Mefloquine
Generic name: Mefloquine
Pronounced:
ME-floe-kwin
Brand name:Lariam
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DESCRIPTION
Lariam (mefloquine hydrochloride) is an antimalarial agent available
as 250-mg tablets of mefloquine hydrochloride (equivalent to 228.0
mg of the free base) for oral administration.
Mefloquine hydrochloride is a 4-quinolinemethanol derivative with
the specific chemical name of (R*, S*)-(±)-(alpha)-2-piperidinyl-2,8-bis
(trifluoromethyl)-4-quinolinemethanol hydrochloride. It is a 2-aryl
substituted chemical structural analog of quinine. The drug is
a white to almost white crystalline compound, slightly soluble
in water.
Mefloquine hydrochloride has a calculated molecular weight of
414.78 The inactive ingredients are ammonium-calcium alginate,
corn starch, crospovidone, lactose, magnesium stearate, microcrystalline
cellulose, poloxamer #331, and talc.
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CLINICAL
PHARMACOLOGY
Mefloquine is an antimalarial agent which acts as a blood schizonticide.
Its exact mechanism of action is not known.
Pharmacokinetic studies of mefloquine in healthy male subjects
showed that a significant lagtime occurred after drug administration,
and the terminal elimination half-life varied widely (13 to 24
days) with a mean of about 3 weeks. Mefloquine is a mixture of
enantiomeric molecules whose rates of release, absorption, transport,
action, degradation and elimination may differ. A valid pharmacokinetic
model may not exist in such a case.
Additional studies in European subjects showed slightly greater
concentrations of drug for longer periods of time. The absorption
half-life was 0.36 to 2 hours, and the terminal elimination half-life
was 15 to 33 days. The primary metabolite was identified and its
concentrations were found to surpass the concentrations of mefloquine.
Multiple-dose kinetic studies confirmed the long elimination half-lives
previously observed. The mean metabolite to mefloquine ratio measured
at steady-state was found to range between 2.3 and 8.6.
The total clearance of the drug, which is essentially all hepatic,
is approximately 30 mL/min. The volume of distribution, approximately
20 L/kg, indicates extensive distribution. The drug is highly
bound (98%) to plasma proteins and concentrated in blood erythrocytes,
the target cells in malaria, at a relatively constant erythrocyte-to-plasma
concentration ratio of about 2.
The pharmacokinetics of mefloquine in patients with compromised
renal function and compromised hepatic function have not been
studied.
In vitro and in vivo studies showed no hemolysis associated with
glucose-6-phosphate dehydrogenase deficiency (see ANIMAL TOXICOLOGY
).
Microbiology Strains of Plasmodium falciparum resistant to mefloquine
have been reported.
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INDICATIONS AND USAGE
Treatment of Acute Malaria Infections: Lariam 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 Lariam,
are at high risk of relapse because Lariam does not eliminate
exoerythrocytic (hepatic phase) parasites. To avoid relapse, after
initial treatment of the acute infection with Lariam, patients
should subsequently be treated with an 8-aminoquinoline (eg, primaquine).
Prevention of Malaria: Lariam is indicated for the prophylaxis
of P. falciparum and P. vivax malaria infections, including prophylaxis
of chloroquine-resistant strains of P. falciparum .
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CONTRAINDICATIONS
Use of Lariam is contraindicated in patients with a known hypersensitivity
to mefloquine or related compounds (eg, quinine and quinidine).
Lariam should not be prescribed for prophylaxis in patients with
active depression or with a history of psychosis or convulsions.
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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, Lariam may be given to complete the course of therapy.
Data on the use of halofantrine subsequent to administration of
Lariam suggests a significant, potentially fatal prolongation
of the QTc interval of the ECG. Therefore, halofantrine must not
be given simultaneously with or subsequent to Lariam. No data
are available on the use of Lariam after halofantrine (see PRECAUTIONS:
Drug Interactions ).
Concomitant administration of Lariam and quinine or quinidine
may produce electrocardiographic abnormalities.
Concomitant administration of Lariam and quinine or chloroquine
may increase the risk of convulsions.
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PRECAUTIONS
General: In patients with epilepsy, Lariam 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 ).
Caution should be exercised with regard to activities requiring
alertness and fine motor coordination such as driving, piloting
aircraft and operating machinery, 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 Lariam. These
effects may occur after therapy is discontinued due to the long
half-life of the drug. During prophylactic use, if signs of 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. Lariam should be used with caution
in patients with psychiatric disturbances because mefloquine use
has been associated with emotional disturbances (see ADVERSE REACTIONS
).
