Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

PENTOXIFYLLINE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pentoxifylline is a methyl substituted xanthine derivative used to treat the symptoms of peripheral vascular disease.

Specific Substances

    1) 1-(5'-oxohexyl)-3,7-dimethylxanthine
    2) 1-(5-oxohexyl)theobromine
    3) 3,7-Dimethyl-1-(5-oxohexyl)xanthine
    4) BL 191
    5) Oxpentifylline
    6) Vasofirin
    7) CAS 6493-05-6
    1.2.1) MOLECULAR FORMULA
    1) C13H18N4O3

Available Forms Sources

    A) FORMS
    1) Pentoxifylline is available as 400-mg extended-release tablets (Prod Info TRENTAL(R) oral tablets, 2012).
    B) USES
    1) Pentoxifylline is approved for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs (Prod Info TRENTAL(R) oral tablets, 2012).

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: Pentoxifylline is approved for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.
    B) PHARMACOLOGY: Pentoxifylline reduces blood viscosity and improves the flow properties of blood. It increases blood flow to the affected microcirculation and tissue oxygenation in patients with chronic peripheral arterial disease. It also produces dose-related hemorrheologic effects, improves erythrocyte flexibility, increases leukocyte deformability and inhibits neutrophil adhesion and activation.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON: Nausea, vomiting, dyspepsia, bloating, abdominal discomfort, and dizziness. RARE: The following adverse effects have rarely been reported in postmarketing surveillance of pentoxifylline therapy, however, causality was not established: Tachycardia, hypotension, dysrhythmias, aplastic anemia, leukopenia, thrombocytopenia, jaundice, seizures, anaphylactoid reactions and anaphylactic reactions.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: In several overdose cases, onset of symptoms was within 4 to 5 hours of ingestion and lasted for about 12 hours. Nausea, vomiting, and abdominal pain are common. Myoclonus may be seen.
    2) SEVERE TOXICITY: Flushing, somnolence, loss of consciousness, confusion, disorientation, hypokalemia, tachycardia, bradycardia with AV block, hypotension, hyperreflexia, seizures, agitation, fever, heart failure leading to respiratory insufficiency with hypoxemia have been reported. Death due to refractory shock has been reported.
    0.2.20) REPRODUCTIVE
    A) Animal studies with doses of 240 to 600 mg/kg resulted in no fetal malformation; the higher dose resulted in increased resorption. There are no human data in pregnancy.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs and mental status.
    D) Monitor for possible CNS signs/symptoms of seizures or CNS depression following severe overdose.
    E) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    F) Obtain an ECG, and institute continuous cardiac monitoring following significant overdose.

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. Control agitation with benzodiazepines.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Monitor CVP to prevent volume overload.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    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) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, and significant CNS or respiratory depression.
    E) ANTIDOTE
    1) None.
    F) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION
    1) Due to it's large volume of distribution (241 to 511 L), hemodialysis and hemoperfusion are unlikely to be of benefit in pentoxifylline overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home with medical follow-up.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with persistent cardiac dysrhythmias, mental status changes, seizures, and respiratory failure should be admitted to an ICU setting.
    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.
    I) PITFALLS
    1) When managing a suspected pentoxifylline overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) EXTENDED RELEASE: Tmax: within 2 to 4 hours after therapeutic doses (400 mg) of the extended-release tablets. Absorption: rapidly and completely absorbed (greater than 95%) following oral administration, but undergoes extensive (60% to 70%) first-pass metabolism. Vd: 241 to 511 Liters. Excretion: almost completely metabolized prior to renal excretion; 95% of the dose is recovered in the urine as active metabolites. Elimination half-life: 3.43 hours (extended-release).
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension, seizures, and CNS or respiratory depression.

Range Of Toxicity

    A) TOXICITY: Flushing, seizures, hypotension, loss of consciousness and agitation have been reported following pentoxifylline doses up to 80 mg/kg. An overdose of 30.8 g (513 mg/kg) produced moderate symptoms, which included vomiting, mental status changes, respiratory alkalosis, hypokalemia and hyperglycemia. An adult died after ingesting 20 to 24 g.
    B) THERAPEUTIC DOSE: EXTENDED-RELEASE TABLETS: 400 mg 3 times daily.

