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Malarone (Atovaquone / Proguanil Hydrochloride) - Side Effects and Adverse Reactions

 
 



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 The design of this clinical trial required that any patient who vomited be withdrawn from the trial.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)

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)

* Adverse experiences that started while receiving active study drug.

In a third active-controlled study, MALARONE (n = 110) was compared with chloroquine/proguanil (n = 111) for the prophylaxis of malaria in 221 non-immune pediatric patients (see CLINICAL STUDIES). The mean duration of exposure was 23 days for MALARONE, 46 days for chloroquine, and 43 days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with MALARONE 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 or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving MALARONE discontinued due to adverse events.

Post-Marketing Adverse Reactions

In addition to adverse events reported from clinical trials, the following events have been identified during world-wide post-approval use of MALARONE. 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.

Blood and Lymphatic System Disorders

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

Immune System Disorders

Allergic reactions including angioedema, urticaria, and rare cases of anaphylaxis and vasculitis.

Nervous System Disorders

Rare cases of seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established.

Gastrointestinal Disorders

Stomatitis.

Hepatobiliary Disorders

Elevated liver function tests and rare cases of hepatitis, cholestasis; a single case of hepatic failure requiring transplant has been reported.

Skin and Subcutaneous Tissue Disorders

Photosensitivity, rash, and rare cases of erythema multiforme and Stevens-Johnson syndrome.



REPORTS OF SUSPECTED MALARONE SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Malarone. The information is not vetted and should not be considered as verified clinical evidence.

Possible Malarone side effects / adverse reactions in 29 year old female

Reported by a pharmacist from Ireland on 2011-10-04

Patient: 29 year old female weighing 58.0 kg (127.6 pounds)

Reactions: Myalgia, Amenorrhoea, Musculoskeletal Stiffness, Dizziness, Headache, Mobility Decreased

Suspect drug(s):
Malarone

Other drugs received by patient: Drospirenone and Ethinyl Estradiol; Hepatyrix



Possible Malarone side effects / adverse reactions in 50 year old male

Reported by a physician from United Kingdom on 2011-10-17

Patient: 50 year old male

Reactions: Neuropathy Peripheral, Paraesthesia

Suspect drug(s):
Malarone



Possible Malarone side effects / adverse reactions in 17 year old male

Reported by a consumer/non-health professional from United Kingdom on 2011-10-18

Patient: 17 year old male

Reactions: Abnormal Dreams, Malaise, Nausea, Presyncope, Motion Sickness, Treatment Noncompliance

Suspect drug(s):
Malarone



See index of all Malarone side effect reports >>

Drug label data at the top of this Page last updated: 2008-06-30

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