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PENTAMIDINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pentamidine isethionate is an aromatic diamidine antiprotozoal agent, used in the treatment of Pneumocystis carinii pneumonia (PCP). The mode of action is not fully understood. In vitro studies indicate that it may interfere with nuclear metabolism and inhibit the synthesis of DNA, RNA, phospholipids, and protein synthesis.

Specific Substances

    1) Pentamidine Isethionate
    2) M&B-800
    3) Pentamidini Isethionas
    4) CAS 100-33-4 (pentamidine)
    5) CAS 140-64-7 (pentamidine isethionate)
    1.2.1) MOLECULAR FORMULA
    1) C19H24N4O2-2C2H6O4S

Available Forms Sources

    A) FORMS
    1) Pentamidine is available as 300 mg powder for solution for inhalation and 300 mg powder for solution for injection (Prod Info NebuPent(R) oral inhalation, 2011; Prod Info PENTAM(R) 300 injection, 2002).
    B) USES
    1) Aerosolized pentamidine is indicated for the prevention of Pneumocystis jiroveci pneumonia (PCP) in high-risk patients (16 years of age and older) infected with human immunodeficiency virus (HIV); high risk is defined as a history of PCP and/or a peripheral CD4+ count of 200/cubic millimeter or less. Intravenous pentamidine is indicated for the treatment of Pneumocystis jiroveci pneumonia (Prod Info NebuPent(R) oral inhalation, 2011; Prod Info PENTAM(R) 300 injection, 2002).

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: Pentamidine is indicated for the prevention or treatment of Pneumocystis jiroveci pneumonia.
    B) PHARMACOLOGY: Pentamidine isethionate, an aromatic diamidine, is a nonpyrogenic, lyophilized, antifungal agent that interferes with microbial nuclear metabolism by inhibiting DNA, RNA, phospholipid, and protein synthesis. The mode of action is not completely understood.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Rash, decreased appetite, nausea, vomiting, and pharyngitis. INFREQUENT/RARE: Bronchospasm, dyspnea, headache, hypotension, prolonged QT, cardiac arrest, Stevens-Johnson Syndrome, toxic epidermal necrolysis, hypoglycemia, hyperglycemia, hyperkalemia, hypomagnesemia (infrequent), hypocalcemia, pancreatitis, acute renal failure, nephritis, conjunctivitis, blurred vision, and blepharitis, granulocytopenia, neutropenia, megaloblastic anemia, leukopenia, thrombocytopenia, anemia, elevated liver enzymes, dizziness, paresthesia, neuropathy, neuralgia, seizures, tremors, ataxia, amnesia, depression, confusion, hallucinations, anxiety, insomnia, vertigo, drowsiness, and pneumothorax.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Clinical events following exposure are anticipated to be an extension of adverse events. A child developed severe hypotension and cardiac arrest after inadvertently receiving 1600 mg of pentamidine (40 times the recommended dose of 4 mg/kg).
    0.2.20) REPRODUCTIVE
    A) Pentamidine is classified as FDA pregnancy category C. Increases in embryolethality were observed in pregnant rats treated with IV pentamidine.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring as an increase in the QT interval and dysrhythmias may develop following pentamidine exposure.
    C) Monitor CBC with differential and platelet count, serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    D) Monitor blood glucose.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.

