Mefloquine Hcl

Drug overview for MEFLOQUINE HCL (mefloquine hcl):

Generic name: MEFLOQUINE HCL (MEFF-low-kwin)
Drug class: Antimalarial Drugs
Therapeutic class: Anti-Infective Agents

Mefloquine, a 4-quinolinemethanol derivative and quinine analog, is an antimalarial agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

MEFLOQUINE HCL 250 MG TABLET

The following indications for MEFLOQUINE HCL (mefloquine hcl) have been approved by the FDA:

Indications:
Chloroquine-resistant Plasmodium falciparum malaria prevention
Chloroquine-resistant Plasmodium falciparum malaria
Plasmodium vivax malaria prevention
Plasmodium vivax malaria

Professional Synonyms:
Benign tertian malaria prophylaxis
Benign tertian malaria
Chloroquine-resistant aestivoautumnal fever
Chloroquine-resistant falciparum fever
Chloroquine-resistant falciparum malaria prophylaxis
Chloroquine-resistant falciparum malaria
Chloroquine-resistant malaria due to Plasmodium falciparum
Chloroquine-resistant malignant tertian fever
Chloroquine-resistant malignant tertian malaria
Chloroquine-resistant pernicious malaria
Chloroquine-resistant subtertian malaria
Malaria due to Plasmodium vivax prophylaxis
Malaria due to Plasmodium vivax
Tertian fever prophylaxis
Tertian fever
Tertian malaria prophylaxis
Tertian malaria
Vivax fever prophylaxis
Vivax fever
Vivax malaria prophylaxis
Vivax malaria

The following dosing information is available for MEFLOQUINE HCL (mefloquine hcl):

Dosing
Administration
MEFLOQUINE HCL
MEFLOQUINE HCL

In the US, dosage of mefloquine hydrochloride is expressed in terms of the salt. Each 250-mg tablet of mefloquine hydrochloride commercially available in the US is equivalent to 228 mg of mefloquine base. Other formulations (e.g., 275-mg mefloquine hydrochloride tablets containing 250 mg of the base) may be available in other countries.

Dosage of mefloquine hydrochloride in children is based on body weight.

For prevention or chemoprophylaxis of malaria in adults, the recommended dosage of mefloquine hydrochloride is 250 mg once weekly given on the same day each week, preferably after the main meal.

For prevention or chemoprophylaxis of malaria in pediatric patients weighing 45 kg or less, the recommended dosage of mefloquine hydrochloride is approximately 5 mg/kg once weekly given on the same day each week, preferably after the main meal.

For prevention or chemoprophylaxis of malaria, children weighing more than 19 kg up to 30 kg should receive mefloquine hydrochloride in a dosage of 125 mg (one-half of a 250-mg tablet) once weekly; children weighing more than 30 kg up to 45 kg should receive 187.5 mg (three-fourths of a 250-mg tablet) once weekly; and children weighing more than 45 kg should receive the usual adult dosage (250 mg once weekly).

Although only limited data are available regarding use of mefloquine hydrochloride in children weighing less than 20 kg (especially those weighing less than 5 kg), the US Centers for Disease Control and Prevention (CDC) and other experts state that those weighing 9 kg or less can receive a dosage of 5 mg/kg (extemporaneously prepared and dispensed by a pharmacist) once weekly and those weighing more than 9 kg up to 19 kg may receive 62.5 mg (one-fourth of a tablet; extemporaneously prepared and dispensed by a pharmacist) once weekly for prevention or chemoprophylaxis of malaria. (See Dosage and Administration: Administration.)

For the treatment of uncomplicated malaria caused by mefloquine-susceptible P. falciparum or P. vivax, the manufacturer recommends that adults receive 1250 mg of mefloquine hydrochloride (five 250-mg tablets) given as a single dose.

The CDC and other experts recommend that adults receive a 2-dose regimen of mefloquine hydrochloride that involves an initial 750-mg oral dose (three 250-mg tablets) followed by a 500-mg oral dose (two 250-mg tablets) given 6-12 hours after the initial dose (total dose of 1250 mg).