Clinical Effects

Summary Of Exposure

    A) USES: Pentoxifylline is approved for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.
    B) PHARMACOLOGY: Pentoxifylline reduces blood viscosity and improves the flow properties of blood. It increases blood flow to the affected microcirculation and tissue oxygenation in patients with chronic peripheral arterial disease. It also produces dose-related hemorrheologic effects, improves erythrocyte flexibility, increases leukocyte deformability and inhibits neutrophil adhesion and activation.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON: Nausea, vomiting, dyspepsia, bloating, abdominal discomfort, and dizziness. RARE: The following adverse effects have rarely been reported in postmarketing surveillance of pentoxifylline therapy, however, causality was not established: Tachycardia, hypotension, dysrhythmias, aplastic anemia, leukopenia, thrombocytopenia, jaundice, seizures, anaphylactoid reactions and anaphylactic reactions.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: In several overdose cases, onset of symptoms was within 4 to 5 hours of ingestion and lasted for about 12 hours. Nausea, vomiting, and abdominal pain are common. Myoclonus may be seen.
    2) SEVERE TOXICITY: Flushing, somnolence, loss of consciousness, confusion, disorientation, hypokalemia, tachycardia, bradycardia with AV block, hypotension, hyperreflexia, seizures, agitation, fever, heart failure leading to respiratory insufficiency with hypoxemia have been reported. Death due to refractory shock has been reported.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER has been reported in overdose. Hyperthermia occurred in 1 of 44 cases of overdose in one series (Prod Info TRENTAL(R) oral tablets, 2012); Fournier, 1983).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) RETINAL HEMORRHAGE: Twenty-seven cases of retinal bleeding associated with pentoxifylline treatment have been reported in Europe. Predisposing factors were present in most cases, including diabetes or hypertension (Anon, 1994; Prod Info TRENTAL(R) oral tablets, 2012).
    B) WITH POISONING/EXPOSURE
    1) MYDRIASIS: CASE SERIES: Two cases of mydriasis were observed in a series of 44 overdoses (Prod Info TRENTAL(R) oral tablets, 2012); Fournier, 1983), and in one case report of overdose in an infant (Garnier et al, 1986).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has rarely been reported in postmarketing surveillance of pentoxifylline therapy; causality was not established (Prod Info TRENTAL(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: Tachycardia was observed in 3 of 44 overdoses reported to the Paris Poison Control Centre; 170 beats/min after 90 mg/kg in a 12-month-old, 110 beats/min after 80 mg/kg in an adult, and also in an 11-year-old after 60 mg/kg (Prod Info TRENTAL(R) oral tablets, 2012); Fournier, 1983).
    B) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Severe bradycardia (30 to 40 beats per minute) and first and second degree heart block were described in a 22-year-old woman 2 hours after ingesting 4 to 6 grams, and persisted for 16 hours. She recovered after intensive supportive and symptomatic treatment (Sznajder et al, 1984).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has rarely been reported in postmarketing surveillance of pentoxifylline therapy; causality was not established (Prod Info TRENTAL(R) oral tablets, 2012).
    b) For most studies, blood pressure was not significantly affected with oral treatment; however mild hypotension was reported in several patients secondary to the vasodilatory effect of pentoxifylline (Accetto, 1982).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: Hypotension was described in a series of 44 overdoses reported to a poison control center (Prod Info TRENTAL(R) oral tablets, 2012).
    b) CASE REPORT: Suarez-Penaranda et al (1998) report the case of a 54-year-old man who died from refractory shock 24 hr following the suicidal ingestion of 20 to 24 grams of pentoxifylline (Suarez-Penaranda et al, 1998).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Dysrhythmias have rarely been reported in postmarketing surveillance of pentoxifylline therapy; causality was not established (Prod Info TRENTAL(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Irregular bigeminy was noted on ECG in an 84-year-old woman approximately 7 hours after the ingestion of 30.8 grams of pentoxifylline (513 mg/kg). It should be noted that a baseline ECG was not available for this patient, and over the following 6 weeks her ECG remained unchanged (Dolgin et al, 1994).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY ALKALOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Respiratory alkalosis (pH 7.43, PCO2 27, HCO3 25) was reported in an 84-year-old woman following the ingestion of 30,800 mg pentoxifylline (513 mg/kg) (Dolgin et al, 1994).