Treatment Overview

    0.4.3) INHALATION EXPOSURE
    A) Monitor respiratory function following significant aerosolized pentamidine exposure; monitor pulse oximetry and ABGs as indicated. Refer to PARENTERAL SECTIONS for specific treatment information.
    0.4.6) 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. Myelosuppression has rarely been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. Therapeutic doses of pentamidine may cause prolongation of the QT interval or torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities; overdrive pacing may be necessary. Treat ventricular dysrhythmias using ACLS protocols.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral and inhalation routes.
    D) AIRWAY MANAGEMENTS
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, severe respiratory distress, or hemodynamic instability.
    E) ANTIDOTE
    1) None.
    F) VENTRICULAR DYSRHYTHMIAS
    1) Pentamidine may have proarrhythmic activity. QT prolongation has been reported following therapeutic use. Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Correct electrolyte abnormalities. Consider lidocaine. Because pentamidine has caused QT prolongation, amiodarone should be used with extreme caution. Unstable rhythms require immediate cardioversion.
    G) TORSADES DE POINTES
    1) Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities; overdrive pacing may be necessary. AVOID: Class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, sotalol).
    H) HYPOGLYCEMIA
    1) DEXTROSE: Give dextrose if symptomatic or BS less than 60 mg/dL. DOSE: ADULT: 0.5 to 1 g/kg of D50W (50% dextrose) IV push; ADOLESCENT: 0.5 to 1 g/kg (1 to 2 mL/kg) of 50% dextrose IV push; INFANT and CHILD: 0.5 to 1 g/kg (2 to 4 mL/kg) of 25% dextrose IV push. Follow with an infusion of 10% dextrose; titrate to a BS of 100 mg/dL. DIET: When the patient is awake and alert, supplement IV glucose with carbohydrate intake.
    I) ENHANCED ELIMINATION
    1) Hemodialysis is likely not to be of value because of the large volume of distribution. Charcoal hemoperfusion stabilized one pediatric patient following an accidental overdose with pentamidine.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure to the inhalation product, that remains asymptomatic can be managed at home.
    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, severe respiratory symptoms, or severe neutropenia should be admitted.
    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.
    K) PITFALLS
    1) When managing a suspected pentamidine overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of pentamidine. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative.
    L) PHARMACOKINETICS
    1) Tmax, IV: 60 minutes. Vd, inhalation, nebulization: unknown. Vd, IM or IV: variable; very extensive tissue binding; in one study of 12 AIDS patients, Vd at steady state (Vss) was 821 L when administered IV, and 2724 L after IM injection. Elimination half-life: 6.4 to 9 hours.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or cardiac dysrhythmias.

Range Of Toxicity

    A) TOXICITY: A 17-month-old child developed severe hypotension and cardiac arrest after inadvertently receiving 160 mg/kg of pentamidine (40 times the recommended dose of 4 mg/kg; total dose: 1600 mg). He recovered following supportive care, including a standard 4-hour course of charcoal hemoperfusion.
    B) THERAPEUTIC DOSE: ADULT: 4 mg/kg IV or IM once daily for 14 to 21 days. INHALATION: Primary and secondary prophylaxis, 300 mg by inhalation via the Respirgard(R) II nebulizer every 4 wk. PEDIATRIC: 4 months of age and older: 4 mg/kg IV or IM once daily for 14 to 21 days. INHALATION: 16 years of age and older: Primary and secondary prophylaxis: 300 mg by inhalation via the Respirgard(R) II nebulizer every 4 wk (manufacturer dosing); 5 years of age and older: Primary and secondary prophylaxis: 300 mg by inhalation via the Respirgard(R) II nebulizer every month (guideline dosing).

