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PRIMAQUINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Primaquine, an 8-aminoquinoline, is an antimalarial agent, effective as a tissue schizontocide.

Specific Substances

    1) Primaquine phosphate
    2) (RS)-8-(4-amino-1-methylbutylamino)-6-methoxyquinoline diphosphate
    3) CAS 90-34-6 (primaquine)
    4) CAS 63-45-6 (primaquine phosphate)
    1.2.1) MOLECULAR FORMULA
    1) Primaquine phosphate - C15-H21-N3-O, 2H3-P-O4

Available Forms Sources

    A) FORMS
    1) Primaquine phosphate is available as 26.3 mg (equivalent to 15 mg primaquine base) tablets (Prod Info primaquine phosphate oral tablets, 2007).
    B) USES
    1) Primaquine is indicated for the radical cure (prevention of relapse) of vivax malaria (Prod Info primaquine phosphate oral tablets, 2007).

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: An antimalarial agent, effective as a tissue schizonticide, indicated for the radical cure (prevention of relapse) of vivax malaria.
    B) PHARMACOLOGY: Primaquine is an 8-aminoquinoline compound that eliminates exoerythrocytic (tissue) infection, thereby preventing the development of the erythrocytic forms of the parasite responsible for relapses in vivax malaria.
    C) TOXICOLOGY: Primaquine is an oxidizing agent that can cause methemoglobinemia or hemolytic anemia, especially in susceptible populations.
    D) EPIDEMIOLOGY: Primaquine overdose is rare in the United States, but may be common in areas where malaria is endemic.
    E) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, and abdominal cramps are frequently reported with primaquine therapy.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, abdominal pain, and headaches have occurred at doses of 60 to 240 mg/day.
    2) SEVERE TOXICITY: Hematologic effects, including methemoglobinemia, hemolytic anemia, leukopenia, and granulocytopenia, have been reported following high doses of primaquine.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, an FDA pregnancy category for primaquine was not available. Due to the potential for hemolytic effects and the unclear G6PD status of the infant, primaquine is not recommended during pregnancy.

Laboratory Monitoring

    A) Primaquine concentrations are not readily available or useful to guide therapy.
    B) Obtain CBC with differential, free plasma hemoglobin, haptoglobin, and methemoglobin concentrations.
    C) Monitor fluids and electrolyte status in patients with significant vomiting.
    D) Monitor urinalysis for evidence of hemolysis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat methemoglobinemia with methylene blue. Monitor CBC with differential for evidence of severe bone marrow suppression. Leukopenia, granulocytopenia, and hemolytic anemia have been reported following high doses of primaquine. Massive hemolysis may need be treated with blood transfusions and supportive care with careful monitoring for hyperkalemia and rhabdomyolysis.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in a patient with a recent, significant overdose who is alert or in whom airway is protected.
    2) HOSPITAL: Consider activated charcoal in a patient with a recent, significant overdose who is alert or in whom airway is protected.
    D) ANTIDOTE
    1) If patients develop methemoglobinemia, treat with methylene blue.
    E) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    F) HEMODIALYSIS
    1) May be treated with hydration and blood transfusion if needed. Monitor for and treat hyperkalemia and renal failure. Hydrate well with intravenous fluids.
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factor for neutropenic fever. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes OR sargramostim 250 mcg/m(2)/day IV over 4 hours.
    H) ENHANCED ELIMINATION
    1) Due to primaquine's fairly large volume of distribution, hemodialysis or hemoperfusion is unlikely to be beneficial.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Only asymptomatic adults with small, inadvertent ingestions can be monitored at home.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions, symptomatic patients, or children with inadvertent ingestions should be sent to a healthcare facility for observation for at least 4 hours. Symptomatic patients should be observed for 24 hours.
    3) ADMISSION CRITERIA: Any cyanotic or dyspneic patient with clinically significant methemoglobinemia, or any patient with a methemoglobin concentration greater than 20%, should be admitted to the intensive care unit, even if improvement has occurred after appropriate emergency department management.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    J) PITFALLS
    1) When managing a suspected primaquine overdose, the treating physician should be cognizant of the possibility of multi-drug involvement.
    K) PHARMACOKINETICS
    1) Primaquine is rapidly absorbed following oral administration with a bioavailability of 96%. Volume of distribution, following administration of a single 15-mg dose, was 269 +/- 120.9 liters. Extensively metabolized by the liver; carboxyprimaquine is the primary metabolite. The plasma elimination half-life in patients with vivax malaria following administration of 15 mg primaquine was 3.76 +/- 1.80 hours; carboxyprimaquine: 15.7 +/- 12.2 hours.
    L) PREDISPOSING CONDITIONS
    1) Patients with HIV infections, with nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency or with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are at an increased risk for development of methemoglobinemia. G-6-PD-deficient patients are also at an increased risk for developing hemolytic reactions.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes other drugs or chemicals that may cause methemoglobinemia or myelosuppression.

