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Malarone Adults

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Malarone Adults uses


1 INDICATIONS AND USAGE

Malarone Adults is an antimalarial indicated for:

1.1 Prevention of Malaria

Malarone Adults® is indicated for the prophylaxis of Plasmodium falciparum malaria, including in areas where chloroquine resistance has been reported.

1.2 Treatment of Malaria

Malarone Adults is indicated for the treatment of acute, uncomplicated P. falciparum malaria. Malarone Adults 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.

2 DOSAGE AND ADMINISTRATION

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


Prophylaxis :


Treatment (2.2):


Renal Impairment (2.3):

2.1 Prevention of Malaria

Start prophylactic treatment with Malarone Adults 1 or 2 days before entering a malaria‑endemic area and continue daily during the stay and for 7 days after return.

Adults

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

Pediatric Patients

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


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

Adults

Four Malarone Adults Tablets as a single daily dose for 3 consecutive days.

Pediatric Patients

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


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 Adults 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.

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3 DOSAGE FORMS AND STRENGTHS

Each Malarone Adults Tablet (adult strength) contains 250 mg Malarone Adults and 100 mg proguanil hydrochloride. Malarone Adults Tablets are pink, film‑coated, round, biconvex tablets engraved with “GX CM3” on one side.

Each Malarone Adults Pediatric Tablet contains 62.5 mg Malarone Adults and 25 mg proguanil hydrochloride. Malarone Adults Pediatric Tablets are pink, film‑coated, round, biconvex tablets engraved with “GX CG7” on one side.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Malarone Adults is contraindicated in individuals with known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme or Stevens-Johnson syndrome, angioedema, vasculitis) to Malarone Adults or proguanil hydrochloride or any component of the formulation.

4.2 Severe Renal Impairment

Malarone Adults is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min) because of pancytopenia in patients with severe renal impairment treated with proguanil .

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5 WARNINGS AND PRECAUTIONS

5.1 Vomiting and Diarrhea

Absorption of Malarone Adults may be reduced in patients with diarrhea or vomiting. If Malarone Adults 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 Adults. 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.

5.2 Relapse of Infection

In mixed P. falciparum and Plasmodium vivax infections, P. vivax parasite relapse occurred commonly when patients were treated with Malarone Adults alone.

In the event of recrudescent P. falciparum infections after treatment with Malarone Adults or failure of chemoprophylaxis with Malarone Adults, patients should be treated with a different blood schizonticide.

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 Adults.

5.4 Severe or Complicated Malaria

Malarone Adults 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.

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6 ADVERSE REACTIONS


To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Because Malarone Adults contains Malarone Adults and proguanil hydrochloride, the type and severity of adverse reactions associated with each of the compounds may be expected. The lower prophylactic doses of Malarone Adults were better tolerated than the higher treatment doses.

Prophylaxis of P. falciparum Malaria

In 3 clinical trials (2 of which were placebo‑controlled) 381 adults (mean age: 31 years) received Malarone Adults for the prophylaxis of malaria; the majority of adults were black (90%) and 79% were male. In a clinical trial for the prophylaxis of malaria, 125 pediatric patients (mean age: 9 years) received Malarone Adults; all subjects were black and 52% were male. Adverse experiences reported in adults and pediatric patients, considered attributable to therapy, occurred in similar proportions of subjects receiving Malarone Adults or placebo in all studies. Prophylaxis with Malarone Adults was discontinued prematurely due to a treatment‑related adverse experience in 3 of 381 (0.8%) adults and 0 of 125 pediatric patients.

In a placebo‑controlled study of malaria prophylaxis with Malarone Adults involving 330 pediatric patients (aged 4 to 14 years) in Gabon, a malaria-endemic area, the safety profile of Malarone Adults was consistent with that observed in the earlier prophylactic studies in adults and pediatric patients. The most common treatment‑emergent adverse events with Malarone Adults were abdominal pain (13%), headache (13%), and cough (10%). Abdominal pain (13% vs. 8%) and vomiting (5% vs. 3%) were reported more often with Malarone Adults than with placebo. No patient withdrew from the study due to an adverse experience with Malarone Adults. No routine laboratory data were obtained during this study.

