bramer et al, 1999; Mallikaarjun & Bramer, 1999; Beebe et al, 1999; Elam et al, 1998; Money et al, 1998; Dawson et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) Severe headache may occur with cilostazol overdose (Prod Info PLETAL oral tablets, 2007).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, dizziness occurred in 9%, 10%, and 6% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007; Beebe et al, 1999; Money et al, 1998; Elam et al, 1998).
    C) VERTIGO
    1) WITH THERAPEUTIC USE
    a) In clinical trials, vertigo was reported in 3%, 1%, and 1% of patients taking cilostazol 50 and 100 mg twice daily or placebo, respectively (Prod Info PLETAL(R) oral tablet, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, diarrhea occurred in 12%, 19%, and 7% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007; Beebe et al, 1999; Dawson et al, 1998; Elam et al, 1998; Money et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea may occur with cilostazol overdose (Prod Info PLETAL oral tablets, 2007).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, abdominal pain occurred in 4%, 5%, and 3% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL oral tablets, 2007; Beebe et al, 1999a; Dawson et al, 1998a; Elam et al, 1998a; Money et al, 1998a).
    C) STOOL FINDING
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, abnormal stools occurred in 12%, 15%, and 4% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007; Beebe et al, 1999; Dawson et al, 1998; Elam et al, 1998; Money et al, 1998).
    D) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, dyspepsia occurred in 6%, 6%, and 4% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007).
    E) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, flatulence occurred in 2%, 3%, and 2% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007; Dawson et al, 1998).
    F) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, nausea occurred in 6%, 7%, and 6% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007; Dawson et al, 1998).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) Cilostazol reversibly inhibits platelet aggregation. During postmarketing surveillance of cilostazol, a bleeding tendency was reported (Prod Info PLETAL oral tablets, 2007).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) There have been rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis was reversible on discontinuation of cilostazol (Prod Info PLETAL oral tablets, 2007).
    b) During postmarketing surveillance of cilostazol, thrombocytopenia was reported (Prod Info PLETAL oral tablets, 2007).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) There have been rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis was reversible on discontinuation of cilostazol (Prod Info PLETAL oral tablets, 2007).
    b) During postmarketing surveillance of cilostazol, leukopenia was reported (Prod Info PLETAL oral tablets, 2007).
    D) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) There have been rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis was reversible on discontinuation of cilostazol (Prod Info PLETAL oral tablets, 2007).
    b) During postmarketing surveillance of cilostazol, agranulocytosis was reported (Prod Info PLETAL oral tablets, 2007).
    E) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance of cilostazol, aplastic anemia was reported (Prod Info PLETAL oral tablets, 2007). However, a causal relationship could not be established.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rash has been reported with therapeutic use (Kozuma et al, 2001; Tsuchikane et al, 1999).
    b) In one study, 2 patients developed skin rash with cilostazol (200 milligrams/day) (Tsuchikane et al, 1999).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance of cilostazol, skin eruptions including Stevens-Johnson syndrome were reported (Prod Info PLETAL oral tablets, 2007).
    C) DERMATITIS MEDICAMENTOSA
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance of cilostazol, skin eruptions including dermatitis medicamentosa were reported (Prod Info PLETAL oral tablets, 2007).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) PAIN
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical studies, back pain occurred in 6%, 7%, and 6% of patients treated with cilostazol 50 mg (n=303) or 100 mg (n=998) twice daily or placebo (n=973), respectively (Prod Info PLETAL(R) oral tablet, 2007; Elam et al, 1998).
    b) CASE REPORT: After taking cilostazol for several days, a 92-year-old woman developed lower-extremity pain with weakness, coldness, and bluish discoloration of the limb. She developed ventricular tachycardia 2 days after admission. Symptoms resolved upon discontinuation of cilostazol (Gamssari et al, 2002).

Reproductive

    3.20.1) SUMMARY
    A) Cilostazol is classified as FDA pregnancy category C. Oral administration of large doses of cilostazol to rats were associated with increased incidences of anomalies. In animal studies, transfer of cilostazol into milk has been observed.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Oral administration of cilostazol at doses approximately 5 times the maximum recommended human dose (MRHD) in animals resulted in increased cardiovascular, renal, and skeletal anomalies. Increased incidences of ventricular septal defects and retarded ossification were also observed. At doses lower that the MRHD, retardation of sternum ossification was reported (Prod Info PLETAL(R) oral tablets, 2015a).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified cilostazol as FDA pregnancy category C (Prod Info PLETAL(R) oral tablets, 2015a).
    2) Until more information is available, use cilostazol during pregnancy only if the maternal benefit justifies the potential fetal risk (Prod Info PLETAL(R) oral tablets, 2015a).
    B) ANIMAL STUDIES
    1) Administration of cilostazol at doses approximately 5 times the maximum recommended human dose in animals during late pregnancy and lactation resulted in decreased offspring birth weight and increased incidences of stillborns (Prod Info PLETAL(R) oral tablets, 2015a).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Due to the potential for adverse reactions in the nursing infant, discontinue cilostazol or discontinue nursing (Prod Info PLETAL(R) oral tablets, 2015a).
    B) ANIMAL STUDIES
    1) Transfer of cilostazol into the milk of lactating animals has been reported (Prod Info PLETAL(R) oral tablets, 2015a).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) No adverse effects on fertility or mating performance were reported in animals administered cilostazol at doses approximately 1.5 to 5 times the maximum recommended human dose (Prod Info PLETAL(R) oral tablets, 2015a).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, CBC with differential and platelet count following an overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    D) Monitor serial hemoglobin and hematocrit in patients with suspected bleeding.
    E) Obtain an ECG in symptomatic patients, and institute continuous cardiac monitoring.

