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All about: Malarone

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Generic Name: atovaquone and proguanil hydrochloride
Dosage Form: Tablets

Malarone Description

Malarone (atovaquone and proguanil hydrochloride) is a fixed-dose combination of the antimalarial agents atovaquone and proguanil hydrochloride. The chemical name of atovaquone is trans-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 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:

Malarone Tablets and Malarone Pediatric Tablets are for oral administration. Each Malarone Tablet 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.

Malarone - Clinical Pharmacology

Microbiology

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.

Activity In Vitro and In Vivo

Atovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of Plasmodium spp. Enhanced efficacy of the combination compared to either atovaquone or proguanil hydrochloride alone was demonstrated in clinical studies in both immune and non-immune patients (see CLINICAL STUDIES).

Drug Resistance

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

Pharmacokinetics

Absorption

Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone shows considerable inter-individual variability.

Dietary fat taken with atovaquone 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 atovaquone when taken with food is 23%. Malarone Tablets should be taken with food or a milky drink.

Proguanil hydrochloride is extensively absorbed regardless of food intake.

Distribution

Atovaquone is highly protein bound (>99%) over the concentration range of 1 to 90 mcg/mL. A population pharmacokinetic analysis demonstrated that the apparent volume of distribution of atovaquone (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 >15 years of age with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients ≤15 years of age 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 atovaquone and proguanil was unaffected by the presence of the other.

Metabolism

In a study where 14C-labeled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone 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 atovaquone 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 atovaquone and proguanil are related to the body weight. The values CL/F for both atovaquone and proguanil in subjects with body weight ≥11 kg are shown in Table 1.

Table 1. Apparent Clearance for Atovaquone and Proguanil in Patients as a Function of Body Weight

Body Weight

Atovaquone

Proguanil

N

CL/F (L/hr)

Mean ± SD* (range)

N

CL/F (L/hr)

Mean ± SD* (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)

*SD = standard deviation.

The pharmacokinetics of atovaquone and proguanil in patients with body weight below 11 kg have not been adequately characterized.

Special Populations

Pediatrics

The pharmacokinetics of proguanil and cycloguanil are similar in adult patients and pediatric patients. However, the elimination half-life of atovaquone is shorter in pediatric patients (1 to 2 days) than in adult patients (2 to 3 days). In clinical trials, plasma trough levels of atovaquone 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 atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (age 65 to 79 years) to 13 younger subjects (age 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate = 2.36, 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).

Hepatic Impairment

In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, 4 moderate, as indicated by the Child-Pugh method) to 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared to healthy subjects, there were no marked differences (<50%) in the rate or extent of systemic exposure of atovaquone. However, in subjects with moderatehepatic impairment, the elimination half-life of atovaquone was increased (point estimate = 1.28, 90% CI = 1.00 to 1.63). Proguanil AUC, Cmax, and its t1/2 increased in subjects with mild hepatic impairment when compared to healthy subjects (Table 2). Also, the proguanil AUC and its t1/2 increased in subjects with moderate hepatic impairment when compared to 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 to healthy volunteers (Table 2). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment (see DOSAGE AND ADMINISTRATION). The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of Malarone have not been studied in patients with severe hepatic impairment.

Table 2. Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects With Mild and Moderate Hepatic Impairment Compared to Healthy Volunteers

Parameter

Comparison

Proguanil

Cycloguanil

AUC(0-inf)*

mild:healthy

1.96 (1.51, 2.54)

0.32 (0.22, 0.45)

Cmax*

mild:healthy

1.41 (1.16, 1.71)

0.35 (0.24, 0.50)

t1/2

mild:healthy

1.21 (0.92, 1.60)

0.86 (0.49, 1.48)

AUC(0-inf)*

moderate:healthy

1.64 (1.14, 2.34)

ND

Cmax*

moderate:healthy

0.97 (0.69, 1.36)

ND

t1/2

moderate:healthy

1.46 (1.05, 2.05)

ND

ND = not determined due to lack of quantifiable data.

*Ratio of geometric means.

Mean difference.

Renal Impairment

In patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), oral clearance and/or AUC data for atovaquone, 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 atovaquone was comparable between patients with normal renal function and mild renal impairment. No data exist on the use of Malarone for long-term prophylaxis (over 2 months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance <30 mL/min), atovaquone 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 (see CONTRAINDICATIONS).

Drug Interactions

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

Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone.

Concomitant treatment with metoclopramide has also been associated with decreased bioavailability of atovaquone.

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively (see PRECAUTIONS: Drug Interactions). The mechanisms of these interactions are unknown.

Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely (see PRECAUTIONS: Drug Interactions). Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions with other substrates or inhibitors of this pathway are unknown.

