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PROGUANIL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Proguanil, a biguanide compound, is a prodrug that metabolizes to cycloguanil, the active dihydrofolate reductase inhibitor antimalarial agent.

Specific Substances

    1) 1-(4-Chlorophenyl)-5-isopropylbiguanide hydrochloride
    2) Bigumalum
    3) Chloriguane
    4) Chloriguane Hydrochloride
    5) Chloroguanide Hydrochloride
    6) Proguanide
    7) Proguanide Hydrochloride
    8) Proguanil DCF
    9) Proguanil hydrochloride
    10) Proguanile cloridato
    11) Proguanili hydrochloridum
    12) RP-3359
    13) SN-12,837
    14) Molecular Formula: C11-H16-Cl-N5
    15) CAS 500-92-5 (proguanil)
    16) CAS 637-32-1 (proguanil hydrochloride)

Available Forms Sources

    A) FORMS
    1) In the United States, proguanil is only available as a combination agent with atovaquone, as 250 mg atovaquone/100 mg proguanil tablets and 62.5 mg atovaquone/25 mg proguanil pediatric tablets (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013; Prod Info MALARONE(R) oral tablets, 2008).
    B) USES
    1) Proguanil, in combination with atovaquone, is an antimalarial agent indicated for the prophylaxis and treatment of acute, uncomplicated Plasmodium falciparum malaria, particularly in areas where chloroquine resistance has been reported (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013; Prod Info MALARONE(R) oral tablets, 2008).

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: Proguanil is used in combination with atovaquone for the prophylaxis and treatment of acute, uncomplicated Plasmodium falciparum malaria, particularly in areas where chloroquine resistance has been reported. Refer to "ATOVAQUONE" management for more information on atovaquone toxicity.
    B) PHARMACOLOGY: Atovaquone and proguanil, antimalarial agents, act against the erythrocytic and exoerythrocytic stages of plasmodium species. Proguanil is metabolized into the active metabolite cycloguanil which inhibits dihydrofolate reductase required for deoxythymidylate (pyrimidine) synthesis, with subsequent disruption of DNA synthesis in the malarial parasite. Atovaquone selectively inhibits mitochondrial electron transport.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Mouth ulceration, headaches, dizziness, nausea, vomiting, abdominal pain, photosensitivity, and rash may occur following therapeutic administration of proguanil. Megaloblastic anemia and pancytopenia have been reported in patients with severe renal impairment. Disseminated intravascular coagulation was reported following proguanil therapy for malarial prophylaxis.
    2) ATOVAQUONE/PROGUANIL: The following adverse effects have been reported in patients receiving atovaquone in combination with proguanil: Skin rash, erythema multiforme, Stevens-Johnson syndrome, photosensitivity, pruritus, nausea, vomiting, diarrhea, abdominal pain, anorexia, stomatitis, anorexia, neutropenia, anemia, hepatitis and fatal liver failure, cholestasis, hypersensitivity reactions, anaphylaxis, dizziness, asthenia, and cough.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Ingestions of 1 gram or more may result in vomiting, diarrhea, abdominal pain, and hematuria.
    0.2.20) REPRODUCTIVE
    A) Proguanil is classified as FDA pregnancy category B. Atovaquone/proguanil is classified as FDA pregnancy category C

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    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 severe allergic reactions.
    E) ANTIDOTES
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Absorption: Rapidly and extensively absorbed. Tmax: Within 4 hours post-ingestion. Protein binding: 75%. Vd: Approximately 42 L/kg. Metabolism: Proguanil, a prodrug, is metabolized in the liver primarily via CYP2C19. Excretion: Between 40% and 60% of proguanil is renally excreted, of which 60% is excreted unchanged and 30% is excreted as cycloguanil, the active metabolite of proguanil. Approximately 10% of proguanil is fecally excreted. Elimination half-life: 12 to 21 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established. A proguanil overdose of 1500 mg occurred with complete recovery. Doses of up to 700 mg twice daily for greater than 2 weeks resulted in no serious toxicity.
    B) THERAPEUTIC DOSE: ATOVAQUONE/PROGUANIL: ADULT: MALARIAL PROPHYLAXIS: 1 tablet (proguanil 100 mg/atovaquone 250 mg) daily. Therapy should extend from 1 to 2 days before travel to a malaria-endemic area to 7 days after return. ACUTE MALARIA: 4 tablets (total dose of proguanil 400 mg/atovaquone 1 g) as a single daily dose for 3 consecutive days. PEDIATRIC: Varies with weight.