Range Of Toxicity

    A) A specific toxic dose has not been delineated. Doses of 60 to 240 mg/day have resulted in abdominal cramps, nausea, and headache. One child developed methemoglobinemia after receiving twice the prescribed dose of 0.3 mg/kg/day.
    B) THERAPEUTIC DOSE: ADULT: Manufacturer dosing: 1 primaquine phosphate 26.3 mg tablet (equivalent to 15 mg of primaquine base) daily for 14 days. CDC guideline dosing: 52.6 mg orally once daily for 14 days in combination with appropriate blood-stage antimalarial agent. Alternate regimen: 78.9 mg orally once weekly for 8 weeks in combination with appropriate blood-stage antimalarial agent. CHILDREN: CDC guideline dosing: 0.8 mg/kg orally once daily for 14 days; MAX 52.6 mg/day in combination with appropriate blood-stage antimalarial agent.

Clinical Effects

Summary Of Exposure

    A) USES: An antimalarial agent, effective as a tissue schizonticide, indicated for the radical cure (prevention of relapse) of vivax malaria.
    B) PHARMACOLOGY: Primaquine is an 8-aminoquinoline compound that eliminates exoerythrocytic (tissue) infection, thereby preventing the development of the erythrocytic forms of the parasite responsible for relapses in vivax malaria.
    C) TOXICOLOGY: Primaquine is an oxidizing agent that can cause methemoglobinemia or hemolytic anemia, especially in susceptible populations.
    D) EPIDEMIOLOGY: Primaquine overdose is rare in the United States, but may be common in areas where malaria is endemic.
    E) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, and abdominal cramps are frequently reported with primaquine therapy.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, abdominal pain, and headaches have occurred at doses of 60 to 240 mg/day.
    2) SEVERE TOXICITY: Hematologic effects, including methemoglobinemia, hemolytic anemia, leukopenia, and granulocytopenia, have been reported following high doses of primaquine.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Visual accommodation disturbances have been observed infrequently in patients administered primaquine; however, reports are poorly documented and/or may be complicated by administration of other drugs (Clyde, 1981).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Doses of 60 to 240 mg/day have resulted in abdominal cramps, nausea, and headache (Jaeger et al, 1987).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported with primaquine use (Prod Info primaquine phosphate oral tablets, 2007). The severity of symptoms appears to be dose-related in most patients (Clyde, 1981).
    2) WITH POISONING/EXPOSURE
    a) Doses of 60 to 240 mg/day have resulted in abdominal cramps, nausea, and headaches (Jaeger et al, 1987).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain or cramps and epigastric distress have been reported following primaquine use (Prod Info primaquine phosphate oral tablets, 2007) and can occur, particularly if administered on an empty stomach. Occasionally, the gastrointestinal effects may be severe, and patients may develop anorexia, nausea, and vomiting. The severity of symptoms appears to be dose-related in most patients (Clyde, 1981).
    2) WITH POISONING/EXPOSURE
    a) Doses of 60 to 240 mg/day have resulted in abdominal cramps, nausea, and headaches (Jaeger et al, 1987).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) Serious methemoglobinemia associated with primaquine therapy occurred in a patient being treated for Pneumocystis carinii pneumonia with clindamycin/primaquine (Kantor, 1992).
    b) Primaquine rarely causes methemoglobinemia at doses used for malaria. The incidence increases with chronic administration and high doses (Sin & Shafran, 1996; Clyde, 1981). Patients with HIV infections, nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency (Prod Info primaquine phosphate oral tablets, 2007), or glucose-6-phosphate dehydrogenase deficiency may have an increased risk for developing methemoglobinemia (Raman et al, 2003; Sin & Shafran, 1996).
    c) CASE REPORT: A 40-year-old man with HIV became cyanotic and dyspneic with a methemoglobin level of 11.4% after completing a 10-day course of primaquine (15 mg/day) and clindamycin (2.4 g/day) for treatment of Pneumocystis jirovecii pneumonia. He received supportive care, and his methemoglobin level decreased to 9.4% 24 hours later (Hamill et al, 2007).
    2) WITH POISONING/EXPOSURE
    a) Methemoglobinemia was reported in a child who received twice the prescribed dose of primaquine (prescribed dose 0.3 mg/kg/day) (Raman et al, 2003).
    B) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Primaquine is an oxidizing agent and can cause moderate to severe hemolytic reactions in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and those with a family or personal history of favism. Hemolytic anemia has also been reported following high doses of primaquine (Prod Info primaquine phosphate oral tablets, 2007). The hemolysis generally appears 2 to 3 days after primaquine administration and continues for 5 to 7 days. The severity of red blood cell hemolysis is dependent on the dose of the drug, the degree of enzyme deficiency, and other factors that can increase hemolysis (eg, other drugs, liver disease, infection) (Clyde, 1981).
    b) There is a high prevalence of glucose-6-phosphate dehydrogenase deficiency in Africa, southern Europe, the Mediterranean region, the Middle East, Southeast Asia, and Oceania. In these regions, due to a congenital deficiency of erythrocytic G-6-PD, individuals have a greater tendency to develop hemolytic anemia while receiving primaquine and related drugs (Prod Info primaquine phosphate oral tablets, 2007).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia and granulocytopenia have been reported following high doses of primaquine (Prod Info primaquine phosphate oral tablets, 2007; Clyde, 1981).
    D) LEUKOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Primaquine can cause mild leukocytosis due to bone marrow stimulation (Clyde, 1981).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, an FDA pregnancy category for primaquine was not available. Due to the potential for hemolytic effects and the unclear G6PD status of the infant, primaquine is not recommended during pregnancy.
    3.20.3) EFFECTS IN PREGNANCY
    A) SUMMARY
    1) There is no data on the safety of primaquine in pregnant women. Due to the potential for hemolytic effects and the unclear G6PD status of the infant, primaquine is not recommended for use during pregnancy. If a radical cure with primaquine is indicated, it is suggested that symptoms be suppressed with chloroquine until delivery (Prod Info primaquine phosphate oral tablets, 2007; Hill et al, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if primaquine is found in human breast milk. However, exposed neonates and premature infants should be monitored for hemolysis and jaundice (signs of G6PD-deficiency) before primaquine is administered to the mother (Hill et al, 2006).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS90-34-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS63-45-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Genotoxicity

