Atovaquone 250 MG / proguanil hydrochloride 100 MG Oral Tablet [Malarone]

Details

DRUG INTERACTIONS

7 Administration with rifampin or rifabutin is known to reduce atovaquone concentrations; concomitant use with MALARONE is not recommended.

( ) • 7.1 Proguanil may potentiate anticoagulant effect of warfarin and other coumarin-based anticoagulants.

Caution advised when initiating or withdrawing MALARONE in patients on anticoagulants; coagulation tests should be closely monitored.

( ) • 7.2 Tetracycline may reduce atovaquone concentrations; parasitemia should be closely monitored.

( ) • 7.3 7.1 Rifampin/Rifabutin Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations .

The concomitant administration of MALARONE and rifampin or rifabutin is not recommended.

[see Clinical Pharmacology (12.3)] 7.2 Anticoagulants Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin-based anticoagulants.

The mechanism of this potential drug interaction has not been established.

Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with MALARONE in patients on continuous treatment with coumarin-based anticoagulants.

When these products are administered concomitantly, coagulation tests should be closely monitored.

7.3 Tetracycline Concomitant treatment with tetracycline has been associated with a reduction in plasma concentrations of atovaquone .

Parasitemia should be closely monitored in patients receiving tetracycline.

[see Clinical Pharmacology (12.3)] 7.4 Metoclopramide While antiemetics may be indicated for patients receiving MALARONE, metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available .

[see Clinical Pharmacology (12.3)] 7.5 Indinavir Concomitant administration of atovaquone and indinavir did not result in any change in the steady‑state AUC and C of indinavir but resulted in a decrease in the C of indinavir .

Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough concentrations of indinavir.

max trough [see Clinical Pharmacology (12.3)]

OVERDOSAGE

10 There is no information on overdoses of MALARONE substantially higher than the doses recommended for treatment.

There is no known antidote for atovaquone, and it is currently unknown if atovaquone is dialyzable.

Overdoses up to 31,500 mg of atovaquone have been reported.

In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred.

Rash has also been reported after overdose.

Overdoses of proguanil hydrochloride as large as 1,500 mg have been followed by complete recovery, and doses as high as 700 mg twice daily have been taken for over 2 weeks without serious toxicity.

Adverse experiences occasionally associated with proguanil hydrochloride doses of 100 to 200 mg/day, such as epigastric discomfort and vomiting, would be likely to occur with overdose.

There are also reports of reversible hair loss and scaling of the skin on the palms and/or soles, reversible aphthous ulceration, and hematologic side effects.

DESCRIPTION

11 MALARONE (atovaquone and proguanil hydrochloride) Tablets (adult strength) and MALARONE (atovaquone and proguanil hydrochloride) Pediatric Tablets, for oral administration, contain a fixed‑dose combination of the antimalarial agents atovaquone and proguanil hydrochloride.

The chemical name of atovaquone is -2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione.

Atovaquone is a yellow crystalline solid that is practically insoluble in water.

It has a molecular weight of 366.84 and the molecular formula C H ClO .

The compound has the following structural formula: trans 22 19 3 The chemical name of proguanil hydrochloride is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride.

Proguanil hydrochloride is a white crystalline solid that is sparingly soluble in water.

It has a molecular weight of 290.22 and the molecular formula C H ClN •HCl.

The compound has the following structural formula: 11 16 5 Each MALARONE Tablet (adult strength) contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride and each MALARONE Pediatric Tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride.

The inactive ingredients in both tablets are low‑substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, and sodium starch glycolate.

The tablet coating contains hypromellose, polyethylene glycol 400, polyethylene glycol 8000, red iron oxide, and titanium dioxide.

atovaquone molecular structure proguanil hydrochloride molecular structure

CLINICAL STUDIES

14 14.1 Prevention of Malaria P.

falciparum MALARONE was evaluated for prophylaxis of malaria in 5 clinical trials in malaria‑endemic areas and in 3 active‑controlled trials in non‑immune travelers to malaria‑endemic areas.

falciparum Three placebo‑controlled trials of 10 to 12 weeks’ duration were conducted among residents of malaria‑endemic areas in Kenya, Zambia, and Gabon.