Indications and Usage for Malarone

Prevention of Malaria

Malarone is indicated for the prophylaxis of P. falciparum malaria, including in areas where chloroquine resistance has been reported (see CLINICAL STUDIES).

Treatment of Malaria

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

Contraindications

Malarone is contraindicated in individuals with known hypersensitivity to atovaquone or proguanil hydrochloride or any component of the formulation. Rare cases of anaphylaxis following treatment with atovaquone/proguanil have been reported.

Malarone is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min) (see CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment).

Warnings

Precautions

General

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.

Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If Malarone is used in patients who are vomiting (see DOSAGE AND ADMINISTRATION), 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 of Malarone, 15.3% of adults who were treated with atovaquone/proguanil received an antiemetic drug during that part of the trial when they received atovaquone/proguanil. Of these patients, 98.3% were successfully treated. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

Parasite relapse occurred commonly when P. vivax malaria was treated with Malarone alone.

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

Information for Patients

Patients should be instructed:

  • to take Malarone tablets 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.
  • 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 (see Pregnancy section).

Drug Interactions

Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone. Parasitemia should be closely monitored in patients receiving tetracycline. 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.

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively. The concomitant administration of Malarone and rifampin or rifabutin is not recommended.

Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely.

Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Atovaquone

Carcinogenicity studies in rats were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from approximately 5 to 8 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. Atovaquone 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.

Proguanil

No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-1 mice (doses up to 1.5 times the average systemic human exposure based on AUC) and in Wistar Hannover rats (doses up to 1.1 times the average systemic human exposure).

Proguanil was negative with or without metabolic activation in the Ames Salmonellamutagenicity 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.

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

Pregnancy

Pregnancy Category C. 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 (see Information for Patients) in addition to antimalarials.

Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at maternal plasma concentrations up to 5 to 6.5 times the estimated human exposure during treatment of malaria. Following single-dose administration of 14C-labeled atovaquone to pregnant rats, concentrations of radiolabel in rat fetuses were 18% (mid-gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. In rabbits, atovaquone caused maternal toxicity at plasma concentrations that were approximately 0.6 to 1.3 times the estimated human exposure during treatment of malaria. 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. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations.

The combination of atovaquone and proguanil hydrochloride was not teratogenic in rats at plasma concentrations up to 1.7 and 0.10 times, respectively, the estimated human exposure during treatment of malaria. In rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at plasma concentrations up to 0.34 and 0.82 times, respectively, the estimated human exposure during treatment of malaria.

While there are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women, Malarone may be used if the potential benefit justifies the potential risk to the fetus. The proguanil component of Malarone acts by inhibiting the parasitic dihydrofolate reductase (see CLINICAL PHARMACOLOGY: Microbiology: Mechanism of Action). However, there are no clinical data indicating that folate supplementation diminishes drug efficacy, and for women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements may be continued while taking Malarone.

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.

Pediatric Use

Treatment of Malaria

The efficacy and safety of Malarone for the treatment of malaria have been established in controlled studies involving pediatric patients weighing 5 kg or more (see CLINICAL STUDIES). Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg.

Prophylaxis of Malaria

The efficacy and safety of Malarone have been established for the prophylaxis of malaria in controlled studies involving pediatric patients weighing 11 kg or more (see CLINICAL STUDIES). Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg.

Geriatric Use

Clinical studies of Malarone did not include sufficient numbers of subjects aged 65 and over 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 (see CLINICAL PHARMACOLOGY: Special Populations: Geriatrics), and the greater frequency of concomitant disease or other drug therapy.

Adverse Reactions

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

Among adults who received Malarone for treatment of malaria, 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 adults treated with Malarone.

Among pediatric patients (weighing 11 to 40 kg) who received Malarone for the treatment of malaria, 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 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, 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 for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥5% of patients as an adverse experience attributable to Malarone. 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 malaria patients being treated with Malarone. The frequency of these abnormalities varied substantially across studies of treatment and were not observed in the randomized portions of the prophylaxis trials.

In one phase III trial of malaria treatment in Thai adults, early elevations of ALT and AST were observed to occur more frequently in patients treated with Malarone compared to patients treated with an active control drug. Rates for patients who had normal baseline levels of these clinical laboratory parameters were: Day 7: ALT 26.7% vs. 15.6%; AST 16.9% vs. 8.6%. By day 14 of this 28-day study, the frequency of transaminase elevations equalized across the 2 groups.

In this and other studies in which transaminase elevations occurred, they were noted to persist for up to 4 weeks following treatment with Malarone for malaria. None were associated with untoward clinical events.