Non‑immune travelers visiting a malaria‑endemic area received Malarone Adults (n = 1,004) for prophylaxis of malaria in 2 active-controlled clinical trials. In one study (n = 493), the mean age of subjects was 33 years and 53% were male; 90% of subjects were white, 6% of subjects were black and the remaining were of other racial/ethnic groups. In the other study (n = 511), the mean age of subjects was 36 years and 51% were female; the majority of subjects (97%) were white. Adverse experiences occurred in a similar or lower proportion of subjects receiving Malarone Adults than an active comparator (Table 3). Fewer neuropsychiatric adverse experiences occurred in subjects who received Malarone Adults than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving Malarone Adults than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving Malarone Adults had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 3). Prophylaxis with Malarone Adults was discontinued prematurely due to a treatment‑related adverse experience in 7 of 1,004 travelers.


Percent of Subjects with Adverse Experiencesa

(Percent of Subjects with Adverse Experiences Attributable to Therapy)


Study 1


Study 2


Malarone Adults

n = 493

(28 days)b


Mefloquine

n = 483

(53 days)b


Malarone Adults

n = 511

(26 days)b


Chloroquine plus Proguanil

n = 511

(49 days)b


Diarrhea

38

(8)

36

(7)

34

(5)

39

(7)

Nausea

14

(3)

20

(8)

11

(2)

18

(7)

Abdominal pain

17

(5)

16

(5)

14

(3)

22

(6)

Headache

12

(4)

17

(7)

12

(4)

14

(4)

Dreams

7

(7)

16

(14)

6

(4)

7

(3)

Insomnia

5

(3)

16

(13)

4

(2)

5

(2)

Fever

9

(<1)

11

(1)

8

(<1)

8

(<1)

Dizziness

5

(2)

14

(9)

7

(3)

8

(4)

Vomiting

8

(1)

10

(2)

8

(0)

14

(2)

Oral ulcers

9

(6)

6

(4)

5

(4)

7

(5)

Pruritus

4

(2)

5

(2)

3

(1)

2

(<1)

Visual difficulties

2

(2)

5

(3)

3

(2)

3

(2)

Depression

<1

(<1)

5

(4)

<1

(<1)

1

(<1)

Anxiety

1

(<1)

5

(4)

<1

(<1)

1

(<1)

Any adverse experience

64

(30)

69

(42)

58

(22)

66

(28)

Any neuropsychiatric event

20

(14)

37

(29)

16

(10)

20

(10)

Any GI event

49

(16)

50

(19)

43

(12)

54

(20)

a Adverse experiences that started while receiving active study drug.

b Mean duration of dosing based on recommended dosing regimens.

In a third active‑controlled study, Malarone Adults (n = 110) was compared with chloroquine/proguanil (n = 111) for the prophylaxis of malaria in 221 non-immune pediatric patients (aged 2 to 17 years). The mean duration of exposure was 23 days for Malarone Adults, 46 days for chloroquine, and 43 days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with Malarone Adults reported abdominal pain (2% vs. 7%) or nausea (<1% vs. 7%) than children who received chloroquine/proguanil. Oral ulceration (2% vs. 2%), vivid dreams (2% vs. <1%), and blurred vision (0% vs. 2%) occurred in similar proportions of patients receiving either Malarone Adults or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving Malarone Adults discontinued due to adverse events.

Treatment of Acute, Uncomplicated P. falciparum Malaria

In 7 controlled trials, 436 adolescents and adults received Malarone Adults for treatment of acute, uncomplicated P. falciparum malaria. The range of mean ages of subjects was 26 to 29 years; 79% of subjects were male. In these studies, 48% of subjects were classified as other racial/ethnic groups, primarily Asian; 42% of subjects were black and the remaining subjects were white. Attributable adverse experiences that occurred in ≥5% of patients were abdominal pain (17%), nausea (12%), vomiting (12%), headache (10%), diarrhea (8%), asthenia (8%), anorexia (5%), and dizziness (5%). Treatment was discontinued prematurely due to an adverse experience in 4 of 436 (0.9%) adolescents and adults treated with Malarone Adults.

