Atovaquone and Proguanil Hydrochloride Pediatric

Atovaquone and proguanil hydrochloride tablets are an antimalarial indicated for:

• prophylaxis of Plasmodium falciparum malaria, including in areas where chloroquine resistance has been reported. ( 1.1 )
• treatment of acute, uncomplicated P. falciparum malaria. ( 1.2 )

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.

Each atovaquone and proguanil hydrochloride tablet (adult strength) contains 250 mg atovaquone USP and 100 mg proguanil hydrochloride USP. Atovaquone and proguanil hydrochloride tablets are pinkish brown to brown colored, circular, biconvex beveled edge, film-coated tablets with ‘404’ debossed on one side and ‘G’ debossed on the other side. Atovaquone and proguanil hydrochloride pediatric tablets contain 62.5 mg atovaquone USP and 25 mg proguanil hydrochloride USP. Atovaquone and proguanil hydrochloride pediatric tablets are pinkish brown to brown colored, circular, biconvex beveled edged, film coated tablets with ‘70’ debossed on one side and ‘G’ debossed on the other side.

• Tablets (adult strength): 250 mg atovaquone and 100 mg proguanil hydrochloride. ( 3 )
• Pediatric tablets: 62.5 mg atovaquone and 25 mg proguanil hydrochloride. ( 3 )

• Known serious hypersensitivity reactions to atovaquone or proguanil hydrochloride or any component of the formulation. ( 4 )
• Prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min). ( 4 )
• Atovaquone and proguanil hydrochloride is contraindicated in individuals with known hypersensitivity reactions to atovaquone or proguanil hydrochloride or any component of the formulation [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.2 )].
• Atovaquone and proguanil hydrochloride 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 [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )].

• Atovaquone absorption may be reduced in patients with diarrhea or vomiting. If used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required. ( 5.1 )
• In mixed P. falciparum and Plasmodium vivax infection, P. vivax relapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone. ( 5.2 )
• In the event of recrudescent P. falciparum infections after treatment or prophylaxis failure, patients should be treated with a different blood schizonticide. ( 5.2 )
• Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use. ( 5.3 )
• Severe Cutaneous Adverse Reactions (SCARs): Cases of SCARs such as Stevens-Johnson syndrome (SJS) have been reported. SCARs can be life-threatening or fatal. If symptoms or signs of SCARs develop, discontinue atovaquone and proguanil hydrochloride immediately and institute appropriate therapy. ( 5.4 )
• Atovaquone and proguanil hydrochloride has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria. Patients with severe malaria are not candidates for oral therapy. ( 5.5 )

5.1 Vomiting and Diarrhea Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If atovaquone and proguanil hydrochloride is 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. 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 alone. In the event of recrudescent P. falciparum infections after treatment with atovaquone and proguanil hydrochloride or failure of chemoprophylaxis with atovaquone and proguanil hydrochloride, 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.

5.4 Severe Cutaneous Adverse Reactions Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and erythema multiforme (EM) have been reported in patients treated with atovaquone and proguanil hydrochloride [see Adverse Reactions ( 6.2 )] . SCARs can be life-threatening or fatal. If symptoms or signs of SCARs develop, discontinue atovaquone and proguanil hydrochloride immediately and institute appropriate therapy. Patients who have developed SCARs with the use of atovaquone and proguanil hydrochloride must not receive atovaquone and proguanil hydrochloride [see Contraindications ( 4 )].

5.5 Severe or Complicated Malaria Atovaquone and proguanil hydrochloride 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.