    B) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) Severe pentoxifylline overdoses have resulted in shock, with heart failure, and subsequent respiratory insufficiency with hypoxemia and hypercapnia necessitating mechanical ventilation (Suarez-Penaranda et al, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ALTERED MENTAL STATUS
    1) WITH POISONING/EXPOSURE
    a) Mental status changes, including somnolence, loss of consciousness, confusion, disorientation, and dizziness have been reported following overdoses (Prod Info TRENTAL(R) oral tablets, 2012; Dolgin et al, 1994).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance or clinical trials, seizures developed in less than 1% of patients treated with pentoxifylline; causality was not established (Prod Info TRENTAL(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: Seizures were observed in two of 44 overdoses reported to a poison control center. These occurred following the ingestion of pentoxifylline 75 mg/kg in a 24-month-old and 91 mg/kg in a 12-month-old (Prod Info TRENTAL(R) oral tablets, 2012); Fournier, 1983).
    C) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Severe agitation and hyperreflexia have been reported after overdose (Sznajder et al, 1984).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Dizziness was reported 1.9% (extended release) to 11.9% (immediate release) of patients receiving therapeutic doses (Prod Info TRENTAL(R) oral tablets, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are dose-related effects and were seen in 1% to 2% of patients taking the extended-release tablet and 4.5% to 28.8% of patients taking immediate-release capsules (Prod Info TRENTAL(R) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: Nausea, vomiting, and abdominal cramps were seen during the first 6 hours post-ingestion in a 22-year-old woman (Sznajder et al, 1984). In a series of 44 overdoses, 11 cases had vomiting and 6 had abdominal cramps (Prod Info TRENTAL(R) oral tablets, 2012); Fournier, 1983).
    b) CASE REPORT: An overdose of 30.8 grams in an 84-year-old woman resulted in several episodes of vomiting, with pill fragments noted in the vomitus (Dolgin et al, 1994).
    B) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia was observed in 2.8% of patients taking the extended-release tablet and 9.6% of patients taking immediate-release capsules (Prod Info TRENTAL(R) oral tablets, 2012).
    C) SWOLLEN ABDOMEN
    1) WITH THERAPEUTIC USE
    a) Bloating was observed in 9% of patients taking pentoxifylline immediate-release tablet and 3.6% of patients taking placebo(Prod Info TRENTAL(R) oral tablets, 2012).
    D) ESOPHAGITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 54-year-old man developed coffee-ground emesis after ingesting 20 to 24 grams of pentoxifylline. Endoscopy revealed ulcerative esophagitis (Suarez-Penaranda et al, 1998).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) WITH THERAPEUTIC USE
    a) Jaundice has rarely been reported in postmarketing surveillance of pentoxifylline therapy; causality was not established (Prod Info TRENTAL(R) oral tablets, 2012).
    b) CASE REPORT: An 81-year-old woman developed hepatitis with jaundice within 3 weeks of initiation of pentoxifylline. The drug was discontinued; by the seventh week symptoms resolved and laboratory findings returned to baseline. No rechallenge was done. Clinical evaluation ruled out other causes (alcohol, viral) and history was negative. No rash, adenopathy, or eosinophilia was noted, disqualifying the effect as an immunological reaction. Therefore, the effect was thought to be caused by drug toxicity. Other drug exposure at the time included chronic theophylline and albuterol (Saez-Royuela et al, 1995).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Aplastic anemia has rarely been reported in postmarketing surveillance of pentoxifylline therapy; causality was not established (Prod Info TRENTAL(R) oral tablets, 2012).
    b) CASE SERIES: Fatal aplastic anemia was reported in two patients taking therapeutic doses of pentoxifylline. One patient had been taking 400 mg twice a day for two weeks, and one was taking 400 mg three times a day for ten weeks (Mass et al, 1987).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has rarely been reported in postmarketing surveillance of pentoxifylline therapy; causality was not established (Prod Info TRENTAL(R) oral tablets, 2012).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has rarely been reported in postmarketing surveillance of pentoxifylline therapy; causality was not established (Prod Info TRENTAL(R) oral tablets, 2012).