For the treatment of uncomplicated malaria caused by mefloquine-susceptible P. falciparum, the manufacturer recommends that children receive mefloquine hydrochloride in a dosage of 20-25 mg/kg and states that dividing the dosage into 2 doses given 6-8 hours apart may reduce the incidence and severity of adverse effects. The CDC and other experts recommend that children receive a 2-dose regimen of mefloquine hydrochloride that involves an initial dose of 15 mg/kg followed by 10 mg/kg given 6-12 hours after the initial dose (total dose of 25 mg/kg).

Pediatric dosage should not exceed the usual adult dosage (1250 mg). Only limited data are available regarding use of mefloquine hydrochloride in children weighing less than 20 kg (especially those weighing less than 5 kg).

The manufacturer makes no specific recommendations regarding the need for dosage adjustment in individuals with renal impairment. When mefloquine is used for malaria prophylaxis, limited data indicate that dosage adjustment is not necessary in individuals undergoing hemodialysis.

The manufacturer makes no specific recommendations regarding the need for dosage adjustment in individuals with hepatic impairment. Pharmacokinetic data indicate that elimination of mefloquine may be prolonged and plasma concentrations may be increased in patients with impaired hepatic function. (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Mefloquine hydrochloride is administered orally with ample water (at least 8 oz (240 mL) of water for an adult). The drug should not be administered on an empty stomach. If a patient receiving mefloquine for the treatment of malaria vomits within 30 minutes after receiving a dose of the drug, another full dose should be administered as a replacement; if a patient vomits within 30-60 minutes after receiving a dose, 50% of the dose should be administered as a replacement.

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. For administration in children and others who are unable to swallow tablets, mefloquine hydrochloride tablets may be crushed and mixed with a small amount of liquid (e.g., water, milk, other beverage). When mefloquine hydrochloride doses less than 125 mg (less than one-half of a 250-mg tablet) are indicated for pediatric patients, gelatin capsules containing the calculated pediatric dosage should be prepared extemporaneously by a pharmacist using a crushed tablet.

A mefloquine hydrochloride medication guide has been developed to help individuals understand the risks of malaria, risks and benefits of taking mefloquine to prevent malaria, and the rare but potentially serious adverse effects associated with use of the drug. As required by law, a copy of the mefloquine medication guide must be supplied to patients each time mefloquine is dispensed for prevention of malaria; an information wallet card also is supplied to the patient when the drug is dispensed.

Dosing information for MEFLOQUINE HCL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
MEFLOQUINE HCL 250 MG TABLET	Maintenance	Adults take 1 tablet (250 mg) by oral route once weekly start 1 week before departure to endemic area; take with food and at least 8 oz. of water

Generic dosing information for MEFLOQUINE HCL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
MEFLOQUINE HCL 250 MG TABLET	Maintenance	Adults take 1 tablet (250 mg) by oral route once weekly start 1 week before departure to endemic area; take with food and at least 8 oz. of water

The following drug interaction information is available for MEFLOQUINE HCL (mefloquine hcl):