Methods

    A) CHROMATOGRAPHY
    1) Plasma and urine concentrations of cilostazol and its 2 principal metabolites have been determined by reverse-phase gradient high performance liquid chromatography (HPLC) with UV absorbance detection (Suri et al, 1999; Bramer et al, 1999; Mallikaarjun & Bramer, 1999; Akiyama et al, 1985).

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 should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with bleeding should be admitted. Patients with hypotension, or significant hemorrhage, should be admitted to an intensive care unit.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. A hematology consult should also be considered. If significant hemorrhage develops, surgical consultation may be warranted.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with deliberate ingestions, a significant ingestion, or patients with comorbidities, should be referred to a healthcare facility for observation. All symptomatic patients should be sent to a healthcare facility for observation. Patients who are asymptomatic and who have normal bleeding time can be followed as an outpatient or on a psychiatric ward with twice daily check of their bleeding time.

Monitoring

    A) Monitor vital signs, CBC with differential and platelet count following an overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    D) Monitor serial hemoglobin and hematocrit in patients with suspected bleeding.
    E) Obtain an ECG in symptomatic patients, and institute continuous cardiac monitoring.

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).
    6.5.2) 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) MONITORING OF PATIENT
    1) Monitor vital signs, CBC with differential and platelet count following an overdose.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    3) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    4) Monitor serial hemoglobin and hematocrit in patients with suspected bleeding.
    5) Obtain an ECG in symptomatic patients, and institute continuous cardiac monitoring.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) MYELOSUPPRESSION
    1) There have been rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis was reversible on discontinuation of cilostazol (Prod Info PLETAL oral tablets, 2007).
    2) 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.
    3) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.
    D) VENTRICULAR ARRHYTHMIA
    1) Ventricular tachycardia was reported in less than 2% of patients receiving cilostazol in 8 placebo-controlled clinical trials of 2274 patients receiving cilostazol 50 mg or 100 mg twice daily (n=1301) for a median of 127 days, or placebo (n=973) for a median of 134 days (Prod Info PLETAL oral tablets, 2007). However, a causal relationship could not be established.
    2) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    3) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    4) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    5) PROCAINAMIDE
    a) PROCAINAMIDE/INDICATIONS
    1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: 100 mg orally twice a day. CHILDREN: safety and efficacy in children have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) The recommended dose for intermittent claudication is 100 mg twice daily taken at least one-half hour before or 2 hours after morning and evening meals (Prod Info cilostazol oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) The safety and effectiveness of cilostazol in children have not been established (Prod Info cilostazol oral tablets, 2013).

Minimum Lethal Exposure

    A) No lethal overdoses with cilostazol have been reported in humans.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) >1 gm/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) >5 gm/kg (RTECS , 2001)
    3) LD50- (INTRAMUSCULAR)RAT:
    a) >1 gm/kg (RTECS , 2001)
    4) LD50- (ORAL)RAT:
    a) >5 gm/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism of action for cilostazol in reducing symptoms of intermittent claudication is not fully understood. Cilostazol and its active metabolites are cyclic-AMP (cAMP) phosphodiesterase III inhibitors, inhibiting phosphodiesterase activity, suppressing cAMP degradation, increasing cAMP within platelets and blood vessels, inhibiting platelet aggregation and causing vasodilation. It reversibly inhibits platelet aggregation induced by ADP, thromboxane A2, collagen, arachidonic acid, epinephrine, and shear stress (Prod Info PLETAL(R) oral tablets, 2015).

Physicochemical

Physical Characteristics

    A) Cilostazol occurs as white to off-white crystals or crystalline powder; slightly soluble in methanol and ethanol and almost insoluble in water (Prod Info Pletal(R), cilostazol tablets, 1999).

Molecular Weight

    A) 369.47 (Prod Info Pletal(R), cilostazol tablets, 1999)

References

General Bibliography

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