Clinical Effects

Summary Of Exposure

    A) USES: Proguanil is used in combination with atovaquone for the prophylaxis and treatment of acute, uncomplicated Plasmodium falciparum malaria, particularly in areas where chloroquine resistance has been reported. Refer to "ATOVAQUONE" management for more information on atovaquone toxicity.
    B) PHARMACOLOGY: Atovaquone and proguanil, antimalarial agents, act against the erythrocytic and exoerythrocytic stages of plasmodium species. Proguanil is metabolized into the active metabolite cycloguanil which inhibits dihydrofolate reductase required for deoxythymidylate (pyrimidine) synthesis, with subsequent disruption of DNA synthesis in the malarial parasite. Atovaquone selectively inhibits mitochondrial electron transport.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Mouth ulceration, headaches, dizziness, nausea, vomiting, abdominal pain, photosensitivity, and rash may occur following therapeutic administration of proguanil. Megaloblastic anemia and pancytopenia have been reported in patients with severe renal impairment. Disseminated intravascular coagulation was reported following proguanil therapy for malarial prophylaxis.
    2) ATOVAQUONE/PROGUANIL: The following adverse effects have been reported in patients receiving atovaquone in combination with proguanil: Skin rash, erythema multiforme, Stevens-Johnson syndrome, photosensitivity, pruritus, nausea, vomiting, diarrhea, abdominal pain, anorexia, stomatitis, anorexia, neutropenia, anemia, hepatitis and fatal liver failure, cholestasis, hypersensitivity reactions, anaphylaxis, dizziness, asthenia, and cough.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Ingestions of 1 gram or more may result in vomiting, diarrhea, abdominal pain, and hematuria.

