Atovaquone and Proguanil Hydrochloride: Package Insert and Label Information

ATOVAQUONE AND PROGUANIL HYDROCHLORIDE- atovaquone and proguanil hydrochloride tablet, film coated
Mylan Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

1.1 Prevention of Malaria

Atovaquone and proguanil hydrochloride tablets are indicated for the prophylaxis of Plasmodium falciparum malaria, including in areas where chloroquine resistance has been reported.

1.2 Treatment of Malaria

Atovaquone and proguanil hydrochloride tablets are indicated for the treatment of acute, uncomplicated P. falciparum malaria. Atovaquone and proguanil hydrochloride tablets have 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.

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

2.1 Prevention of Malaria

Start prophylactic treatment with atovaquone and proguanil hydrochloride tablets 1 or 2 days before entering a malaria-endemic area and continue daily during the stay and for 7 days after return.

Adults

One atovaquone and proguanil hydrochloride 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).

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 atovaquone and proguanil hydrochloride pediatric tablet daily

21-30

125 mg/50 mg

2 atovaquone and proguanil hydrochloride pediatric tablets as a single daily dose

31-40

187.5 mg/75 mg

3 atovaquone and proguanil hydrochloride pediatric tablets as a single daily dose

> 40

250 mg/100 mg

1 atovaquone and proguanil hydrochloride tablet (adult strength) as a single daily dose

2.2 Treatment of Acute Malaria

Adults

Four atovaquone and proguanil hydrochloride tablets (adult strength; total daily dose 1 g atovaquone/400 mg proguanil hydrochloride) 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).

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 atovaquone and proguanil hydrochloride pediatric tablets daily for 3 consecutive days

9-10

187.5 mg/75 mg

3 atovaquone and proguanil hydrochloride pediatric tablets daily for 3 consecutive days

11-20

250 mg/100 mg

1 atovaquone and proguanil hydrochloride tablet (adult strength) daily for 3 consecutive days

21-30

500 mg/200 mg

2 atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days

31-40

750 mg/300 mg

3 atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days

> 40

1 g/400 mg

4 atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days

2.3 Renal Impairment

Do not use atovaquone and proguanil hydrochloride tablets for malaria prophylaxis in patients with severe renal impairment (creatinine clearance < 30 mL/min) [see Contraindications (4)]. 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 Clinical Pharmacology (12.3).]

3 DOSAGE FORMS AND STRENGTHS

Atovaquone and Proguanil Hydrochloride Tablets are available containing 250 mg of atovaquone, USP and 100 mg of proguanil hydrochloride, USP.

The 250 mg/100 mg tablets are buff, film-coated, round, unscored tablets debossed with A-P over 2 on one side of the tablet and M on the other side.

Atovaquone and Proguanil Hydrochloride Pediatric Tablets are available containing 62.5 mg of atovaquone, USP and 25 mg of proguanil hydrochloride, USP.

The 62.5 mg/25 mg tablets are buff, film-coated, round, unscored tablets debossed with A-P over 1 on one side of the tablet and M on the other side.

4 CONTRAINDICATIONS

Atovaquone and proguanil hydrochloride tablets are contraindicated in individuals with known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme or Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone or proguanil hydrochloride or any component of the formulation.
Atovaquone and proguanil hydrochloride tablets are 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 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Vomiting and Diarrhea

Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If atovaquone and proguanil hydrochloride tablets are used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered [see Dosage and Administration (2)]. Vomiting occurred in up to 19% of pediatric patients given treatment doses of atovaquone and proguanil hydrochloride tablets. 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 atovaquone and proguanil hydrochloride tablets alone.

In the event of recrudescent P. falciparum infections after treatment with atovaquone and proguanil hydrochloride tablets or failure of chemoprophylaxis with atovaquone and proguanil hydrochloride tablets, 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 atovaquone and proguanil hydrochloride tablets.

5.4 Severe or Complicated Malaria

Atovaquone and proguanil hydrochloride tablets have 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.

6 ADVERSE REACTIONS

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 atovaquone and proguanil hydrochloride tablets contain atovaquone and proguanil hydrochloride, the type and severity of adverse reactions associated with each of the compounds may be expected. The lower prophylactic doses of atovaquone and proguanil hydrochloride tablets 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 atovaquone and proguanil hydrochloride tablets 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 atovaquone and proguanil hydrochloride tablets; 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 atovaquone and proguanil hydrochloride tablets or placebo in all studies. Prophylaxis with atovaquone and proguanil hydrochloride tablets 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 atovaquone and proguanil hydrochloride tablets involving 330 pediatric patients (aged 4 to 14 years) in Gabon, a malaria-endemic area, the safety profile of atovaquone and proguanil hydrochloride tablets was consistent with that observed in the earlier prophylactic studies in adults and pediatric patients. The most common treatment-emergent adverse events with atovaquone and proguanil hydrochloride tablets were abdominal pain (13%), headache (13%), and cough (10%). Abdominal pain (13% vs. 8%) and vomiting (5% vs. 3%) were reported more often with atovaquone and proguanil hydrochloride tablets than with placebo. No patient withdrew from the study due to an adverse experience with atovaquone and proguanil hydrochloride tablets. No routine laboratory data were obtained during this study.

Non-immune travelers visiting a malaria-endemic area received atovaquone and proguanil hydrochloride tablets (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 atovaquone and proguanil hydrochloride tablets than an active comparator (Table 3). Fewer neuropsychiatric adverse experiences occurred in subjects who received atovaquone and proguanil hydrochloride tablets than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving atovaquone and proguanil hydrochloride tablets than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving atovaquone and proguanil hydrochloride tablets had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 3). Prophylaxis with atovaquone and proguanil hydrochloride tablets was discontinued prematurely due to a treatment-related adverse experience in 7 of 1,004 travelers.

Table 3. Adverse Experiences in Active-Controlled Clinical Trials of Atovaquone and Proguanil Hydrochloride Tablets for Prophylaxis of P. falciparum Malaria

*
Adverse experiences that started while receiving active study drug.
Mean duration of dosing based on recommended dosing regimens.

Percent of Subjects with Adverse Experiences * (Percent of Subjects with Adverse Experiences Attributable to Therapy)

Study 1

Study 2

Atovaquone and Proguanil Hydrochloride Tablets n = 493 (28 days)

Mefloquine n = 483 (53 days)

Atovaquone and Proguanil Hydrochloride Tablets n = 511 (26 days)

Chloroquine plus Proguanil n = 511 (49 days)

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)

In a third active-controlled study, atovaquone and proguanil hydrochloride tablets (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 atovaquone and proguanil hydrochloride tablets, 46 days for chloroquine, and 43 days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with atovaquone and proguanil hydrochloride tablets 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 atovaquone and proguanil hydrochloride tablets or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving atovaquone and proguanil hydrochloride tablets discontinued due to adverse events.

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