Clinical Effects

Summary Of Exposure

    A) USES: Pentamidine is indicated for the prevention or treatment of Pneumocystis jiroveci pneumonia.
    B) PHARMACOLOGY: Pentamidine isethionate, an aromatic diamidine, is a nonpyrogenic, lyophilized, antifungal agent that interferes with microbial nuclear metabolism by inhibiting DNA, RNA, phospholipid, and protein synthesis. The mode of action is not completely understood.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Rash, decreased appetite, nausea, vomiting, and pharyngitis. INFREQUENT/RARE: Bronchospasm, dyspnea, headache, hypotension, prolonged QT, cardiac arrest, Stevens-Johnson Syndrome, toxic epidermal necrolysis, hypoglycemia, hyperglycemia, hyperkalemia, hypomagnesemia (infrequent), hypocalcemia, pancreatitis, acute renal failure, nephritis, conjunctivitis, blurred vision, and blepharitis, granulocytopenia, neutropenia, megaloblastic anemia, leukopenia, thrombocytopenia, anemia, elevated liver enzymes, dizziness, paresthesia, neuropathy, neuralgia, seizures, tremors, ataxia, amnesia, depression, confusion, hallucinations, anxiety, insomnia, vertigo, drowsiness, and pneumothorax.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Clinical events following exposure are anticipated to be an extension of adverse events. A child developed severe hypotension and cardiac arrest after inadvertently receiving 1600 mg of pentamidine (40 times the recommended dose of 4 mg/kg).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Conjunctivitis, blurred vision, and blepharitis have been reported in 1% or fewer of patients treated with nebulized pentamidine (Prod Info NebuPent(R) oral inhalation, 2011).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Episodes of hypotension have been reported with either intravenous or intramuscular administration of pentamidine. In one case series comparing intramuscular and intravenous use, 78% and 67%, respectively, developed at least one episode of hypotension (Helmick & Green, 1985).
    b) INCIDENCE: Severe symptoms of hypotension (SBP less than 60 mm Hg) including fatalities have been reported in 1.7% (n=424) of patients receiving IM or IV pentamidine. Moderate hypotension has occurred in approximately 4% of patients (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    c) Initial symptoms of hypotension and tachycardia have been suggestive of a vasomotor reaction following IM injections of pentamidine isethionate (O'Brien et al, 1997; Western et al, 1970).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-month-old child developed severe hypotension and cardiac arrest after inadvertently receiving 160 mg/kg of pentamidine (40 times the recommended dose of 4 mg/kg; total dose: 1600 mg). He recovered following supportive care, including a standard 4-hour course of charcoal hemoperfusion (Watts et al, 1997).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) A proarrhythmic effect has been associated with pentamidine isethionate; its structure appears similar to procainamide (Wharton et al, 1987).
    b) Syncope and sudden death secondary to pentamidine therapy, may have been related to pentamidine-induced dysrhythmias (Krogstad et al, 1971; Jha, 1983; Western et al, 1970).
    c) ECG changes including ST segment depression, T-wave inversion, and QT prolongation have been observed (Wharton et al, 1987).
    C) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) QT prolongation has occurred following therapeutic pentamidine therapy (Wharton et al, 1987).
    b) INCIDENCE: In a case series of 37 patients with PCP, cumulative incidence of QT interval prolongation was 27% after 7 days and 50% during 14 to 21 days of intravenous pentamidine therapy (Stein et al, 1991).
    1) Unlike other studies, Stein reported a high incidence of QT prolongation which developed early in the course of therapy. No cases developed after pentamidine was discontinued.
    2) Although multiple factors are likely to be present in QT prolongation and torsade de pointes in AIDS patients, Stein et al (1991) noted that repolarization abnormalities could not be directly related to hypokalemia.
    c) CASE REPORT: A 34-year-old hemophiliac with AIDS developed QT prolongation with bouts of ventricular tachycardia following intravenous pentamidine; the dysrhythmias responded to lidocaine therapy. Symptoms resolved 2 days after pentamidine was discontinued (Loescher et al, 1987).
    d) LACK OF EFFECT: Girgis et al (1997) conducted a small (n=16) prospective study to evaluate the frequency of ventricular dysrhythmias and QTc prolongation in HIV-infected patients. The authors could find no increase in the occurrence of QTc prolongation or dysrhythmic activity and concluded that the incidence may be less than previously reported (Girgis et al, 1997).
    D) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) Multiple cases of torsade de pointes (TDP) preceded by QT prolongation have occurred following therapeutic pentamidine administration in immunocompromised patients (Lindsay et al, 1990; Mitchell et al, 1989).
    1) Most cases appeared after prolonged use (greater than 10 days) (Gonzalez et al, 1991a; Taylor et al, 1991) and resolved with discontinuation of therapy and/or temporary antiarrhythmic therapy (Mitchell et al, 1989; Lindsay et al, 1990; Mani et al, 1993).
    b) Electrolyte abnormalities (hypomagnesemia and hypokalemia) and malnutrition have been cited as possible causes of TDP in clinical settings with pentamidine (Stein et al, 1991). It is suggested that intravenous pentamidine and concurrent hypomagnesemia may have a synergistic effect in causing TDP (Mani et al, 1993).
    c) CASE REPORT: Persistent ventricular dysrhythmias including torsades occurred in a 43-year-old female 13 days after discontinuation of pentamidine. The ongoing dysrhythmias, the authors concluded, may have been attributable to the patient's renal impairment (Cortese et al, 1992).
    d) CASE REPORT: Gonzalez et al (1991) reported a case in which no predisposing factors were present and a late occurrence of torsades (QTc 630 msec/QT 560 msec) occurred 5 to 20 days after therapy was begun; effects resolved within 7 days of discontinuation. The authors were unable to determine a specific mechanism (Gonzalez et al, 1991).
    e) CASE REPORT: A 58-year-old renal transplant patient developed hypotension and TDP following 10 days of pentamidine therapy. Despite antiarrhythmic therapy, polymorphic dysrhythmias continued. A temporary pacemaker was inserted; efforts to wean the patient from the pacemaker failed. The patient died on hospital day 29, requesting no further intervention. It is suggested that the patient's renal insufficiency may have prolonged the duration of the dysrhythmias (Green et al, 1990).
