Larinate-MF

Mefloquine:

• Warning
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Animal toxicology
• Medication guidemefloquine hydrochloride tablets usp(mef'-loe-kwin hye-droe-klor-ide)rx only
• Larinate-MF (Mefloquine) reviews

WARNING

Larinate-MF (Mefloquine) may cause neuropsychiatric adverse reactions that can persist after Larinate-MF (Mefloquine) has been discontinued. Larinate-MF (Mefloquine) should not be prescribed for prophylaxis in patients with major psychiatric disorders. During prophylactic use, if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.

DESCRIPTION

Larinate-MF (Mefloquine) Hydrochloride Tablets USP is an antimalarial agent available as 250 mg tablets of Larinate-MF (Mefloquine) hydrochloride USP (equivalent to 228 mg of the free base) for oral administration.

Larinate-MF (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.

Larinate-MF (Mefloquine) hydrochloride has a calculated molecular weight of 414.8 and the following structural formula:

The inactive ingredients are ammonium-calcium alginate blend, colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer 331, povidone and pregelatinized starch.

Chemical Structure

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption

The absolute oral bioavailability of Larinate-MF 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 Larinate-MF (Mefloquine). In a similar group of volunteers, maximum plasma concentrations in mcg/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 mcg/L). In healthy volunteers, a dose of 250 mg once weekly produces maximum steady-state plasma concentrations of 1000 to 2000 mcg/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. Larinate-MF (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%.

Larinate-MF (Mefloquine) crosses the placenta. Excretion into breast milk appears to be minimal.

Metabolism

Larinate-MF is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved.

Two metabolites of Larinate-MF (Mefloquine) 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 Larinate-MF (Mefloquine), were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and Larinate-MF (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 Larinate-MF (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 Larinate-MF (Mefloquine) is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged Larinate-MF (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 Larinate-MF. 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. Larinate-MF (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 Larinate-MF (Mefloquine) may increase in late pregnancy, in general, pregnancy has no clinically relevant effect on the pharmacokinetics of Larinate-MF (Mefloquine).

The pharmacokinetics of Larinate-MF (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 Larinate-MF (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.

Microbiology

Mechanism of Action

Larinate-MF is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action is not known.

Activity In Vitro and In Vivo

Larinate-MF (Mefloquine) is active against the erythrocytic stages of Plasmodium species. However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite. Larinate-MF (Mefloquine) is effective against malaria parasites resistant to chloroquine.

Drug Resistance

Strains of P. falciparum with decreased susceptibility to Larinate-MF can be selected in vitro or in vivo. Resistance of P. falciparum to Larinate-MF (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 Larinate-MF (Mefloquine) and halofantrine and cross-resistance between Larinate-MF (Mefloquine) and quinine have been observed in some regions.

INDICATIONS AND USAGE

Treatment of Acute Malaria Infections

Larinate-MF 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 Larinate-MF (Mefloquine) in malaria caused by P. ovale or P. malariae.

Note: Patients with acute P. vivax malaria, treated with Larinate-MF (Mefloquine), are at high risk of relapse because Larinate-MF (Mefloquine) does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse, after initial treatment of the acute infection with Larinate-MF (Mefloquine), patients should subsequently be treated with an 8-aminoquinoline derivative (e.g., primaquine).

Prevention of Malaria

Larinate-MF (Mefloquine) is indicated for the prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.

CONTRAINDICATIONS

Use of Larinate-MF (Mefloquine) is contraindicated in patients with a known hypersensitivity to Larinate-MF (Mefloquine) or related compounds (e.g., quinine and quinidine) or to any of the excipients contained in the formulation. Larinate-MF (Mefloquine) should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders, or with a history of convulsions.

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, Larinate-MF (Mefloquine) may be given to complete the course of therapy.

QTc Interval Prolongation and Drug Interactions

Halofantrine should not be administered with Larinate-MF (Mefloquine) or within 15 weeks of the last dose of Larinate-MF (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 Larinate-MF (Mefloquine) or within 15 weeks of the last dose of Larinate-MF (Mefloquine) due to the risk of a potentially fatal prolongation of the QTc interval. Ketoconazole increases plasma concentrations and elimination half-life of Larinate-MF (Mefloquine) following co-administration (see CLINICAL

Pharmacology: Pharmacokinetics: Elimination and PRECAUTIONS: Drug Interactions).