In 2 controlled trials, 116 pediatric patients (weighing 11 to 40 kg) (mean age: 7 years) received Malarone Adults for the treatment of malaria. The majority of subjects were black (72%); 28% were of other racial/ethnic groups, primarily Asian. Attributable adverse experiences that occurred in ≥5% of patients were vomiting (10%) and pruritus (6%). Vomiting occurred in 43 of 319 (13%) pediatric patients who did not have symptomatic malaria but were given treatment doses of Malarone Adults for 3 days in a clinical trial. The design of this clinical trial required that any patient who vomited be withdrawn from the trial. Among pediatric patients with symptomatic malaria treated with Malarone Adults, treatment was discontinued prematurely due to an adverse experience in 1 of 116 (0.9%).

In a study of 100 pediatric patients (5 to <11 kg body weight) who received Malarone Adults for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥5% of patients as an adverse experience attributable to Malarone Adults. In 3 patients (3%), treatment was discontinued prematurely due to an adverse experience.

Abnormalities in laboratory tests reported in clinical trials were limited to elevations of transaminases in patients with malaria being treated with Malarone Adults. The frequency of these abnormalities varied substantially across trials of treatment and were not observed in the randomized portions of the prophylaxis trials.

One active-controlled trial evaluated the treatment of malaria in Thai adults (n = 182); the mean age of subjects was 26 years (range: 15 to 63 years); 80% of subjects were male. Early elevations of ALT and AST occurred more frequently in patients treated with Malarone Adults (n = 91) compared with patients treated with an active control, mefloquine (n = 91). On Day 7, rates of elevated ALT and AST with Malarone Adults and mefloquine (for patients who had normal baseline levels of these clinical laboratory parameters) were ALT 26.7% vs. 15.6%; AST 16.9% vs. 8.6%, respectively. By Day 14 of this 28‑day study, the frequency of transaminase elevations equalized across the 2 groups.

6.2 Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of Malarone Adults. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Malarone Adults.

Blood and Lymphatic System Disorders

Neutropenia and anemia. Pancytopenia in patients with severe renal impairment treated with proguanil .

Immune System Disorders

Allergic reactions including anaphylaxis, angioedema, and urticaria, and vasculitis.

Nervous System Disorders

Seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established.

Gastrointestinal Disorders

Stomatitis.

Hepatobiliary Disorders

Elevated liver laboratory tests, hepatitis, cholestasis; hepatic failure requiring transplant has been reported.

Skin and Subcutaneous Tissue Disorders

Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome.

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7 DRUG INTERACTIONS

7.1 Rifampin/Rifabutin

Concomitant administration of rifampin or rifabutin is known to reduce Malarone Adults concentrations . The concomitant administration of Malarone Adults and rifampin or rifabutin is not recommended.

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 Adults 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 Malarone Adults . Parasitemia should be closely monitored in patients receiving tetracycline.

7.4 Metoclopramide

While antiemetics may be indicated for patients receiving Malarone Adults, metoclopramide may reduce the bioavailability of Malarone Adults and should be used only if other antiemetics are not available .

7.5 Indinavir

Concomitant administration of Malarone Adults and indinavir did not result in any change in the steady‑state AUC and Cmax of indinavir but resulted in a decrease in the Ctrough of indinavir . Caution should be exercised when prescribing Malarone Adults with indinavir due to the decrease in trough concentrations of indinavir.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Malarone Adults

Malarone Adults 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, Malarone Adults 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.

In a pre- and post-natal study in rats, Malarone Adults 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.

Proguanil

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.

Malarone Adults and Proguanil

The combination of Malarone Adults and proguanil hydrochloride was not teratogenic in pregnant rats at Malarone Adults: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 Malarone Adults and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at Malarone Adults: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.

There are no adequate and well‑controlled studies of Malarone Adults and/or proguanil hydrochloride in pregnant women. Malarone Adults 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.

The proguanil component of Malarone Adults 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 Adults.

8.3 Nursing Mothers

It is not known whether Malarone Adults is excreted into human milk. In a rat study, Malarone Adults concentrations in the milk were 30% of the concurrent Malarone Adults concentrations in the maternal plasma.

Proguanil is excreted into human milk in small quantities.

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

8.4 Pediatric Use

Prophylaxis of Malaria

Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg. The efficacy and safety of Malarone Adults have been established for the prophylaxis of malaria in controlled trials involving pediatric patients weighing 11 kg or more .

Treatment of Malaria

Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg. The efficacy and safety of Malarone Adults for the treatment of malaria have been established in controlled trials involving pediatric patients weighing 5 kg or more .