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) EPISTAXIS: Epistaxis was reported in several patients, with chronic renal failure, who developed pancytopenia following proguanil therapy for malarial prophylaxis (Sirsat & Dasgupta, 1997; Tattersall et al, 1987; Boots et al, 1982).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) ULCERS: Mouth ulceration was reported in several patients following proguanil therapy. The ulceration resolved upon discontinuation of therapy (Drysdale et al, 1990; Daniels, 1986; Davidson, 1986; Mulley, 1974).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: Cough was reported in 10% of pediatric patients receiving atovaquone/proguanil for malaria prophylaxis (n=330) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported following therapy with proguanil as the sole agent and in combination with atovaquone or sulfisoxazole (Van der Berg et al, 1999; Pang et al, 1989).
    b) ATOVAQUONE/PROGUANIL: Headache was reported in 10% of adult patients receiving atovaquone/proguanil for the treatment of malaria in 7 controlled trials (n=436) and in 13% of pediatric patients receiving atovaquone/proguanil (n=330) for malaria prophylaxis (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has occurred following therapy with proguanil as the sole agent and in combination with sulfisoxazole (Pang et al, 1989).
    b) ATOVAQUONE/PROGUANIL: Dizziness was reported in 5% of adult patients receiving atovaquone/proguanil for the treatment of malaria in 7 controlled studies (n=436) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: Asthenia was reported in 8% of adult patients receiving atovaquone/proguanil for the treatment of malaria in 7 controlled trials (n=436) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    D) SEIZURE
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, seizures and psychotic events, such as hallucinations, have been rarely reported with atovaquone/proguanil therapy; however, a causal relationship has not been established (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been frequently reported with proguanil therapy, in doses ranging from 100 to 500 mg daily (Kaneko et al, 1999; Kaneko et al, 1999a; Pang et al, 1989; Nevill et al, 1988).
    b) INCIDENCE: Vomiting was reported in 24% of patients (n=37) who were taking proguanil, 300 mg daily (Kaneko et al, 1999).
    c) ATOVAQUONE/PROGUANIL: Nausea was reported in 12% of adult patients receiving atovaquone/proguanil for the treatment of malaria (n=436). Nausea was reported in less than 1% of pediatric patients (2 to 17 years old; n=110) who received atovaquone/proguanil compared with 7% of pediatric patients who received chloroquine/proguanil (n=111) for malaria treatment (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    d) ATOVAQUONE/PROGUANIL: For malaria prophylaxis, vomiting was reported in 5% of children receiving atovaquone/proguanil (n=330; age range, 4 to 14 years), compared with 3% of those receiving placebo. Vomiting was also reported in 10% of pediatric patients (weight 11 to 40 kg; n=116) and 12% of adolescent and adult patients receiving atovaquone/proguanil for the treatment of malaria (n=436) and in 13% of pediatric patients with no malaria symptoms who received atovaquone/proguanil for 3 days (n=319) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Large doses (1 gram) may result in vomiting and diarrhea (Tracy & Webster, 1996; Jaeger et al, 1987).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been frequently reported with proguanil therapy, in doses ranging from 100 to 500 mg daily (Kaneko et al, 1999; Kaneko et al, 1999a; Pang et al, 1989; Nevill et al, 1988).
    b) ATOVAQUONE/PROGUANIL: Diarrhea was reported in 6% of pediatric patients (weight 5 to less than 11 kg; n=100) and in 8% of adult patients receiving atovaquone/proguanil for the treatment of malaria (n=436). Diarrhea and vomiting may become severe and persistent and affect the absorption of atovaquone/proguanil; therefore, alternative antimalarial therapy may be required (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Large doses (1 gram) may result in vomiting and diarrhea (Tracy & Webster, 1996; Jaeger et al, 1987).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been frequently reported with proguanil therapy, in doses ranging from 300 to 500 mg daily (Kaneko et al, 1999; Kaneko et al, 1999a).
    b) ATOVAQUONE/PROGUANIL: For malaria prophylaxis, abdominal pain was reported in 13% of pediatric patients (aged 4 to 14 years; n=330) receiving atovaquone/proguanil compared with 8% of patients receiving placebo. For malaria treatment, abdominal pain was reported in 17% of adolescent and adult patients receiving atovaquone/proguanil (n=436) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Large doses (1 gram) may result in abdominal pain (Tracy & Webster, 1996; Jaeger et al, 1987).
    D) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, stomatitis has been reported in patients receiving atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: Anorexia was reported in 5% of adolescent and adult patients receiving atovaquone/proguanil for the treatment of malaria (n=436) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GASTROINTESTINAL DISORDER
    a) RATS: Mucosal hyperplasia of the cecum was observed in rats given proguanil, 20 mg/kg/day for 6 months (approximately 1.6 times the recommended daily human dose for malaria prophylaxis on a mg/m(2) basis) (Prod Info Malarone(TM) tablets, atovaquone and proguanil hydrochloride., 2002).
    b) DOGS: Bile duct hyperplasia and gall bladder mucosal atrophy was observed in dogs following administration of proguanil, 4 mg/kg/day for 6 months (approximately 1.3 times the recommended daily human dose for malaria prophylaxis on a mg/m(2) basis) (Prod Info Malarone(TM) tablets, atovaquone and proguanil hydrochloride., 2002). The gall bladder effects did not appear to be reversible.