    A) The Ames mutagenicity assay has indicated that primaquine is weakly mutagenic. Primaquine is also genotoxic, according to in vivo sister chromatid exchange and chromosome aberration assays conducted from the bone marrow cells of mice (Chatterjee et al, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Primaquine concentrations are not readily available or useful to guide therapy.
    B) Obtain CBC with differential, free plasma hemoglobin, haptoglobin, and methemoglobin concentrations.
    C) Monitor fluids and electrolyte status in patients with significant vomiting.
    D) Monitor urinalysis for evidence of hemolysis.

Methods

    A) CHROMATOGRAPHY
    1) High performance liquid chromatography with electrochemical detection has been used for determination and quantitation of primaquine and its metabolite, carboxyprimaquine, in plasma. The limits of detection for primaquine and carboxyprimaquine were 2 ng/mL and 5 ng/mL, respectively, and the limits of quantitation were 5 ng/mL and 20 ng/mL, respectively (Dean et al, 1994).
    2) Ward et al (1984) described a reversed-phase high-performance liquid chromatographic method utilized for determination of primaquine in plasma and urine (Ward et al, 1984).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Any cyanotic or dyspneic patient with clinically significant methemoglobinemia, or any patient with a methemoglobin concentration greater than 20%, should be admitted to the intensive care unit, even if improvement has occurred after appropriate emergency department management.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Only asymptomatic adults with small, inadvertent ingestions can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions, symptomatic patients, or children with inadvertent ingestions should be sent to a healthcare facility for observation for at least 4 hours. Symptomatic patients should be observed for 24 hours.

Monitoring

    A) Primaquine concentrations are not readily available or useful to guide therapy.
    B) Obtain CBC with differential, free plasma hemoglobin, haptoglobin, and methemoglobin concentrations.
    C) Monitor fluids and electrolyte status in patients with significant vomiting.
    D) Monitor urinalysis for evidence of hemolysis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In case of primaquine overdose, treatment is symptomatic and supportive. There is no antidote available.
    B) MONITORING OF PATIENT
    1) Primaquine concentrations are not readily available or useful to guide therapy.
    2) Obtain CBC with differential, free plasma hemoglobin, haptoglobin, and methemoglobin concentrations.
    3) Monitor fluids and electrolyte status in patients with significant vomiting.
    4) Monitor urinalysis for evidence of hemolysis.
    C) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    D) MYELOSUPPRESSION
    1) Monitor CBC with differential for evidence of severe bone marrow suppression. Leukopenia and granulocytopenia have been reported following high doses of primaquine.
    2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.