8.5 Geriatric Use

Clinical trials of Malarone Adults 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.

8.6 Renal Impairment

Do not use Malarone Adults for malaria prophylaxis in patients with severe renal impairment. 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.

8.7 Hepatic Impairment

No dosage adjustments are needed in patients with mild or moderate hepatic impairment . No trials have been conducted in patients with severe hepatic impairment.

10 OVERDOSAGE

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

There is no known antidote for Malarone Adults, and it is currently unknown if Malarone Adults is dialyzable. Overdoses up to 31,500 mg of Malarone Adults 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.

11 DESCRIPTION

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

The chemical name of Malarone Adults is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Malarone Adults is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19ClO3. The compound has the following structural formula:

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 C11H16ClN5-HCl. The compound has the following structural formula:

Each Malarone Adults Tablet (adult strength) contains 250 mg of Malarone Adults and 100 mg of proguanil hydrochloride and each Malarone Adults Pediatric Tablet contains 62.5 mg of Malarone Adults 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.

Malarone Adults molecular structure proguanil hydrochloride molecular structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The constituents of Malarone Adults, Malarone Adults and proguanil hydrochloride, interfere with 2 different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. Malarone Adults 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.

12.2 Pharmacodynamics

No trials of the pharmacodynamics of Malarone Adults have been conducted.

12.3 Pharmacokinetics

Absorption

Malarone Adults is a highly lipophilic compound with low aqueous solubility. The bioavailability of Malarone Adults shows considerable inter‑individual variability.

Dietary fat taken with Malarone Adults increases the rate and extent of absorption, increasing AUC 2 to 3 times and Cmax 5 times over fasting. The absolute bioavailability of the tablet formulation of Malarone Adults when taken with food is 23%. Malarone Adults should be taken with food or a milky drink.

Distribution

Malarone Adults is highly protein bound over the concentration range of 1 to 90 mcg/mL. A population pharmacokinetic analysis demonstrated that the apparent volume of distribution of Malarone Adults (V/F) in adult and pediatric patients after oral administration is approximately 8.8 L/kg.

Proguanil is 75% protein bound. A population pharmacokinetic analysis demonstrated that the apparent V/F of proguanil in adult and pediatric patients older than 15 years with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients 15 years and younger with body weights from 11 to 56 kg, the V/F of proguanil ranged from 462 to 966 L.

In human plasma, the binding of Malarone Adults and proguanil was unaffected by the presence of the other.

Metabolism

In a study where 14C‑labeled Malarone Adults was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged Malarone Adults in the feces over 21 days. There was little or no excretion of Malarone Adults in the urine (less than 0.6%). There is indirect evidence that Malarone Adults may undergo limited metabolism; however, a specific metabolite has not been identified. Between 40% to 60% of proguanil is excreted by the kidneys. Proguanil is metabolized to cycloguanil (primarily via CYP2C19) and 4-chlorophenylbiguanide. The main routes of elimination are hepatic biotransformation and renal excretion.

Elimination

The elimination half‑life of Malarone Adults is about 2 to 3 days in adult patients.

The elimination half‑life of proguanil is 12 to 21 hours in both adult patients and pediatric patients, but may be longer in individuals who are slow metabolizers.

A population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both Malarone Adults and proguanil is related to the body weight. The values CL/F for both Malarone Adults and proguanil in subjects with body weight ≥11 kg are shown in Table 4.


Body Weight


Malarone Adults


Proguanil


n


CL/F (L/hr)

Mean ± SDa (range)


n


CL/F (L/hr)

Mean ± SDa (range)


11-20 kg

159

1.34 ± 0.63

(0.52-4.26)

146

29.5 ± 6.5

(10.3-48.3)

21-30 kg

117

1.87 ± 0.81

(0.52-5.38)

113

40.0 ± 7.5

(15.9-62.7)

31-40 kg

95

2.76 ± 2.07

(0.97-12.5)

91

49.5 ± 8.30

(25.8-71.5)

>40 kg

368

6.61 ± 3.92

(1.32-20.3)

282

67.9 ± 19.9

(14.0-145)

a SD = Standard deviation.

The pharmacokinetics of Malarone Adults and proguanil in patients with body weight less than 11 kg have not been adequately characterized.

