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MEFLOQUINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Mefloquine, a 4-quinolinemethanol derivative, is an antimalarial agent that directly acts as a blood schizonticide.

Specific Substances

    1) (R,S)+-(alpha-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol) hydrochloride
    2) Mefloquine hydrochloride
    3) Ro-21-5998 (mefloquine)
    4) Ro-21-5998/001 (mefloquine hydrochloride)
    5) WR-142490 (mefloquine)
    6) Molecular Formula: C17-H16-F6-N2-O, HCl
    7) CAS 53230-10-7 (mefloquine)
    8) CAS 51773-92-3 (mefloquine hydrochloride)

Available Forms Sources

    A) FORMS
    1) Mefloquine is available in the United States as 250-milligram tablets (equivalent to 228 milligrams of the free base) (Prod Info LARIAM(R) oral tablets, 2009).
    B) USES
    1) Mefloquine is indicated for the prevention and treatment of mild to moderate malaria due to Plasmodium falciparum (including chloroquine-resistant strains) and P vivax in adults and children 6 months of age and older (Prod Info LARIAM(R) oral tablets, 2009).

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: Mefloquine is indicated for the prevention and treatment of mild to moderate malaria due to Plasmodium falciparum (including chloroquine-resistant strains) and Plasmodium vivax in adults and children aged 6 months and older.
    B) PHARMACOLOGY: Mefloquine is an antimalarial drug that directly acts as a Plasmodium schizonticide. It exhibits its effect on the erythrocytic stages of Plasmodium species; however, its exact mechanism is still unknown.
    C) EPIDEMIOLOGY: Mefloquine overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Gastrointestinal effects (eg, nausea, vomiting, diarrhea, and abdominal pain) and mild CNS effects (eg, headache, dizziness, loss of balance, somnolence, and sleep disorders). OTHER EFFECTS: Neuropsychiatric symptoms (eg, insomnia, visual and auditory hallucinations, panic attacks, depression, anxiety, psychosis, and seizures), skin rashes, urticaria, pruritus, muscle weakness, myalgia, elevated liver enzymes, bradycardia, prolongation of the QTc interval, tachycardia, hypoglycemia, and rarely thrombocytopenia and leukopenia. Pneumonitis, possibly of allergic etiology, has been infrequently reported during postmarketing surveillance of mefloquine. Since mefloquine has a long elimination half-life (13 to 24 days), adverse effects may persist for several weeks after drug cessation.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. An anticholinergic syndrome, including mydriasis, agitation, delirium, rigors, and fever, has been reported after an overdose. Overdose can also cause dizziness, vertigo, headache, panic attacks, and a variety of neuropsychiatric symptoms, such as psychosis and seizures. These effects may persist for several weeks.
    0.2.20) REPRODUCTIVE
    A) Mefloquine is FDA pregnancy category B. Animal studies suggest potential teratogenicity and/or embryotoxicity; however, many published human studies, including randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series, with more than 700 mefloquine exposures in the first trimester and over 2000 exposure in the second and third trimesters, have shown that pregnant women who took mefloquine at various doses for both prevention and treatment of malaria, did not have an increased risk of teratogenic effects or adverse pregnancy outcomes compared with background rate in the general population.

