Mefloquinum

Uses

Mefloquinum is used for-

• Acute Malaria Infections caused by Mefloquinum-susceptible strains of Plasmodium falciparum (both chloroquine- susceptible and resistant strains) or by P. vivax
• Prophylaxis of P. falciparum and P. vivax malaria infections

Mefloquinum is also used to associated treatment for these conditions: Malaria caused by Plasmodium falciparum, Malaria caused by plasmodium vivax

How Mefloquinum works

The mechanism of action of mefloquine is not completely understood. Some studies suggest that mefloquine specifically targets the 80S ribosome of the Plasmodium falciparum, inhibiting protein synthesis and causing subsequent schizonticidal effects. There are other studies in the literature with limited in vitro data on mefloquine's mechanism of action.

Dosage

Mefloquinum dosage

Adult:

• Malaria prevention: 1 tablet (250 mg) once per week starting 1-2 weeks before departure and continued for 4 weeks after leaving malarious area.
• Malaria treatment: 5 tablets (5 x 250 mg) in a single dose (up to max. 1.5 gm) or preferably in 2 divided doses 6 to 8 hours apart.

In Children 6 Months and Older:

• Malaria prevention: Approximately 5 mg/kg body weight once per week (250 mg for children weighing over 45 kg, decreasing in proportion to body weight for children weighing 45 kg or less).
• Malaria treatment: 20 to 25 mg/kg body weight which may be split into two doses 6 to 8 hours apart to reduce the occurrence or severity of adverse reactions.

Geriatric Use: Experiences have not identified differences in responses between the elderly and younger patients.

Should be taken with food. Best taken with meals & a full glass of water.

Side Effects

Among subjects who received Mefloquinum for prophylaxis of malaria, following side effects was observed:

• The most frequently observed sied-effects were vomiting, dizziness, syncope, extrasystoles and other complaints affecting less than 1%. Among subjects who received Mefloquinum for treatment, following side-effects was observed:
• The most frequently observed side-effects included : dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhoea, skin rash, abdominal pain fatigue, loss of appetite, and tinnitus

Toxicity

The oral TDLO of mefloquine in humans is 11 mg/kg/2W (intermittent) and 880 mg/kg in the rat. Intraperitoneal LD50 in the rat is 130 mg/kg. Symptoms of an overdose with mefloquine may manifest as a worsening of adverse effects. In the case of an overdose, symptomatic and supportive care should be provided. There is no known antidote for an overdose with mefloquine. Monitor cardiac function by ECG, follow neuropsychiatric status for at least 24 hours, and provide treatment as required.

Precaution

Warnings: Mefloquinum may cause psychiatric symptoms in a number of patients, ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior. Rare cases of suicidal ideation and suicide have been reported though no relationship to drug administration has been confirmed. Mefloquinum should be used with caution in patients with a previous history of depression. Concomitant administration of Mefloquinum and quinine or quinidine may produce electrocardiographic abnormalities and may increase risk of convulsions.

Precautions: In patients with epilepsy, Mefloquinum may increase the risk of convulsions. Caution should be exercised with regard to activities requiring alertness and fine motor coordination such as driving, piloting aircraft and operating machinery. Mefloquinum should be used with caution in patients with psychiatric disturbances. In patients with impaired liver function the elimination of Mefloquinum may be prolonged, leading to higher plasma levels.

Interaction

Increased risk of ECG abnormalities with quinine or chloroquine, antihistamines, TCAs and phenothiazines. May increase risk of seizure with quinidine or quinine. Concomitant use with valproic acid, phenobarbital, carbamazepine and phenytoin may cause loss of seizure control and lower plasma levels of anticonvulsants. Increased risk of QT prolongation and arrhythmia with ketoconazole. Concomitant use with digoxin, Ca channel blockers, antiarrhythmics and β-blockers may increase the risk of cardiotoxicity. Increased risk of ventricular arrhythmias with amiodarone. Concomitant use with TCAs, SSRIs, buprion, antipsychotic, tramadol may increase the risk of convulsions. Increased plasma levels with metoclopromide. May compromise adequate immunisation by live typhoid vaccine. Vaccinations with attenuated live bacteria should be completed at least 3 days prior the 1st dose of mefloquine.