    b) CASE REPORT: Idiosyncratic, asymptomatic thrombocytopenia to 50,000/mm(3) developed in a patient taking pentoxifylline 400 mg three times daily for stasis ulcer. Dechallenge resulted in prompt improvement over 48 hours. Rechallenge with a three times daily regimen one month later showed recurrence within 48 hours, again with rapid resolution after discontinuation. No other blood cell line was affected (Acharya & Nair, 1997).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Flushing was described in a series of 44 overdoses reported to a poison control center . (Prod Info TRENTAL(R) oral tablets, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MYOCLONUS
    1) WITH POISONING/EXPOSURE
    a) In two case reports of pentoxifylline overdose in infants, myoclonus was noted (Garnier et al, 1986).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) HYPOGLYCEMIA/HYPERGLYCEMIA are theoretically possible, especially in diabetic patients. This has not been documented in IV studies in non-diabetic volunteers or in published overdose cases (Lenti et al, 1975). High parenteral doses of pentoxifylline may potentiate hypoglycemic effects of insulin in diabetic patients (S Sweetman , 2001).
    2) WITH POISONING/EXPOSURE
    a) HYPOGLYCEMIA/HYPERGLYCEMIA are theoretically possible, especially in diabetic patients. This has not been documented in IV studies in non-diabetic volunteers or in published overdose cases (Lenti et al, 1975).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylactoid reactions and anaphylactic reactions including anaphylactic shock have rarely been reported in postmarketing surveillance of pentoxifylline therapy (Prod Info TRENTAL(R) oral tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Animal studies with doses of 240 to 600 mg/kg resulted in no fetal malformation; the higher dose resulted in increased resorption. There are no human data in pregnancy.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info TRENTAL(R) oral tablets, 2012).
    B) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) RATS, RABBITS: No human studies of pregnancy outcomes after exposure to pentoxifylline have been published, and there have been no reports of outcomes after inadvertent exposure during pregnancy. No evidence of fetal malformation was found in studies conducted in rats and rabbits using oral doses up to 576 mg/kg and 264 mg/kg, respectively. These doses were 24 and 11 times the maximum recommended human daily dose (MRHD) on a weight basis, and 4.2 and 3.5 times the MRHD on a body-surface-area basis (Prod Info TRENTAL(R) oral tablets, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info TRENTAL(R) oral tablets, 2012).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified pentoxifylline as FDA pregnancy category C (Prod Info TRENTAL(R) oral tablets, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Pentoxifylline and its metabolites are excreted into human breast milk (Prod Info TRENTAL(R) oral tablets, 2012; Witter & Smith, 1985). Because of the potential for tumorigenicity demonstrated in rat studies of pentoxifylline, it is recommended to discontinue nursing or discontinue the drug, taking into consideration the importance of the drug to the mother (Prod Info TRENTAL(R) oral tablets, 2012).
    2) Single dose studies, using pentoxifylline 400 mg (controlled release tablets), revealed milk-plasma ratios of 0:1 to 1.65:1 at 4 hours post-ingestion (Witter & Smith, 1985).
    a) It is suggested that a 2500-gram infant ingesting 4 ounces of breast milk would receive a maximum theoretical dose of 0.04 mg/kg (Witter & Smith, 1985).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs and mental status.
    D) Monitor for possible CNS signs/symptoms of seizures or CNS depression following severe overdose.
    E) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    F) Obtain an ECG, and institute continuous cardiac monitoring following significant overdose.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Pentoxifylline levels are not routinely available. Interference with assays for other xanthines such as theophylline, is not likely (Cummings et al, 1985; Morton et al, 1989).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Pentoxifylline can be assayed by HPLC, UV spectrophotometry or thin layer chromatography.
    2) Clinically achievable concentrations of pentoxifylline and its metabolites were not found to interfere with theophylline assays using TDx, EMIT, and HPLC methods (Cohen et al, 1988; Morton et al, 1989).
    a) Pentoxifylline overdosage in theophylline-treated patients may produce erroneous results when the EMIT assay is employed (Cohen et al, 1988).