The following clinically significant adverse reactions are discussed in another section of the labeling:

• Vomiting and Diarrhea [see Warnings and Precautions ( 5.1 )].
• Hepatotoxicity [see Warnings and Precautions ( 5.3 )].
• Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.4 )].
• Prophylaxis: Common adverse reactions (≥4%) in adults were diarrhea, dreams, oral ulcers, and headache; these events occurred in a similar or lower proportion of subjects receiving atovaquone and proguanil hydrochloride than an active comparator. Common adverse reactions (≥5%) in pediatric patients included abdominal pain, headache, cough, and vomiting. ( 6.1 )
• Treatment: Common adverse reactions (≥5%) in adolescents and adults were abdominal pain, nausea, vomiting, headache, diarrhea, asthenia, anorexia, and dizziness. Common adverse reactions (≥6%) in pediatric patients included vomiting, pruritus, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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 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 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 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; 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 or placebo in all studies. Prophylaxis with atovaquone and proguanil hydrochloride 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 involving 330 pediatric patients (aged 4 to 14 years) in Gabon, a malaria-endemic area, the safety profile of atovaquone and proguanil hydrochloride 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 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 than with placebo. No patient withdrew from the study due to an adverse experience with atovaquone and proguanil hydrochloride. No routine laboratory data were obtained during this study. Non-immune travelers visiting a malaria-endemic area received atovaquone and proguanil hydrochloride (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 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 was discontinued prematurely due to a treatment-related adverse experience in 7 of 1,004 travelers. Table 3. Adverse Reactions in Active-Controlled Clinical Trials of Atovaquone and Proguanil Hydrochloride for Prophylaxis of P. falciparum Malaria Adverse Experience Percent of Subjects with Adverse Experiences a (Percent of Subjects with Adverse Experiences Attributable to Therapy) Study 1 Study 2 Atovaquone and proguanil hydrochloride n = 493 (28 days) b Mefloquine n = 483 (53 days) b Atovaquone and proguanil hydrochloride 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, atovaquone and proguanil hydrochloride (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, 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 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 or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving atovaquone and proguanil hydrochloride discontinued due to adverse events. Treatment of Acute, Uncomplicated P. falciparum Malaria In 7 controlled trials, 436 adolescents and adults received atovaquone and proguanil hydrochloride 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 atovaquone and proguanil hydrochloride. […]

• Administration with rifampin or rifabutin is known to reduce atovaquone concentrations; concomitant use with atovaquone and proguanil hydrochloride is not recommended. ( 7.1 )
• Proguanil may potentiate anticoagulant effect of warfarin and other coumarin-based anticoagulants. Caution advised when initiating or withdrawing atovaquone and proguanil hydrochloride in patients on anticoagulants; coagulation tests should be closely monitored. ( 7.2 )
• Tetracycline may reduce atovaquone concentrations; parasitemia should be closely monitored. ( 7.3 )

7.1 Rifampin/Rifabutin Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations [see Clinical Pharmacology ( 12.3 )] . The concomitant administration of atovaquone and proguanil hydrochloride 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 atovaquone and proguanil hydrochloride in patients on continuous treatment with coumarin-based anticoagulants. When these products are administered concomitantly, coagulation tests should be closely monitored.

7.3 Tetracycline Concomitant treatment with tetracycline has been associated with a reduction in plasma concentrations of atovaquone [see Clinical Pharmacology ( 12.3 )] . Parasitemia should be closely monitored in patients receiving tetracycline.

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

7.5 Indinavir Concomitant administration of atovaquone and indinavir did not result in any change in the steady-state AUC and C max of indinavir but resulted in a decrease in the C trough of indinavir [see Clinical Pharmacology ( 12.3 )] . Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough concentrations of indinavir.

Renal impairment: contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment. ( 8.6 )