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 55-year-old man presented with fever and jaundice after returning from a 3-week trip to India. He had been taking proguanil, 200 mg once daily for 6 weeks, for malaria prophylaxis. The patient was not on any other medications. The patient also experienced vomiting, mild abdominal cramping, and loss of appetite. Laboratory analysis revealed elevated bilirubin and liver enzyme levels. Cultures of blood and stools for pathogenic bacteria were negative, as was examination of stools for parasites. A liver biopsy showed hepatitis with lymphocytic and eosinophilic periportal infiltrates, indicating drug-induced hepatitis. The patient gradually recovered within 4 months after discontinuation of proguanil therapy(Oostweegel et al, 1998). The authors believed that the proguanil-associated hepatitis in this patient was a combined allergic and idiosyncratic manifestation.
    b) ATOVAQUONE/PROGUANIL: In postmarketing surveillance, rare cases of hepatitis have been reported in patients receiving atovaquone/proguanil therapy. Hepatic failure requiring liver transplant has also been reported among patients receiving atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) CHOLESTASIS
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, cholestasis has been reported in patients receiving atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) Large doses (1 gram) of proguanil may result in hematuria and the transient appearance of epithelial cells and casts in the urine (Tracy & Webster, 1996).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Renal Tubular Disorder
    a) RATS: Renal tubular basophilia was observed in rats given proguanil, 20 mg/kg/day for 6 months (approximately 1.6 times the recommended daily human dose for malaria prophylaxis on a mg/m(2) basis(Prod Info Malarone(TM) tablets, atovaquone and proguanil hydrochloride., 2002). The renal effects did not appear to be reversible.
    2) Pyelonephritis
    a) DOGS: Pyelonephritis was observed in dogs following administration of proguanil, 12 mg/kg/day for 6 months (approximately 3.9 times the recommended daily human dose for malaria prophylaxis on a mg/m(2) basis)(Prod Info Malarone(TM) tablets, atovaquone and proguanil hydrochloride., 2002).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, anemia has been reported rarely in patients receiving atovaquone/proguanil (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) MEGALOBLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Megaloblastic anemia occurred in several patients, with chronic renal failure, who were taking proguanil for malaria prophylaxis. The anemia gradually resolved in all patients following discontinuation of proguanil therapy administration of red cell transfusions and folinic acid (Sirsat & Dasgupta, 1997; Tattersall et al, 1987; Boots et al, 1982).
    C) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 59-year-old woman developed aplastic anemia several months after beginning proguanil/chloroquine combination therapy. Despite treatment, the patient's condition deteriorated, ending in death 26 months later (Eriksson et al, 1991).
    D) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, neutropenia has been reported in patients receiving atovaquone/proguanil (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    E) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) Pancytopenia, including leukopenia, granulocytopenia, and thrombocytopenia, has been reported in chronic renal failure patients following therapeutic administration of proguanil. Proguanil therapy was discontinued and the pancytopenia gradually resolved with supportive care (Sirsat & Dasgupta, 1997; Houben & Hoorntje, 1995; Humphrey et al, 1990; Tattersall et al, 1987; Boots et al, 1982).
    b) CASE REPORT: Thrombocytopenia (platelet count of 53 x 10(9)/liter) was reported in a 25-year-old woman following long-term proguanil therapy, 100 mg daily. The patient's platelet count increased to 135 x 10(9)/liter following discontinuation of proguanil (Eriksson et al, 1991).
    c) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, pancytopenia has been reported in patients with severe renal impairment receiving proguanil (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    F) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 53-year-old man, with a past medical history of disseminated intravascular coagulation with anemia and thrombocytopenia associated with pyrimethamine therapy, developed myalgia and urine discoloration a few days after beginning proguanil therapy as malarial prophylaxis. The symptoms disappeared following discontinuation of the medication. Re-challenge with proguanil several months later resulted in bruises on the extremities, abdominal tenderness, and hematuria. Laboratory analysis showed a hemoglobin nadir of 8 g/100 mL, platelets 12,000/mm(3), and urea 59 mg/100 mL, and the red cells showed schistocytes and fragmentation. Despite aggressive therapy with heparin, the patient lapsed into a coma and died. Autopsy revealed an enlarged heart, lung congestion, presence of petechiae in the visceral pericardium, myocardium, and endocardium, and thrombi in the small vessels of the heart and brain (Gon & Reid, 1975).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CUTANEOUS ERUPTION
    1) WITH THERAPEUTIC USE
    a) Urticarial rashes were reported in several patients following therapeutic administration of proguanil as sole therapy and in combination therapy with chloroquine(Eriksson et al, 1991).
    b) CASE REPORT: A generalized erythematous rash progressing to desquamation was reported in a 47-year-old man, with end-stage renal failure, approximately one week after beginning proguanil therapy for malarial prophylaxis. The rash gradually resolved several weeks after discontinuation of proguanil therapy (Tattersall et al, 1987).
    c) CASE REPORT: A 35-year-old man developed a purpuric rash over his trunk and extremities approximately 1 week after beginning proguanil therapy, 100 mg/day, for malarial prophylaxis. The rash resolved following the discontinuation of proguanil(Boots et al, 1982).
    d) CASE REPORT: A 34-year-old woman, with a past medical history of mefloquine-associated maculopapular skin rash, presented with a 2-day history of a generalized erythematous, pruritic, and pustular rash. The patient had been taking chloroquine, 100 mg/day, and proguanil, 200 mg/day, for 10 days for malarial prophylaxis. The rash resolved 8 days later following discontinuation of proguanil and chloroquine therapy (Janier et al, 1998).