The mean age of subjects was 30 (range 17‑55), 32 (range 16‑64), and 10 (range 5‑16) years, respectively.

Of a total of 669 randomized patients (including 264 pediatric patients 5 to 16 years of age), 103 were withdrawn for reasons other than falciparum malaria or drug‑related adverse events (55% of these were lost to follow‑up and 45% were withdrawn for protocol violations).

The results are listed in Table 6.

Table 6.

Prevention of Parasitemia in Placebo Controlled Clinical Trials of MALARONE for Prophylaxis of P.

falciparum Malaria in Residents of Malaria Endemic Areas a MALARONE Placebo Total number of patients randomized 326 343 Failed to complete study 57 46 Developed parasitemia ( ) P.

falciparum 2 92 Free of parasitemia during the 10 to 12-week period of prophylactic therapy.

a In another study, 330 Gabonese pediatric patients (weighing 13 to 40 kg, and aged 4 to 14 years) who had received successful open‑label radical cure treatment with artesunate, were randomized to receive either MALARONE (dosage based on body weight) or placebo in a double‑blind fashion for 12 weeks.

Blood smears were obtained weekly and any time malaria was suspected.

Nineteen of the 165 children given MALARONE and 18 of 165 patients given placebo withdrew from the study for reasons other than parasitemia (primary reason was lost to follow-up).

One out of 150 evaluable patients (<1%) who received MALARONE developed parasitemia while receiving prophylaxis with MALARONE compared with 31 (22%) of the 144 evaluable placebo recipients.

falciparum In a 10‑week study in 175 South African subjects who moved into malaria‑endemic areas and were given prophylaxis with 1 MALARONE Tablet daily, parasitemia developed in 1 subject who missed several doses of medication.

Since no placebo control was included, the incidence of malaria in this study was not known.

Two active-controlled trials were conducted in non‑immune travelers who visited a malaria‑endemic area.

The mean duration of travel was 18 days (range 2 to 38 days).

Of a total of 1,998 randomized patients who received MALARONE or controlled drug, 24 discontinued from the study before follow-up evaluation 60 days after leaving the endemic area.

Nine of these were lost to follow-up, 2 withdrew because of an adverse experience, and 13 were discontinued for other reasons.

These trials were not large enough to allow for statements of comparative efficacy.

In addition, the true exposure rate to malaria in both trials is unknown.

The results are listed in Table 7.

falciparum Table 7.

Prevention of Parasitemia in Active-Controlled Clinical Trials of MALARONE for Prophylaxis of P.

falciparum Malaria in Non-Immune Travelers a MALARONE Mefloquine Chloroquine plus Proguanil Total number of randomized patients who received study drug 1,004 483 511 Failed to complete study 14 6 4 Developed parasitemia ( ) P.

falciparum 0 0 3 Free of parasitemia during the period of prophylactic therapy.

a A third randomized, open‑label study was conducted which included 221 otherwise healthy pediatric patients (weighing ≥11 kg and 2 to 17 years of age) who were at risk of contracting malaria by traveling to an endemic area.

The mean duration of travel was 15 days (range 1 to 30 days).

Prophylaxis with MALARONE (n = 110, dosage based on body weight) began 1 or 2 days before entering the endemic area and lasted until 7 days after leaving the area.

A control group (n = 111) received prophylaxis with chloroquine/proguanil dosed according to WHO guidelines.

No cases of malaria occurred in either group of children.

However, the study was not large enough to allow for statements of comparative efficacy.

In addition, the true exposure rate to malaria in this study is unknown.

falciparum In separate trials with small numbers of volunteers, atovaquone and proguanil hydrochloride were independently shown to have causal prophylactic activity directed against liver‑stage parasites of .