Pediatrics

The pharmacokinetics of proguanil and cycloguanil are similar in adult patients and pediatric patients. However, the elimination half‑life of Malarone Adults is shorter in pediatric patients (1 to 2 days) than in adult patients (2 to 3 days). In clinical trials, plasma trough concentrations of Malarone Adults and proguanil in pediatric patients weighing 5 to 40 kg were within the range observed in adults after dosing by body weight.

Geriatrics

In a single‑dose study, the pharmacokinetics of Malarone Adults, proguanil, and cycloguanil were compared in 13 elderly subjects (aged 65 to 79 years) with those of 13 younger subjects (aged 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate = 2.36, 90% CI = 1.70, 3.28). Tmax was longer in elderly subjects (median: 8 hours) compared with younger subjects (median 4 hours) and average elimination half‑life was longer in elderly subjects (mean: 14.9 hours) compared with younger subjects (mean 8.3 hours).

Renal Impairment

In patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), oral clearance and/or AUC data for Malarone Adults, proguanil, and cycloguanil are within the range of values observed in patients with normal renal function (creatinine clearance >80 mL/min). In patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min), mean oral clearance for proguanil was reduced by approximately 35% compared with patients with normal renal function (creatinine clearance >80 mL/min) and the oral clearance of Malarone Adults was comparable between patients with normal renal function and mild renal impairment. No data exist on the use of Malarone Adults for long-term prophylaxis (over 2 months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance <30 mL/min), Malarone Adults Cmax and AUC are reduced but the elimination half‑lives for proguanil and cycloguanil are prolonged, with corresponding increases in AUC, resulting in the potential of drug accumulation and toxicity with repeated dosing .

Hepatic Impairment

In a single‑dose study, the pharmacokinetics of Malarone Adults, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, 4 moderate, as indicated by the Child‑Pugh method) with those of 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared with healthy subjects, there were no marked differences (<50%) in the rate or extent of systemic exposure of Malarone Adults. However, in subjects with moderate hepatic impairment, the elimination half‑life of Malarone Adults was increased (point estimate = 1.28, 90% CI = 1.00 to 1.63). Proguanil AUC, Cmax, and its elimination half-life increased in subjects with mild hepatic impairment when compared with healthy subjects (Table 5). Also, the proguanil AUC and its elimination half-life increased in subjects with moderate hepatic impairment when compared with healthy subjects. Consistent with the increase in proguanil AUC, there were marked decreases in the systemic exposure of cycloguanil (Cmax and AUC) and an increase in its elimination half‑life in subjects with mild hepatic impairment when compared with healthy volunteers (Table 5). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment. The pharmacokinetics of Malarone Adults, proguanil, and cycloguanil after administration of Malarone Adults have not been studied in patients with severe hepatic impairment.


Parameter


Comparison


Proguanil


Cycloguanil


AUC(0-inf) a


mild:healthy

1.96 (1.51, 2.54)

0.32 (0.22, 0.45)

Cmax a


mild:healthy

1.41 (1.16, 1.71)

0.35 (0.24, 0.50)

t1/2 b


mild:healthy

1.21 (0.92, 1.60)

0.86 (0.49, 1.48)

AUC(0-inf) a


moderate:healthy

1.64 (1.14, 2.34)

ND

Cmax a


moderate:healthy

0.97 (0.69, 1.36)

ND

t1/2 b


moderate:healthy

1.46 (1.05, 2.05)

ND

ND = Not determined due to lack of quantifiable data.

a Ratio of geometric means.

b Mean difference.

Drug Interactions

There are no pharmacokinetic interactions between Malarone Adults and proguanil at the recommended dose.

Malarone Adults is highly protein bound (>99%) but does not displace other highly protein‑bound drugs in vitro.

Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown.

Rifampin/Rifabutin: Concomitant administration of rifampin or rifabutin is known to reduce Malarone Adults concentrations by approximately 50% and 34%, respectively. The mechanisms of these interactions are unknown.

Tetracycline: Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of Malarone Adults.

Metoclopramide: Concomitant treatment with metoclopramide has been associated with decreased bioavailability of Malarone Adults.

Indinavir: Concomitant administration of Malarone Adults (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady‑state AUC and Cmax of indinavir but resulted in a decrease in the Ctrough of indinavir (23% decrease [90% CI = 8%, 35%]).