    e) Scaling of the skin on the palms and soles has been reported in several patients several months after beginning proguanil therapy, and was reversible upon proguanil cessation (Hanson et al, 1989).
    f) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, skin rash and erythema multiforme have been reported in association with atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, Stevens-Johnson syndrome has been rarely reported in association with atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    C) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A phototoxic reaction was reported in a 41-year-old woman approximately 1 week after beginning proguanil therapy(Eriksson et al, 1991).
    b) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, photosensitivity has been reported in association with atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    D) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: Pruritus was reported in 6% of pediatric patients (weight 11 to 40 kg) receiving atovaquone/proguanil for the treatment of malaria (n=116) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    E) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Total alopecia was reported in several patients following chronic proguanil therapy. The severity of alopecia was directly proportional to the duration of proguanil use and appeared to be reversible upon discontinuation of the medication (Hanson et al, 1989; Tattersall et al, 1987; Boots et al, 1982).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) A severe but self-limiting hypersensitivity reaction, including acute eosinophilic pneumonia (AEP) and skin eruption, developed in a 40-year-old woman following a short course of prophylactic atovaquone and proguanil. Though another course administered one year prior had caused no complications, fever, nonproductive cough, and dyspnea began the evening of treatment initiation, with shortness of breath that progressed as she extended treatment another week after a 4-day trip to Senegal. Outpatient therapy with amoxicillin plus clavulanic acid and later, telithromycin, did not ease her respiratory symptoms, and a widespread nonpruritic maculopapular rash that emerged after 3 days of antibiotic treatment led to inpatient care. Atovaquone and proguanil were withdrawn after hospitalization. The rash was negative for Nikolsky's sign with no spread to the mucosa. Respiratory signs included tachypnea with diffuse inspiratory crackles. Arterial blood gas analysis with room air showed 68 mmHg and 32 mmHg oxygen and carbon dioxide tension, respectively, with an oxygen saturation of 94%. Imaging tests revealed a bilateral, ground-glass pattern characterized by nonspecific consolidations and linear opacities. Bronchoaveolar lavage on day 4 yielded a total cell count of 780,000 cells/mL (67% macrophages, 2% lymphocytes, 3% neutrophils, and 28% eosinophils). Cell infiltration of lymphocytes with some eosinophils was deemed minor through skin biopsy, with no vasculitis. Her WBC count began at 26 x 10(3) cells mm(3) (11% eosinophils) on admission and peaked at 28 x 10(3) cells mm(3) (39% eosinophils) on day 4. Other tests for pathogens, parasites, antinuclear antibody, HIV, and rheumatoid factor were all negative. Symptoms resolved within a week without steroid therapy. Prick, intradermal, and patch tests done 2 months later revealed a strong positive reaction to atovaquone-proguanil and proguanil only (but not atovaquone alone) when scored at 48 and 72 hours (Just et al, 2011).
    b) ATOVAQUONE/PROGUANIL: Serious cases of allergic reaction, including angioedema, urticaria, and rare cases of anaphylaxis and vasculitis, have been reported with atovaquone/proguanil therapy during worldwide postmarketing surveillance (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    B) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) ATOVAQUONE/PROGUANIL: In worldwide postmarketing surveillance, rare cases of anaphylaxis have been reported with atovaquone/proguanil therapy (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Proguanil is classified as FDA pregnancy category B. Atovaquone/proguanil is classified as FDA pregnancy category C
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) There was no significant association between atovaquone-proguanil use during early pregnancy (week 3 through week 8 and in the first trimester) and major birth defects in a retrospective cohort study of the Danish Medical Birth Register (n=570,877). Researchers cross-referenced prescription drug records and birth defect incidence (during a 1-year follow-up post birth) associated with live births recorded between January 2000 and September 2008 to find infants exposed to atovaquone-proguanil between 3 and 8 weeks' gestation (n=93) and during the first trimester (n=149). Within these cohorts, 1.1% (n=1) and 1.3% (n=2), respectively, of infants had major birth defects, yielding an adjusted prevalence odds ratio of 0.43 (95% confidence interval (CI), 0.06 to 3.11) and 0.55 (95% CI, 0.14 to 2.21) in the 3- to 8-weeks' gestation and first-trimester cohorts, respectively. Study limitations included a small number of exposed cases and the potential for bias in the results due to possible maternal noncompliance with the medication; furthermore, the analysis could only exclude a more than 3-times higher risk of birth defects with drug exposure (Pasternak & Hviid, 2011).
    B) ANIMAL STUDIES
    1) No adverse effects were observed in a pre- and post-natal study in Sprague-Dawley rats administered doses up to 16 mg/kg/day (approximately 0.04 times the estimated human exposure based on AUC) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) Pregnancy Category
    1) Proguanil is classified as FDA pregnancy category B (Briggs et al, 1998). Atovaquone/proguanil is classified as FDA pregnancy category C (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) Breast Milk
    1) Although small amounts of proguanil are excreted in milk, it is believed that the use of proguanil is probably safe during nursing; however, the specific amount of proguanil excreted has not been reported. Studies are needed to measure the amount of proguanil and its metabolite, cycloguanil, that is excreted in order to determine the precise safety of exposure to the nursing infant(Briggs et al, 1998).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) No adverse effects were observed in a fertility study in Sprague-Dawley rats administered doses up to 16 mg/kg/day (approximately 0.04 times the estimated human exposure based on AUC) (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS500-92-5 (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 CAS637-32-1 (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