Six patients given a single dose of atovaquone 250 mg 24 hours prior to malaria challenge were protected from developing malaria, whereas all 4 placebo‑treated patients developed malaria.

Causal Prophylaxis: P.

falciparum During the 4 weeks following cessation of prophylaxis in clinical trial participants who remained in malaria‑endemic areas and were available for evaluation, malaria developed in 24 of 211 (11.4%) subjects who took placebo and 9 of 328 (2.7%) who took MALARONE.

While new infections could not be distinguished from recrudescent infections, all but 1 of the infections in patients treated with MALARONE occurred more than 15 days after stopping therapy.

The single case occurring on day 8 following cessation of therapy with MALARONE probably represents a failure of prophylaxis with MALARONE.

The possibility that delayed cases of malaria may occur some time after stopping prophylaxis with MALARONE cannot be ruled out.

Hence, returning travelers developing febrile illnesses should be investigated for malaria.

falciparum 14.2 Treatment of Acute, Uncomplicated Malaria Infections P.

falciparum In 3 phase II clinical trials, atovaquone alone, proguanil hydrochloride alone, and the combination of atovaquone and proguanil hydrochloride were evaluated for the treatment of acute, uncomplicated malaria caused by .

Among 156 evaluable patients, the parasitological cure rate (elimination of parasitemia with no recurrent parasitemia during follow‑up for 28 days) was 59/89 (66%) with atovaquone alone, 1/17 (6%) with proguanil hydrochloride alone, and 50/50 (100%) with the combination of atovaquone and proguanil hydrochloride.

falciparum MALARONE was evaluated for treatment of acute, uncomplicated malaria caused by in 8 phase III randomized, open-label, controlled clinical trials (N = 1,030 enrolled in both treatment groups).

The mean age of subjects was 27 years and 16% were children ≤12 years of age; 74% of subjects were male.

Evaluable patients included those whose outcome at 28 days was known.

Among 471 evaluable patients treated with the equivalent of 4 MALARONE Tablets once daily for 3 days, 464 had a sensitive response (elimination of parasitemia with no recurrent parasitemia during follow‑up for 28 days) (Table 8).

Seven patients had a response of RI resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28 days after starting treatment).

In these trials, the response to treatment with MALARONE was similar to treatment with the comparator drug in 4 trials.

falciparum Table 8.

Parasitological Response in 8 Clinical Trials of MALARONE for Treatment of P.

falciparum Malaria Study Site MALARONE a Comparator Evaluable Patients (n) % Sensitive Response b Drug(s) Evaluable Patients (n) % Sensitive Response b Brazil 74 98.6% Quinine and tetracycline 76 100.0% Thailand 79 100.0% Mefloquine 79 86.1% France c 21 100.0% Halofantrine 18 100.0% Kenya c,d 81 93.8% Halofantrine 83 90.4% Zambia 80 100.0% Pyrimethamine/ sulfadoxine (P/S) 80 98.8% Gabon c 63 98.4% Amodiaquine 63 81.0% Philippines 54 100.0% Chloroquine (Cq) Cq and P/S 23 32 30.4% 87.5% Peru 19 100.0% Chloroquine P/S 13 7 7.7% 100.0% MALARONE = 1,000 mg atovaquone and 400 mg proguanil hydrochloride (or equivalent based on body weight for patients weighing ≤40 kg) once daily for 3 days.

a Elimination of parasitemia with no recurrent parasitemia during follow‑up for 28 days.

b Patients hospitalized only for acute care.

Follow‑up conducted in outpatients.

c Study in pediatric patients 3 to 12 years of age.

d When these 8 trials were pooled and 2 additional trials evaluating MALARONE alone (without a comparator arm) were added to the analysis, the overall efficacy (elimination of parasitemia with no recurrent parasitemia during follow‑up for 28 days) in 521 evaluable patients was 98.7%.

The efficacy of MALARONE in the treatment of the erythrocytic phase of nonfalciparum malaria was assessed in a small number of patients.

Of the 23 patients in Thailand infected with and treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg daily for 3 days, parasitemia cleared in 21 (91.3%) at 7 days.