Contraindicated
Severe
Moderate

There are 6 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Mefloquine/Chloroquine; Hydroxychloroquine; Quinidine; Quinine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The exact mechanism is unknown, but may involve additive effects between mefloquine and antimalarials including chloroquine, hydroxychloroquine, quinidine or quinine. CLINICAL EFFECTS: Concurrent administration of mefloquine with chloroquine, hydroxychloroquine, quinidine or quinine may result in electrocardiographic abnormalities, cardiac arrest, and/or an increased risk of convulsions.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of mefloquine with chloroquine, hydroxychloroquine, quinidine, or quinine is contraindicated. If these agents are used in the initial treatment of malaria, the administration of mefloquine should be delayed until 12 hours after the last dose of chloroquine, hydroxychloroquine, quinidine, or quinine.(1) DISCUSSION: There is little clinical information to support this interaction. An in vitro study in human liver microsomes showed that quinine inhibits the metabolism of mefloquine.(2) The manufacturer of mefloquine states that concurrent administration of mefloquine with quinine or quinidine may produce electrocardiographic abnormalities or cardiac arrest and that the concurrent administration of mefloquine and quinine or chloroquine may increase the risk of convulsions.(1) The manufacturer of mefloquine states that if quinine or quinidine are used in the treatment of malaria, 12 hours should elapse between the their last dose and the first dose of mefloquine.(1)	CHLOROQUINE PHOSPHATE, HYDROXYCHLOROQUINE SULFATE, NUEDEXTA, PLAQUENIL, QUALAQUIN, QUINIDINE GLUCONATE, QUINIDINE SULFATE, QUININE HCL, QUININE SULFATE, SOVUNA
Ziprasidone/Selected QT Prolonging Agents SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Ziprasidone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) CLINICAL EFFECTS: The concurrent use of ziprasidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) PREDISPOSING FACTORS: Bradycardia, hypokalemia, hypomagnesemia, and the presence of congenital prolongation of the QT interval may increase the risk of torsades de pointes and/or sudden death.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes), hypocalcemia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction.(3) PATIENT MANAGEMENT: The manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QT interval such as dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)	GEODON, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE
BCG Vaccines/Mefloquine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Mefloquine may attenuate the immunization response to vaccines with attenuated live bacteria, such as BCG vaccine.(1) CLINICAL EFFECTS: Concurrent use may make the vaccine ineffective.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of mefloquine states that vaccinations with vaccines containing attenuated live bacteria should be completed three days before the initiation of mefloquine.(1) DISCUSSION: The manufacturer of mefloquine states that attenuation of immunization response to vaccines with attenuated live bacteria cannot be excluded and therefore the manufacturer of mefloquine states that vaccinations with vaccines containing attenuated live bacteria should be completed three days before the initiation of mefloquine.(1)	BCG (TICE STRAIN), BCG VACCINE (TICE STRAIN)
Artemether; Lumefantrine/Antimalarials SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Halofantrine and quinine may inhibit the metabolism of lumefantrine by CYP2D6.(1) The combination of artemether-lumefantrine and antimalarials may result in additive effects on the QT interval.(1) CLINICAL EFFECTS: Concurrent use may result in toxicity and/or prolongation of the QT interval, which may result in life-threatening arrhythmias.(1,2) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: The UK manufacturer of artemether-lumefantrine states that the concurrent use of artemether-lumefantrine with other antimalarials is contraindicated.(1) The US manufacturer of artemether-lumefantrine states that artemether-lumefantrine should not be given concurrently with antimalarials.(2) If a patient deteriorates during artemether-lumefantrine therapy and requires another antimalarial agent, it may be started immediately, but the UK manufacturer of artemether-lumefantrine recommends ECG and potassium monitoring.(1) In patients who have previously received halofantrine, both the UK and US manufacturers of artemether-lumefantrine recommends that one month elapse between the last dose of halofantrine and the initiation of artemether-lumefantrine.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a study in 14 healthy subjects, administration of a single intravenous dose of quinine (10 mg/kg) 2 hours after the sixth dose of artemether-lumefantrine had no effect on lumefantrine or dihydroartemisinin levels. Artemether levels were decreased; however, this was not believed to be clinically significant.(1,2) Concurrent quinine and artemether-lumefantrine produced a slight, but significant increase on the QTc interval.(1)	COARTEM
Penicillamine/Antimalarial Agents SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Concurrent use may result in additive or synergistic effects on the blood and kidneys(1) or increased penicillamine levels.(2) CLINICAL EFFECTS: Concurrent use of penicillamine with antimalarials may result in serious hematologic or renal toxicity(1,2) or elevated levels of penicillamine.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent therapy with antimalarial agents.(1) DISCUSSION: In patients with rheumatoid arthritis, concurrent chloroquine increased penicillamine plasma concentrations by 34% when compared to penicillamine alone.(2) In a 2-year controlled, double-blind trial of penicillamine, hydroxychloroquine, or combination therapy, patients on combination therapy did not do as well as patients receiving penicillamine alone.(3) Because antimalarial agents are associated with hematologic and renal toxicity, the manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent antimalarials.(1)	CUPRIMINE, D-PENAMINE, DEPEN, PENICILLAMINE, PENICILLAMINE(D-)
Mefloquine/Ketoconazole; Levoketoconazole SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Ketoconazole and levoketoconazole may inhibit the metabolism of mefloquine by CYP3A4 and the transport of mefloquine by P-glycoprotein.(1,4) CLINICAL EFFECTS: Concurrent use of ketoconazole or levoketoconazole may result in elevated levels of and toxicity from mefloquine, including prolongation of the QTc interval, which may be fatal.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: The US manufacturer of mefloquine states that ketoconazole should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine.(1) The manufacture of levoketoconazole states that concurrent use of levoketoconazole with substrates of CYP3A4 and P-gp is not recommended.(4) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In an open-label, cross-over study in 7 healthy subjects, ketoconazole (400 mg daily for 10 days) increased the area-under-curve (AUC), maximum concentration (Cmax), and half-life (T1/2) of a single dose of mefloquine (500 mg) by 79%, 64%, and 39%, respectively.(1,2)	KETOCONAZOLE, RECORLEV