Laboratory Monitoring

    A) Mefloquine concentrations are not readily available or useful to guide therapy.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG and institute continuous cardiac monitoring after a significant overdose.
    D) Monitor blood glucose and liver enzymes after a significant overdose.
    E) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the diagnosis is uncertain.
    F) CPK should be obtained if the patient has had psychomotor agitation or seizure activity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) All patients with symptoms of mefloquine toxicity should be evaluated by a healthcare professional. Treatment is symptomatic and supportive. In the case of neuropsychiatric symptoms, supportive pharmacotherapy such as antipsychotic medications or benzodiazepines may be given. Antiemetics may be administered for gastrointestinal symptoms as needed.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In the case of neuropsychiatric symptoms, supportive pharmacotherapy such as antipsychotic medications or benzodiazepines may be given. Orotracheal intubation for airway protection should be performed early in cases of severe psychomotor agitation, repeated seizure activity, or evidence of severe cardiotoxicity. Treat bradycardia with atropine; if unresponsive, use beta adrenergic agonists (eg, isoproterenol). Consider temporary pacemaker insertion. Therapeutic doses of mefloquine may cause prolongation of the QT interval. Concomitant use of mefloquine and other drugs that prolong the QT interval may increase the risk of torsade de pointes. Treat torsade de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal should be avoided in the prehospital setting because of the risk of seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal in a patient with a recent, significant overdose who is alert or in whom airway is protected.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (ie, seizures, severe agitation, signs of cardiotoxicity).
    E) ANTIDOTE
    1) Physostigmine reversed anticholinergic signs and symptoms in one patient with mefloquine overdose. Usual dose is 1 to 2 mg slowly intravenously.
    F) DELIRIUM
    1) Liberal use of benzodiazepines until patient is sedated. Consider physostigmine if patient has anticholinergic findings on exam.
    G) PSYCHOTIC DISORDER
    1) Benzodiazepines and antipsychotics may be used until symptoms resolve, which may take several weeks.
    H) BRADYCARDIA
    1) Usually does not require treatment. If hypotension develops treat with atropine; if unresponsive, use beta adrenergic agonists (eg, isoproterenol). Consider temporary pacemaker insertion.
    I) TACHYCARDIA
    1) Tachycardia may develop secondary to agitation or anticholinergic effects, and generally responds to sedation.
    J) TORSADES DE POINTES
    1) Has not bee reported but might develop secondary to QTc prolongation. Treat with magnesium sulfate (adults 2 g IV), correct electrolyte abnormalities. Overdrive pacing may be necessary.
    K) SEIZURES
    1) Administer IV benzodiazepines; add propofol, or barbiturates if seizures recur or persist.
    L) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis and hemoperfusion are unlikely to be of benefit because of the large volume of distribution and extensive protein binding of mefloquine.
    M) 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 as symptoms of severe toxicity will likely develop within this time period. Symptomatic patients should be observed for 24 hours.
    3) ADMISSION CRITERIA: Patients with significant persistent central nervous stimulation and/or abnormal vital signs should be admitted. Patients with seizures, dysrhythmias, or any other life-threatening result of toxicity or intubated patients should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    N) PITFALLS
    1) Not aggressively managing the patient's airway, breathing, and circulation. Not recognizing mefloquine toxicity and, thus, not initiating the appropriate treatment. The treating physician should also be aware of the possibility of multi-drug involvement.
    O) PHARMACOKINETICS
    1) Highly bound to plasma proteins (98%); Vd: approximately 20 L/kg. Extensively metabolized in the liver by the cytochrome P450 system (CYP3A4, the major isoform). Excreted mainly in the feces and bile. Urinary excretion of unchanged mefloquine and its main metabolite: 9% and 4% of the dose, respectively. Mean elimination half-life: 2 to 4 weeks (average about 3 weeks).
    P) DIFFERENTIAL DIAGNOSIS
    1) CNS infection or sepsis, intracerebral hemorrhage, manic or psychotic episode due to psychiatric illness, ethanol/benzodiazepine/barbiturate withdrawal, hypoglycemia, hypoxia, or cocaine or other stimulant intoxication. Overdose with sodium channel blocking agent (ie, tricyclic antidepressants).

Range Of Toxicity

    A) TOXICITY: The toxic dose of mefloquine in humans has not been established. A man developed severe neurologic disturbances (ie, agitation, progressive delirium, and generalized rigors), mydriasis, and hyperpyrexia after taking 1500 mg of mefloquine.
    B) THERAPEUTIC DOSE: ADULTS: 1250 mg as a single oral dose. CHILDREN: 20 to 25 mg/kg orally in 2 divided doses given 6 to 8 hours apart.