Parasite relapse occurred commonly when malaria was treated with MALARONE alone.

Relapsing malarias including and require additional treatment to prevent relapse.

vivax P.

ovale The efficacy of MALARONE in treating acute uncomplicated malaria in children weighing ≥5 and <11 kg was examined in an open‑label, randomized trial conducted in Gabon.

Patients received either MALARONE (2 or 3 MALARONE Pediatric Tablets once daily depending upon body weight) for 3 days (n = 100) or amodiaquine (10 mg/kg/day) for 3 days (n = 100).

In this study, the MALARONE Tablets were crushed and mixed with condensed milk just prior to administration.

An adequate clinical response (elimination of parasitemia with no recurrent parasitemia during follow‑up for 28 days) was obtained in 95% (87/92) of the evaluable pediatric patients who received MALARONE and in 53% (41/78) of those evaluable who received amodiaquine.

A response of RI resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28 days after starting treatment) was noted in 3% and 40% of the patients, respectively.

Two cases of RIII resistance (rising parasite count despite therapy) were reported in the patients receiving MALARONE.

There were 4 cases of RIII in the amodiaquine arm.

falciparum

HOW SUPPLIED

16 /STORAGE AND HANDLING NDC:54569-5762-0 in a BOTTLE of 12 TABLET, FILM COATEDS

GERIATRIC USE

8.5 Geriatric Use Clinical trials of MALARONE did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, the higher systemic exposure to cycloguanil, and the greater frequency of concomitant disease or other drug therapy.

[See Clinical Pharmacology (12.3).]

DOSAGE FORMS AND STRENGTHS

3 Each MALARONE Tablet (adult strength) contains 250 mg atovaquone and 100 mg proguanil hydrochloride.

MALARONE Tablets are pink, film‑coated, round, biconvex tablets engraved with “GX CM3” on one side.

Each MALARONE Pediatric Tablet contains 62.5 mg atovaquone and 25 mg proguanil hydrochloride.

MALARONE Pediatric Tablets are pink, film‑coated, round, biconvex tablets engraved with “GX CG7” on one side.

Tablets (adult strength): 250 mg atovaquone and 100 mg proguanil hydrochloride.

( ) • 3 Pediatric Tablets: 62.5 mg atovaquone and 25 mg proguanil hydrochloride.

( ) • 3

MECHANISM OF ACTION

12.1 Mechanism of Action The constituents of MALARONE, atovaquone and proguanil hydrochloride, interfere with 2 different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication.

Atovaquone is a selective inhibitor of parasite mitochondrial electron transport.

Proguanil hydrochloride primarily exerts its effect by means of the metabolite cycloguanil, a dihydrofolate reductase inhibitor.

Inhibition of dihydrofolate reductase in the malaria parasite disrupts deoxythymidylate synthesis.

INDICATIONS AND USAGE

1 MALARONE is an antimalarial indicated for: prophylaxis of malaria, including in areas where chloroquine resistance has been reported.

( ) • Plasmodium falciparum 1.1 treatment of acute, uncomplicated malaria.

( ) • P.

falciparum 1.2 1.2 Treatment of Malaria MALARONE is indicated for the treatment of acute, uncomplicated malaria.

MALARONE has been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

falciparum

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg.

The efficacy and safety of MALARONE have been established for the prophylaxis of malaria in controlled trials involving pediatric patients weighing 11 kg or more .

Prophylaxis of Malaria: [see Clinical Studies (14.1)] Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg.

The efficacy and safety of MALARONE for the treatment of malaria have been established in controlled trials involving pediatric patients weighing 5 kg or more .

Treatment of Malaria: [see Clinical Studies (14.2)]

PREGNANCY

8.1 Pregnancy Pregnancy Category C Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at doses up to 1,000 mg/kg/day corresponding to maternal plasma concentrations up to 7.3 times the estimated human exposure during treatment of malaria based on AUC.

