Prescription Drugs

CLINICAL PHARMACOLOGY Pharmacokinetics Absorption The absolute oral bioavailability of mefloquine has not been determined since an intravenous formulation is not available. The bioavailability of the tablet formation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24 hours (median, about 17 hours) after a single dose of Lariam (mefloquine) . In a similar group of volunteers, maximum plasma concentrations in µg/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 µg/L). In healthy volunteers, a dose of 250 mg once weekly produces maximum steady-state plasma concentrations of 1000 to 2000 µg/L, which are reached after 7 to 10 weeks. Distribution In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes was found to be reversible. Protein binding is about 98%. Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal (see PRECAUTIONS: Nursing Mothers). Metabolism Two metabolites have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only. Elimination In several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite under steady-state condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other metabolites could not be measured in the urine. Pharmacokinetics in Special Clinical Situations Children and the Elderly No relevant age-related changes have been observed in the pharmacokinetics of mefloquine. Therefore, the dosage for children has been extrapolated from the recommended adult dose. No pharmacokinetic studies have been performed in patients with renal insufficiency since only a small proportion of the drug is eliminated renally. Mefloquine and its main metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma similar to those in healthy persons. Although clearance of mefloquine may increase in late pregnancy, in general, pregnancy has no clinically relevant effect on the pharmacokinetics of mefloquine. The pharmacokinetics of mefloquine may be altered in acute malaria. Pharmacokinetic differences have been observed between various ethnic populations. In practice, however, these are of minor importance compared with host immune status and sensitivity of the parasite. During long-term prophylaxis ( > 2 years), the trough concentrations and the elimination half-life of mefloquine were similar to those obtained in the same population after 6 months of drug use, which is when they reached steady state. In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate dehydrogenase deficiency (see Animal Toxicology). Microbiology Mechanism of Action Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action is not known. Activity In Vitro and In Vivo Mefloquine is active against the erythrocytic stages of Plasmodium species (see INDICATIONS). However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective against malaria parasites resistant to chloroquine (see INDICATIONS). Drug Resistance Strains of P. falciparum with decreased susceptibility to mefloquine can be selected in vitro or in vivo. Resistance of P. falciparum to mefloquine has been reported in areas of multi-drug resistance in South East Asia. Increased incidences of resistance have also been reported in other parts of the world. Cross-Resistance Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions. 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.

LARIAM® (mefloquine hydrochloride) Tablets 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*)-(±)-α-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 and the following structural formula: The inactive ingredients are ammonium-calcium alginate, corn starch, crospovidone, lactose, magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.

INDICATIONS Treatment of Acute Malaria Infections Lariam (mefloquine) 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 (mefloquine) , are at high risk of relapse because Lariam (mefloquine) does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse, after initial treatment of the acute infection with Lariam (mefloquine) , patients should subsequently be treated with an 8-aminoquinoline derivative (eg, primaquine). Prevention of Malaria Lariam (mefloquine) is indicated for the prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum. DOSAGE AND ADMINISTRATION (see INDICATIONS) 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 with Lariam (mefloquine) does not lead to improvement within 48 to 72 hours, Lariam (mefloquine) should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, Lariam (mefloquine) should not be used for curative treatment. Note: Patients with acute P. vivax malaria, treated with Lariam (mefloquine) , are at high risk of relapse because Lariam (mefloquine) does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse after initial treatment of the acute infection with Lariam (mefloquine) , patients should subsequently be treated with an 8-aminoquinoline derivative (eg, primaquine). Malaria Prophylaxis One 250 mg Lariam (mefloquine) tablet once weekly. Prophylactic drug administration should begin 1 week before arrival in an endemic area. Subsequent weekly doses should be taken regularly, always on the same day of each week, preferably after the main meal. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued for 4 additional weeks to ensure suppressive blood levels of the drug when merozoites emerge from the liver. 