Clinical Effects

Summary Of Exposure

    A) USES: Mefloquine is indicated for the prevention and treatment of mild to moderate malaria due to Plasmodium falciparum (including chloroquine-resistant strains) and Plasmodium vivax in adults and children aged 6 months and older.
    B) PHARMACOLOGY: Mefloquine is an antimalarial drug that directly acts as a Plasmodium schizonticide. It exhibits its effect on the erythrocytic stages of Plasmodium species; however, its exact mechanism is still unknown.
    C) EPIDEMIOLOGY: Mefloquine overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Gastrointestinal effects (eg, nausea, vomiting, diarrhea, and abdominal pain) and mild CNS effects (eg, headache, dizziness, loss of balance, somnolence, and sleep disorders). OTHER EFFECTS: Neuropsychiatric symptoms (eg, insomnia, visual and auditory hallucinations, panic attacks, depression, anxiety, psychosis, and seizures), skin rashes, urticaria, pruritus, muscle weakness, myalgia, elevated liver enzymes, bradycardia, prolongation of the QTc interval, tachycardia, hypoglycemia, and rarely thrombocytopenia and leukopenia. Pneumonitis, possibly of allergic etiology, has been infrequently reported during postmarketing surveillance of mefloquine. Since mefloquine has a long elimination half-life (13 to 24 days), adverse effects may persist for several weeks after drug cessation.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. An anticholinergic syndrome, including mydriasis, agitation, delirium, rigors, and fever, has been reported after an overdose. Overdose can also cause dizziness, vertigo, headache, panic attacks, and a variety of neuropsychiatric symptoms, such as psychosis and seizures. These effects may persist for several weeks.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Hyperpyrexia has been reported in a 47-year-old man following ingestion of 1500 mg of mefloquine (Speich & Haller, 1994).
    2) FEVER: In a 5-year Danish retrospective study, fever was reported in 16% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Bradycardia has been reported with therapeutic use and might occur in overdose (ter Kuile et al, 1995).
    B) WITH POISONING/EXPOSURE
    1) Bradycardia may occur in overdose (ter Kuile et al, 1995).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS, as part of a central anticholinergic syndrome, was reported in a 47-year-old man who ingested 1500 mg of mefloquine. The patient recovered following intravenous administration of physostigmine (Speich & Haller, 1994).
    2) ABNORMAL VISION: In a 5-year Danish retrospective study, abnormal vision was reported in 49% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).
    B) ANIMAL STUDIES
    1) ANIMAL STUDIES: Rats receiving 30 mg/kg/day for 2 years developed retinal degeneration, lens opacity, and retinal edema. Corneal lesions were observed in rats receiving 5 mg/kg/day for 2 years (Prod Info Lariam(R), mefloquine, 1998).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) In a 5-year Danish retrospective study, tinnitus and hearing loss were reported in 18% and 12% of 73 patients with mefloquine side effects, respectively (Ringqvist et al, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia may occur with therapeutic use (Prod Info Lariam(R), mefloquine, 1999).
    b) CASE SERIES: In a prospective series of adult patients receiving mefloquine for acute falciparum malaria, 3.6% of those patients who had ECGs performed on admission had bradycardia; 17% of those who had ECGs performed on the third day of therapy had bradycardia; and 26% of those who had ECGs on the seventh day of therapy had bradycardia (ter Kuile et al, 1995).
    2) WITH POISONING/EXPOSURE
    a) Bradycardia may occur following overdose (Prod Info Lariam(R), mefloquine, 1999; ter Kuile et al, 1995) .
    B) ATRIAL ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 63-year-old man developed atrial flutter with 1:1 conduction 2 days after taking his first dose of mefloquine 250 mg for malaria prophylaxis (Fonteyne et al, 1996).
    C) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported infrequently in patients receiving mefloquine hydrochloride therapy (Prod Info LARIAM(R) oral tablets, 2008).
    b) CASE REPORT: A physician reported developing tachycardia associated with vivid dreams and visual distortions after taking a single dose of mefloquine (Lench, 1995).
    D) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) Volunteers developed slight prolongation in the QTc interval (not beyond normal limits) while taking mefloquine 250 mg/wk (Davis et al, 1996).
    E) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Extrasystole and other transient cardiac conduction alterations may develop with therapeutic use (Prod Info Lariam(R), mefloquine, 1999).
    b) CASE REPORT: A 32-year-old man developed palpitations, dizziness, and vertigo 2 days after taking the fourth mefloquine 250 mg tablet for malaria prophylaxis. Similar symptoms developed after his next three doses and disappeared within 2 days. Three days after his seventh dose, an ECG revealed aberrantly conducted supraventricular beats followed by aberrantly conducted premature echo beats. Follow-up ECGs revealed an underlying short PR interval (possibly Lown-Ganong-Levine syndrome) (Richter et al, 1997).