Concomitant administration of Larinate-MF (Mefloquine) and quinine or quinidine may produce electrocardiographic abnormalities.

Psychiatric and Neurologic Adverse Reactions

Larinate-MF (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 non-verbal children.

Psychiatric Adverse Reactions

Psychiatric symptoms ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior can occur with Larinate-MF (Mefloquine) use. Symptoms may occur early in the course of Larinate-MF (Mefloquine) use. In some cases, these symptoms have been reported to continue for months or years after Larinate-MF (Mefloquine) has been stopped. Cases of suicidal ideation and suicide have been reported. Larinate-MF (Mefloquine) should not be prescribed for prophylaxis in patients with active depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders. Larinate-MF (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 Larinate-MF (Mefloquine) use and in some cases have been reported to continue for months or years after Larinate-MF (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.

Larinate-MF (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. Concomitant administration of Larinate-MF (Mefloquine) and quinine or chloroquine may increase the risk of convulsions.

Occular Effects

Eye disorders, including but not limited to optic neuropathy and retinal disorders, have been reported during treatment with Larinate-MF (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 Larinate-MF (Mefloquine).

PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions have been reported with Larinate-MF use.

Use in Patients with Hepatic Impairment

In patients with impaired liver function, the elimination of Larinate-MF (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. Periodic ophthalmic examinations are recommended.

Cardiac Effects

Parenteral studies in animals show that Larinate-MF (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 Larinate-MF (Mefloquine) on the compromised cardiovascular system has not been evaluated. However, transitory and clinically silent ECG alterations have been reported during the use of Larinate-MF (Mefloquine); alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block, prolongation of the QTc interval and abnormal T waves. The benefits of Larinate-MF (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 Larinate-MF has been reported, predominantly in areas of multi-drug resistance in South-East Asia. Cross-resistance between Larinate-MF (Mefloquine) and halofantrine and cross-resistance between Larinate-MF (Mefloquine) and quinine have been observed in some regions.

Agranulocytosis and Aplastic Anemia

Cases of agranulocytosis and aplastic anemia have been reported.

Laboratory Tests

Periodic evaluation of hepatic function should be performed during prolonged prophylaxis.

Information for Patients

Medication Guide: As required by law, a Larinate-MF Medication Guide is supplied to patients when Larinate-MF (Mefloquine) is dispensed. An information wallet card is also supplied to patients when Larinate-MF (Mefloquine) is dispensed. Patients should be instructed to read the Medication Guide when Larinate-MF (Mefloquine) is received and to carry the information wallet card with them when they are taking Larinate-MF (Mefloquine). The complete text of the Medication Guide and information wallet card is reprinted at the end of this document.

Patients should be advised:

• that malaria can be a life-threatening infection;
• that Larinate-MF (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 Larinate-MF (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 with Larinate-MF (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). The effects of Larinate-MF (Mefloquine) on the compromised cardiovascular system have not been evaluated. The benefits of Larinate-MF (Mefloquine) therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.

Halofantrine

Halofantrine should not be administered with Larinate-MF or within 15 weeks of the last dose of Larinate-MF (Mefloquine) due to the risk of a potentially fatal prolongation of the QTc interval.

Other Antimalarial Drugs

Concomitant administration of Larinate-MF (Mefloquine) and other related antimalarial compounds (e.g., quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions. If these drugs are to be used in the initial treatment of severe malaria, Larinate-MF (Mefloquine) administration should be delayed at least 12 hours after the last dose. Clinically significant QTc prolongation has not been found with Larinate-MF (Mefloquine) alone.

Ketoconazole (Potent Inhibitor of CYP3A4)

Co-administration of a single 500 mg oral dose of Larinate-MF (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 Larinate-MF (Mefloquine) by 64% and 79%, respectively, and an increase in the mean elimination half-life of Larinate-MF (Mefloquine) from 322 hours to 448 hours. Ketoconazole should not be administered with Larinate-MF (Mefloquine) or within 15 weeks of the last dose of Larinate-MF (Mefloquine) due to the risk of a potentially fatal prolongation of the QTc interval.

Other Drugs that Prolong the QTc Interval

Co-administration of other drugs known to alter cardiac conduction might also contribute to a prolongation of the QTc interval. There are no data that conclusively establish whether the concomitant administration of Larinate-MF (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 Larinate-MF (Mefloquine) may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking anti-seizure medication and Larinate-MF (Mefloquine) should have the blood level of their anti-seizure medication monitored and the dosage adjusted appropriately.