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) Monitor vital signs in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Methods

    A) Chromatography
    1) High-performance liquid chromatography with solid-phase extraction was used to quantitatively determine the presence of proguanil and its metabolites in human plasma, whole blood, and urine. The limit of determination of proguanil and its metabolites in plasma and whole blood, using this method, were 20 nmol/L and 50 nmol/L, respectively(Bergqvist et al, 1998; Taylor et al, 1987).
    2) High-performance liquid chromatography with ultraviolet detection was conducted for the determination of proguanil and its metabolites in human plasma, whole blood, and urine. The limits of quantification for proguanil, using this method were 5.6 ng/mL, 6.6 ng/mL, and 10 ng/mL for plasma, whole blood, and urine, respectively. For cycloguanil, the active metabolite of proguanil, the limits of quantification were 6.8 ng/mL, 5.2 ng/mL, and 2.9 ng/mL for plasma, whole blood, and urine, respectively(Chaulet et al, 1994).
    3) The sweeping technique of Micellar electrokinetic chromatography (MEKC) was used to determine the limits of detection of proguanil and cycloguanil in human plasma and urine. The limits of detection of proguanil, using this method, in plasma and urine were 10 ng/mL and 250 ng/mL, respectively, and the limits of detection of cycloguanil in plasma and urine were 20 ng/mL and 175 ng/mL, respectively.
    a) In comparison, the limits of detection of proguanil and cycloguanil, using liquid chromatography (LC), were 1 ng/mL and 0.5 ng/mL, respectively, for both plasma and urine, indicating that the sweeping technique of MEKC is a less sensitive method as compared with LC for the detection of proguanil and cycloguanil in human plasma and urine(Taylor et al, 2001).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional 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, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs in symptomatic patients.
    3) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) MYELOSUPPRESSION
    1) 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.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

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

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established. A proguanil overdose of 1500 mg occurred with complete recovery. Doses of up to 700 mg twice daily for greater than 2 weeks resulted in no serious toxicity.
    B) THERAPEUTIC DOSE: ATOVAQUONE/PROGUANIL: ADULT: MALARIAL PROPHYLAXIS: 1 tablet (proguanil 100 mg/atovaquone 250 mg) daily. Therapy should extend from 1 to 2 days before travel to a malaria-endemic area to 7 days after return. ACUTE MALARIA: 4 tablets (total dose of proguanil 400 mg/atovaquone 1 g) as a single daily dose for 3 consecutive days. PEDIATRIC: Varies with weight.