    F) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) The following circulatory disturbances can develop with therapeutic use: hypotension, hypertension, flushing, and syncope (Prod Info Lariam(R), mefloquine, 1999).
    G) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) In a 5-year Danish retrospective study, palpitations were reported in 42% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Pneumonitis, possibly of allergic etiology, has been infrequently reported during postmarketing surveillance of mefloquine (Prod Info LARIAM(R) oral tablets, 2008a).
    b) Thirteen cases of pneumonitis or eosinophilic pneumonia associated with mefloquine therapy have been reported to the United States Food and Drug Administration (FDA) during postmarketing surveillance of mefloquine between May 1989 and January 2008. The 13 patients, ranging in age from 4 to 68 years (median, 53 years), were receiving mefloquine for malaria treatment (n=5), malaria prophylaxis (n=6), or an unknown reason (n=2). In all cases, patients were hospitalized with respiratory illness, including pneumonitis, diffuse interstitial pneumopathy, and dyspnea/lung infiltration, following a median time-to-onset from first dose of mefloquine to respiratory symptoms of 2 days (range, 1 to 84 days). Radiographic imaging revealed bilateral lung infiltrates in 7 patients. Elevated eosinophils and neutrophils were indicated in fluid obtained from bronchoalveolar lavage (n=2), and autoimmune interstitial alveolitis was determined from a lung biopsy (n=1). One child, a 4-year-old girl, died after developing pulmonary fibrosis and interstitial pneumonitis after receiving several prophylactic doses of mefloquine. Of the 13 patients, 10 (77%) fully recovered after mefloquine was discontinued. Improvement was observed with systemic corticosteroid therapy in 5 (38%) of the patients. A case of interstitial pneumonia and a positive rechallenge was also described in a 60-year-old woman following initiation of mefloquine 250 mg/wk for malaria travel prophylaxis (US Food and Drug Administration, 2008).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported with therapeutic use of mefloquine (both as treatment and as prophylaxis for malaria) in patients without a history of seizure disorder (Garg et al, 1996; Pous et al, 1995; Ruff et al, 1994) .
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Vertigo or dizziness has been reported with therapeutic use (Sowunmi et al, 1993).
    b) INCIDENCE: Dizziness is one of the most frequently reported adverse effects, which usually decreases with prolonged use (Prod Info Lariam(R), mefloquine, 1999).
    c) In a 5-year Danish retrospective study, dizziness was reported in 57% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) A postmalaria neurological syndrome has been reported, consisting of confusion, psychosis, seizure, or tremor developing after treatment for malaria (Mai et al, 1996). In one study, this syndrome was more common in patients with severe malaria who had received mefloquine (4.4%; 10 of 228) than in patients with severe malaria who had not received mefloquine (0.5%; 1 of 210) (Mai et al, 1996).
    b) Other CNS effects that can occur frequently with therapeutic use include headache, somnolence, and sleep disorders (eg, insomnia and abnormal dreams) (Prod Info Lariam(R), mefloquine, 1999).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a 5-year Danish retrospective study, fatigue was reported in 49% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).
    E) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a 5-year Danish retrospective study, headache was reported in 36% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).
    F) VERTIGO
    1) WITH THERAPEUTIC USE
    a) In a 5-year Danish retrospective study, vertigo was reported in 38% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).
    G) NUMBNESS
    1) WITH THERAPEUTIC USE
    a) In a 5-year Danish retrospective study, numbness of arms and legs was reported in 30% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting may develop at therapeutic doses (Sowunmi et al, 1993).
    b) INCIDENCE: Symptoms are reported frequently during therapeutic use and often decrease with prolonged use (Prod Info Lariam(R), mefloquine, 1999).
    c) In a 5-year Danish retrospective study, gastrointestinal symptoms were reported in 57% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).
    d) In a large series of patients receiving mefloquine for treatment of malaria, nausea developed in approximately 40% and vomiting developed in approximately 15%. Vomiting was more common in children younger than 15 years (ter Kuile et al, 1995).