There are 2 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Selected Antimalarials/Strong CYP3A4 Inducers; Selected Barbiturates, Hydantoin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of mefloquine, quinidine, and quinine. CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of mefloquine, quinidine, or quinine. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: In patients receiving concurrent strong CYP3A4 inducers, monitor mefloquine, quinidine, or quinine serum levels and observe the patient for symptoms of reduced efficacy. Adjust the dosage accordingly. The US manufacturer of quinine recommends avoiding the concurrent use of rifampin, a strong CYP3A4 inducer, because of the increased risk of malaria treatment failure. DISCUSSION: Several studies document the reduction in quinidine response in patients receiving concurrent rifampin. Decreased elimination half-life, reduced area-under-curve (AUC), and low serum quinidine level were observed. In healthy volunteers, quinine AUC and maximum concentration (Cmax) were reduced 85% and 55%, respectively, after a single dose of rifampin was added after two weeks of quinine therapy.(6) In a randomized control trial of 59 male patients with Plasmodium falciparum malaria, treatment with concomitant quinine and rifampin was associated with a cure rate of only 35% compared to 88% in those treated with quinine monotherapy. The AUC of quinine during treatment days 3 through 7 was significantly reduced in the quinine plus rifampin group compared to those treated with quinine alone (11.7 vs. 47.5 mcg/ml/day; p < 0.004).(7) In an open-label, cross-over study in 7 healthy subjects, concurrent rifampin (600 mg daily) decreased the AUC and Cmax of a single dose of mefloquine (500 mg) by 68% and 19%, respectively.(8,9) Agents linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, ethotoin, fosphenytoin, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(10)	ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, XTANDI
Selected CYP3A4 Substrates/Lonafarnib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lonafarnib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus. CLINICAL EFFECTS: Concurrent use of lonafarnib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of lonafarnib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, monitor for adverse effects and consider dose reduction of the CYP3A4 substrate according to its prescribing information.(1) The manufacturer of lonafarnib states that the dose of P-gp substrates may need to be reduced with coadministration with lonafarnib.(1) DISCUSSION: In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%, respectively.(1) In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24% and 21%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: bromocriptine, cabergoline, cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine, mefloquine, nisoldipine, oliceridine, pomalidomide, regorafenib, sirolimus, and zanubrutinib.(1-3)	ZOKINVY

Drug Interaction

Drug Names

Selected Antimalarials/Strong CYP3A4 Inducers; Selected Barbiturates, Hydantoin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of mefloquine, quinidine, and quinine.

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of mefloquine, quinidine, or quinine.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: In patients receiving concurrent strong CYP3A4 inducers, monitor mefloquine, quinidine, or quinine serum levels and observe the patient for symptoms of reduced efficacy. Adjust the dosage accordingly. The US manufacturer of quinine recommends avoiding the concurrent use of rifampin, a strong CYP3A4 inducer, because of the increased risk of malaria treatment failure.