    E) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) Cardiac arrest has rarely been reported after pentamidine therapy.
    b) CASE REPORT: A 28-year-old man with AIDS had a cardiac arrest with ventricular fibrillation secondary to intravenous pentamidine-induced nephrotoxicity and hyperkalemia after 18 days of pentamidine (4 mg/kg/day) therapy (Balslev et al, 1992).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-month-old child developed severe hypotension and cardiac arrest after inadvertently receiving 160 mg/kg of pentamidine (40 times the recommended dose of 4 mg/kg; total dose: 1600 mg). He recovered following supportive care, including a standard 4-hour course of charcoal hemoperfusion (Watts et al, 1997).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) In clinical trials, cough and bronchospasm were the most frequently reported adverse effects associated with inhaled pentamidine (300 mg) administration (38% and 15%, respectively) (Prod Info NebuPent(R) oral inhalation, 2011).
    B) RESPIRATORY DISTRESS
    1) WITH THERAPEUTIC USE
    a) Shortness of breath was reported following nebulized pentamidine therapy (Prod Info NebuPent(R) oral inhalation, 2011).
    C) PNEUMOTHORAX
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Pneumothorax has occurred in 1% to 5% of patients, however, a causal relationship has not been determined (Shanley et al, 1991; Squire et al, 1991; Cuthbert et al, 1991; Prod Info NebuPent(R), pentamidine isothionate, 1997).
    b) CASE REPORTS: Pneumothorax has been reported in several cases. Cuthbert et al (1991) described 4 of 13 HIV-positive hemophiliacs developing pneumothorax following prophylactic pentamidine therapy (Cuthbert et al, 1991a). In a larger series of 162 HIV-infected patients, only 4 cases of pneumothorax following primary or secondary prophylaxis with aerosolized pentamidine occurred (Squire et al, 1991).
    D) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 25-year-old woman with asymptomatic HIV received one dose of aerosolized pentamidine (300 mg) prophylactically to prevent PCP. Approximately 8 days following the dose, mild dyspnea and a cough were present and the patient was diagnosed with acute eosinophilic pneumonia. On rechallenge with a second dose, symptoms reoccurred and were thought to be due to an immunoallergic response (Dupon et al, 1993).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported with parenteral administration of pentamidine (Prod Info PENTAM(R) 300 IV, IM injection, 2008).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Neurological symptoms that have occurred in less than 1% of patients during clinical trials with nebulized pentamidine included: paresthesia, neuropathy, neuralgia, seizures, tremors, ataxia, amnesia, depression, confusion, hallucinations, anxiety, insomnia, vertigo, and drowsiness (Prod Info NebuPent(R) oral inhalation, 2011).
    b) CASE REPORT/FACIAL NUMBNESS: A 21-year-old man with hemophilia and positive HIV status was treated with intravenous pentamidine (300 mg) and developed immediate dizziness (without hypotension) accompanied by bilateral facial numbness. Symptoms reoccurred with each dose and the patient was changed to aerosolized pentamidine with no further neurological symptoms (Lin & Smith, 1991).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported in patients receiving aerosolized pentamidine therapy (Prod Info NebuPent(R) oral inhalation, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) The most common adverse gastrointestinal effect reported with nebulized pentamidine includes a decreased appetite and a metallic taste in 53% to 72% of patients treated (Prod Info NebuPent(R), pentamidine isothionate, 1997).
    B) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and pharyngitis have occurred in 10% to 23% of patients treated with nebulized pentamidine (Prod Info NebuPent(R), pentamidine isothionate, 1997); approximately 6% of patients have had moderate symptoms of nausea and anorexia following parenteral administration (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    b) Diarrhea and abdominal pain have been reported in 1% to 5% of patients treated (Prod Info NebuPent(R), pentamidine isothionate, 1997).
    C) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Multiple cases of pancreatitis some of which have resulted in death have been associated with therapeutic pentamidine therapy (Murphy & Josephs, 1981; (Zuger et al, 1986; Murphy et al, 1990; O'Neil et al, 1991; Villamil et al, 1991; Wood et al, 1991; Sauleda et al, 1994; Prod Info Pentam(R) 300, pentamidine isothionate, 1998). Although the mechanism is uncertain, it is postulated that pentamidine toxicity may extend to the pancreatic acinar cells (Wood, 1991).
    b) At the time of this review, an association between pentamidine and acute pancreatitis is probable, but has not been definitely proven (Wilmink & Frick, 1996).
    c) Although infrequently reported, cases of fatal acute pancreatitis have been associated with therapeutic pentamidine use (Zuger et al, 1986; Kumar et al, 1989; Murphy et al, 1990; Villamil et al, 1991; Sauleda et al, 1994).
    d) CASE REPORT: A 30 year-old man with PCP developed abdominal pain five days after starting pentamidine therapy accompanied by an elevated serum amylase. Death occurred 48 hours later and acute pancreatitis was observed at necropsy (Sauleda et al, 1994).
    e) CASE REPORTS: A 33-year-old man with PCP developed diffuse abdominal pain and an elevated serum potassium (8.0 mEq/L) 4 days after completing a 14-day course of pentamidine. Death was due to severe acute pancreatitis complicated by esophageal perforation (Kumar et al, 1989).
    f) CASE REPORTS: Zugar et al (1986) described a similar case of severe hemorrhagic pancreatitis in a patient with AIDS following 14 days of pentamidine therapy. Autopsy revealed findings consistent with ARDS and the pancreas was grossly necrotic (including both islet and nonislet tissue) (Zuger et al, 1986).
    g) CASE REPORTS: Edematous pancreatitis along with fatty infiltration of the liver was found on postmortem exam in a 37-year-old male who was HIV-positive with suspected PCP and had been treated with pentamidine (Villamil et al, 1991).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Abnormal liver function tests have been reported in 8.7% to 9.6% of patients during therapeutic parenteral administration (Walzer et al, 1974) .