    e) A dose of mefloquine hydrochloride (15 mg/kg) was administered to 7 healthy adult volunteers. Some subjects experienced nausea; reactions did not correlate with dose and were transient (Patchen et al, 1989).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea developed in approximately 6% of patients receiving mefloquine for treatment of malaria in one large study and was more common in children younger than 5 years (ter Kuile et al, 1995).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain developed in 20% to 25% of patients in one large series of patients receiving mefloquine for treatment of malaria (ter Kuile et al, 1995).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Transient elevations in transaminase levels have been reported in patients being treated for malaria and in prophylactic administration of mefloquine to indigenous populations in malaria-endemic areas (Prod Info Lariam(R), mefloquine, 1999).
    B) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 68-year-old man developed progressive malaise, fatigue, and nausea of several weeks duration after a 6-week course of mefloquine (250 mg/wk). The patient had stopped the medication 1 week prior to admission. On exam, mild jaundice was present with a mildly enlarged liver without tenderness. Laboratory tests were as follows: alanine aminotransferase 1277 units/L (normal 6 to 53 units/L), aspartate aminotransferase 1344 units/L (normal 2 to 60 units/L), and total bilirubin 1.87 mg/dL (normal 0.3 to 1.0 mg/dL). Mefloquine was not restarted, and liver function studies gradually improved (Gotsman et al, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 21-year-old man developed aplastic anemia while taking mefloquine 250 mg/wk for malaria prophylaxis. The anemia was unresponsive to corticosteroids, granulocyte colony-stimulating factor, immune globulin, and erythropoietin, and he received autologous bone marrow transplant (Stracher et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) The following dermatologic effects have occurred with therapy: rash, exanthema, erythema, urticaria, and pruritus. Hair loss and sweating have also been described (Prod Info Lariam(R), mefloquine, 1999).
    B) GENERALIZED EXFOLIATIVE DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 42-year-old man developed an erythematous, pruritic, papular rash 1 day after taking his second weekly dose of mefloquine 250 mg. The rash progressed to diffuse, erythematous, confluent plaques and eventually desquamation developed. Biopsy revealed subacute dermatitis (Martin et al, 1993).
    C) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 62-year-old woman developed pruritic petechiae of her lower extremities, myalgias, and arthralgias after ingesting the fifth weekly mefloquine 250 mg dose . Biopsy revealed cutaneous vasculitis. Signs and symptoms resolved with corticosteroid therapy (White et al, 1995).
    b) CASE REPORT: A 44-year-old man developed petechiae on the vermilion border of his lip and a pruritic, purpuric maculopapular rash on his lower legs after taking his fourth dose of mefloquine 250 mg/wk. No constitutional symptoms developed (Scerri & Pace, 1993).
    D) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 6-year-old girl developed toxic epidermal necrolysis with exfoliation of 95% of her body surface area over 48 hours, 35 days after starting mefloquine prophylaxis (125 mg/wk). She subsequently developed multiple complications including klebsiella sepsis and died 19 days after hospital admission (McBride et al, 1997).
    E) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) In a 5-year Danish retrospective study, skin symptoms and reduced nociception of the skin were reported in 36% and 10% of 73 patients with mefloquine side effects, respectively (Ringqvist et al, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Muscle weakness and muscle cramps have been reported with mefloquine therapy (Prod Info Lariam(R), mefloquine, 1999).
    b) In a 5-year Danish retrospective study, leg cramps were reported in 14% of 73 patients with mefloquine side effects (Ringqvist et al, 2015).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia and arthralgia may occur with therapeutic use (Prod Info Lariam(R), mefloquine, 1999).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 40-year-old man with AIDS and intractable diarrhea secondary to cryptosporidiosis developed hypoglycemic coma 3 hours after receiving mefloquine 1500 mg orally over 48 hours (blood glucose 2.3 mmol/L, cerebrospinal fluid glucose 1.7 mmol/L, plasma cortisol 600 nanomoles/dL). The patient was also receiving ketoconazole, penicillin, cotrimoxazole, and ranitidine. Hypoglycemia was corrected with intravenous dextrose and did not recur after mefloquine was discontinued (Assan et al, 1995).
    b) In a double-blind, randomized, placebo-controlled study, mefloquine was associated with decreased serum glucose levels and increased serum insulin levels (Davis et al, 1996).
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IN VITRO STUDIES
    a) Mefloquine caused an increase in insulin release in a collagenase digested rat islet of Langerhans preparation (Assan et al, 1995).