DISCUSSION: Several studies document the reduction in quinidine response in patients receiving concurrent rifampin. Decreased elimination half-life, reduced area-under-curve (AUC), and low serum quinidine level were observed. In healthy volunteers, quinine AUC and maximum concentration (Cmax) were reduced 85% and 55%, respectively, after a single dose of rifampin was added after two weeks of quinine therapy.(6)

In a randomized control trial of 59 male patients with Plasmodium falciparum malaria, treatment with concomitant quinine and rifampin was associated with a cure rate of only 35% compared to 88% in those treated with quinine monotherapy. The AUC of quinine during treatment days 3 through 7 was significantly reduced in the quinine plus rifampin group compared to those treated with quinine alone (11.7 vs. 47.5 mcg/ml/day; p < 0.004).(7) In an open-label, cross-over study in 7 healthy subjects, concurrent rifampin (600 mg daily) decreased the AUC and Cmax of a single dose of mefloquine (500 mg) by 68% and 19%, respectively.(8,9)

Agents linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, ethotoin, fosphenytoin, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(10)

ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, XTANDI

Selected CYP3A4 Substrates/Lonafarnib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lonafarnib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus.

CLINICAL EFFECTS: Concurrent use of lonafarnib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lonafarnib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, monitor for adverse effects and consider dose reduction of the CYP3A4 substrate according to its prescribing information.(1) The manufacturer of lonafarnib states that the dose of P-gp substrates may need to be reduced with coadministration with lonafarnib.(1)

DISCUSSION: In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%, respectively.(1) In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24% and 21%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: bromocriptine, cabergoline, cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine, mefloquine, nisoldipine, oliceridine, pomalidomide, regorafenib, sirolimus, and zanubrutinib.(1-3)

ZOKINVY

There are 3 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Mefloquine; Quinidine/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Quinidine may inhibit the oxidative metabolism of beta-blockers. In addition, beta-blockers and quinidine exert a negative inotropic action on the heart. Mefloquine is a chemical analogue of quinine which possess 20% of the antifibrillatory action of quinidine. Alterations in electrocardiograms have been observed during mefloquine therapy. CLINICAL EFFECTS: The pharmacologic effects of certain beta-blockers may be increased during concurrent therapy with quinidine. During concurrent therapy with mefloquine, electrocardiographic abnormalities or cardiac arrest may occur. PREDISPOSING FACTORS: Cardiac disease. PATIENT MANAGEMENT: Monitor the response of the patient and adjust the dose of the beta-blocker as needed. The benefits of mefloquine therapy in patients with preexisting cardiac disease should be weighed carefully. DISCUSSION: Quinidine and beta-blockers have been used therapeutically to treat cardiac arrhythmias; however, they should be used cautiously since quinidine and beta-blockers exert a negative inotropic action on the heart. Quinidine has been associated with an increase in serum metoprolol levels. A reduction in propranolol clearance has been demonstrated in one study, although others have failed to show an interaction between propranolol and quinidine. A patient using timolol eyedrops developed bradycardia following administration of quinidine. There is one report of cardiac arrest, which was successfully treated, in a patient receiving concurrent mefloquine and propranolol. The manufacturer of mefloquine states that concurrent use may produce electrocardiographic abnormalities and cardiac arrest. The manufacturer also recommends weighing the benefits of mefloquine therapy against the risk of adverse effects in patients with cardiac disease.	ATENOLOL, ATENOLOL-CHLORTHALIDONE, HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, KAPSPARGO SPRINKLE, LOPRESSOR, METOPROLOL SUCCINATE, METOPROLOL TARTRATE, METOPROLOL-HYDROCHLOROTHIAZIDE, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID, TENORETIC 100, TENORETIC 50, TENORMIN, TOPROL XL
Typhoid Vaccine Live Attenuated/Mefloquine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Mefloquine may attenuate the immunization response to vaccines with attenuated live bacteria.(1) CLINICAL EFFECTS: Concurrent use may make the vaccine ineffective.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of mefloquine states that administration of vaccines which contain attenuated live bacteria should be completed three days before the initiation of mefloquine.(1) To optimize vaccine effectiveness, the Centers for Disease Control(CDC) recommends, when feasible, delay of antibacterial drug therapy for one week after the last dose of oral typhoid vaccine.(2) The manufacturer of oral typhoid Ty21a vaccine states concomitant treatment with mefloquine does not significantly reduce immune response rate.(3) DISCUSSION: The manufacturer of mefloquine states that attenuation of immunization response to vaccines with attenuated live bacteria cannot be excluded and therefore the manufacturer of mefloquine states that vaccinations with vaccines containing attenuated live bacteria should be completed three days before the initiation of mefloquine.(1)	VIVOTIF
Mefloquine/Selected Strong CYP3A4 Inhibitors;Protease Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of mefloquine.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors or protease inhibitors with mefloquine may result in elevated levels of mefloquine and toxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of mefloquine states that concurrent use with strong CYP3A4 inhibitors should be approached with caution.(1) The US Department of Health and Human Services HIV guidelines recommend considering alternative therapies to protease inhibitors or monitoring for adverse events and virologic response.(2) DISCUSSION: In a study in 8 healthy subjects, administration of ketoconazole (400 mg daily) for 10 days followed by a single 500 mg dose of mefloquine resulted in an increase in the AUC of mefloquine by 79%. The elimination half-life was increased from 322 hours to 448 hours.(1) Strong CYP3A4 inhibitors and protease inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4)	APTIVUS, ATAZANAVIR SULFATE, CLARITHROMYCIN, CLARITHROMYCIN ER, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, PREZISTA, REYATAZ, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, VORICONAZOLE (HPBCD), ZYDELIG, ZYKADIA

