Mefloquine

Usage

• Mefloquine is prescribed for the prevention and treatment of malaria, caused by mefloquine-susceptible strains of Plasmodium falciparum (both chloroquine-susceptible and resistant strains) and Plasmodium vivax.
• Pharmacological Classification: Antimalarial.
• Mechanism of Action: Mefloquine destroys the malaria parasite within red blood cells by inhibiting heme polymerization. It accumulates in infected red blood cells where it forms toxic complexes with heme, a substance released during hemoglobin digestion by the parasite. This build-up disrupts the parasite’s metabolic processes and ultimately leads to its death.

Alternate Names

• Mefloquine hydrochloride
• Brand Name: Lariam (no longer marketed in the US)

How It Works

• Pharmacodynamics: Mefloquine concentrates within parasitized red blood cells, interfering with the parasite’s ability to detoxify heme, a byproduct of hemoglobin breakdown. This heme accumulation is toxic to the malaria parasite. Mefloquine also appears to interfere with parasite DNA replication and protein synthesis, thus halting parasite growth and multiplication.
• Pharmacokinetics:
  • Absorption: Well-absorbed orally, enhanced by food intake.
  • Metabolism: Hepatic metabolism (mainly via CYP3A4), with a long elimination half-life (2-4 weeks).
  • Elimination: Primarily biliary excretion, with minimal renal clearance.
• Mode of Action: Blood schizonticide and some tissue schizonticidal activity.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: The precise molecular mechanisms of mefloquine’s action are not fully elucidated. Although it appears to bind to parasite DNA, specific receptors have not yet been identified.
• Elimination Pathways: Primarily biliary excretion, with a small fraction (<10%) excreted unchanged in urine.

Dosage

Standard Dosage

Adults:

• Treatment: 1250 mg (five 250 mg tablets or a single 1250 mg dose) orally as a single dose. A divided dose (two doses 6-8 hours apart) may reduce gastrointestinal side effects.
• Prevention: 250 mg orally once a week, starting 1-3 weeks before travel to a malaria-endemic area. Continue weekly dosing during travel and for 4 weeks after leaving the area.

Children:

• Treatment: 20-25 mg/kg as a single dose or divided into two doses (6-8 hours apart). The doctor should always determine the dose.
• Prevention: Based on weight:

  • 45 kg: Same as adult dose

  • 30-45 kg: 187.5 mg (¾ tablet) weekly
  • 20-30 kg: 125 mg (½ tablet) weekly
  • 10-19 kg: 62.5 mg (¼ tablet) weekly
• Children under 6 months: Use and dosage must be determined by a doctor.

Special Cases:

• Elderly Patients: Dosage adjustments may be needed due to potential age-related decline in liver and kidney function. Monitor closely.
• Patients with Renal Impairment: Dose adjustments usually not necessary due to minimal renal excretion.
• Patients with Hepatic Dysfunction: Use with caution, as mefloquine is primarily metabolized by the liver. Close monitoring and dose adjustments may be required.
• Patients with Comorbid Conditions: Pre-existing psychiatric conditions (e.g., depression, anxiety, psychosis) or seizure disorders are contraindications. Caution is advised in patients with cardiac conduction abnormalities.

Clinical Use Cases

Mefloquine is specifically indicated for malaria prevention and treatment, not for the listed clinical settings (Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations). These procedures are not relevant to mefloquine’s therapeutic use.

Dosage Adjustments

Dose modification is not usually required except for hepatic dysfunction and comorbid conditions mentioned above.

Side Effects

Common Side Effects

• Nausea, vomiting, diarrhea, abdominal discomfort
• Headache, dizziness, lightheadedness
• Difficulty sleeping (insomnia), abnormal dreams, vivid dreams
• Muscle pain, weakness
• Anxiety, restlessness

Rare but Serious Side Effects

• Seizures, convulsions
• Severe psychiatric symptoms: psychosis, hallucinations, paranoia, depression, suicidal thoughts
• Vertigo, loss of balance, tinnitus
• Cardiac arrhythmias (QT prolongation)
• Hepatotoxicity (rare)
• Severe allergic reactions (rare)

Long-Term Effects

• Some neurological and psychiatric symptoms (e.g., dizziness, anxiety, depression, sleep disturbances) can persist for months or even years after discontinuation of the medication.