Reproductive

    3.20.1) SUMMARY
    A) Mefloquine is FDA pregnancy category B. Animal studies suggest potential teratogenicity and/or embryotoxicity; however, many published human studies, including randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series, with more than 700 mefloquine exposures in the first trimester and over 2000 exposure in the second and third trimesters, have shown that pregnant women who took mefloquine at various doses for both prevention and treatment of malaria, did not have an increased risk of teratogenic effects or adverse pregnancy outcomes compared with background rate in the general population.
    3.20.2) TERATOGENICITY
    A) CONGENITAL MALFORMATIONS
    1) In a study evaluating the effects of mefloquine exposure during pregnancy or in either the pre- and peri-conception period, 2506 cases of mefloquine exposure during pregnancy from 4 different countries (France, n=783; United Kingdom, n=661; Germany, n=645; United States, n=138) were evaluated from January 1986 to October 2010, with peak reporting occurring between 1994 and 1998. Approximately 98% (n=2477) of cases were reported spontaneously with a median age of 29 and 30 years for prospective and retrospective cases, respectively. Of the 2246 maternal prospective cases, 95.2% (n=2139) had exposure to mefloquine prior to conception and/or during the first trimester. Of 1383 cases with known outcome, there were 978 (70.7%) deliveries, 405 (29.3%) abortions (112 spontaneous, 293 therapeutic), 43 infants with birth defects, and 43 infants with other disorders (a birth defect prevalence of 4.39%; 43 of 978). These disorders included neonatal jaundice (n=12), premature delivery (n=8), placental disorder (n=8), fetal growth restriction (n=6), small-for-dates infant (n=4), fetal distress syndrome (n=4), stillbirth or intrauterine death (n=3), bradycardia (n=2), blighted ovum (n=2), unspecified neonatal disorder (n=2), and neonatal asphyxia (n=2) (Schlagenhauf et al, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Mefloquine is FDA pregnancy category B (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablet, 2011).
    2) Animal studies suggest potential teratogenicity and/or embryotoxicity; however, many published human studies, including randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series, with more than 700 mefloquine exposures in the first trimester and over 2000 exposure in the second and third trimesters, have shown that pregnant women who took mefloquine at various doses for both prevention and treatment of malaria, did not have an increased risk of teratogenic effects or adverse pregnancy outcomes compared with background rate in the general population (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablet, 2011). The Centers for Disease Control considers mefloquine safe to take in prophylactic doses during the second and third trimesters of pregnancy (Anon, 2003). During the first trimester of pregnancy, most evidence suggests that mefloquine is safe (Anon, 2003). The apparently minimal risks from mefloquine use are likely outweighed by the significant morbidity and mortality that malaria may cause in a pregnant woman and her fetus. However, the manufacturer recommends the use of mefloquine during pregnancy only if clearly needed. Nonpregnant women are advised to use birth control while taking mefloquine and for 3 months thereafter (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablet, 2011).
    B) ABORTION
    1) In a study of 72 women who inadvertently received mefloquine for malaria prophylaxis during early pregnancy, there were 17 elective abortions, 12 spontaneous abortions, 1 molar pregnancy and 23 live births of normal children (Smoak et al, 1997). Outcome was unknown in 19 cases. The incidence of spontaneous abortions was higher than expected, but may have been artificially elevated due to reporting bias.
    2) In a study evaluating the effects of mefloquine exposure during pregnancy or in either the pre- and peri-conception period, 2506 cases of mefloquine exposure during pregnancy from 4 different countries (France, n=783; United Kingdom, n=661; Germany, n=645; United States, n=138) were evaluated from January 1986 to October 2010, with peak reporting occurring between 1994 and 1998. Approximately 98% (n=2477) of cases were reported spontaneously with a median age of 29 and 30 years for prospective and retrospective cases, respectively. Of the 2246 maternal prospective cases, 95.2% (n=2139) had exposure to mefloquine prior to conception and/or during the first trimester. Of 1383 cases with known outcome, there were 978 (70.7%) deliveries, 405 (29.3%) abortions (112 spontaneous, 293 therapeutic), 43 infants with birth defects, and 43 infants with other disorders (a birth defect prevalence of 4.39%; 43 of 978). These disorders included neonatal jaundice (n=12), premature delivery (n=8), placental disorder (n=8), fetal growth restriction (n=6), small-for-dates infant (n=4), fetal distress syndrome (n=4), stillbirth or intrauterine death (n=3), bradycardia (n=2), blighted ovum (n=2), unspecified neonatal disorder (n=2), and neonatal asphyxia (n=2) (Schlagenhauf et al, 2012).
    C) STILLBIRTH
    1) In an investigational study of 3,587 pregnancies, treatment with mefloquine during pregnancy was associated with an increased risk of stillbirth. Drug therapy was not associated with abortion, low birth weight, neurological retardation, or congenital malformations (Nosten et al, 1999).
    D) LACK OF EFFECT
    1) In a double-blind, placebo controlled trial of mefloquine prophylaxis during pregnancy (greater than 20 weeks gestation), mefloquine had no adverse effects on the mother, the pregnancy, infant survival or development during the first 2 years of life (Nosten et al, 1994).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) In a small number of subjects, 3% to 4% of a 250-mg mefloquine dose was excreted in human milk (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablet, 2011). In addition, milk-to-plasma ratios have ranged from 0.13 to 0.16 over the first 4 days after administration (Edstein et al, 1988).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) Studies in adult human males, at doses of 250 mg once a week for 22 weeks, have not shown that mefloquine causes any adverse effects on spermatozoa (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablet, 2011).
    B) ANIMAL STUDIES
    1) Studies in rats given doses of 5, 20, and 50 mg/kg daily have shown that mefloquine causes adverse effects on fertility in males at doses of 50 mg/kg daily and in females at doses of 20 and 50 mg/kg daily. In addition, degenerative lesions in the epididymides of male rats have been reported at doses of 20 and 50 mg/kg daily (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablet, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Mefloquine concentrations are not readily available or useful to guide therapy.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG and institute continuous cardiac monitoring after a significant overdose.
    D) Monitor blood glucose and liver enzymes after a significant overdose.
    E) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the diagnosis is uncertain.
    F) CPK should be obtained if the patient has had psychomotor agitation or seizure activity.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum mefloquine levels are not widely available or clinically useful.
    2) Therapeutic use of mefloquine is associated with a decrease in blood glucose levels and an increase in serum insulin (Davis et al, 1996). Monitor blood glucose levels after significant overdose.
    3) Monitor liver enzymes following an overdose.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Institute continuous cardiac monitoring and obtain an ECG after significant overdose.

