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.
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
co-administration (see CLINICAL
PHARMACOLOGY: Pharmacokinetics:
Elimination
and 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. 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 mefloquine and quinine or
quinidine may produce electrocardiographic abnormalities.
Concomitant administration of mefloquine and quinine or
chloroquine may increase the risk of convulsions.
PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions ranging from mild cutaneous events to
anaphylaxis cannot be predicted.
In patients with epilepsy, 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 Effects
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, as dizziness or vertigo, a loss of
balance, or other disorders of the central or peripheral nervous system have
been reported during and following the use of 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 or vertigo and loss of balance have been
reported to continue for months after discontinuation of the drug (see
ADVERSE REACTIONS:
Postmarketing).
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 Impairment
In patients with impaired liver function the elimination of
mefloquine may be prolonged, leading to higher plasma levels.
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 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 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.
Laboratory Tests
Periodic evaluation of hepatic function should be performed
during prolonged prophylaxis.
Information for Patients
Medication Guide: As required by law, a Mefloquine 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 in the traveler;
- that mefloquine hydrochloride tablets are being prescribed to help prevent
or treat this serious infection;
- that in a small percentage of cases, 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. Although side effects of
dizziness or vertigo and loss of balance are usually mild and do not cause
people to stop taking the medication, in a small number of patients it has been
reported that these symptoms may continue for months after discontinuation of
the drug;
- 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 symptoms such as acute anxiety,
depression, restlessness or confusion, 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;
- that no chemoprophylactic regimen is 100% effective, and protective
clothing, insect repellents, and bednets are important components of malaria
prophylaxis;
- to seek medical attention for any febrile illness that occurs after return
from a malarious area and to inform their physician that they may have been
exposed to malaria.
Drug Interactions
Drug-drug interactions with mefloquine have not been explored in
detail. There is one report of cardiopulmonary arrest, with full recovery, in a
patient who was taking a beta blocker (propranolol) (see
PRECAUTIONS: Cardiac
Effects). The effects of mefloquine on the compromised cardiovascular
system have not been evaluated. The benefits of mefloquine therapy should be
weighed against the possibility of adverse effects in patients with cardiac
disease.
Halofantrine and Other Antimalarials
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
WARNINGS).
Concomitant administration of mefloquine and other related antimalarial
compounds (eg, quinine, quinidine and chloroquine) may produce
electrocardiographic abnormalities and increase the risk of convulsions (see
WARNINGS). If these
drugs are to be used in the initial treatment of severe malaria, mefloquine
administration should be delayed at least 12 hours after the last dose.
Clinically significant QTc prolongation has not been found with mefloquine
alone.
Ketoconazole (Potent Inhibitor of CYP3A4)
Co-administration of a single 500 mg oral dose of mefloquine with
400 mg of ketoconazole once daily for 10 days in 8 healthy volunteers resulted
in an increase in the mean Cmax and AUC of mefloquine by
64% and 79%, respectively, and an increase in the mean elimination half-life of
mefloquine from 322 hours to 448 hours. 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 (see WARNINGS).
Other Drugs that Prolong the QTc Interval
Co-administration of other drugs known to alter cardiac
conduction (eg, anti-arrhythmic or beta-adrenergic blocking agents, calcium
channel blockers, antihistamines or H1-blocking agents,
tricyclic antidepressants and phenothiazines) might also contribute to a
prolongation of the QTc interval. There are no data that conclusively establish
whether the concomitant administration of mefloquine and the above listed agents
has an effect on cardiac function.
Anticonvulsants
In patients taking an anticonvulsant (eg, valproic acid,
carbamazepine, phenobarbital or phenytoin), the concomitant use of mefloquine
may reduce seizure control by lowering the plasma levels of the anticonvulsant.
Therefore, patients concurrently taking antiseizure medication and mefloquine
should have the blood level of their antiseizure medication monitored and the
dosage adjusted appropriately (see
PRECAUTIONS).
Vaccines
When mefloquine is taken concurrently with oral live typhoid
vaccines, attenuation of immunization cannot be excluded. Vaccinations with
attenuated live bacteria should therefore be completed at least 3 days before
the first dose of mefloquine hydrochloride tablets.
Rifampin (Potent Inducer of CYP3A4)
Co-administration of a single 500 mg oral dose of mefloquine and
600 mg of rifampin once daily for 7 days in 7 healthy Thai volunteers resulted
in a decrease in the mean Cmax and AUC of mefloquine by
19% and 68%, respectively, and a decrease in the mean elimination half-life of
mefloquine from 305 hours to 113 hours. Rifampin should be used cautiously in
patients taking mefloquine.
Inhibitors and Inducers of CYP3A4
Mefloquine does not inhibit or induce the CYP 450 enzyme system.
Thus, concomitant administration of mefloquine and substrates of the CYP 450
enzyme system is not expected to result in a drug interaction. However,
co-administration of CYP 450 inhibitors or inducers may increase or decrease
mefloquine plasma concentrations, respectively.
Substrates and Inhibitors of P-glycoprotein
It has been shown in vitro that
mefloquine is a substrate and an inhibitor of P-glycoprotein. Therefore,
drug-drug interactions could also occur with drugs that are substrates or are
known to modify the expression of this transporter. The clinical relevance of
these interactions is not known to date.
Other Potential Interactions
No other drug interactions are known. Nevertheless, the effects
of mefloquine on travelers receiving comedication, particularly diabetics or
patients using anticoagulants, should be checked before departure.
In clinical trials, the concomitant administration of sulfadoxine and
pyrimethamine did not alter the adverse reaction profile of mefloquine.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Carcinogenesis
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.
Mutagenesis
The 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 Fertility
Fertility 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 Effects
Pregnancy 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 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
mefloquine and for up to 3 months thereafter. However, in the case of unplanned
pregnancy, malaria chemoprophylaxis with mefloquine is not considered an
indication for pregnancy termination.
Nursing Mothers
Mefloquine 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 Use
Use of mefloquine to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by
evidence from adequate and well-controlled studies of mefloquine in adults with
additional data from published open-label and comparative trials using
mefloquine to treat malaria caused by P. falciparum
in patients younger than 16 years of age. The safety and effectiveness of
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 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 Use
Clinical studies of 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 mefloquine (see
PRECAUTIONS) and underlying cardiac
disease is more prevalent in elderly than in younger patients, the benefits of
mefloquine therapy should be weighed against the possibility of adverse cardiac
effects in elderly patients.
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