Enhanced Elimination

    A) HEMODIALYSIS/HEMOPERFUSION
    1) Due to primaquine's fairly large volume of distribution, hemodialysis or hemoperfusion is unlikely to be beneficial.

Range Of Toxicity

Summary

    A) A specific toxic dose has not been delineated. Doses of 60 to 240 mg/day have resulted in abdominal cramps, nausea, and headache. One child developed methemoglobinemia after receiving twice the prescribed dose of 0.3 mg/kg/day.
    B) THERAPEUTIC DOSE: ADULT: Manufacturer dosing: 1 primaquine phosphate 26.3 mg tablet (equivalent to 15 mg of primaquine base) daily for 14 days. CDC guideline dosing: 52.6 mg orally once daily for 14 days in combination with appropriate blood-stage antimalarial agent. Alternate regimen: 78.9 mg orally once weekly for 8 weeks in combination with appropriate blood-stage antimalarial agent. CHILDREN: CDC guideline dosing: 0.8 mg/kg orally once daily for 14 days; MAX 52.6 mg/day in combination with appropriate blood-stage antimalarial agent.

Therapeutic Dose

    7.2.1) ADULT
    A) MANUFACTURER DOSING: 1 primaquine phosphate 26.3-mg tablet (equivalent to 15 mg of primaquine base) daily for 14 days (Prod Info primaquine phosphate oral tablets, 2013).
    B) CDC GUIDELINE DOSING: The CDC recommends primaquine phosphate 52.6 mg (2 tablets) orally daily for 14 days as an adjunct to an appropriate primary (ie, blood-stage) treatment agent, such as chloroquine, in the treatment of uncomplicated Plasmodium vivax or P ovale malaria. An alternative primaquine dose, which may be used in patients who are borderline glucose-6-phosphate dehydrogenase (G6PD) deficient, is primaquine phosphate 78.9 mg (3 tablets) orally once weekly for 8 weeks (Centers for Disease Control and Prevention (CDC), 2013; Centers for Disease Control and Prevention (CDC), 2013).
    7.2.2) PEDIATRIC
    A) CDC GUIDELINE DOSING: The CDC recommends primaquine phosphate 0.8 mg/kg orally daily for 14 days as an adjunct to an appropriate primary (ie, blood-stage) treatment agent, such as chloroquine, in the treatment of uncomplicated Plasmodium vivax or P ovale malaria (Centers for Disease Control and Prevention (CDC), 2013).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been delineated.
    B) Doses of 60 to 240 mg/day have resulted in abdominal cramps, nausea, and headache (Jaeger et al, 1987).
    C) One child developed methemoglobinemia after receiving twice the prescribed primaquine dose of 0.3 mg/kg/day (Raman et al, 2003).

Workplace Standards

    A) ACGIH TLV Values for CAS90-34-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS63-45-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS90-34-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS63-45-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS90-34-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS63-45-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS90-34-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS63-45-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 100 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Primaquine is an 8-aminoquinoline antimalarial agent which eliminates exoerythrocytic (tissue) infection, thereby preventing the development of the erythrocytic forms of the parasite which are responsible for relapses in vivax malaria (Prod Info primaquine phosphate oral tablets, 2007).

Toxicologic Mechanism

    A) HEMOLYTIC ANEMIA - 6-methoxy-8-aminoquinoline, a metabolite of primaquine, underwent N-hydroxylation to form 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH) , which was then injected into rats who had been infused with radiolabeled erythrocytes 48 hours earlier. A 250 mg/kg dose of MAQ-NOH produced a statistically significant increase in the rate of removal of the radiolabeled erythrocytes, indicating that MAQ-NOH has hemolytic activity in vivo. An in vitro experiment was also conducted whereby rat radiolabeled erythrocytes, suspended in an isotonic-phosphate buffered saline solution supplemented with glucose, were incubated with various concentrations of MAQ-NOH for 2 hours. Under these conditions, there was no hemolysis observed, although rapid formation of methemoglobin occurred (peak of 25% within an hour of MAQ-NOH exposure); however, when the cells were then washed once and administered intravenously to the rats, serial blood samples, obtained over the course of 15 days, showed a concentration-dependent decrease in erythrocyte survival. It is unclear the contribution of MAQ-NOH is to the hemotoxicity of primaquine in vivo; further studies are warranted (Bolchoz et al, 2001).

Physicochemical

Physical Characteristics

    A) Primaquine phosphate is an orange-red, odorless, crystalline powder that is insoluble in chloroform and in ether, and is soluble 1 in 15 of water (Sweetman, 2007).

Molecular Weight

    A) 455.3 (Sweetman, 2007)

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