Methods

    A) CHROMATOGRAPHY
    1) Mefloquine concentrations can be measured in biologic fluids by HPLC (Bergqvist et al, 1988).

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 significant persistent central nervous stimulation and/or abnormal vital signs should be admitted. Patients with seizures, dysrhythmias, or any other life-threatening result of toxicity or intubated patients should be admitted to an intensive care setting.
    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 not clear.
    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 as symptoms of severe toxicity will likely develop within this time period. Symptomatic patients should be observed for 24 hours.

Monitoring

    A) Mefloquine concentrations are not readily available or useful to guide therapy.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG and institute continuous cardiac monitoring after a significant overdose.
    D) Monitor blood glucose and liver enzymes after a significant overdose.
    E) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the diagnosis is uncertain.
    F) CPK should be obtained if the patient has had psychomotor agitation or seizure activity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Activated charcoal should be avoided in the prehospital setting because of the risk of seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Mefloquine concentrations are not readily available or useful to guide therapy.
    2) Monitor vital signs and mental status.
    3) Obtain an ECG and institute continuous cardiac monitoring after a significant overdose.
    4) Monitor blood glucose and liver enzymes after a significant overdose.
    5) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the diagnosis is not clear.
    6) CPK should be obtained if the patient has had psychomotor agitation or seizure activity.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    2) ISOPROTERENOL INDICATIONS
    a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    D) VENTRICULAR ARRHYTHMIA
    1) Therapeutic doses of mefloquine cause slight prolongation of the QTc interval. In overdose, prolonged QTc may lead to ventricular dysrhythmias, including torsade de pointes, although this has not yet been reported.
    2) DO NOT use quinidine, procainamide or disopyramide as their effects may be additive.
    3) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    E) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis and hemoperfusion are unlikely to be of benefit because of the large volume of distribution and extensive protein binding of mefloquine.

Range Of Toxicity

Summary

    A) TOXICITY: The toxic dose of mefloquine in humans has not been established. A man developed severe neurologic disturbances (ie, agitation, progressive delirium, and generalized rigors), mydriasis, and hyperpyrexia after taking 1500 mg of mefloquine.
    B) THERAPEUTIC DOSE: ADULTS: 1250 mg as a single oral dose. CHILDREN: 20 to 25 mg/kg orally in 2 divided doses given 6 to 8 hours apart.