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 (see PRECAUTIONS: DRUG INTERACTIONS). When prophylaxis with Lariam (mefloquine) fails, physicians should carefully evaluate which antimalarial to use for therapy. Pediatric Patients Treatment of mild to moderate malaria in pediatric patients caused by mefloquine-susceptible strains of P. falciparum Twenty (20) to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses taken 6 to 8 hours apart may reduce the occurrence or severity of adverse effects. Experience with Lariam (mefloquine) in pediatric patients weighing less than 20 kg is limited. The drug should not be taken on an empty stomach and should be administered with ample water. The tablets may be crushed and suspended in a small amount of water, milk or other beverage for administration to small children and other persons unable to swallow them whole. If a full-treatment course with Lariam (mefloquine) does not lead to improvement within 48 to 72 hours, Lariam (mefloquine) should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, Lariam (mefloquine) should not be used for curative treatment. In pediatric patients, the administration of Lariam (mefloquine) 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 (mefloquine) 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 (mefloquine) to treat malaria in pediatric patients below the age of 6 months have not been established. Malaria Prophylaxis The recommended prophylactic dose of Lariam (mefloquine) is approximately 5 mg/kg body weight once weekly. One 250 mg Lariam (mefloquine) 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: 3/4 tablet 20 to 30 kg: 1/2 tablet Experience with Lariam (mefloquine) in pediatric patients weighing less than 20 kg is limited. HOW SUPPLIED Lariam (mefloquine) 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 (mefloquine) 250 ROCHE Tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Manufactured by: F. HOFFMANN-LA ROCHE LTD, Basel, Switzerland. Distributed by: Roche Laboratories Inc. 340 Kingsland Street, Nutley, New Jersey 07110-1199.

PATIENT INFORMATION MEDICATION GUIDE This Medication Guide is intended only for travelers who are taking Lariam (mefloquine) to prevent malaria. The information may not apply to patients who are sick with malaria and who are taking Lariam (mefloquine) to treat malaria. An information wallet card is provided with this Medication Guide. Carry it with you when you are taking Lariam (mefloquine) . This Medication Guide was revised in September 2008. Please read it before you start taking Lariam (mefloquine) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your prescriber (doctor or other health care provider) about Lariam (mefloquine) and malaria prevention. Only you and your prescriber can decide if Lariam (mefloquine) is right for you. If you cannot take Lariam (mefloquine) , you may be able to take a different medicine to prevent malaria. What is the most important information I should know about Lariam (mefloquine) ? 1. Take Lariam (mefloquine) exactly as prescribed to prevent malaria. Malaria is an infection that can cause death and is spread to humans through mosquito bites. If you travel to parts of the world where the mosquitoes carry the malaria parasite, you must take a malaria prevention medicine. Lariam (mefloquine) is one of a small number of medications approved to prevent and to treat malaria. If taken correctly, Lariam (mefloquine) is effective at preventing malaria but, like all medications, it may produce side effects in some patients. 2. Lariam (mefloquine) can rarely cause serious mental problems in some patients. The most frequently reported side effects with Lariam (mefloquine) , such as nausea, difficulty sleeping, and bad dreams are usually mild and do not cause people to stop taking the medicine. However, people taking Lariam (mefloquine) occasionally experience severe anxiety, feelings that people are against them, hallucinations (seeing or hearing things that are not there, for example), depression, unusual behavior, or feeling disoriented. There have been reports that in some patients these side effects continue after Lariam (mefloquine) is stopped. Some patients taking Lariam (mefloquine) think about killing themselves, and there have been rare reports of suicides. It is not known whether Lariam (mefloquine) was responsible for these suicides. 3. You need to take malaria prevention medicine before you travel to a malaria area, while you are in a malaria area, and after you return from a malaria area. Medicines approved in the United States for malaria prevention include Lariam (mefloquine) , doxycycline, atovaquone/proguanil, hydroxychloroquine, and chloroquine. Not all of these drugs work equally as well in all areas of the world where there is malaria. The chloroquines, for example, do not work in areas where the malaria parasite has developed resistance to chloroquine. Lariam (mefloquine) may be effective against malaria that is resistant to chloroquine or other drugs. All drugs to treat malaria have side effects that are different for each one. For example, some may make your skin more sensitive to sunlight (Lariam (mefloquine) does not do this). However, if you use Lariam (mefloquine) to prevent malaria and you develop a sudden onset of anxiety, depression, restlessness, confusion (possible signs of more serious mental problems), or you develop other serious side effects, contact a doctor or other health care provider. It may be necessary