In cases of overdosage with Tropicur, the symptoms mentioned under ADVERSE REACTIONS may be more pronounced.
TreatmentPatients should be managed by symptomatic and supportive care following Tropicur (mefloquine) overdose. There are no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status for at least 24 hours. Provide symptomatic and intensive supportive treatment as required, particularly for cardiovascular disturbances.
Use of Tropicur (mefloquine) is contraindicated in patients with a known hypersensitivity to mefloquine or related compounds (eg, quinine and quinidine) or to any of the excipients contained in the formulation. Tropicur (mefloquine) should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders, or with a history of convulsions.
At the doses used for treatment of acute malaria infections, the symptoms possibly attributable to drug administration cannot be distinguished from those symptoms usually attributable to the disease itself.
Among subjects who received mefloquine for prophylaxis of malaria, the most frequently observed adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other complaints affecting less than 1% were also reported.
Among subjects who received mefloquine for treatment, the most frequently observed adverse experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhea, skin rash, abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less than 1% included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient emotional disturbances and telogen effluvium (loss of resting hair). Seizures have also been reported.
Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after ingesting a single prophylactic dose of mefloquine while concomitantly using propranolol (see PRECAUTIONS: DRUG INTERACTIONS), and encephalopathy of unknown etiology during prophylactic mefloquine administration. The relationship of encephalopathy to drug administration could not be clearly established.
PostmarketingPostmarketing surveillance indicates that the same kind of adverse experiences are reported during prophylaxis, as well as acute treatment. Because these experiences are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Tropicur (mefloquine) exposure.
The most frequently reported adverse events are nausea, vomiting, loose stools or diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence, and sleep disorders (insomnia, abnormal dreams). These are usually mild and may decrease despite continued use. In a small number of patients it has been reported that dizziness or vertigo and loss of balance may continue for months after discontinuation of the drug.
Occasionally, more severe neuropsychiatric disorders have been reported such as: sensory and motor neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or restlessness, anxiety, depression, mood changes, panic attacks, forgetfulness, confusion, hallucinations, aggression, psychotic or paranoid reactions and encephalopathy. Rare cases of suicidal ideation and suicide have been reported though no relationship to drug administration has been confirmed.
Other infrequent adverse events include:
Cardiovascular Disorders: circulatory disturbances (hypotension, hypertension, flushing, syncope), chest pain, tachycardia or palpitation, bradycardia, irregular pulse, extrasystoles, A-V block, and other transient cardiac conduction alterations
Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema multiforme, and Stevens-Johnson syndrome
Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and arthralgia
Respiratory Disorders: dyspnea, pneumonitis of possible allergic etiology
Other Symptoms: visual disturbances, vestibular disorders including tinnitus and hearing impairment, asthenia, malaise, fatigue, fever, sweating, chills, dyspepsia and loss of appetite
LaboratoryThe most frequently observed laboratory alterations which could be possibly attributable to drug administration were decreased hematocrit, transient elevation of transaminases, leukopenia and thrombocytopenia. These alterations were observed in patients with acute malaria who received treatment doses of the drug and were attributed to the disease itself.
During prophylactic administration of mefloquine to indigenous populations in malaria-endemic areas, the following occasional alterations in laboratory values were observed: transient elevation of transaminases, leukocytosis or thrombocytopenia.
Because of the long half-life of mefloquine, adverse reactions to Tropicur (mefloquine) may occur or persist up to several weeks after the last dose.
Tropicur (mefloquine) is indicated for the treatment of mild to moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by Plasmodium vivax. There are insufficient clinical data to document the effect of mefloquine in malaria caused by P. ovale or P. malariae.
Note: Patients with acute P. vivax malaria, treated with Tropicur (mefloquine) , are at high risk of relapse because Tropicur (mefloquine) does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse, after initial treatment of the acute infection with Tropicur (mefloquine) , patients should subsequently be treated with an 8-aminoquinoline derivative (eg, primaquine).
Prevention of MalariaTropicur (mefloquine) is indicated for the prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.
The absolute oral bioavailability of mefloquine has not been determined since an intravenous formulation is not available. The bioavailability of the tablet formation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24 hours (median, about 17 hours) after a single dose of Tropicur (mefloquine). In a similar group of volunteers, maximum plasma concentrations in µg/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 µg/L). In healthy volunteers, a dose of 250 mg once weekly produces maximum steady-state plasma concentrations of 1000 to 2000 µg/L, which are reached after 7 to 10 weeks.
DistributionIn healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes was found to be reversible. Protein binding is about 98%.
Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal (see PRECAUTIONS: Nursing Mothers).
MetabolismTwo metabolites have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.
EliminationIn several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite under steady-state condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other metabolites could not be measured in the urine.
In case of life-threatening, serious or overwhelming malaria infections due to P. falciparum, patients should be treated with an intravenous antimalarial drug. Following completion of intravenous treatment, Tropicur (mefloquine) may be given to complete the course of therapy.