Therapeutic Dose

    7.2.1) ADULT
    A) MALARIA PROPHYLAXIS
    1) The recommended dose is 250 mg orally once a week; begin at least 2 weeks before departure (guideline dosing) (Arguin & Mali, 2013) or 1 week before departure (manufacturer dosing) (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013). Continue while in area, and for 4 weeks after leaving endemic area (Arguin & Mali, 2013; Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013).
    B) TREATMENT OF MILD TO MODERATE VIVAX OR FALCIPARUM MALARIA
    1) The recommended initial dose is 750 mg orally followed by 500 mg orally 6 to 12 hours after initial dose (guideline dosing) (Centers for Disease Control and Prevention (CDC), 2013) or 1250 mg orally as a single dose (manufacturer dosing) (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013).
    2) For Plasmodium vivax or P ovale malaria, give in combination with primaquine phosphate 52.6 mg orally daily for 14 days (guideline dosing) (Centers for Disease Control and Prevention (CDC), 2013).
    7.2.2) PEDIATRIC
    A) MALARIA PROPHYLAXIS
    1) AGE 6 MONTHS AND OLDER, WEIGHT LESS THAN 45 KG: 5 mg/kg orally once a week; begin at least 2 weeks before departure (guideline dosing) (Arguin & Mali, 2013) or 1 week before departure (manufacturer dosing) (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013). Continue while in area, and for 4 weeks after leaving endemic area (Arguin & Mali, 2013; Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013).
    2) AGE 6 MONTHS AND OLDER, WEIGHT GREATER THAN 45 KG: 250 mg orally once a week; begin at least 2 weeks before departure (guideline dosing) (Arguin & Mali, 2013) or 1 week before departure (manufacturer dosing) (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013). Continue while in area, and for 4 weeks after leaving endemic area (Arguin & Mali, 2013; Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013).
    B) TREATMENT OF MILD TO MODERATE VIVAX OR FALCIPARUM MALARIA
    1) Initial, 15 mg/kg orally followed by 10 mg/kg orally 6 to 12 hours after initial dose; total dose of 25 mg/kg, up to a maximum dose of 750 mg, with a maximum total dose of 1250 mg (guideline dosing) (Centers for Disease Control and Prevention (CDC), 2013) or (6 MONTHS OR OLDER) 20 to 25 mg/kg orally as single dose or in 2 divided doses 6 to 8 hours apart, with a maximum dose of 1250 mg (manufacturer dosing) (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013)
    2) For Plasmodium vivax or P ovale malaria, give in combination with primaquine phosphate 0.8 mg/kg orally daily for 14 days (guideline dosing) (Centers for Disease Control and Prevention (CDC), 2013).
    3) Vomiting within 30 minutes of initial dose; give a second full dose of mefloquine (manufacturer dosing) (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013).
    4) Vomiting within 30 to 60 minutes of initial dose; give an additional half-dose of mefloquine (manufacturer dosing) (Prod Info MEFLOQUINE HYDROCHLORIDE oral tablets, 2013).

Maximum Tolerated Exposure

    A) The toxic dose of mefloquine in humans has not been established.
    B) CASE REPORT: A 47-year-old man developed severe neurologic disturbances (ie, agitation, progressive delirium, and generalized rigors), mydriasis, and hyperpyrexia after taking 1500 mg of mefloquine. A diagnosis of central anticholinergic syndrome was made and physostigmine was given IV. Symptoms resolved one hour later (Speich & Haller, 1994).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Mefloquine is an antimalarial drug that directly acts as a Plasmodium schizonticide. It exhibits its effect on the erythrocytic stages of Plasmodium species although its exact mechanism of action is still unknown (Prod Info LARIAM(R) oral tablets, 2009).

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Anon: Pregnancy, breast-feeding, and travel. 2003-2004 information. Centers for Disease Control and Prevention. Atlanta, GA. 2003. Available from URL: http://www.cdc.gov/travel/pregnant.htm. As accessed 07/24/2003.
    4) Arguin PM & Mali S: Malaria. In: Centers for Disease Control and Prevention, Brunette GW, eds. CDC Health Information for International Travel 2014, The Yellow Book, Oxford University Press, New York, NY, 2013.
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