Vaccines

When Larinate-MF 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 Larinate-MF (Mefloquine) hydrochloride tablets.

Rifampin (Potent Inducer of CYP3A4)

Co-administration of a single 500 mg oral dose of Larinate-MF (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 Larinate-MF (Mefloquine) by 19% and 68%, respectively, and a decrease in the mean elimination half-life of Larinate-MF (Mefloquine) from 305 hours to 113 hours. Rifampin should be used cautiously in patients taking Larinate-MF (Mefloquine).

Inhibitors and Inducers of CYP3A4

Larinate-MF does not inhibit or induce the CYP 450 enzyme system. Thus, concomitant administration of Larinate-MF (Mefloquine) hydrochloride tablets and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction. However, Larinate-MF (Mefloquine) is metabolized by CYP3A4 and inhibitors of CYP3A4 may modify the pharmacokinetics/metabolism of Larinate-MF (Mefloquine), leading to an increase in Larinate-MF (Mefloquine) plasma concentrations and potential risk of adverse reactions. Therefore, Larinate-MF (Mefloquine) hydrochloride tablets should be used with caution when administered concomitantly with CYP3A4 inhibitors. Similarly, inducers of CYP3A4 may modify the pharmacokinetics/metabolism of Larinate-MF (Mefloquine), leading to a decrease in Larinate-MF (Mefloquine) plasma concentrations and potential reduction in efficacy of Larinate-MF (Mefloquine) hydrochloride tablets. Therefore, Larinate-MF (Mefloquine) hydrochloride tablets should also be used with caution when administered concomitantly with CYP3A4 inducers.

Substrates and Inhibitors of P-glycoprotein

It has been shown in vitro that Larinate-MF (Mefloquine) is a substrate and an inhibitor of P-glycoprotein. Therefore, drug-drug interactions could also occur with drugs that are substrates or are known to modify the expression of this transporter. The clinical relevance of these interactions is not known to date.

Other Potential Interactions

No other drug interactions are known. Nevertheless, the effects of Larinate-MF on travelers receiving concomitant medications, 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 of Larinate-MF (Mefloquine).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of Larinate-MF 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 Larinate-MF (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 Larinate-MF (Mefloquine).

Impairment of Fertility

Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of Larinate-MF 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 Larinate-MF (Mefloquine) (base) in adult males for 22 weeks failed to reveal any deleterious effects on human spermatozoa.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Data from published studies in pregnant women have shown no increase in the risk of teratogenic effects or adverse pregnancy outcomes following Larinate-MF (Mefloquine) treatment or prophylaxis during pregnancy. Reproduction studies in mice, rats and rabbits have shown teratogenic effects at doses similar to the clinical acute treatment dose in humans. Because the studies in humans cannot rule out the possibility of harm, Larinate-MF (Mefloquine) should be used during pregnancy only if clearly needed.

Published data on Larinate-MF (Mefloquine) use during pregnancy include randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series. These data showed that pregnant women who took Larinate-MF (Mefloquine) at various doses for both prevention and treatment of malaria did not have an increased risk of teratogenic effects or adverse pregnancy outcomes compared to the background rate in the general population. These data include more than 700 exposures to Larinate-MF (Mefloquine) in the first trimester of pregnancy and over 2,000 exposures in the second and third trimester.

Larinate-MF (Mefloquine) administered to pregnant mice, rats, and rabbits was teratogenic at doses similar to the clinical acute treatment dose of 21 to 25 mg/kg, based on body surface area comparisons. In all three animal species, CNS effects (e.g., exencephaly, hydrocephaly or partially missing medulla oblongata) and craniofacial malformations were observed. At the same doses, Larinate-MF (Mefloquine) was also embryotoxic in mice and rabbits. All of these findings were observed at doses that were maternally toxic.

Nursing Mothers

Larinate-MF 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 Larinate-MF (Mefloquine) were excreted in human milk following a dose equivalent to 250 mg of the free base. Caution should be exercised when administered to a nursing woman.