to stop taking Lariam (mefloquine) and use another malaria prevention medicine instead. If you can't get another medicine, leave the malaria area. However, be aware that leaving the malaria area may not protect you from getting malaria. You still need to take a malaria prevention medicine. Who should not take Lariam (mefloquine) ? Do not take Lariam (mefloquine) to prevent malaria if you have depression or had depression recently have had recent mental illness or problems, including anxiety disorder, schizophrenia (a severe type of mental illness), or psychosis (losing touch with reality) have or had seizures (epilepsy or convulsions) are allergic to quinine or quinidine (medicines related to Lariam (mefloquine) ) Tell your prescriber about all your medical conditions. Lariam (mefloquine) may not be right for you if you have certain conditions, especially the ones listed below: Heart disease. Lariam (mefloquine) may not be right for you. Pregnancy. Tell your prescriber if you are pregnant or plan to become pregnant. It is dangerous for the mother and for the unborn baby (fetus) to get malaria during pregnancy. Therefore, ask your prescriber if you should take Lariam (mefloquine) or another medicine to prevent malaria while you are pregnant. Breast-feeding. Lariam (mefloquine) can pass through your milk and may harm the baby. Therefore, ask your prescriber whether you will need to stop breastfeeding or use another medicine. Liver problems. Tell your prescriber about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may give you a higher chance of having serious side effects from Lariam (mefloquine) . How should I take Lariam (mefloquine) ? Take Lariam (mefloquine) exactly as prescribed. If you are an adult or pediatric patient weighing 45 kg (99 pounds) or less, your prescriber will tell you the correct dose based on your weight. To prevent malaria For adults and pediatric patients weighing over 45 kg, take 1 tablet of Lariam (mefloquine) at least 1 week before you travel to a malaria area (or 2 to 3 weeks before you travel to a malaria area, if instructed by your prescriber). This starts the prevention and also helps you see how Lariam (mefloquine) affects you and the other medicines you take. Take 1 Lariam (mefloquine) tablet once a week, on the same day each week, while in a malaria area. Continue taking Lariam (mefloquine) for 4 weeks after returning from a malaria area. If you cannot continue taking Lariam (mefloquine) due to side effects or for other reasons, contact your prescriber. Take Lariam (mefloquine) just after a meal and with at least 1 cup (8 ounces) of water. For children, Lariam (mefloquine) can be given with water or crushed and mixed with water or sugar water. The prescriber will tell you the correct dose for children based on the child's weight. If you are told by a doctor or other health care provider to stop taking Lariam (mefloquine) due to side effects or for other reasons, it will be necessary to take another malaria medicine. You must take malaria prevention medicine before you travel to a malaria area, while you are in a malaria area, and after you return from a malaria area. If you don't have access to a doctor or other health care provider or to another medicine besides Lariam (mefloquine) and have to stop taking it, leave the malaria area. However, be aware that leaving the malaria area may not protect you from getting malaria. You still need to take a malaria prevention medicine. What should I avoid while taking Lariam (mefloquine) ? Halofantrine (marketed under various brand names), a medicine used to treat malaria. Taking both of these medicines together can cause serious heart problems that can cause death. Do not become pregnant. Women should use effective birth control while taking Lariam (mefloquine) . Quinine, quinidine, or chloroquine (other medicines used to treat malaria). Taking these medicines with Lariam (mefloquine) could cause changes in your heart rate or increase the risk of seizures. In addition: Be careful driving or in other activities needing alertness and careful movements (fine motor coordination). Lariam (mefloquine) can cause dizziness or loss of balance, even after you stop taking Lariam (mefloquine) (see “What are the possible side effects of Lariam (mefloquine) ?”). Be aware that certain vaccines may not work if given while you are taking Lariam (mefloquine) . Your prescriber may want you to finish taking your vaccines at least 3 days before starting Lariam (mefloquine) . What are the possible side effects of Lariam (mefloquine) ? Lariam (mefloquine) , like all medicines, may cause side effects in some patients. The most frequently reported side effects with Lariam (mefloquine) when used for prevention of malaria include nausea, vomiting, diarrhea, dizziness, loss of balance, difficulty sleeping, and bad dreams. These side effects are usually mild and do not cause people to stop taking the medicine. However, in a small number of patients, it has been reported that dizziness and loss of balance may continue for months after stopping Lariam (mefloquine) . Lariam (mefloquine) may cause serious mental problems in some patients (see “What is the most important information I should know about Lariam (mefloquine) ?”). Lariam (mefloquine) may affect your liver and your eyes if you take it for a long time. Your prescriber will tell you if you should have your eyes and liver checked while taking Lariam (mefloquine) . Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What else should I know about preventing malaria? Find out whether you need malaria prevention. Before you travel, talk with your prescriber about your travel plans to determine whether you need to take medicine to prevent malaria. Even in those countries where malaria is present, there may be areas of the country that are free of malaria. In general, malaria is more common in rural (country) areas than in big cities, and it is more common during rainy seasons, when mosquitoes are most common. You can get information about the areas of the world where malaria occurs from the Centers for Disease Control and Prevention (CDC) and from local authorities in the countries you visit. If possible, plan your travel to reduce the risk of malaria. Take medicine to prevent malaria infection. Without malaria prevention medicine, you have a higher risk of getting malaria. Malaria starts with flu-like symptoms, such as chills, fever, muscle pains, and headaches. However, malaria can make you very sick or cause death if you don't seek medical help immediately. These symptoms may disappear for a while, and you may think you are well. But, the symptoms return later and then it may be too late for successful treatment. Malaria can cause confusion, coma, and seizures. It can cause kidney failure, breathing problems, and severe damage to red blood cells. However, malaria can be easily diagnosed with a blood test, and if caught in time, can be effectively treated. If you get flu-like symptoms (chills, fever, muscle pains, or headaches) after you return from a malaria area, get medical help right away and tell your prescriber that you may have been exposed to malaria. People who have lived for many years in areas with malaria may have some immunity to malaria (they do not get it as easily) and may not take malaria prevention medicine. This does not mean that you don't need to take malaria prevention medicine. Protect against mosquito bites. Medicines do not always completely prevent your catching malaria from mosquito bites. So protect yourself very well against mosquitoes. Cover your skin with long sleeves and long pants, and use mosquito repellent and bednets while in malaria areas. If you are out in the bush, you may want to pre-wash your clothes with permethrin. This is a mosquito repellent that may be effective for weeks after use. Ask your prescriber for other ways to protect yourself. General information about the safe and effective use of Lariam (mefloquine) . Medicines are sometimes prescribed for conditions not listed in Medication Guides. If you have any concerns about Lariam (mefloquine) , ask your prescriber. This Medication Guide contains certain important information for travelers visiting areas with malaria. Your prescriber or pharmacist can give you information about Lariam (mefloquine) that was written for health care professionals. Do not use Lariam (mefloquine) for a condition for which it was not prescribed. Do not share Lariam (mefloquine) with other people. This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guide Revised: September 2008 Reprint of information wallet card: Roche Lariam® (mefloquine hydrochloride) Tablets Carry this information wallet card with you when you are taking Lariam. You need to take malaria prevention medicine before you travel to a malaria area, while you are in a malaria area, and after you return from a malaria area. Other medicines approved in the United States for malaria prevention include: doxycycline, atovaquone/proguanil, hydroxychloroquine, and chloroquine. If taken correctly, Lariam is effective at preventing malaria but, like all medications, it may produce side effects in some patients. Not all malaria medicines work equally well in malaria areas. The chloroquines, for example, do not work in many parts of the world. If you can't get another medicine, leave the malaria area. If you use Lariam to prevent malaria and you develop a sudden onset of anxiety, depression, restlessness, confusion (possible signs of more serious mental problems), or you develop other serious side effects, contact a doctor or other health care provider. It may be necessary to stop taking Lariam and use another malaria prevention medicine instead. However, be aware that leaving the malaria area may not protect you from getting malaria. You still need to take a malaria prevention medicine. Please read the Medication Guide for additional information on Lariam (mefloquine) . Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.Card Revised: September 2008

OVERDOSE Symptoms and Signs In cases of overdosage with Lariam, the symptoms mentioned under ADVERSE REACTIONS may be more pronounced. Treatment Patients should be managed by symptomatic and supportive care following Lariam (mefloquine) overdose. There are no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status for at least 24 hours. Provide symptomatic and intensive supportive treatment as required, particularly for cardiovascular disturbances. CONTRAINDICATIONS Use of Lariam (mefloquine) is contraindicated in patients with a known hypersensitivity to mefloquine or related compounds (eg, quinine and quinidine) or to any of the excipients contained in the formulation. Lariam (mefloquine) 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.