Treatment

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    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) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Control agitation with benzodiazepines.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Monitor CVP to prevent volume overload.
    B) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary unless otherwise clinically indicated.
    2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    3) Monitor vital signs and mental status.
    4) Monitor for possible CNS signs/symptoms of seizures or CNS depression following severe overdose.
    5) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    6) Obtain an ECG, and institute continuous cardiac monitoring following significant overdose.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) 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).
    E) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    F) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Monitor and correct electrolyte abnormalities. Hypokalemia has been easily correctable. Hypoglycemia or hyperglycemia may theoretically occur.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to it's large volume of distribution (241 to 511 L) (Ings et al, 1982), hemodialysis and hemoperfusion are unlikely to be of benefit in pentoxifylline overdose.

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 persistent cardiac dysrhythmias, mental status changes, seizures, and respiratory failure should be admitted to an ICU setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home with medical follow-up.
    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.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs and mental status.
    D) Monitor for possible CNS signs/symptoms of seizures or CNS depression following severe overdose.
    E) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    F) Obtain an ECG, and institute continuous cardiac monitoring following significant overdose.

Abstracts

Case Reports

    A) ADVERSE EFFECTS
    1) A report of 44 patients who ingested the enteric coated preparation described flushing, hypotension, seizures, somnolence, loss of consciousness, fever and agitation. The usual toxic dose ingested was 80 mg/kg. Symptoms usually began 4 to 5 hours after ingestion and lasted 12 hours (Prod Info TRENTAL(R) oral tablets, 2012); Fournier, 1983). No deaths were reported.
    B) INFANT
    1) A 12-month-old, 11 kilogram boy ingested one gram of pentoxifylline. Four hours later, he was agitated, disoriented, and hypertonic, and was vomiting profusely. A generalized tonic-clonic seizure was noted. Five hours later, he was noted to have profuse bloody emesis, abdominal distention, and diffuse hypertonia. Arterial systolic pressure was 50 mm Hg, and tachycardia (170 beats/minute) was observed. Serum glucose and electrolytes, ECG, and chest X-ray were normal. The infant recovered rapidly after intramuscular diazepam and fluid resuscitation, and was discharged three days post-ingestion without incident (Garnier et al, 1986).
    C) ADULT
    1) A 22-year-old woman who ingested 4 to 6 grams of pentoxifylline developed bradycardia and first and second degree atrioventricular block two hours postingestion which persisted for 16 hours. Hypokalemia was easily corrected. Nausea, abdominal cramps and vomiting were seen 2 to 6 hours postingestion. Severe excitation and hyperreflexia were noted for up to 24 hours (Sznajder et al, 1984).
    D) PEDIATRIC
    1) A 24-month-old, 19.5 kilogram infant ingested 1,500 mg pentoxifylline along with 120 mg clobazam. Several hours later, she was comatose, with bilateral mydriasis. She had a generalized hypertonia and myoclonus of the upper limbs, which responded to intravenous diazepam. She was intubated and mechanically ventilated, at which time hypothermia (35.8 degrees C) was observed. Profuse vomiting was noted. Her arterial systolic pressure was 90 mm Hg, but a short period of asystole ensued. It was not specified whether the asystole resolved without treatment, or required intervention. Subsequent serum glucose and electrolytes, as well as EKG, EEG, and lumbar puncture, were normal. Symptoms resolved in less than 24 hours (Garnier et al, 1986).

Range Of Toxicity

Summary

    A) TOXICITY: Flushing, seizures, hypotension, loss of consciousness and agitation have been reported following pentoxifylline doses up to 80 mg/kg. An overdose of 30.8 g (513 mg/kg) produced moderate symptoms, which included vomiting, mental status changes, respiratory alkalosis, hypokalemia and hyperglycemia. An adult died after ingesting 20 to 24 g.
    B) THERAPEUTIC DOSE: EXTENDED-RELEASE TABLETS: 400 mg 3 times daily.

Therapeutic Dose

    7.2.1) ADULT
    A) EXTENDED-RELEASE TABLETS: One tablet (400 mg) 3 times daily (Prod Info pentoxifylline oral extended-release tablets, 2014).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of pentoxifylline have not been established in pediatric patients (Prod Info pentoxifylline oral extended-release tablets, 2014).