In rabbits, atovaquone caused adverse fetal effects and maternal toxicity at a dose of 1,200 mg/kg/day corresponding to plasma concentrations that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC.

Adverse fetal effects in rabbits, including decreased fetal body lengths and increased early resorptions and post-implantation losses, were observed only in the presence of maternal toxicity.

Atovaquone: In a pre- and post-natal study in rats, atovaquone did not produce adverse effects in offspring at doses up to 1,000 mg/kg/day corresponding to AUC exposures of approximately 7.3 times the estimated human exposure during treatment of malaria.

A pre- and post-natal study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.04-times the average human exposure based on AUC).

Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

Proguanil: The combination of atovaquone and proguanil hydrochloride was not teratogenic in pregnant rats at atovaquone:proguanil hydrochloride (50:20 mg/kg/day) corresponding to plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during treatment of malaria based on AUC.

In pregnant rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at atovaquone:proguanil hydrochloride (100:40 mg/kg/day) corresponding to plasma concentrations of approximately 0.3 and 0.5 times, respectively, the estimated human exposure during treatment of malaria based on AUC.

Atovaquone and Proguanil: There are no adequate and well‑controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women.

MALARONE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Falciparum malaria carries a higher risk of morbidity and mortality in pregnant women than in the general population.

Maternal death and fetal loss are both known complications of falciparum malaria in pregnancy.

In pregnant women who must travel to malaria‑endemic areas, personal protection against mosquito bites should always be employed in addition to antimalarials.

[See Patient Counseling Information (17).] The proguanil component of MALARONE acts by inhibiting the parasitic dihydrofolate reductase .

However, there are no clinical data indicating that folate supplementation diminishes drug efficacy.

For women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements may be continued while taking MALARONE.

[see Clinical Pharmacology (12.1)]

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether atovaquone is excreted into human milk.

In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.

Proguanil is excreted into human milk in small quantities.

Caution should be exercised when MALARONE is administered to a nursing woman.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Atovaquone absorption may be reduced in patients with diarrhea or vomiting.

If used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered.

In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

( ) • 5.1 In mixed and infection, relapse occurred commonly when patients were treated with MALARONE alone.

( ) • P.

falciparum Plasmodium vivax P.

vivax 5.2 In the event of recrudescent infections after treatment or prophylaxis failure, patients should be treated with a different blood schizonticide.

( ) • P.

falciparum 5.2 Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use.

( ) • 5.3 MALARONE has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria.

Patients with severe malaria are not candidates for oral therapy.

( ) • 5.4 5.1 Vomiting and Diarrhea Absorption of atovaquone may be reduced in patients with diarrhea or vomiting.

If MALARONE is used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered.

Vomiting occurred in up to 19% of pediatric patients given treatment doses of MALARONE.

In the controlled clinical trials, 15.3% of adults received an antiemetic when they received atovaquone/proguanil and 98.3% of these patients were successfully treated.

In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

[See Dosage and Administration (2).] 5.2 Relapse of Infection In mixed and infections, parasite relapse occurred commonly when patients were treated with MALARONE alone.

falciparum Plasmodium vivax P.

vivax In the event of recrudescent infections after treatment with MALARONE or failure of chemoprophylaxis with MALARONE, patients should be treated with a different blood schizonticide.

falciparum 5.3 Hepatotoxicity Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of MALARONE.

5.4 Severe or Complicated Malaria MALARONE has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasitemia, pulmonary edema, or renal failure.

Patients with severe malaria are not candidates for oral therapy.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Patients should be instructed: to take MALARONE at the same time each day with food or a milky drink.

• to take a repeat dose of MALARONE if vomiting occurs within 1 hour after dosing.

• to take a dose as soon as possible if a dose is missed, then return to their normal dosing schedule.

However, if a dose is skipped, the patient should not double the next dose.

• that rare serious adverse events such as hepatitis, severe skin reactions, neurological, and hematological events have been reported when MALARONE was used for the prophylaxis or treatment of malaria.