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure (serum creatinine greater than 6 mg/dL) has occurred in 0.5% of patients receiving parenteral pentamidine therapy (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    b) INCIDENCE : Renal failure and nephritis have been reported in 1% or less of patients taking nebulized pentamidine with no causal relationship established (Prod Info NebuPent(R) oral inhalation, 2011).
    c) CASE REPORT: A 29-year-old man with AIDS and PCP developed acute renal failure with renal magnesium wasting after a 10 day course of intravenous pentamidine isethionate (4 mg/kg/daily). Renal function returned to baseline after 10 days of drug cessation (Shah et al, 1990).
    B) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Moderate elevations in serum creatinine levels (2.4 to 6 mg/dL) have been reported in 23% of patients following parenteral therapy (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    b) CASE REPORT: A 68-year-old woman with Babesia (intraerythrocytic parasites) was treated with intramuscular pentamidine (4mg/kg daily) and developed an elevated creatinine (2.6 mg/dL) after seven injections. Symptoms improved with drug discontinuation (Francioli et al, 1981).
    C) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 3-year-old girl with acute lymphoblastic leukemia and PCP developed fatal azotemia and toxic epidermal necrolysis approximately 2 weeks after completing pentamidine therapy (Wang et al, 1970).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Granulocytopenia, neutropenia or megaloblastic anemia have been rarely reported following pentamidine therapy (Anon & 1984, 1984; Havlichek, 1988; O'Brien et al, 1997). Hematologic abnormalities have been reported in less than 1% of patients receiving nebulized pentamidine (Prod Info NebuPent(R) oral inhalation, 2011).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported in approximately 10.4% of patients following parenteral use (Prod Info PENTAM(R) 300 IV, IM injection, 2008).
    b) Severe leukopenia (less than 1000/mm(3)) occurred in 2.8% of patients (n=424) after pentamidine use; moderate leukopenia was reported in 7.5% of patients (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    c) CASE SERIES: 15% of AIDS patients (26 of 179 patients) developed leukopenia; 12 patients required withdrawal from therapy (Anon & 1984, 1984).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Severe thrombocytopenia (less than 20,000/mm(3)) developed in 2.6% (n=424) of patients during parenteral therapy (Prod Info PENTAM(R) 300 IV, IM injection, 2008). Thrombocytopenia resulting in moderate clinical effects has been reported in less than 1% to 6% of patients following parenteral pentamidine (O'Brien et al, 1997) .
    D) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has occurred in 1.2% of patients receiving parenteral pentamidine (Prod Info PENTAM(R) 300 IV, IM injection, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Rash has been reported in 31% to 47% of patients following nebulized pentamidine (Prod Info NebuPent(R), pentamidine isothionate, 1997); and to a much lesser extent (3.3%) with parenteral use (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    b) INCIDENCE: Pruritus, dry skin, and urticaria have occurred in 1% or less of patients following nebulized pentamidine (Prod Info NebuPent(R), pentamidine isothionate, 1997). Phlebitis has been reported in less than 1% of patients receiving parenteral therapy (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Stevens-Johnson Syndrome has been reported in 0.2% of 424 patients receiving parenteral pentamidine (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epidermal necrolysis has been rarely reported (Bolognia, 1991; Wang et al, 1970).
    b) CASE REPORT: Fatal toxic epidermal necrolysis developed in a 3-year-old girl two weeks after being treated with pentamidine for PCP (Wang et al, 1970).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hypoglycemia has been reported following intravenous and aerosolized forms of pentamidine (Fitzgerald & Young, 1984; Coyle et al, 1996). Severe hypoglycemia resulting in some fatalities has occurred with therapeutic use of pentamidine (Prod Info Pentam(R) 300, pentamidine isothionate, 1998).