Minimum Lethal Exposure

    A) ADULT
    1) Death due to refractory shock and heart failure has resulted following an overdose of 20 to 24 g of pentoxifylline in a 54-year-old male (Suarez-Penaranda et al, 1998).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) A 22-year-old woman who ingested 4 to 6 grams of pentoxifylline developed bradycardia and first and second degree atrioventricular block 2 hours postingestion which persisted for 16 hours. Hypokalemia was easily corrected. Nausea, abdominal cramps and vomiting were seen 2 to 6 hours postingestion. Severe excitation and hyperreflexia were noted for up to 24 hours (Sznajder et al, 1984).
    2) A report of 44 patients who ingested the enteric coated preparation described flushing, hypotension, seizures, somnolence, loss of consciousness, fever and agitation. The usual toxic dose ingested was 80 mg/kg. Symptoms usually began 4 to 5 hours after ingestion and lasted 12 hours (Prod Info TRENTAL(R) oral tablets, 2012); Fournier, 1983).
    3) One study reported a pentoxifylline overdose of 30.8 g (513 mg/kg) in an 84-year-old woman, with moderate symptoms. She presented to the ED with vomiting and altered mental status. Laboratory results included: hypokalemia, hyperglycemia, respiratory alkalosis, and an ECG reading of irregular bigeminy. It should be noted that no baseline ECG or mental status was available (Dolgin et al, 1994).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) OVERDOSE: A pentoxifylline serum concentration of 51 mcg/mL (normal, 0.1 to 0.4 mcg/mL) was reported approximately 7 hours after the ingestion of 30,800 mg in an 84-year-old woman (Dolgin et al, 1994). In another case, pentoxifylline serum level as high as 32.5 mcg/mL was reported after an ingestion of 20 to 24 grams in a 54-year-old man (Suarez-Penaranda et al, 1998).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 239 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 1,385 mg/kg (Budavari, 1996)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 480 mg/kg (RTECS , 2001)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 230 mg/kg (RTECS , 2001)
    5) LD50- (ORAL)RAT:
    a) 1,170 mg/kg (RTECS , 2001)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 375 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pentoxifylline improves flexibility of erythrocytes, thus increases blood flow properties and oxygen supply. Blood viscosity is decreased additionally by reduction in plasma fibrinogen and platelet aggregation (Prod Info Trental®, 98; Krogh & editor, 1999; Ward & Clissold, 1987).

Physicochemical

Physical Characteristics

    A) Pentoxifylline is a white crystalline powder (Budavari, 1996); it is soluble in water and ethanol, and sparingly soluble in toluene (Prod Info TRENTAL(R) oral tablets, 2012).