SIDE EFFECTS 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: DRUG INTERACTIONS), 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 kind of adverse experiences are reported during prophylaxis, as well as acute treatment. Because these experiences 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 Lariam (mefloquine) exposure. The most frequently reported adverse events 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 are usually mild and may decrease despite continued use. In a small number of patients it has been reported that dizziness or vertigo and loss of balance may continue for months after discontinuation of the drug. Occasionally, 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 changes, panic attacks, forgetfulness, confusion, hallucinations, aggression, psychotic or paranoid reactions and encephalopathy. Rare cases of suicidal ideation and suicide have been reported though no relationship to drug administration has been confirmed. Other infrequent adverse events include: Cardiovascular Disorders: circulatory disturbances (hypotension, hypertension, flushing, syncope), chest pain, tachycardia or palpitation, bradycardia, irregular pulse, 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 etiology Other Symptoms: visual disturbances, vestibular disorders including tinnitus and hearing impairment, asthenia, malaise, fatigue, fever, sweating, chills, dyspepsia and loss of appetite 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 (mefloquine) may occur or persist up to several weeks after the last dose. DRUG INTERACTIONS Drug-drug interactions with Lariam (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 Lariam (mefloquine) 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 must not be given simultaneously with or subsequent to Lariam (see WARNINGS). Concomitant administration of Lariam (mefloquine) and other related 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, Lariam (mefloquine) 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 (mefloquine) , 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 (mefloquine) may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking antiseizure medication and Lariam (mefloquine) should have the blood level of their antiseizure medication monitored and the dosage adjusted appropriately (see PRECAUTIONS). When Lariam (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 Lariam (mefloquine) . No other drug interactions are known. Nevertheless, the effects of Lariam (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.

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 (mefloquine) may be given to complete the course of therapy. Data on the use of halofantrine subsequent to administration of Lariam (mefloquine) suggest a significant, potentially fatal prolongation of the QTc interval of the ECG. Therefore, halofantrine must not be given simultaneously with or subsequent to Lariam (mefloquine) . No data are available on the use of Lariam (mefloquine) after halofantrine (see 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. Lariam (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 Lariam (mefloquine) and quinine or quinidine may produce electrocardiographic abnormalities. Concomitant administration of Lariam (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, Lariam (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, a loss of balance, or other disorders of the central or peripheral nervous system have been reported during and following the use of Lariam (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 and loss of balance have been reported to continue for months after mefloquine has been stopped (see ADVERSE REACTIONS: Postmarketing). Lariam (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 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. 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 Lariam (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 Lariam (mefloquine) Medication Guide is supplied to patients when Lariam (mefloquine) is dispensed. An information wallet card is also supplied to patients when Lariam (mefloquine) is dispensed. Patients should be instructed to read the Medication Guide when Lariam (mefloquine) is received and to carry the information wallet card with them when they are taking Lariam. 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 Lariam (mefloquine) 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, including dizziness and loss of balance, and it may be necessary to change medications. Although side effects of dizziness 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 Lariam (mefloquine) should be taken 1 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. 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 Lariam (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 Lariam (mefloquine) and for up to 3 months thereafter. However, in the case of unplanned pregnancy, malaria chemoprophylaxis with Lariam (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 Lariam (mefloquine) to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by evidence from adequate and well-controlled studies of Lariam (mefloquine) in adults with additional data from published open-label and comparative trials using Lariam (mefloquine) to treat malaria caused by P. falciparum in patients younger than 16 years of age. The safety and effectiveness of Lariam (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 Lariam (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 Lariam (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 Lariam (mefloquine) (see PRECAUTIONS) and underlying cardiac disease is more prevalent in elderly than in younger patients, the benefits of Lariam (mefloquine) therapy should be weighed against the possibility of adverse cardiac effects in elderly patients.