Adverse Drug Reactions (ADR)

• Angioedema, anaphylaxis
• Severe psychiatric symptoms
• Syncope, seizures
• Hepatotoxicity
• QT prolongation, torsade de pointes

Contraindications

• Hypersensitivity to mefloquine or related compounds (quinine, quinidine)
• History of epilepsy or other seizure disorders
• Active psychiatric disorders (depression, anxiety, psychosis, schizophrenia)
• History of severe psychiatric reactions to mefloquine
• Cardiac conduction abnormalities, particularly QT prolongation

Drug Interactions

• CYP450 Interactions: Mefloquine is metabolized by CYP3A4. Inhibitors (e.g., ketoconazole, erythromycin) may increase mefloquine levels, while inducers (e.g., rifampin, phenytoin) can decrease levels.
• Other Interactions:
  • Halofantrine, ketoconazole (contraindicated due to risk of cardiotoxicity)
  • Quinine, quinidine, chloroquine (increased risk of seizures, cardiac effects)
  • Anticonvulsants (may reduce mefloquine effectiveness)
  • Beta-blockers (increased risk of bradycardia)
  • Alcohol (may worsen dizziness, drowsiness)
  • Live attenuated vaccines (efficacy may be reduced)

Pregnancy and Breastfeeding

• Pregnancy Safety Category: While generally considered safe for all trimesters, mefloquine should only be used if the benefits outweigh the risks. Malaria infection poses significant risks during pregnancy. Consult a physician for thorough assessment and counseling.
• Fetal Risks: No evidence of increased risk of congenital malformations or adverse pregnancy outcomes.
• Drug Excretion in Breast Milk: Mefloquine is excreted in breast milk in small amounts, but it is generally considered safe for breastfeeding.
• Neonatal Side Effects: Limited data on neonatal effects, but generally considered safe.

Drug Profile Summary

• Mechanism of Action: Inhibits heme polymerization within the malaria parasite, disrupting its metabolic processes.
• Side Effects: Nausea, vomiting, dizziness, sleep disturbances, headache; rarely seizures, psychiatric symptoms, cardiac arrhythmias.
• Contraindications: Psychiatric disorders, epilepsy, cardiac conduction abnormalities, hypersensitivity.
• Drug Interactions: Ketoconazole, halofantrine, quinine, quinidine, anticonvulsants, CYP3A4 inhibitors/inducers.
• Pregnancy & Breastfeeding: Generally considered safe, but individualized risk-benefit assessment needed.
• Dosage: Treatment: 1250 mg single dose (adults); Prevention: 250 mg weekly (adults). Pediatric doses are weight-based.
• Monitoring Parameters: Monitor for psychiatric and neurological symptoms, cardiac rhythm (ECG if clinically indicated), liver function tests if long-term use.

Popular Combinations

Mefloquine is typically used as monotherapy. Combination therapy with artesunate is recommended for treatment of P. falciparum infections in some regions with high rates of mefloquine resistance.

Precautions

• General Precautions: Assess for history of psychiatric disorders, epilepsy, cardiac abnormalities.
• Pregnant Women: Careful assessment of risks and benefits.
• Breastfeeding Mothers: Generally considered safe.
• Children & Elderly: Pediatric dosage based on weight; elderly may require closer monitoring for adverse effects.
• Lifestyle Considerations: Limit alcohol consumption. Caution with activities requiring alertness (driving, operating machinery).

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Mefloquine?

A: For malaria treatment in adults, a single dose of 1250mg is recommended. For prevention in adults, 250mg weekly is recommended, starting 1-3 weeks before travel and continuing for 4 weeks after leaving the malaria-endemic area. Pediatric doses are weight-based.

Q2: What are the most common side effects of Mefloquine?

A: Common side effects include nausea, vomiting, dizziness, headache, difficulty sleeping, and vivid dreams.

Q3: Who should not take Mefloquine?

A: Patients with a history of psychiatric disorders (including depression, anxiety, psychosis), epilepsy, or cardiac conduction abnormalities should not take mefloquine.

Q4: Are there any serious side effects associated with Mefloquine?

A: Yes, rare but serious side effects can include seizures, severe psychiatric symptoms (hallucinations, psychosis, depression), cardiac arrhythmias, and neurological disturbances.

Q5: Can Mefloquine be taken during pregnancy or breastfeeding?

A: Although generally considered safe for use during both pregnancy and breastfeeding, a doctor should assess the specific risks and benefits for each individual case, as malaria itself presents significant risks during pregnancy.

Q6: What are the important drug interactions with Mefloquine?

A: Mefloquine interacts with several medications, most notably halofantrine and ketoconazole, which are contraindicated due to increased cardiac risks. Other significant interactions include quinine, quinidine, chloroquine, and some anticonvulsants.

Q7: How does Mefloquine work against malaria?

A: Mefloquine inhibits heme polymerization within the malaria parasite, leading to a toxic build-up of heme and disrupting vital metabolic processes, ultimately killing the parasite.

Q8: How long do Mefloquine side effects last?

A: Most common side effects are mild and resolve quickly. However, some neurological and psychiatric effects can persist for months to years after stopping the drug.

Q9: What should I do if my patient experiences vomiting after taking Mefloquine?

A: If vomiting occurs within 30 minutes of taking the medication, repeat the full dose. If vomiting occurs 30-60 minutes after dosing, repeat half the dose. If vomiting persists, contact a physician for guidance.

Q10: Can Mefloquine be used for all types of malaria?

A: No, Mefloquine is only effective against mefloquine-susceptible strains of P. falciparum and P. vivax. It is not effective against other malarial species (e.g., P. ovale, P. malariae) or against resistant strains of P. falciparum.