Molecular Weight

    A) 278.35 (Budavari, 1996)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Accetto B: Beneficial hemorheologic therapy of chronic peripheral arterial disorders with pentoxifylline: results of double-blind study versus vasodilator-nylidrin. Am Heart J 1982; 103:864-869.
    3) Acharya S & Nair BC: Pentoxifylline-induced thrombocytopenia (letter). Int J Dermatol 1997; 36:634-639.
    4) Anon: BGA-Arzneimittel-Schnellinformation. Netzhautblutungen unter Pentoxifyllintherapie?. DAZ 1994; 134(8):641.
    5) Aviado DM & Porter JM: Pentoxifylline: a new drug for the treatment of intermittent claudication. Pharmacotherapy 1984; 4:297-307.
    6) Beermann B, Ings R, & Mansby J: Kinetics of intravenous and oral pentoxifylline in healthy subjects. Clin Pharmacol Ther 1985; 37:25.
    7) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    8) Budavari S: The Merck Index, 12th ed, Merck & Company Inc, Whitehouse Station, NJ, 1996.
    9) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    10) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    11) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    12) Christ O, Gleixner K, Kellner HM, et al: Pharmakokinetische Untersuchungen nach oraler verabreichung von 3,7-dimethyl-1-(5'oxohexyl)-xanthin-(14)C(BL 191-(14)C) an rat ten, hunde und menschen. Arzneimittelforschung 1972; 22:1933-1937.
    13) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    14) Cohen IA, Johnson CE, & Wesolowicz L: Effect of pentoxifylline and its metabolites on three theophylline assays. Clin Pharm 1988; 7:457-461.
    15) Cummings DM, Rocci ML, & Green P: Interference potential of pentoxifylline and its major metabolite with theophylline assays. Am J Hosp Pharm 1985; 42:2717-2718.
    16) Dolgin J, Abrams B, & Tucker J: Survival with massive pentoxifylline overdose & high serum levels (abstract # 121), North American Congress of Clinical Toxicology, Salt Lake City, UT, 1994.
    17) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    18) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    19) Garnier R, Riboulet-Delmas G, & Chatenet T: Intoxication aigue par la pentoxifylline chez l'enfant (Acute pentoxifylline poisoning in children). Ann Pediatr (Paris) 1986; 33:62-63.
    20) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    21) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    22) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    23) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    24) Hinze VHJ, Bedessem, & Soder A: Zur pharmakokinetik von 3,7-dimethyl-1-(5-oxo-hexyl)-xanthins (BL 191) beim menschen. Arzneimittelforschung 1972; 22:1144-1151.
    25) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    26) Ings RMJ, Nudemberg F, & Burrows JL: The pharmacokinetics of oxpentifylline in man when administered by constant intravenous infusion. Eur J Clin Pharmacol 1982; 23:539-543.
    27) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    28) Krogh CME & editor: CPS Compendium of Pharmaceuticals and Specialties, 34. Canadian Pharmaceutical Association, Ottawa, 1999, pp 1828-1829.
    29) Lenti G, Pagano G, & Angotzi G: Effects of xanthine derivative (BL 191) on insulin secretion in normal man. Eur J Clin Pharmacol 1975; 9:189-192.
    30) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    31) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    32) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    33) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    34) Mass RD, Venook AP, & Linker CA: Pentoxifylline and aplastic anemia (letter). Ann Intern Med 1987; 107:427-428.
    35) Morton MR, Parish RC, & Spurill WJ: Lack of theophylline assay interference from pentoxifylline and its metabolites. Ther Drug Monit 1989; 11:347-348.
    36) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    37) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    38) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    39) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    40) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    41) Product Information: PENTOXIL(R) extended-release oral tablets, pentoxifylline extended-release oral tablets. Upsher-Smith Laboratories,Inc, Minneapolis, MN, 2005.
    42) Product Information: TRENTAL(R) oral tablets, pentoxifylline oral tablets. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2012.
    43) Product Information: Trental(R), pentoxifylline. Hoechst-Roussel Pharmaceuticals, Kansas City, MO, 1998.
    44) Product Information: Trental(R), pentoxifylline. Hoechst-Roussel Pharmaceuticals, Kansas City, MO, USA, 2000.
    45) Product Information: Trental®, pentoxifylline. Hoechst Marion Roussel, MO, USA, 98.
    46) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    47) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    48) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    49) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    50) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    51) Product Information: pentoxifylline oral extended-release tablets, pentoxifylline oral extended-release tablets. Apotex Corp. (per DailyMed), Weston, FL, 2014.
    52) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires July/31/2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    53) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    54) S Sweetman : Martindale: The Complete Drug Reference. Pharmaceutical Press. London, UK (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    55) Saez-Royuela F, Lopez-Vazquez A, Lopez-Morante A, et al: Pentoxifylline-induced acute hepatitis. J Hepatol 1995; 23:482-484.
    56) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    57) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    58) Suarez-Penaranda JM, Rico-Boquete R, & Lopez-Rivadulla M: A fatal case of suicidal pentoxifylline intoxication. Int J Legal Med 1998; 111:151-153.
    59) Sznajder IJ, Bentur Y, & Taitelman U: First and second degree atrioventricular block in oxpentifylline overdose. Br Med J 1984; 288:26.
    60) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    61) Ward A & Clissold SP: Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy.. Drugs 1987; 34:50-97.
    62) Witter FR & Smith RV: The excretion of pentoxifylline and its metabolites into human breast milk.. Am J Obstet Gynecol 1985; 151:1094-1097.