Pediatric Use

Use of Larinate-MF (Mefloquine) to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by evidence from adequate and well-controlled studies of Larinate-MF (Mefloquine) in adults with additional data from published open-label and comparative trials using Larinate-MF (Mefloquine) to treat malaria caused by P. falciparum in patients younger than 16 years of age. The safety and effectiveness of Larinate-MF (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 Larinate-MF (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.

Geriatric Use

Clinical studies of Larinate-MF (Mefloquine) did not include sufficient numbers of subjects aged 65 and older 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 Larinate-MF (Mefloquine) and underlying cardiac disease is more prevalent in elderly than in younger patients, the benefits of Larinate-MF (Mefloquine) therapy should be weighed against the possibility of adverse cardiac effects in elderly patients.

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 Larinate-MF 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 Larinate-MF (Mefloquine) while concomitantly using propranolol, and encephalopathy of unknown etiology during prophylactic Larinate-MF (Mefloquine) administration. The relationship of encephalopathy to drug administration could not be clearly established.

Among subjects who received Larinate-MF (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 Larinate-MF (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 Larinate-MF (Mefloquine), adverse reactions to Larinate-MF (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 Larinate-MF (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 Larinate-MF (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 etiology

Hepatobiliary Disorders: drug-related hepatic disorders from asymptomatic transient transaminase elevations to hepatic failure

Blood and Lymphatic System Disorders: agranulocytosis, aplastic anemia

Ocular Disorders: Visual impairment, vision blurred, cataracts, retinal disorders, optic neuropathy

Other Symptoms: asthenia, malaise, fatigue, fever, hyperhidrosis, chills, dyspepsia and loss of appetite.

OVERDOSAGE

Symptoms and Signs

In cases of overdosage with Larinate-MF, the symptoms mentioned under ADVERSE REACTIONS may be more pronounced.

Treatment

Patients should be managed by symptomatic and supportive care following Larinate-MF (Mefloquine) overdose. There are no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status. Provide symptomatic and intensive supportive treatment as required.

DOSAGE AND ADMINISTRATION

Malaria Treatment in Adults

Treatment of mild to moderate malaria in adults caused by mefloquine-susceptible strains of P. falciparum or by P. vivax: Dosage: Five tablets Larinate-MF (Mefloquine) hydrochloride USP 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 Larinate-MF (Mefloquine) does not lead to improvement within 48 to 72 hours, Larinate-MF (Mefloquine) should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with Larinate-MF (Mefloquine) has failed, Larinate-MF (Mefloquine) should not be used for curative treatment.

Note: Patients with acute P. vivax malaria, treated with Larinate-MF (Mefloquine), are at high risk of relapse because Larinate-MF (Mefloquine) does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse after initial treatment of the acute infection with Larinate-MF (Mefloquine), patients should subsequently be treated with an 8-aminoquinoline derivative (e.g., primaquine).

Malaria Prophylaxis in Adults

Dosage: One 250 mg Larinate-MF (Mefloquine) hydrochloride 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, e.g., 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.

When prophylaxis with Larinate-MF (Mefloquine) fails, physicians should carefully evaluate which antimalarial to use for therapy.

Malaria Treatment in Pediatric Patients

Treatment of mild to moderate malaria in pediatric patients caused by mefloquine-susceptible strains of P. falciparum: Dosage: 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. The pediatric dose should not exceed the adult dose.

Experience with Larinate-MF in pediatric patients weighing less than 20 kg is limited.

The drug shouId 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 Larinate-MF (Mefloquine) does not lead to improvement within 48 to 72 hours, Larinate-MF (Mefloquine) should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with Larinate-MF (Mefloquine) has failed, Larinate-MF (Mefloquine) should not be used for curative treatment.

In pediatric patients, the administration of Larinate-MF (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. If a significant loss of drug product is observed or suspected because of vomiting, a second full dose of Larinate-MF (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 Larinate-MF (Mefloquine) to treat malaria in pediatric patients below the age of 6 months have not been established.

Malaria Prophylaxis in Pediatric Patients

The recommended prophylactic dose of Larinate-MF (Mefloquine) hydrochloride is approximately 5 mg/kg body weight once weekly. One 250 mg Larinate-MF (Mefloquine) hydrochloride 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 Larinate-MF (Mefloquine) in pediatric patients weighing less than 20 kg is limited.

HOW SUPPLIED

Larinate-MF Hydrochloride Tablets USP

250 mg tablet is supplied as a speckled off-white to yellow, round flat faced beveled edge tablet with product identification “54 111” debossed on one side and scored on the other side. Each tablet contains 250 mg of Larinate-MF (Mefloquine) hydrochloride USP.