The following contraindication information is available for MEFLOQUINE HCL (mefloquine hcl):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

No enhanced Contraindications information available for this drug.

There are 5 contraindications. Absolute contraindication.

Contraindication List
Depression
Generalized anxiety disorder
Psychotic disorder
Schizophrenia
Seizure disorder

There are 1 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Sinus bradycardia

There are 6 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Ataxia
Atrioventricular block
Disease of liver
Myasthenia gravis
Prolonged QT interval
Sinus node dysfunction

The following adverse reaction information is available for MEFLOQUINE HCL (mefloquine hcl):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 37 severe adverse reactions.

More Frequent	Less Frequent
Concentration difficulty	Dyspnea

Rare/Very Rare
Abnormal hepatic function tests Acute cognitive impairment Agranulocytosis Anaphylaxis Aplastic anemia Ataxia Bradycardia Cardiac arrest Cardiac arrhythmia Depression Drug-induced psychosis Encephalopathy Erythema multiforme Hallucinations Hepatic failure Hypersensitivity pneumonitis Hypertension Hypotension Leukocytosis Mood changes Muscle weakness Nervousness Panic disorder Paranoid disorder Paresthesia Prolonged QT interval Seizure disorder Stevens-johnson syndrome Suicidal Suicidal ideation Syncope Thrombocytopenic disorder Tremor Urticaria Vertigo

Rare/Very Rare

Abnormal hepatic function tests
Acute cognitive impairment
Agranulocytosis
Anaphylaxis
Aplastic anemia
Ataxia
Bradycardia
Cardiac arrest
Cardiac arrhythmia
Depression
Drug-induced psychosis
Encephalopathy
Erythema multiforme
Hallucinations
Hepatic failure
Hypersensitivity pneumonitis
Hypertension
Hypotension
Leukocytosis
Mood changes
Muscle weakness
Nervousness
Panic disorder
Paranoid disorder
Paresthesia
Prolonged QT interval
Seizure disorder
Stevens-johnson syndrome
Suicidal
Suicidal ideation
Syncope
Thrombocytopenic disorder
Tremor
Urticaria
Vertigo