Data on the use of halofantrine subsequent to administration of Tropicur (mefloquine) suggest a significant, potentially fatal prolongation of the QTc interval of the ECG. Therefore, halofantrine must not be given simultaneously with or subsequent to Tropicur (mefloquine). No data are available on the use of Tropicur (mefloquine) after halofantrine (see PRECAUTIONS: DRUG INTERACTIONS).
Mefloquine may cause psychiatric symptoms in a number of patients, ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior. On occasions, these symptoms have been reported to continue long after mefloquine has been stopped. Rare cases of suicidal ideation and suicide have been reported though no relationship to drug administration has been confirmed. To minimize the chances of these adverse events, mefloquine should not be taken for prophylaxis in patients with active depression or with a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders. Tropicur (mefloquine) should be used with caution in patients with a previous history of depression.
During prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.
Concomitant administration of Tropicur (mefloquine) and quinine or quinidine may produce electrocardiographic abnormalities.
Concomitant administration of Tropicur (mefloquine) and quinine or chloroquine may increase the risk of convulsions.
PRECAUTIONS Hypersensitivity ReactionsHypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be predicted.
In patients with epilepsy, Tropicur (mefloquine) may increase the risk of convulsions. The drug should therefore be prescribed only for curative treatment in such patients and only if there are compelling medical reasons for its use (see PRECAUTIONS: DRUG INTERACTIONS).
Central and Peripheral Nervous System EffectsCaution should be exercised with regard to activities requiring alertness and fine motor coordination such as driving, piloting aircraft, operating machinery, and deep-sea diving, as dizziness, a loss of balance, or other disorders of the central or peripheral nervous system have been reported during and following the use of Tropicur (mefloquine). These effects may occur after therapy is discontinued due to the long half-life of the drug. In a small number of patients, dizziness and loss of balance have been reported to continue for months after mefloquine has been stopped (see ADVERSE REACTIONS: Postmarketing).
Tropicur (mefloquine) should be used with caution in patients with psychiatric disturbances because mefloquine use has been associated with emotional disturbances (see ADVERSE REACTIONS).
Use in Patients with Hepatic ImpairmentIn patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels.
Long-Term UseThis drug has been administered for longer than 1 year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests should be performed.
Although retinal abnormalities seen in humans with long-term chloroquine use have not been observed with mefloquine use, long-term feeding of mefloquine to rats resulted in dose-related ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher) (see Animal Toxicology). Therefore, periodic ophthalmic examinations are recommended.
Cardiac EffectsParenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the anti-fibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated. However, transitory and clinically silent ECG alterations have been reported during the use of mefloquine. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block, prolongation of the QTc interval and abnormal T waves (see also cardiovascular effects under PRECAUTIONS: DRUG INTERACTIONS and ADVERSE REACTIONS). The benefits of Tropicur (mefloquine) therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
Laboratory TestsPeriodic evaluation of hepatic function should be performed during prolonged prophylaxis.
Information for PatientsMedication Guide: As required by law, a Tropicur (mefloquine) Medication Guide is supplied to patients when Tropicur (mefloquine) is dispensed. An information wallet card is also supplied to patients when Tropicur (mefloquine) is dispensed. Patients should be instructed to read the Medication Guide when Tropicur (mefloquine) is received and to carry the information wallet card with them when they are taking Tropicur. The complete texts of the Medication Guide and information wallet card are reprinted at the end of this document.
Patients should be advised:
The carcinogenic potential of mefloquine was studied in rats and mice in 2-year feeding studies at doses of up to 30 mg/kg/day. No treatment-related increases in tumors of any type were noted.
MutagenesisThe mutagenic potential of mefloquine was studied in a variety of assay systems including: Ames test, a host-mediated assay in mice, fluctuation tests and a mouse micronucleus assay. Several of these assays were performed with and without prior metabolic activation. In no instance was evidence obtained for the mutagenicity of mefloquine.
Impairment of FertilityFertility studies in rats at doses of 5, 20, and 50 mg/kg/day of mefloquine have demonstrated adverse effects on fertility in the male at the high dose of 50 mg/kg/day, and in the female at doses of 20 and 50 mg/kg/day. Histopathological lesions were noted in the epididymides from male rats at doses of 20 and 50 mg/kg/day. Administration of 250 mg/week of mefloquine (base) in adult males for 22 weeks failed to reveal any deleterious effects on human spermatozoa.