NDC 0054-0025-11: Bottle of 25 Tablets

Storage

Larinate-MF (Mefloquine) hydrochloride should be stored at 20˚ to 25°C (68˚ to 77°F).

ANIMAL TOXICOLOGY

Ocular lesions were observed in rats fed Larinate-MF (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.

Male Wistar rats orally administered Larinate-MF (Mefloquine) daily for 22 days at the equivalent human therapeutic plasma concentration showed CNS penetration of Larinate-MF (Mefloquine), with a 30 to 50 fold greater brain/plasma drug ratio up to 10 days after the final dose administered.¹

REFERENCES

• Baudry S., Pham YT., Baune B., Vidrequin S., Crevoisier CH., Gimenez F., Fainotti R. (1997). Stereoselective passage of Larinate-MF (Mefloquine) through the blood brain barrier in the rat. J. Pharm. Pharmacol. 49: 1086-1090.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10002082/13

Revised August 2016

MEDICATION GUIDE

Larinate-MF Hydrochloride Tablets USP

(mef'-loe-kwin HYE-droe-KLOR-ide)

Rx Only

Important:

Your doctor or pharmacist will give you an Information Wallet Card along with this Medication Guide. It has important information about Larinate-MF (Mefloquine) and should be carried with you at all times while you take Larinate-MF (Mefloquine).

What is the most important information I should know about Larinate-MF (Mefloquine)?

Larinate-MF (Mefloquine) can cause serious side effects, including:

1. Heart Problems.

Do not take halofantrine (used to treat malaria) or ketoconazole (used for fungal infections) with Larinate-MF (Mefloquine) or within 15 weeks of your last dose of Larinate-MF (Mefloquine). You may get serious heart problems (problems with the electrical system of your heart called QT prolongation) that can lead to death. Do not take quinine (Qualaquin) or quinidine (used to treat malaria or irregular heart beat) with Larinate-MF (Mefloquine). You may get serious heart problems.

2. Mental problems. Symptoms of serious mental problems may include:

• severe anxiety
• paranoia (feelings of mistrust towards others)
• hallucinations (seeing or hearing things that are not there)
• depression
• feeling restless
• unusual behavior
• feeling confused

Some people who take Larinate-MF (Mefloquine) think about suicide (putting an end to their life). Some people who were taking Larinate-MF (Mefloquine) committed suicide. It is not known if Larinate-MF (Mefloquine) was responsible for those suicides.

If you have any of these serious mental problems, or you develop other serious side effects or mental problems, you should contact your doctor right away as it may be necessary to stop taking Larinate-MF (Mefloquine) and use a different medicine to prevent malaria.

3. Problems with your body’s nervous system. Symptoms of serious nervous system problems may include:

• dizziness
• a feeling that you or things around you are moving or spinning (vertigo)
• loss of balance
• ringing sound in your ears (tinnitus)
• convulsions (seizures) in people who already have seizures (epilepsy)
• convulsions (seizures) in people who take quinine or chloroquine (used to treat malaria) with Larinate-MF (Mefloquine). Do not take quinine (Qualaquin) or chloroquine (Aralen) with Larinate-MF (Mefloquine).
• Unable to sleep (insomnia)

Dizziness, vertigo, tinnitus, and loss of balance can go on for months or years after Larinate-MF (Mefloquine) is stopped or may become permanent in some people.

Important:

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.

• If you are told by a doctor to stop taking Larinate-MF (Mefloquine) because of the side effects or for other reasons, you will need to take different malaria medicine.
• If you do not have access to a doctor or to another medicine and have to stop taking Larinate-MF (Mefloquine), leave the malaria area and contact a doctor as soon as possible because leaving the malaria area may not protect you from getting malaria. You will still need to take a malaria prevention medicine for another 4 weeks after you leave the malaria area.

What is Larinate-MF (Mefloquine)?

Larinate-MF (Mefloquine) is a prescription medicine used to prevent and treat malaria. Malaria can be a life-threatening infection. Larinate-MF (Mefloquine) does not work for all types of malaria.

It is not known if Larinate-MF (Mefloquine) is safe and effective in children under 6 months old for the treatment of malaria. It is not known how well Larinate-MF (Mefloquine) works to prevent malaria in children weighing less than 44 pounds (20 kilograms).