Among subjects who received Malarone for prophylaxis of malaria in placebo-controlled trials, adverse experiences occurred in similar proportions of subjects receiving Malarone or placebo (Table 3). The most commonly reported adverse experiences possibly attributable to Malarone or placebo were headache and abdominal pain. Prophylaxis with Malarone was discontinued prematurely due to a treatment-related adverse experience in 3 of 381 adults and 0 of 125 pediatric patients.

Table 3. Adverse Experiences in Placebo-Controlled Clinical Trials of Malarone for Prophylaxis of Malaria

Adverse Experience

Percent of Subjects With Adverse Experiences

(Percent of Subjects With Adverse Experiences Attributable to Therapy)

Adults

Children and Adolescents

Placebo

n = 206

Malarone*

n = 206

Malarone

n = 381

Placebo

n = 140

Malarone

n = 125

Headache

27

(7)

22

(3)

17

(5)

21

(14)

19

(14)

Fever

13

(1)

5

(0)

3

(0)

11

(<1)

6

(0)

Myalgia

11

(0)

12

(0)

7

(0)

0

(0)

0

(0)

Abdominal pain

10

(5)

9

(4)

6

(3)

29

(29)

33

(31)

Cough

8

(<1)

6

(<1)

4

(1)

9

(0)

9

(0)

Diarrhea

8

(3)

6

(2)

4

(1)

3

(1)

2

(0)

Upper respiratory infection

7

(0)

8

(0)

5

(0)

0

(0)

<1

(0)

Dyspepsia

5

(4)

3

(2)

2

(1)

0

(0)

0

(0)

Back pain

4

(0)

8

(0)

4

(0)

0

(0)

0

(0)

Gastritis

3

(2)

3

(3)

2

(2)

0

(0)

0

(0)

Vomiting

2

(<1)

1

(<1)

<1

(<1)

6

(6)

7

(7)

Flu syndrome

1

(0)

2

(0)

4

(0)

6

(0)

9

(0)

Any adverse experience

65

(32)

54

(17)

49

(17)

62

(41)

60

(42)

* Subjects receiving the recommended dose of atovaquone and proguanil hydrochloride in placebo-controlled trials.

Subjects receiving the recommended dose of atovaquone and proguanil hydrochloride in any trial.

In an additional placebo-controlled study of malaria prophylaxis with Malarone involving 330 pediatric patients in a malaria-endemic area (see CLINICAL STUDIES), the safety profile of Malarone was consistent with that described above. The most common treatment-emergent adverse events with Malarone 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 than with placebo, while fever (5% vs. 12%) and diarrhea (1% vs. 5%) were more common with placebo. No patient withdrew from the study due to an adverse experience with Malarone. No routine laboratory data were obtained during this study.

Among subjects who received Malarone for prophylaxis of malaria in clinical trials with an active comparator, adverse experiences occurred in a similar or lower proportion of subjects receiving Malarone than an active comparator (Table 4). The mean durations of dosing and the periods for which the adverse experiences are summarized in Table 4, were 28 days (Study 1) and 26 days (Study 2) for Malarone, 53 days for mefloquine, and 49 days for chloroquine plus proguanil (reflecting the different recommended dosing regimens). Fewer neuropsychiatric adverse experiences occurred in subjects who received Malarone than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving Malarone than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving Malarone had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 4). Prophylaxis with Malarone was discontinued prematurely due to a treatment-related adverse experience in 7 of 1,004 travelers.

Table 4. Adverse Experiences in Active-Controlled Clinical Trials of Malarone for Prophylaxis of Malaria

Percent of Subjects With Adverse Experiences*

(Percent of Subjects With Adverse Experiences Attributable to Therapy)

Study 1

Study 2

Adverse Experience

Malarone

n = 493

Mefloquine

n = 483

Malarone

n = 511

Chloroquine plus Proguanil

n = 511

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)

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Some commonly used brand names are: In the U.S.— DexFerrum 4 Femiron 1 Feosol Caplets 3 Feosol Tablets 3 Feostat 1 Feostat Drops 1 Feratab 3 Fer-gen-sol 3 Fergon 2 Fer-In-Sol Drops 3 Fer-In-Sol Syrup 3 Fer-Iron Drops 3 Fero-Gradumet 3 Ferospace 3 Ferralet 2 Ferralet Slow Release 2 Ferraly more...

I-Tropine Ophthalmic I-Tropine Ophthalmic
Some commonly used brand names are: In the U.S.— AK-Homatropine 2 Atropair 1 Atropine Care 1 Atropine Sulfate S.O.P. 1 Atropisol 1 Atrosulf 1 I-Homatrine 2 Isopto Atropine 1 Isopto Homatropine 2 Isopto Hyoscine 3 I-Tropine 1 Ocu-Tropine 1 Spectro-Homatropine 2 In Canada— Atropisol more...