12.4 Microbiology

Activity In Vitro and In Vivo

Malarone Adults and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of Plasmodium spp. Enhanced efficacy of the combination compared with either Malarone Adults or proguanil hydrochloride alone was demonstrated in clinical trials in both immune and non-immune patients .

Drug Resistance

Strains of P. falciparum with decreased susceptibility to Malarone Adults or proguanil/cycloguanil alone can be selected in vitro or in vivo. The combination of Malarone Adults and proguanil hydrochloride may not be effective for treatment of recrudescent malaria that develops after prior therapy with the combination.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity studies have not been performed with Malarone Adults in combination with proguanil. Effects of Malarone Adults on male and female reproductive performance are unknown.

Malarone Adults

A 24‑month carcinogenicity study in CD rats was negative for neoplasms at doses up to 500 mg/kg/day corresponding to approximately 54 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. In CD-1 mice, a 24‑month study showed treatment‑related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which correlated with at least 15 times the average steady‑state plasma concentrations in humans during prophylaxis of malaria.

Malarone Adults was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.

Malarone Adults did not impair fertility in male and female rats at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately 7.3 times the estimated human exposure during treatment of malaria based on AUC.

Proguanil

No evidence of a carcinogenic effect was observed in 24‑month studies conducted in CD-1 mice at doses up to 16 mg/kg/day corresponding to 1.5 times the average human plasma exposure during prophylaxis of malaria based on AUC, and in Wistar Hannover rats at doses up 20 mg/kg/day corresponding to 1.1 times the average human plasma exposure during prophylaxis of malaria based on AUC.

Proguanil was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay and the Mouse Lymphoma mutagenesis assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.

Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with cycloguanil, a dihydrofolate reductase inhibitor, were significantly reduced or abolished with folinic acid supplementation.

A fertility 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 during treatment of malaria based on AUC). Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

13.2 Animal Toxicology and/or Pharmacology

Fibrovascular proliferation in the right atrium, pyelonephritis, bone marrow hypocellularity, lymphoid atrophy, and gastritis/enteritis were observed in dogs treated with proguanil hydrochloride for 6 months at a dose of 12 mg/kg/day (approximately 3.9 times the recommended daily human dose for malaria prophylaxis on a mg/m2 basis). Bile duct hyperplasia, gall bladder mucosal atrophy, and interstitial pneumonia were observed in dogs treated with proguanil hydrochloride for 6 months at a dose of 4 mg/kg/day (approximately 1.3 times the recommended daily human dose for malaria prophylaxis on a mg/m2 basis). Mucosal hyperplasia of the cecum and renal tubular basophilia were observed in rats treated with proguanil hydrochloride for 6 months at a dose of 20 mg/kg/day (approximately 1.6 times the recommended daily human dose for malaria prophylaxis on a mg/m2 basis). Adverse heart, lung, liver, and gall bladder effects observed in dogs and kidney effects observed in rats were not shown to be reversible.

14 CLINICAL STUDIES

14.1 Prevention of P. falciparum Malaria

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

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, 32 (range: 16 to 64), and 10 (range: 5 to 16) years, respectively. Of a total of 669 randomized patients (including 264 pediatric patients aged 5 to 16 years), 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.


Malarone Adults


Placebo


Total number of patients randomized

326

343

Failed to complete study

57

46

Developed parasitemia (P. falciparum)

2

92

a Free of parasitemia during the 10 to 12-week period of prophylactic therapy.

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 Adults (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 Adults 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 Adults developed P. falciparum parasitemia while receiving prophylaxis with Malarone Adults compared with 31 (22%) of the 144 evaluable placebo recipients.

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 Adults 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 P. falciparum malaria in both trials is unknown. The results are listed in Table 7.


Malarone Adults


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

a Free of parasitemia during the period of prophylactic therapy.

A third randomized, open‑label study was conducted which included 221 otherwise healthy pediatric patients (weighing ≥11 kg and aged 2 to 17 years) 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 Adults (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 P. falciparum malaria in this study is unknown.