Food Interaction

• Avoid alcohol.
• Take with a full glass of water.
• Take with food. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability.

[Moderate] ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of mefloquine.

The proposed mechanism is increased drug solubility in the presence of food.

In 20 healthy volunteers, administration of a single 750 mg oral dose of mefloquine 30 minutes following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of mefloquine by 73% and 40%, respectively, compared to administration in the fasting state.

The Cmax and AUC of the carboxylic acid metabolite were also increased by 35% and 33%, respectively, compared to fasting.

In addition, the time to reach peak plasma concentration (Tmax) of mefloquine was significantly shorter after food intake (17 hours) than in the fasting state (36 hours).

There was no difference in the elimination half-life of mefloquine and metabolite, or the Tmax for the metabolite.

MANAGEMENT: To ensure maximal oral absorption, mefloquine should be administered immediately after a meal with at least 8 ounces of water.

Mefloquinum Drug Interaction

Moderate: hydroxyzine, ciprofloxacin, dexamethasone, pregabalin, quetiapineUnknown: zolpidem, celecoxib, omega-3 polyunsaturated fatty acids, cyclobenzaprine, atovaquone / proguanil, acetaminophen, montelukast, oseltamivir, acetaminophen, cyanocobalamin, pyridoxine, ascorbic acid, cholecalciferol, alprazolam, cetirizine

Mefloquinum Disease Interaction

Major: psychosis/depression, seizuresModerate: ECG abnormalities, liver disease

Volume of Distribution

The apparent volume of distribution is in healthy adults is about 20 L/kg with wide tissue distribution. Various estimates of the total apparent volume of distribution range from 13.3 to 40.9L/kg. Mefloquinum can accumulate in erythrocytes that have been infected with malaria parasites.

Elimination Route

Mefloquinum is readily absorbed from the gastrointestinal tract; food significantly increases absorption and increases bioavailability by 40%. The bioavailability of tablets compared with the oral solution preparation of mefloquine is over 85%. Cmax is achieved in 6 to 24 hours in healthy volunteers after a single dose. Average blood concentrations range between 50 to 110 ng/ml/mg/kg. A weekly dose of 250 mg leads to steady-state plasma concentrations of 1000 to 2000 μg/L, after 7 to 10 weeks of administration.

Half Life

The terminal elimination half-life of mefloquine ranges from 0.9 - 13.8 days, according to one pharmacokinetic review. In various studies of healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with a mean half-life of approximately 21 days.

Clearance

The systemic clearance of mefloquine ranges from 0.022 to 0.073 L/h/kg, with an increased clearance during pregnancy. Prescribing information mentions a clearance rate of 30 mL/min.

Elimination Route

Mefloquinum is believed to be excreted in the bile and feces. In healthy volunteers who have achieved steady-state concentrations of mefloquine, the unchanged drug was excreted at 9% of the ingested dose, and excretion of its carboxylic metabolite under was measured at 4% of the ingested dose. Concentrations of other metabolites could not be determined.

Pregnancy & Breastfeeding use

Use in Pregnancy: There is no adequate and well-controlled study in pregnant women. However, clinical experience with Mefloquinum has not revealed an embrytoxic or teratogenic effect. Mefloquinum should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in Nursing Mothers: Mefloquinum is excreted in breast milk in small amounts. the activity of which is unknown. Because of the potential for serious adverse reactions in nursing infants form Mefloquinum. a decision should be made whether to discontinue the drug taking into account the importance of the drug to the mother.

Contraindication

Use of Mefloquinum is contraindicated in patients with a known hypersensitivity to Mefloquinum or related compounds (e.g. quinine and quinidine). It 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.

Acute Overdose

In cases of overdosage with Mefloquinum, the symptoms 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), neurologic and psychiatric status for at least 24 hours.
• Provide Symptomatic and intensive supportive treatment as required, particularly of cardiovascular disturbance.
• Treat vomiting or diarrhoea with standard fluid therapy.

Storage Condition

Store in a cool dry place. Protect from light.

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