8.1 Pregnancy Risk Summary Available data from published literature and postmarketing experience with use of atovaquone and proguanil hydrochloride in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes . The proguanil component of atovaquone and proguanil hydrochloride tablets acts to inhibit parasitic dihydrofolate reductase; however, pregnant women and females of reproductive potential should continue folate supplementation to prevent neural tube defects [see Clinical Pharmacology ( 12.4 )] . Pregnant women with malaria are at increased risk for adverse pregnancy outcomes (see Clinical Considerations). Atovaquone administered by oral gavage to pregnant rats and rabbits during the period of organogenesis was not associated with fetal malformations at plasma exposures approximately 7 times and equal to, respectively, the estimated human exposure for the treatment of malaria based on AUC. Proguanil administered to pregnant rats and rabbits during the period of organogenesis was not associated with embryo-fetal toxicity at maternally toxic plasma exposures approximately 0.07 and 0.8 times, respectively, the estimated human exposure for treatment of malaria based on AUC (see Data) . The combination of atovaquone and proguanil hydrochloride given orally by gavage during the period of organogenesis was not associated with embryo-fetal developmental effects in pregnant rats or rabbits at atovaquone:proguanil hydrochloride doses of 50:20 mg/kg/day and 100:40 mg/kg/day, respectively (1.7 and 0.1 times and 0.3 and 0.5 times, respectively, the estimated human exposure for treatment of malaria). In a pre- and post-natal study with atovaquone and another pre-and post-natal study with proguanil, neither compound impaired the growth, development, or reproductive ability of first-generation offspring at maternal AUC exposures of approximately 7.3 and 0.04 times, respectively, the estimated human AUC exposure for treatment of malaria (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Data Animal Data: Atovaquone: Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day during organogenesis (Gestation Day [GD] 6 to GD15) in pregnant rats did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma exposures up to 7.3 times the estimated human exposure for the treatment of malaria based on AUC. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day by gavage during organogenesis (GD6 to GD18) was associated with decreased fetal body length at a maternally toxic dose of 1,200 mg/kg/day corresponding to plasma exposures that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC. In a pre- and post-natal study in rats, atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day from GD15 until Lactation Day (LD) 20 did not impair the growth or developmental effects in first-generation 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. Atovaquone crossed the placenta and was present in fetal rat and rabbit tissue. Proguanil: Proguanil administered orally to pregnant rats during organogenesis (GD6 to GD17) was not associated with fetal malformations, but increased ureter variations at a maternally toxic dose of 20 mg/kg/day corresponding to a plasma concentration approximately equal to 0.07 times the estimated human exposure for the treatment of malaria based on AUC. Proguanil given orally by gavage at a maternally toxic dose of 40 mg/kg/day to pregnant rabbits during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal effects at a plasma concentration up to 0.8 times the estimated human exposure for the treatment of malaria based on AUC. In a pre- and post-natal study in female rats, proguanil hydrochloride administered in oral doses of 4, 8, or 16 mg/kg/day from GD6 until LD20 did not impair the growth, development, or reproductive ability of first-generation offspring or the survivability of second generation offspring at doses up to 16 mg/kg/day (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. Atovaquone and Proguanil: The combination of atovaquone and proguanil hydrochloride administered orally to pregnant rats in atovaquone:proguanil hydrochloride doses of 12.5:5, 25:10, and 50:20 mg/kg/day during organogenesis (GD6 to GD17) did not produce maternal toxicity or adverse embryo-fetal developmental effects with doses up to 50:20 mg/kg/day corresponding to plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during treatment of malaria based on AUC. In pregnant rabbits, the combination of atovaquone and proguanil hydrochloride administered orally in atovaquone:proguanil hydrochloride doses of 25:10, 50:20, or 100:40 mg/kg/day during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal developmental effects at a maternally toxic dose of 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.

8.2 Lactation Risk Summary There are no data on the presence of atovaquone in human milk; however, proguanil is present in human milk. Atovaquone is present in rat milk (see Data) . When a drug is present in animal milk, it is likely the drug will be present in human milk. There are no data on the effects of atovaquone and proguanil on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for atovaquone and proguanil hydrochloride and any potential adverse effect on the breastfed child from atovaquone and proguanil hydrochloride or from the underlying maternal condition. Data In a rat study with doses of 10 and 250 mg/kg, given orally by gavage on postpartum Day 11, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

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 atovaquone and proguanil hydrochloride have been established for the prophylaxis of malaria in controlled trials involving pediatric patients weighing 11 kg or more [see Clinical Studies ( 14.1 )] . Treatment of Malaria Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg. The efficacy and safety of atovaquone and proguanil hydrochloride for the treatment of malaria have been established in controlled trials involving pediatric patients weighing 5 kg or more [see Clinical Studies ( 14.2 )] . […]

Atovaquone and proguanil hydrochloride tablets, fixed-dose combination of atovaquone and proguanil hydrochloride is an antimalarial agent [see Microbiology ( 12.4 )] .