    b) It is hypothesized that pentamidine induced hypoglycemia is associated with inappropriately elevated insulin levels (Fitzgerald & Young, 1984). Oral diazoxide (100 mg every 6 hours for 3 days) was found to be effective in treating pentamidine-induced hypoglycemia.
    c) It has been suggested that pancreatic beta cell damage leads to insulin release and hypoglycemia (Shen et al, 1989).
    d) INCIDENCE: Parenteral pentamidine causes hypoglycemia in 6% to 35% of patients and 1% or less in patients treated with nebulized pentamidine (O'Brien et al, 1997; Prod Info NebuPent(R), pentamidine isothionate, 1997; Prod Info Pentam(R) 300, pentamidine isothionate, 1997). Of those patients observed, HIV-seropositive patients were noted to have a higher incidence (Herchline et al, 1991).
    e) OCCURRENCE: Comtois et al (1992) conducted a small prospective study and found that mean serum pentamidine levels (blood levels greater than 100 ng/mL) were higher in patients who experienced hypoglycemia. All patients with blood levels >100 ng/mL developed hypoglycemia (Comtois et al, 1992).
    f) RISK FACTORS: Prolonged duration of therapy, increased dosage, previous pentamidine exposure, and those who experienced azotemia during the treatment were more likely to develop hypoglycemia (Waskin et al, 1988; Herchline et al, 1991).
    g) CASE SERIES: O'Brien et al (1997) reported that 24% of patients developed hypoglycemia after receiving IV pentamidine. Seizures developed in two patients with serum glucose concentration of 15 mg/dL and 40 mg/dL, respectively. Therapy for 5 patients consisted of dextrose 50% (O'Brien et al, 1997a).
    B) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia has been reported in less than 1% of patients receiving nebulized pentamidine; at present no causal relationship can be determined. Hyperglycemia has been rarely reported with IM or IV pentamidine (Prod Info NebuPent, 1997; (Prod Info Pentam(R) 300, pentamidine isothionate, 1997).
    b) INCIDENCE: 1% to 5% of treated patients develop hyperglycemia, due in part to selective, severe, pancreatic beta-cell dysfunction which can lead to permanent insulin-dependent diabetes mellitus (Shen et al, 1989).
    c) Although hypoglycemia is more frequently reported, ongoing pancreatic beta cell damage may eventually lead to insulin deficiency and result in hyperglycemia as a result of pentamidine therapy (Shen et al, 1989).
    C) DIABETES MELLITUS
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Diabetes mellitus has been reported following aerosolized pentamidine isethionate and intravenous forms of pentamidine isethionate and mesylate (Chen et al, 1991; Belehu & Naafs, 1982; Jha & Sharma, 1984; Coyle et al, 1996). Pentamidine isethionate appears to be less pancreatoxic than pentamidine mesylate (Coyle et al, 1996; Belehu & Naafs, 1982).
    b) INCIDENCE: The incidence of diabetes mellitus associated with pentamidine use has ranged between 27.8% and 32% according to Coyle et al (1996) who reported an incidence of 14.6% with pentamidine isethionate (Coyle et al, 1996a).
    c) RISK FACTORS: Diabetogenic effect appears to be due to dose-dependent toxicity (doses of 3.8 to 9 grams) (Jha & Sharma, 1984) (Perrone et al, 1990). Perrone et al (1990) observed that some patients who initially developed hypoglycemia (following parenteral pentamidine mesylate exposure) may go on to develop insulin-dependent diabetes mellitus.
    d) CASE REPORT: Several cases of ketoacidosis have occurred following therapeutic doses of intravenous pentamidine in AIDS patients (Herchline et al, 1991).
    e) CASE REPORT: A 48-year-old man who was HIV-positive with PCP was treated with intravenous pentamidine and developed diabetes mellitus requiring insulin therapy for seven months. It is hypothesized that the patient's latent diabetes mellitus was uncovered by beta cell toxicity from the pentamidine exposure (Millard & Horst, 1991).
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOGLYCEMIA
    a) RATS: An in vitro study in perfused rat islets was conducted to determine if pentamidine-induced beta cell toxicity was preventable by high glucose. The authors concluded that beta cell damage was irreversible and not preventable by incubation with high glucose concentrations (Zhou & Ipp, 1989).