Therapeutic Dose

    7.2.1) ADULT
    A) MALARIA
    1) MALARIAL PROPHYLAXIS: With proguanil/atovaquone combination therapy, the recommended dose is 1 tablet (proguanil 100 mg/atovaquone 250 mg) daily. Therapy should extend from 1 to 2 days before travel to a malaria-endemic area to 7 days after return (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) ACUTE MALARIA: With proguanil/atovaquone combination therapy, the recommended dose is 4 tablets (total dose of proguanil 400 mg/atovaquone 1 g) as a single daily dose for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    7.2.2) PEDIATRIC
    A) MALARIA
    1) MALARIAL PROPHYLAXIS
    a) 11 TO 20 KG: With proguanil/atovaquone combination therapy, the recommended dose is 1 pediatric tablet (proguanil 25 mg/atovaquone 62.5 mg) daily (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    b) 21 TO 30 KG: With proguanil/atovaquone combination therapy, the recommended dose is 2 pediatric tablets (proguanil 50 mg/atovaquone 125 mg) daily (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    c) 31 TO 40 KG: With proguanil/atovaquone combination therapy, the recommended dose is 3 pediatric tablets (proguanil 75 mg/atovaquone 187.5 mg) daily (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    d) GREATER THAN 40 KG: With proguanil/atovaquone combination therapy, the recommended dose is 1 adult tablet (proguanil 100 mg/atovaquone 250 mg) daily (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    e) In pediatric patients, therapy should extend from 1 to 2 days before travel to a malaria-endemic area to 7 days after return (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    2) ACUTE MALARIA
    a) 5 TO 8 KG: With proguanil/atovaquone combination therapy, the recommended dose is 2 pediatric tablets (proguanil 50 mg/atovaquone 125 mg) daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    b) 9 TO 10 KG: With proguanil/atovaquone combination therapy, the recommended dose is 3 pediatric tablets (proguanil 75 mg/atovaquone 187.5 mg) daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    c) 11 TO 20 KG: With proguanil/atovaquone combination therapy, the recommended dose is 1 adult tablet (proguanil 100 mg/atovaquone 250 mg) daily for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    d) 21 TO 30 KG: With proguanil/atovaquone combination therapy, the recommended dose is 2 adult tablets (proguanil 200 mg/atovaquone 500 mg) as a single daily dose for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    e) 31 TO 40 KG: With proguanil/atovaquone combination therapy, the recommended dose is 3 adult tablets (proguanil 300 mg/atovaquone 750 mg) as a single daily dose for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).
    f) GREATER THAN 40 KG: With proguanil/atovaquone combination therapy, the recommended dose is 4 adult tablets (proguanil 400 mg/atovaquone 1 g) as a single daily dose for 3 consecutive days (Prod Info MALARONE(R) oral tablets, pediatric tablets, 2013).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Complete recovery occurred following proguanil overdoses up to 1500 mg (Prod Info Malarone(TM) tablets, atovaquone and proguanil hydrochloride., 2002).
    2) Proguanil doses up to 700 mg twice daily for greater than 2 weeks of therapy were reported without the occurrence of serious toxicity(Prod Info Malarone(TM) tablets, atovaquone and proguanil hydrochloride., 2002).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) A serum proguanil concentration of 1.03 mcg/mL was reported in a 21-year-old male 2 days after discontinuing proguanil therapy, 100 mg/day, due to megaloblastic anemia (normal therapeutic proguanil level is 0.1 mcg/mL 4 hours after ingestion of 100 mg). Eight days after cessation of proguanil therapy, the serum concentration was still elevated at 0.73 mcg/mL(Boots et al, 1982).

Workplace Standards

    A) ACGIH TLV Values for CAS500-92-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS637-32-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS500-92-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS637-32-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS500-92-5 :
    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 CAS637-32-1 :
    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 CAS500-92-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS637-32-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)RAT:
    1) 15 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Proguanil is used for prophylaxis against Plasmodium falciparum and Plasmodium vivax. It is a tissue schizonticide, inhibiting the growth of pre-erythrocytic stages of the plasmodium in the liver, and has some blood schizonticidal effects(Warhurst, 1987). Proguanil itself is a prodrug and must be metabolized to cycloguanil for antimalarial activity. Cycloguanil inhibits plasmodial dihydrofolate reductase, resulting in inhibition of nucleic acid synthesis(Sweetman, 2003). Cycloguanil is also considered a sporontocide, inhibiting oocyst and sporozoite growth when fed directly to the mosquito(Warhurst, 1987).

Physicochemical

Physical Characteristics

    A) Proguanil is a white, odorless or almost odorless, crystalline powder, that is slightly soluble in water, sparingly soluble in alcohol, and practically insoluble in chloroform and ether(Sweetman, 2003).

Molecular Weight

    A) 290.2 (Sweetman, 2003)

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