In patients with impaired liver function the elimination of mefloquine
may be prolonged, leading to higher plasma levels.
This 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.
Parenteral studies in animals show that mefloquine, a myocardial
depressant, possesses 20% of the antifibrillatory 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 Lariam 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: Patients should be advised:
• that malaria can be a life-threatening infection in the
traveler;
• that Lariam is 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, and it may be
necessary to change medications;
• that when used as prophylaxis, the first dose of Lariam
should be taken one week prior to departure;
• that if the patient experiences any symptom that may affect
the patient' ability to take this drug as prescribed, the physician
should be contacted and alternative antimalarial medication should
be considered;
• 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 inform their physician
that they may have been exposed to malaria.
Drug Interactions: Drug-drug interactions with
Lariam 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: General
). The effects of mefloquine on the compromised cardiovascular
system have not been evaluated. The benefits of Lariam therapy
should be weighed against the possibility of adverse effects in
patients with cardiac disease.
Because of the danger of a potentially fatal prolongation of the
QTc interval, halofantrine should not be given simultaneously
with or subsequent to Lariam (see WARNINGS ).
Concomitant administration of Lariam and other related compounds
(eg, quinine, quinidine and chloroquine) may produce electrocardiographic
abnormalities and increase the risk of convulsions (see CONTRAINDICATIONS
). If these drugs are to be used in the initial treatment of severe
malaria, Lariam administration should be delayed at least 12 hours
after the last dose. There is evidence that the use of halofantrine
after mefloquine causes a significant lengthening of the QTc interval.
Clinically significant QTc prolongation has not been found with
mefloquine alone.
This appears to be the only clinically relevant interaction of
this kind with Lariam, although theoretically, coadministration
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.
In patients taking an anticonvulsant (eg, valproic acid, carbamazepine,
phenobarbital or phenytoin), the concomitant use of Lariam may
reduce seizure control by lowering the plasma levels of the anticonvulsant.
Therefore, patients concurrently taking antiseizure medication
and Lariam should have the blood level of their antiseizure medication
monitored and the dosage adjusted appropriately (see PRECAUTIONS:
General ).
When Lariam 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 Lariam.
No other drug interactions are known. Nevertheless, the effects
of Lariam on travelers receiving comedication, particularly those
on anticoagulants or antidiabetics, should be checked before departure.
In clinical trials, the concomitant administration of sulfadoxine
and pyrimethamine did not alter the adverse reaction profile.
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.
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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 Lariam 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 Lariam.
Nursing Mothers: Mefloquine is excreted in human
milk. 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 Lariam to treat acute,
uncomplicated P. falciparum malaria in pediatric patients is supported
by evidence from adequate and well-controlled studies of Lariam
in adults with additional data from published open-label and comparative
trials using Lariam to treat malaria caused by P. falciparum in
patients younger than 16 years of age. The safety and effectiveness
of Lariam for the treatment of malaria in pediatric patients below
the age of 6 months have not been established.
In several studies, the administration of Lariam 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 ).
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ADVERSE
REACTIONS
Clinical 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
), and encephalopathy of unknown etiology during prophylactic
mefloquine administration. The relationship of encephalopathy
to drug administration could not be clearly established.
Postmarketing: Postmarketing surveillance indicates
that the same adverse experiences are reported during prophylaxis,
as well as acute treatment.
The most common adverse reactions to Lariam prophylaxis, namely
nausea, vomiting, and dizziness, are generally mild and may decrease
with prolonged use, in spite of increasing plasma drug levels.
In a large study of tourists receiving various prophylactic antimalarials,
the rate of subjects reporting adverse events on Lariam was similar
to that of tourists on chloroquine.
The most frequently reported adverse events are nausea, vomiting,
dizziness or vertigo, loss of balance, headache, somnolence, sleep
disorders (insomnia, abnormal dreams), loose stools or diarrhea,
and abdominal pain.
Less frequently reported adverse events:
Central and peripheral nervous system: convulsions,
depression, hallucinations, psychotic or paranoid reactions, anxiety,
agitation, aggression, confusion, forgetfulness, hearing impairment,
restlessness, sensory and motor neuropathies (including paresthesia),
tinnitus and vestibular disorders, visual disturbances. Suicidal
ideation has also rarely been reported, but no relationship to
drug administration has been established.