• to consult a healthcare professional regarding alternative forms of prophylaxis if prophylaxis with MALARONE is prematurely discontinued for any reason.

• that protective clothing, insect repellents, and bednets are important components of malaria prophylaxis.

• that no chemoprophylactic regimen is 100% effective; therefore, patients should seek medical attention for any febrile illness that occurs during or after return from a malaria‑endemic area and inform their healthcare professional that they may have been exposed to malaria.

• that falciparum malaria carries a higher risk of death and serious complications in pregnant women than in the general population.

Pregnant women anticipating travel to malarious areas should discuss the risks and benefits of such travel with their physicians.

MLR:6PI

DOSAGE AND ADMINISTRATION

2 The daily dose should be taken at the same time each day with food or a milky drink.

In the event of vomiting within 1 hour after dosing, a repeat dose should be taken.

MALARONE may be crushed and mixed with condensed milk just prior to administration to patients who may have difficulty swallowing tablets.

MALARONE should be taken with food or a milky drink.

• Prophylaxis ( ): 2.1 Start prophylaxis 1 or 2 days before entering a malaria‑endemic area and continue daily during the stay and for 7 days after return.

• Adults: One adult strength tablet per day.

• Pediatric Patients: Dosage based on body weight (see Table 1).

• Treatment ( ): 2.2 Adults: Four adult strength tablets as a single daily dose for 3 days.

• Pediatric Patients: Dosage based on body weight (see Table 2).

• Renal Impairment ): (2.3 Do not use for prophylaxis of malaria in patients with severe renal impairment.

• Use with caution for treatment of malaria in patients with severe renal impairment.

• 2.1 Prevention of Malaria Start prophylactic treatment with MALARONE 1 or 2 days before entering a malaria‑endemic area and continue daily during the stay and for 7 days after return.

One MALARONE Tablet (adult strength = 250 mg atovaquone/100 mg proguanil hydrochloride) per day.

Adults: The dosage for prevention of malaria in pediatric patients is based upon body weight (Table 1).

Pediatric Patients: Table 1.

Dosage for Prevention of Malaria in Pediatric Patients Weight (kg) Atovaquone/ Proguanil HCl Total Daily Dose Dosage Regimen 11-20 62.5 mg/25 mg 1 MALARONE Pediatric Tablet daily 21-30 125 mg/50 mg 2 MALARONE Pediatric Tablets as a single daily dose 31-40 187.5 mg/75 mg 3 MALARONE Pediatric Tablets as a single daily dose >40 250 mg/100 mg 1 MALARONE Tablet (adult strength) as a single daily dose 2.2 Treatment of Acute Malaria Four MALARONE Tablets (adult strength; total daily dose 1 g atovaquone/400 mg proguanil hydrochloride) as a single daily dose for 3 consecutive days.

Adults: The dosage for treatment of acute malaria in pediatric patients is based upon body weight (Table 2).

Pediatric Patients: Table 2.

Dosage for Treatment of Acute Malaria in Pediatric Patients Weight (kg) Atovaquone/ Proguanil HCl Total Daily Dose Dosage Regimen 5-8 125 mg/50 mg 2 MALARONE Pediatric Tablets daily for 3 consecutive days 9-10 187.5 mg/75 mg 3 MALARONE Pediatric Tablets daily for 3 consecutive days 11-20 250 mg/100 mg 1 MALARONE Tablet (adult strength) daily for 3 consecutive days 21-30 500 mg/200 mg 2 MALARONE Tablets (adult strength) as a single daily dose for 3 consecutive days 31-40 750 mg/300 mg 3 MALARONE Tablets (adult strength) as a single daily dose for 3 consecutive days >40 1 g/400 mg 4 MALARONE Tablets (adult strength) as a single daily dose for 3 consecutive days 2.3 Renal Impairment Do not use MALARONE for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min) .

Use with caution for the treatment of malaria in patients with severe renal impairment, only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure.

No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment.

[see Contraindications (4.2)] [See Clinical Pharmacology (12.3).]