Reproductive

    3.20.1) SUMMARY
    A) Pentamidine is classified as FDA pregnancy category C. Increases in embryolethality were observed in pregnant rats treated with IV pentamidine.
    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 NebuPent(R) oral inhalation, 2011).
    B) ANIMAL STUDIES
    1) RATS: Studies conducted in pregnant rats given IV pentamidine doses up to 4 mg/kg/day showed no teratogenic effects (Prod Info NebuPent(R) oral inhalation, 2011).
    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 NebuPent(R) oral inhalation, 2011; Prod Info PENTAM(R) 300 IV, IM injection, 2008).
    B) PREGNANCY CATEGORY
    1) Pentamidine is classified as FDA pregnancy category C (Prod Info NebuPent(R) oral inhalation, 2011; Prod Info PENTAM(R) 300 IV, IM injection, 2008).
    C) ANIMAL STUDIES
    1) RATS: Studies conducted in pregnant rats given IV pentamidine doses up to 4 mg/kg/day showed an increase in embryolethal effects (Prod Info NebuPent(R) oral inhalation, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    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 lactation in humans (Prod Info NebuPent(R) oral inhalation, 2011; Prod Info PENTAM(R) 300 IV, IM injection, 2008).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info PENTAM(R) 300 IV, IM injection, 2008; Prod Info PENTAM(R) 300 IV, IM injection, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring as an increase in the QT interval and dysrhythmias may develop following pentamidine exposure.
    C) Monitor CBC with differential and platelet count, serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    D) Monitor blood glucose.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain chest x-ray in symptomatic patients. Pulse oximetry and ABGs as indicated.

Methods

    A) CHROMATOGRAPHY
    1) Based on existing techniques, Berger et al (1992) suggested that HPLC analysis of pentamidine provides the most sensitive and rapid screening in a clinical setting (Berger et al, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with persistent cardiac dysrhythmias, severe respiratory symptoms, or severe neutropenia should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure to the inhalation product, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    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) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring as an increase in the QT interval and dysrhythmias may develop following pentamidine exposure.
    C) Monitor CBC with differential and platelet count, serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    D) Monitor blood glucose.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended; administered via the parenteral and inhalation routes.

Inhalation Exposure

    6.7.2) TREATMENT
    A) SUPPORT
    1) Monitor respiratory function following significant aerosolized pentamidine exposure; monitor pulse oximetry and ABGs as indicated. Refer to PARENTERAL SECTIONS for specific treatment information.