Who should not take Larinate-MF (Mefloquine)?

Do not take Larinate-MF (Mefloquine) if you have:

• depression or had depression recently
• had recent mental problems, including anxiety disorder, schizophrenia, or psychosis (losing touch with reality)
• seizures or had seizures (epilepsy or convulsions)
• an allergy to quinine, quinidine, Larinate-MF (Mefloquine) or any ingredients in Larinate-MF (Mefloquine). See the end of this Medication Guide for a complete list of ingredients in Larinate-MF (Mefloquine).

Talk to your doctor before you take Larinate-MF (Mefloquine) if you have any of the medical conditions listed above.

What should I tell my doctor before taking Larinate-MF (Mefloquine)?

Before taking Larinate-MF (Mefloquine), tell your doctor about all your medical conditions, including if you have:

• heart disease
• liver problems
• seizures or epilepsy
• diabetes
• blood clotting problems or take blood thinner medicines (anticoagulants)
• mental problems
• are pregnant or plan to become pregnant. It is not known if Larinate-MF (Mefloquine) will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
  • You should use birth control while you take Larinate-MF (Mefloquine) and for 3 months after you stop Larinate-MF (Mefloquine). If you have an unplanned pregnancy, talk to your doctor right away.
• are breastfeeding or plan to breastfeed. Larinate-MF (Mefloquine) can pass into your breast milk and may harm your baby. Ask your doctor if you will need to stop breastfeeding or use a different medicine.

Contact your doctor right away if you have a fever after leaving a malaria area.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Larinate-MF (Mefloquine) and other medicines may affect each other causing side effects.

How should I take Larinate-MF (Mefloquine)?

• Take Larinate-MF (Mefloquine) exactly as your doctor tells you to take it. Your doctor will tell you how many Larinate-MF (Mefloquine) tablets to take and when to take them.
• You will start taking Larinate-MF (Mefloquine) to prevent malaria between 1 to 3 weeks before you travel to a malaria area.
• Take Larinate-MF (Mefloquine) just after eating your largest meal of the day and with at least 1 cup (8 ounces) of water.
• Do not take Larinate-MF (Mefloquine) on an empty stomach.
• If you vomit after taking Larinate-MF (Mefloquine), contact your doctor to see if you should take another dose.
• Continue taking Larinate-MF (Mefloquine) for 4 weeks after returning from a malaria area.
• Larinate-MF (Mefloquine) tablets may be crushed and mixed with a small amount of water, milk or other beverage for children or other people unable to swallow Larinate-MF (Mefloquine) whole. Your doctor will tell you the correct dose for your child based on your child’s weight.
• If you take Larinate-MF (Mefloquine) for a year or longer, your doctor should check your:
  • eyes (especially if you have trouble seeing while you take Larinate-MF (Mefloquine))
  • liver function (to see if there has been damage to your liver)
• Use protective clothing, insect repellents, and bednets to protect you from being bitten by mosquitoes. Medicine alone does not always stop you from catching malaria from mosquito bites.

What should I avoid while taking Larinate-MF (Mefloquine)?

Avoid activities such as driving a car or using heavy machinery or other activities needing alertness and careful movements (fine motor coordination) until you know how Larinate-MF (Mefloquine) affects you. You may feel dizzy or lose your balance. This could happen for months or years after you stop taking Larinate-MF (Mefloquine) and can be permanent in some cases. See “What are the possible side effects of Larinate-MF (Mefloquine)?”

What are the possible side effects of Larinate-MF (Mefloquine)?

See “What is the most important information I should know about Larinate-MF (Mefloquine)?”

Larinate-MF (Mefloquine) may cause serious side effects, including:

• liver problems

Call your healthcare provider right away if you have unexplained symptoms such as nausea or vomiting, stomach pain, fever, weakness, itching, unusual tiredness, loss of appetite, light colored bowel movements, dark colored urine, yellowing of your skin or the white of your eyes.

The most common side effects of Larinate-MF (Mefloquine) include:

• nausea
• vomiting
• diarrhea
• abdominal pain
• headache

The most common side effects in people who take Larinate-MF (Mefloquine) for treatment include:

• muscle pain
• fever
• chills
• skin rash
• fatigue
• loss of appetite
• irregular heart beat

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Larinate-MF (Mefloquine). For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Larinate-MF (Mefloquine)?