Causal Prophylaxis

In separate trials with small numbers of volunteers, Malarone Adults and proguanil hydrochloride were independently shown to have causal prophylactic activity directed against liver‑stage parasites of P. falciparum. Six patients given a single dose of Malarone Adults 250 mg 24 hours prior to malaria challenge were protected from developing malaria, whereas all 4 placebo‑treated patients developed malaria.

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 Adults. While new infections could not be distinguished from recrudescent infections, all but 1 of the infections in patients treated with Malarone Adults occurred more than 15 days after stopping therapy. The single case occurring on Day 8 following cessation of therapy with Malarone Adults probably represents a failure of prophylaxis with Malarone Adults.

The possibility that delayed cases of P. falciparum malaria may occur some time after stopping prophylaxis with Malarone Adults cannot be ruled out. Hence, returning travelers developing febrile illnesses should be investigated for malaria.

14.2 Treatment of Acute, Uncomplicated P. falciparum Malaria Infections

In 3 Phase 2 clinical trials, Malarone Adults alone, proguanil hydrochloride alone, and the combination of Malarone Adults and proguanil hydrochloride were evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum. 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 Malarone Adults alone, 1/17 (6%) with proguanil hydrochloride alone, and 50/50 (100%) with the combination of Malarone Adults and proguanil hydrochloride.

Malarone Adults was evaluated for treatment of acute, uncomplicated malaria caused by P. falciparum in 8 Phase 3 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 and younger; 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 Adults was similar to treatment with the comparator drug in 4 trials.


Study Site


Malarone Adultsa


Comparator


Evaluable Patients

(n)


% Sensitive

Responseb


Drug(s)


Evaluable Patients

(n)


% Sensitive Responseb


Brazil

74

98.6%

Quinine and tetracycline

76

100.0%

Thailand

79

100.0%

Mefloquine

79

86.1%

Francec


21

100.0%

Halofantrine

18

100.0%

Kenyac,d


81

93.8%

Halofantrine

83

90.4%

Zambia

80

100.0%

Pyrimethamine/

sulfadoxine (P/S)

80

98.8%

Gabonc


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%

a Malarone Adults = 1,000 mg Malarone Adults and 400 mg proguanil hydrochloride (or equivalent based on body weight for patients weighing ≤40 kg) once daily for 3 days.

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

c Patients hospitalized only for acute care. Follow‑up conducted in outpatients.

d Study in pediatric patients aged 3 to 12 years.

When these 8 trials were pooled and 2 additional trials evaluating Malarone Adults 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 Adults 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 P. vivax and treated with Malarone Adults 1,000 mg/400 mg daily for 3 days, parasitemia cleared in 21 (91.3%) at 7 days. Parasite relapse occurred commonly when P. vivax malaria was treated with Malarone Adults alone. Relapsing malarias including P. vivax and P. ovale require additional treatment to prevent relapse.

The efficacy of Malarone Adults in treating acute uncomplicated P. falciparum malaria in children weighing ≥5 and <11 kg was examined in an open‑label, randomized trial conducted in Gabon. Patients received either Malarone Adults (2 or 3 Malarone Adults 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 Adults 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 Adults 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 Adults. There were 4 cases of RIII in the amodiaquine arm.

16 HOW SUPPLIED/STORAGE AND HANDLING

Malarone Adults Tablets, containing 250 mg Malarone Adults and 100 mg proguanil hydrochloride.


Malarone Adults Pediatric Tablets, containing 62.5 mg Malarone Adults and 25 mg proguanil hydrochloride.


Storage Conditions

Store at 25°C (77°F). Temperature excursions are permitted to 15° to 30°C (59° to 86°F).

17 PATIENT COUNSELING INFORMATION

Patients should be instructed:


Malarone Adults is a registered trademark of the GSK group of companies.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2016 the GSK group of companies. All rights reserved.

MLR:7PI

Malarone Adults pharmaceutical active ingredients containing related brand and generic drugs:


Malarone Adults available forms, composition, doses:


Malarone Adults destination | category:


Malarone Adults Anatomical Therapeutic Chemical codes:


Malarone Adults pharmaceutical companies:


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References

  1. Dailymed."MEPRON (ATOVAQUONE) SUSPENSION [GLAXOSMITHKLINE LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ATOVAQUONE; PROGUANIL HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "ATOVAQUONE". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Malarone Adults?

Depending on the reaction of the Malarone Adults after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Malarone Adults not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Malarone Adults addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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