Range Of Toxicity

Summary

    A) TOXICITY: A 17-month-old child developed severe hypotension and cardiac arrest after inadvertently receiving 160 mg/kg of pentamidine (40 times the recommended dose of 4 mg/kg; total dose: 1600 mg). He recovered following supportive care, including a standard 4-hour course of charcoal hemoperfusion.
    B) THERAPEUTIC DOSE: ADULT: 4 mg/kg IV or IM once daily for 14 to 21 days. INHALATION: Primary and secondary prophylaxis, 300 mg by inhalation via the Respirgard(R) II nebulizer every 4 wk. PEDIATRIC: 4 months of age and older: 4 mg/kg IV or IM once daily for 14 to 21 days. INHALATION: 16 years of age and older: Primary and secondary prophylaxis: 300 mg by inhalation via the Respirgard(R) II nebulizer every 4 wk (manufacturer dosing); 5 years of age and older: Primary and secondary prophylaxis: 300 mg by inhalation via the Respirgard(R) II nebulizer every month (guideline dosing).

Therapeutic Dose

    7.2.1) ADULT
    A) AEROSOL
    1) PREVENTION OF PNEUMOCYSTIS JIROVECI PNEUMONIA: 300 mg once every 4 weeks administered via a nebulizer. Dose delivery should occur until the nebulizer chamber is empty (approximately 30 to 45 minutes). The flow rate should be 5 to 7 L/min from a 40 to 50 pounds/square inch (PSI) air or oxygen source (Prod Info NebuPent(R) oral inhalation, 2011).
    B) PARENTERAL
    1) PENTAMIDINE ISETHIONATE (IV or deep IM injection): 4 mg/kg once a day for 14 to 21 days; therapy for longer than 21 days has also been administered, but may be associated with increased toxicity. For intravenous administration, the calculated dose should be diluted further in 50 to 250 mL of 5% dextrose solution and infused over a period of 60 to 120 minutes. NOTE: Do NOT use sodium chloride for reconstitution because precipitation will occur (Prod Info PENTAM(R) 300 IV, IM injection, 2008).
    7.2.2) PEDIATRIC
    A) AEROSOL
    1) The safety and effectiveness of the inhaled formulation of pentamidine in pediatric patients (birth to 16 years) have not been established (Prod Info NebuPent(R) oral inhalation, 2011).
    B) PARENTERAL
    1) CHILDREN OLDER THAN 4 MONTHS: PENTAMIDINE ISETHIONATE (IV or deep IM injection): 4 mg/kg once a day for 14 to 21 days; therapy for longer than 21 days has also been administered, but may be associated with increased toxicity. For intravenous administration, the calculated dose should be diluted further in 50 to 250 mL of 5% dextrose solution and infused over a period of 60 to 120 minutes. NOTE: Do NOT use sodium chloride for reconstitution because precipitation will occur (Prod Info PENTAM(R) 300 IV, IM injection, 2008).

Maximum Tolerated Exposure

    A) PEDIATRIC
    1) CASE REPORT: A 17-month-old child developed severe hypotension and cardiac arrest after inadvertently receiving 160 mg/kg of pentamidine (40 times the recommended dose of 4 mg/kg; total dose: 1600 mg). He recovered following supportive care, including a standard 4-hour course of charcoal hemoperfusion (Watts et al, 1997).
    B) ACUTE
    1) TDLo - (IV) HUMAN, Female: 4 mg/kg, hypoglycemia (RTECS , 2001)

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 50 mg/kg (RTECS , 2001)

Physicochemical

Physical Characteristics

    A) PENTAMIDINE ISETHIONATE is a white, crystalline powder that is soluble in glycerin and water, slightly soluble in alcohol and insoluble in chloroform, ether, and acetone (Prod Info PENTAM(R) 300 IV, IM injection, 2008).
    B) PENTAMIDINE MESYLATE is a white or very faintly pink, almost odorless, granular powder.

Molecular Weight

    A) PENTAMIDINE ISETHIONATE: 592.68 (Prod Info PENTAM(R) 300 IV, IM injection, 2008)
    B) PENTAMIDINE MESYLATE: 532.6

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