• Store Larinate-MF (Mefloquine) at 20˚ to 25˚C (68˚ to 77˚F).
• Safely throw away medicine that is out of date or no longer needed.

Keep Larinate-MF (Mefloquine) and all medicines out of the reach of children.

General information about the safe and effective use of Larinate-MF (Mefloquine).

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Larinate-MF (Mefloquine) for a condition for which it was not prescribed. Do not give Larinate-MF (Mefloquine) to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Larinate-MF (Mefloquine). If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Larinate-MF (Mefloquine) that is written for health professionals.

What are the ingredients in Larinate-MF (Mefloquine)?

Active ingredients: Larinate-MF (Mefloquine) hydrochloride USP

Inactive ingredients: ammonium-calcium alginate blend, colloidal silicon dioxide, crospovidone, lactose monohydrate regular, magnesium stearate, microcrystalline cellulose, poloxamer 331, povidone and pregelatinized starch.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10002082/12

Revised March 2016

Information Wallet Card: Larinate-MF hydrochloride tablets

It is important that you read the entire Medication Guide for additional information on Larinate-MF (Mefloquine). Carry this wallet card with you when you are taking Larinate-MF (Mefloquine).

Important: 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.

Larinate-MF (Mefloquine) can cause serious side effects, including:

1. Heart problems.

Do not take halofantrine (used to treat malaria) or ketoconazole (used for fungal infections) with Larinate-MF (Mefloquine) or within 15 weeks of your last dose of Larinate-MF (Mefloquine). You may get serious heart problems that can lead to death. Do not take quinine (Qualaquin) or quinidine (used to treat malaria or irregular heart beat) with Larinate-MF (Mefloquine). You may get serious heart problems. Larinate-MF (Mefloquine) may cause serious problems with the electrical system of your heart, called QT prolongation.

2. Mental problems. Symptoms of serious mental problems may include severe anxiety, paranoia (feelings of mistrust towards others), hallucinations (seeing or hearing things that are not there), depression, feeling restless, unusual behavior or feeling confused. Some people who take Larinate-MF (Mefloquine) think about suicide (putting an end to their life). Some people who were taking Larinate-MF (Mefloquine) committed suicide. It is not known if Larinate-MF (Mefloquine) was responsible for those suicides.

If you have any of these serious mental problems you should contact your doctor right away as it may be necessary to stop taking Larinate-MF (Mefloquine) and use a different medicine to prevent malaria.

3. Problems with your body’s nervous system.

Do not take quinine (Qualaquin) or chloroquine (Aralen) (used to treat malaria) with Larinate-MF (Mefloquine). You may have a greater risk for convulsions (seizures).

Symptoms of serious nervous system problems may include dizziness, a feeling that you or things around you are moving or spinning (vertigo), loss of balance, ringing in your ears (tinnitus), convulsions (seizures) in people who already have seizures, or you are unable to sleep (insomnia).

These serious mental and nervous system side effects can go on for months or years after Larinate-MF (Mefloquine) is stopped or may become permanent in some people.

If you are told by a doctor to stop taking Larinate-MF (Mefloquine) because of the side effects or for other reasons, you will need to take a different malaria medicine.

If you do not have access to a doctor or to a different medicine and have to stop taking Larinate-MF (Mefloquine), leave the malaria area and contact a doctor as soon as possible because leaving the malaria area may not protect you from getting malaria. You will still need to take a malaria prevention medicine for another 4 weeks after you leave the malaria area.

Larinate-MF (Mefloquine) may cause serious liver problems. Symptoms of liver problems include nausea, vomiting, loss of appetite, unusual tiredness, stomach pain, fever, weakness, itching, light-colored bowel movements, dark colored urine, yellowing of your skin or the white of your eyes. The most common side effects of Larinate-MF (Mefloquine) include nausea, vomiting, diarrhea, abdominal pain and headache.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Larinate-MF (Mefloquine). For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088.

What should I avoid while taking Larinate-MF (Mefloquine)?

Avoid activities such as driving a car or using heavy machinery or other activities needing alertness and careful movements (fine motor coordination) until you know how Larinate-MF (Mefloquine) affects you. You may feel dizzy or lose your balance. This could happen for months or years after you stop taking Larinate-MF (Mefloquine) and can be permanent in some cases.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10002082/13

Revised August 2016

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