There are 30 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal pain with cramps Anorexia Diarrhea Dizziness Headache disorder Insomnia Nausea Visual changes Vomiting	Fatigue Myalgia Skin rash

Rare/Very Rare
Alopecia Arthralgia Behavioral disorders Chills Cramps Dream disorder Dyspepsia Edema Erythema Fever General weakness Hyperhidrosis Malaise Memory impairment Polyneuropathy Pruritus of skin Symptoms of anxiety Tinnitus

The following precautions are available for MEFLOQUINE HCL (mefloquine hcl):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

The manufacturer states that mefloquine should be used during pregnancy only when clearly needed and that women of childbearing potential should be advised to use effective contraceptive measures while receiving mefloquine and for up to 3 months after the last dose of the drug. The CDC and American Academy of Pediatrics (AAP) state that mefloquine is the drug of choice for prevention of malaria in women who are pregnant, or likely to become pregnant, if exposure to chloroquine-resistant P. falciparum is unavoidable.

In addition, the CDC states that mefloquine is a drug of choice for the treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or chloroquine-resistant P. vivax in pregnant women.

(See Uses: Malaria.) Published data on use of mefloquine for prevention or treatment of malaria during pregnancy, including data from randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series, have not shown 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 mefloquine in the first trimester of pregnancy and over 2,000 exposures in the second and third trimesters. However, mefloquine was teratogenic in mice, rats, and rabbits when given in dosages that were similar to those used for the treatment of malaria (based on body surface area comparisons).

CNS effects (e.g., exencephaly, hydrocephaly, partially missing medulla oblongata) and craniofacial malformations were observed in all 3 species. Mefloquine also was embryotoxic in mice and rabbits at these dosages. Adverse fetal or pregnancy outcomes were not indicated in a double-blind study and clinical experience that included women who received mefloquine during the second and third trimesters.

In addition, the frequencies of spontaneous abortion and congenital malformations in 1133 women exposed to mefloquine during the first trimester of pregnancy (more than 95% received mefloquine for prophylaxis) were within expected background rates, and the abnormalities did not fit a specific pattern and would be difficult to attribute to a single pathogenic mechanism. Data from a study evaluating the relationship between use of mefloquine for the treatment of malaria during pregnancy and pregnancy outcome indicate that mefloquine exposure during pregnancy was not associated with an increased incidence of abortion, low birthweight, neurologic retardation, or congenital malformations; however, mefloquine exposure was associated with a greater risk of stillbirth than exposure to other antimalarials, including quinine.

Small amounts of mefloquine are distributed into breast milk. In one study in a limited number of women, approximately 3-4% of a single 250-mg mefloquine dose was distributed into breast milk. Following administration of a single 250-mg dose of the drug in one woman, mefloquine concentrations in breast milk at 4 and 56 days were 53 and 32 ng/mL, respectively.

The manufacturer states that mefloquine should be used with caution in nursing women. Because the amount of mefloquine consumed by a nursing infant is likely to be small, some clinicians suggest that the risk to nursing infants of maternal use of prophylactic dosages of mefloquine is low. However, the amount of mefloquine present in breast milk is insufficient to provide adequate protection against malaria in the nursing infant and, if chemoprophylaxis is necessary, such infants should receive recommended dosages of an appropriate antimalarial.

No enhanced Geriatric Use information available for this drug.

Chloroquine-resistant plasmodium falciparum malaria
B50	Plasmodium falciparum malaria
B50.0	Plasmodium falciparum malaria with cerebral complications
B50.8	Other severe and complicated plasmodium falciparum malaria
B50.9	Plasmodium falciparum malaria, unspecified
P37.3	Congenital falciparum malaria
Z16.31	Resistance to antiparasitic drug(s)
Plasmodium vivax malaria
B51	Plasmodium vivax malaria
B51.0	Plasmodium vivax malaria with rupture of spleen
B51.8	Plasmodium vivax malaria with other complications
B51.9	Plasmodium vivax malaria without complication