Mefloquine Hydrochloride 250 mg Tablet, 8-count — NDC 50090-2396-2 (Billing 50090-2396-02)

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. Ocular Effects Eye disorders, including but not limited to optic neuropathy and retinal disorders, have been reported during treatment with mefloquine. Any patient presenting with visual symptoms should be referred to the treating physician and an ophthalmologist as certain conditions (such as retinal disorders or optic neuropathy) may require stopping treatment with mefloquine (see PRECAUTIONS , ANIMAL TOXICOLOGY ).

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.

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, Drug Interactions ), and encephalopathy of unknown etiology during prophylactic mefloquine administration. The relationship of encephalopathy to drug administration could not be clearly established. 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. 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 alterations in laboratory values were observed: transient elevation of transaminases, leukocytosis or thrombocytopenia. Because of the long half-life of mefloquine, adverse reactions to mefloquine may occur or persist up to several weeks after discontinuation of the drug.

Postmarketing Postmarketing surveillance indicates that the same kind of adverse reactions are reported during prophylaxis, as well as acute treatment. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to mefloquine exposure. The most frequently reported adverse reactions are nausea, vomiting, loose stools or diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence, and sleep disorders (insomnia, abnormal dreams).

These adverse reactions may occur early in the course of mefloquine use. It has been reported that dizziness or vertigo, tinnitus and hearing impairment, and loss of balance may continue for months or years after discontinuation of the drug and may be permanent in some cases. More severe neuropsychiatric disorders have been reported such as: sensory and motor neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or restlessness, anxiety, depression, mood swings, panic attacks, memory impairment, confusion, hallucinations, aggression, psychotic or paranoid reactions and encephalopathy.

Cases of suicidal ideation and suicide have been reported. Other less frequently reported adverse reactions include: Cardiovascular Disorders: circulatory disturbances (hypotension, hypertension, flushing, syncope), chest pain, tachycardia or palpitation, bradycardia, irregular heart rate, extrasystoles, A-V block, and other transient cardiac conduction alterations. Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema multiforme, and Stevens-Johnson syndrome.

Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and arthralgia. Respiratory Disorders: dyspnea, pneumonitis of possible allergic etiolo… [Excerpted — this section continues on DailyMed.]

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 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 ). Other Antimalarial Drugs Concomitant administration of mefloquine and other related antimalarial compounds (e.g., 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) Coadministration 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 C max 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 Coadministration of other drugs known to alter cardiac conduction (e.g., anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H 1 -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 (e.g., 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 anti-seizure medication and mefloquine should have the blood level of their anti-seizure 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) Coadministration 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 C max 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 hydrochloride tablets and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction.

However, mefloquine is metabolized by CYP3A4 and inhibitors of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase in mefloquine plasma concentrations and potential risk of adverse reactions. Therefore, mefloquine hydrochloride tablets should be used with caution when administered concomitantly with CYP3A4 inhibitors. Similarly, i… [Excerpted — this section continues on DailyMed.]

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 (see WARNINGS ). 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.

Drug Interactions Drug-drug interactions wit… [Excerpted — this section continues on DailyMed.]