Mefloquine warnings and precautions

# Warnings
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, mefloquine may be given to complete the course of therapy.

## QTc Interval Prolongation and Drug Interactions
Halofantrine should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval (see Clinical Pharmacology, Pharmacokinetics, Elimination).
Ketoconazole should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval. Ketoconazole increases plasma concentrations and elimination half-life of mefloquine following coadministration (see Clinical Pharmacology, Pharmacokinetics, Elimination and Precautions, Drug Interactions).
Concomitant administration of mefloquine and quinine or quinidine may produce electrocardiographic abnormalities.

## Psychiatric and Neurologic Adverse Reactions
Mefloquine may cause neuropsychiatric adverse reactions in adults and children. Neuropsychiatric symptoms can be difficult to identify in children. Therefore, vigilance is required to monitor for the occurrence of these symptoms, especially in nonverbal children.

## Psychiatric Adverse Reactions
Psychiatric symptoms ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior can occur with mefloquine use. Symptoms may occur early in the course of mefloquine use. In some cases, these symptoms have been reported to continue for months or years after mefloquine has been stopped. Cases of suicidal ideation and suicide have been reported.
Mefloquine should not be prescribed for prophylaxis in patients with active depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders. Mefloquine should be used with caution in patients with a previous history of depression.
During prophylactic use, the occurrence of psychiatric symptoms such as acute anxiety, depression, restlessness or confusion suggest a risk for more serious psychiatric disturbances or neurologic adverse reactions. In these cases, the drug should be discontinued and an alternative medication should be substituted.

## Neurologic Adverse Reactions
Neurologic symptoms such as dizziness or vertigo, tinnitus, and loss of balance have been reported. These adverse reactions may occur early in the course of mefloquine use and in some cases have been reported to continue for months or years after mefloquine has been stopped. Dizziness or vertigo, tinnitus, and loss of balance have been reported to be permanent in some cases. During prophylactic use, if neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.
Caution should be exercised with regard to activities requiring alertness and fine motor coordination, such as driving, piloting aircraft, operating machinery, and deep-sea diving, while symptoms persist.
Mefloquine may increase the risk of convulsions in patients with epilepsy. 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).
Concomitant administration of mefloquine and quinine or chloroquine may increase the risk of convulsions.

# Precautions

## Hypersensitivity Reactions
Hypersensitivity reactions have been reported with mefloquine use.

## Use in Patients with Hepatic Impairment
In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels and a higher risk of adverse reactions.

## Long-Term Use
This drug has been administered for longer than one year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests and evaluations for neuropsychiatric effects should be performed (see Warnings  And Adverse Reactions, Postmarketing).
Periodic ophthalmic examinations are recommended. Retinal abnormalities seen in humans with long-term chloroquine use have not been observed with mefloquine use, however, 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).

## Cardiac Effects
Parenteral 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 mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.

## Drug Resistance and Cross-Resistance
Geographical drug resistance patterns of P. falciparum occur and the preferred choice of malaria prophylaxis might be different from one area to another. For example, resistance of P. falciparum to mefloquine has been reported, predominantly in areas of multi-drug resistance in South-East Asia. Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions.

## Agranulocytosis and Aplastic Anemia
Cases of agranulocytosis and aplastic anemia have been reported (see Adverse Reactions).

## Laboratory Tests
Periodic evaluation of hepatic function should be performed during prolonged prophylaxis.

## Information for Patients
Medication Guide: As required by law, a mefloquine hydrochloride tablets Medication Guide is supplied to patients when mefloquine is dispensed. An information wallet card is also supplied to patients when mefloquine is dispensed. Patients should be instructed to read the Medication Guide when mefloquine is received and to carry the information wallet card with them when they are taking mefloquine. The complete texts of the Medication Guide and information wallet card are reprinted at the end of this document.

## Patients should be advised
- that malaria can be a life-threatening infection
- that mefloquine hydrochloride tablets are being prescribed to help prevent or treat this serious infection;
- that some patients are unable to take this medication because of side effects, including dizziness or vertigo and loss of balance, and it may be necessary to change medications. In some patients it has been reported that these symptoms may continue for months or years after discontinuation of the drug and can be permanent in some cases;
- that insomnia may occur
- that when used as prophylaxis, the first dose of mefloquine hydrochloride tablets should be taken one week prior to arrival in an endemic area;
- that if the patients experience psychiatric adverse reactions such as acute anxiety, depression, restlessness or confusion, or suicidal ideation, the drug should be discontinued and an alternative medication should be substituted;
- that no chemoprophylactic regimen is 100% effective, and protective clothing, insect repellents, and bed nets are important components of malaria prophylaxis;
- to seek medical attention for any febrile illness that occurs after return from a malaria area and to inform their physician that they may have been exposed to malaria.