Cardiovascular system: circulatory disturbances
(hypotension, hypertension, flushing, syncope), tachycardia or
palpitations, bradycardia, irregular pulse, extrasystoles and
other transient cardiac conduction alterations.
Skin rash, exanthema, erythema, urticaria, pruritus, hair loss,
sweating.
Musculoskeletal system: muscle weakness, muscle cramps, myalgia,
arthralgia.
General symptoms: asthenia, malaise, fatigue,
fever, chills, loss of appetite.
Isolated cases of erythema multiforme, Stevens-Johnson syndrome,
AV-block, and encephalopathy, have been reported.
Laboratory The 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 Lariam may occur or persist up to several weeks after the last
dose.
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OVERDOSAGE
In cases of overdosage with Lariam, the symptoms mentioned under
ADVERSE REACTIONS may be more pronounced. The following procedure
is recommended in case of overdosage: Induce vomiting or perform
gastric lavage, as appropriate. Monitor cardiac function (if possible
by ECG) and neurologic and psychiatric status for at least 24
hours. Provide symptomatic and intensive supportive treatment
as required, particularly for cardiovascular disturbances. Treat
vomiting or diarrhea with standard fluid therapy.
DOSAGE AND ADMINISTRATION (see INDICATIONS AND
USAGE )
Adult Patients: Treatment 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 has been administered without clinical
cure, alternative treatment should be given. Similarly, if previous
prophylaxis with mefloquine has failed, Lariam should not be used
for curative treatment.
Note: Patients with acute P. vivax malaria, treated
with Lariam, are at high risk of relapse because Lariam does not
eliminate exoerythrocytic (hepatic phase) parasites. To avoid
relapse after initial treatment of the acute infection with Lariam,
patients should subsequently be treated with an 8-aminoquinoline
(eg, primaquine).
Malaria prophylaxis: One 250 mg Lariam tablet
once weekly.
Prophylactic drug administration should begin 1 week before departure
to an endemic area. Subsequent weekly doses should always be taken
on the same day of the week. To reduce the risk of malaria after
leaving an endemic area, prophylaxis should be continued for 4
additional weeks. 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.
Pediatric Patients: Treatment of mild to moderate
malaria in pediatric patients caused by mefloquine-susceptible
strains of P. falciparum: 20 to 25 mg/kg for non-immune patients.
Splitting the total curative dose into 2 doses taken 6 to 8 hours
apart may reduce the occurrence or severity of adverse effects.
Experience with Lariam in infants less than 3 months old or weighing
less than 5 kg is limited. The drug should not be taken on an
empty stomach and should be administered with ample water. For
very young patients, the dose may be crushed, mixed with water
or sugar water and may be administered via an oral syringe.
If a full-treatment course has been administered without clinical
cure, alternative treatment should be given. Similarly, if previous
prophylaxis with mefloquine has failed, Lariam should not be used
for curative treatment.
In pediatric patients, the administration of Lariam 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 Lariam 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 Lariam to treat malaria in pediatric
patients below the age of 6 months have not been established.
Malaria Prophylaxis: The following doses have been extrapolated
from the recommended adult dose. Neither the pharmacokinetics,
nor the clinical efficacy of these doses have been determined
in children owing to the difficulty of acquiring this information
in pediatric subjects. The recommended prophylactic dose of Lariam
is 3 to 5 mg/kg once weekly. One 250 mg Lariam 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: ¾ tablet
>20 to 30 kg: ½ tablet
up to 20 kg: ¼ tablet
Experience with Lariam in infants less than 3 months old or weighing
less than 5 kg is limited.
HOW
SUPPLIED
Lariam is available as scored, white, round tablets, containing
250 mg of mefloquine hydrochloride in unit-dose packages of 25
(NDC 0004-0172-02). Imprint on tablets: LARIAM 250 ROCHE
Tablets should be stored at 15° to 30°C (59° to 86°F).
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ANIMAL
TOXICOLOGY
Ocular lesions were observed in rats fed mefloquine daily for
2 years. All surviving rats given 30 mg/kg/day had ocular lesions
in both eyes characterized by retinal degeneration, opacity of
the lens, and retinal edema. Similar but less severe lesions were
observed in 80% of female and 22% of male rats fed 12.5 mg/kg/day
for 2 years. At doses of 5 mg/kg/day, only corneal lesions were
observed. They occurred in 9% of rats studied.
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