Pregnancy Teratogenic EffectsPregnancy Category C. Mefloquine has been demonstrated to be teratogenic in rats and mice at a dose of 100 mg/kg/day. In rabbits, a high dose of 160 mg/kg/day was embryotoxic and teratogenic, and a dose of 80 mg/kg/day was teratogenic but not embryotoxic. There are no adequate and well-controlled studies in pregnant women. However, clinical experience with Tropicur (mefloquine) has not revealed an embryotoxic or teratogenic effect. Mefloquine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women of childbearing potential who are traveling to areas where malaria is endemic should be warned against becoming pregnant. Women of childbearing potential should also be advised to practice contraception during malaria prophylaxis with Tropicur (mefloquine) and for up to 3 months thereafter. However, in the case of unplanned pregnancy, malaria chemoprophylaxis with Tropicur (mefloquine) is not considered an indication for pregnancy termination.
Nursing MothersMefloquine is excreted in human milk in small amounts, the activity of which is unknown. Based on a study in a few subjects, low concentrations (3% to 4%) of mefloquine were excreted in human milk following a dose equivalent to 250 mg of the free base. Because of the potential for serious adverse reactions in nursing infants from mefloquine, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseUse of Tropicur (mefloquine) to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by evidence from adequate and well-controlled studies of Tropicur (mefloquine) in adults with additional data from published open-label and comparative trials using Tropicur (mefloquine) to treat malaria caused by P. falciparum in patients younger than 16 years of age. The safety and effectiveness of Tropicur (mefloquine) for the treatment of malaria in pediatric patients below the age of 6 months have not been established.
In several studies, the administration of Tropicur (mefloquine) for the treatment of malaria was associated with early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of treatment failure. If a second dose is not tolerated, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time (see DOSAGE AND ADMINISTRATION).
Geriatric UseClinical studies of Tropicur (mefloquine) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Since electrocardiographic abnormalities have been observed in individuals treated with Tropicur (mefloquine) (see PRECAUTIONS) and underlying cardiac disease is more prevalent in elderly than in younger patients, the benefits of Tropicur (mefloquine) therapy should be weighed against the possibility of adverse cardiac effects in elderly patients.
(see INDICATIONS)
Adult PatientsTreatment of mild to moderate malaria in adults caused by P. vivax or mefloquine-susceptible strains of P. falciparum
Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral dose. The drug should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.
If a full-treatment course with Tropicur (mefloquine) does not lead to improvement within 48 to 72 hours, Tropicur (mefloquine) should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, Tropicur (mefloquine) should not be used for curative treatment.
Note: Patients with acute P. vivax malaria, treated with Tropicur (mefloquine) , are at high risk of relapse because Tropicur (mefloquine) does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse after initial treatment of the acute infection with Tropicur (mefloquine) , patients should subsequently be treated with an 8-aminoquinoline derivative (eg, primaquine).
Malaria ProphylaxisOne 250 mg Tropicur (mefloquine) tablet once weekly.
Prophylactic drug administration should begin 1 week before arrival in an endemic area. Subsequent weekly doses should be taken regularly, always on the same day of each week, preferably after the main meal. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued for 4 additional weeks to ensure suppressive blood levels of the drug when merozoites emerge from the liver. Tablets should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.
In certain cases, eg, when a traveler is taking other medication, it may be desirable to start prophylaxis 2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is well tolerated (see PRECAUTIONS: DRUG INTERACTIONS).
When prophylaxis with Tropicur (mefloquine) fails, physicians should carefully evaluate which antimalarial to use for therapy.
Pediatric PatientsTreatment of mild to moderate malaria in pediatric patients caused by mefloquine-susceptible strains of P. falciparum
Twenty (20) to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses taken 6 to 8 hours apart may reduce the occurrence or severity of adverse effects. Experience with Tropicur (mefloquine) in pediatric patients weighing less than 20 kg is limited. The drug should not be taken on an empty stomach and should be administered with ample water. The tablets may be crushed and suspended in a small amount of water, milk or other beverage for administration to small children and other persons unable to swallow them whole.
If a full-treatment course with Tropicur (mefloquine) does not lead to improvement within 48 to 72 hours, Tropicur (mefloquine) should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, Tropicur (mefloquine) should not be used for curative treatment.
In pediatric patients, the administration of Tropicur (mefloquine) for the treatment of malaria has been associated with early vomiting. In some cases, early vomiting has been cited as a possible cause of treatment failure (see PRECAUTIONS). If a significant loss of drug product is observed or suspected because of vomiting, a second full dose of Tropicur (mefloquine) should be administered to patients who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60 minutes after a dose, an additional half-dose should be given. If vomiting recurs, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.
The safety and effectiveness of Tropicur (mefloquine) to treat malaria in pediatric patients below the age of 6 months have not been established.
Malaria ProphylaxisThe recommended prophylactic dose of Tropicur (mefloquine) is approximately 5 mg/kg body weight once weekly. One 250 mg Tropicur (mefloquine) tablet should be taken once weekly in pediatric patients weighing over 45 kg. In pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body weight:
| 30 to 45 kg: | 3/4 tablet |
| 20 to 30 kg: | 1/2 tablet |
Experience with Tropicur (mefloquine) in pediatric patients weighing less than 20 kg is limited.
