Atovaquone And Proguanil Hcl
(Atovaquone And Proguanil Hydrochloride)Atovaquone And Proguanil Hcl Prescribing Information
Atovaquone and Proguanil Hydrochloride tablets are an antimalarial indicated for:
• prophylaxis ofPlasmodium falciparummalaria, including in areas where chloroquine resistance has been reported. ()1.1 Prevention of MalariaAtovaquone and Proguanil Hydrochloride tablets are indicated for the prophylaxis of
Plasmodium falciparummalaria, including in areas where chloroquine resistance has been reported.• treatment of acute, uncomplicatedP. falciparummalaria. ()1.2 Treatment of MalariaAtovaquone and Proguanil Hydrochloride tablets are indicated for the treatment of acute, uncomplicated
P. falciparummalaria. Atovaquone and proguanil hydrochloride 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.
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.
Each Atovaquone and Proguanil Hydrochloride tablet (adult strength), containing 250 mg atovaquone and 100 mg proguanil hydrochloride, is pink, film‑coated, round, biconvex and engraved with “GX CM3” on one side.
Renal impairment: contraindicated for prophylaxis of
Do not use Atovaquone and Proguanil Hydrochloride tablets 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.
• 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 ofP.falciparummalaria 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 (.), Clinical Pharmacology (8.6 Renal ImpairmentDo not use Atovaquone and Proguanil Hydrochloride tablets 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.
[See Clinical Pharmacology .])]12.3 PharmacokineticsAbsorptionAtovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone shows considerable inter‑individual variability.
Effect of Food:Atovaquone and Proguanil Hydrochloride tablets should be taken with food or a milky drink. Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2 to 3 times and Cmax5 times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%.DistributionAtovaquone 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 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 atovaquone and proguanil was unaffected by the presence of the other.
EliminationThe 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.
The main routes of elimination are hepatic biotransformation and renal excretion.
Metabolism:In a study where14C‑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 cytochrome P450 2C19 [CYP2C19]) and 4-chlorophenylbiguanide.Excretion:A population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both atovaquone and proguanil is related to body weight. The values CL/F for both atovaquone and proguanil in subjects with body weight ≥11 kg are shown in Table 2.Table 2. Apparent Clearance for Atovaquone and Proguanil in Patients as a Function of Body Weight aSD = Standard deviation. Body WeightAtovaquoneProguanilnCL/F (L/h)Mean ± SDa(range)nCL/F (L/h)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)
The pharmacokinetics of atovaquone and proguanil in patients with body weight less than 11 kg have not been adequately characterized.
Specific PopulationsPediatric Patients: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 concentrations of atovaquone and proguanil in pediatric patients weighing 5 to 40 kg were within the range observed in adults after dosing by body weight.Geriatric Patients:In a single‑dose study, the pharmacokinetics of atovaquone, 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). Tmaxwas 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).Patients with 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 atovaquone and proguanil hydrochloride 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 Cmaxand 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 (4.2)].Patients with 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) 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 atovaquone. However, in subjects with moderate hepatic 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 elimination half-life increased in subjects with mild hepatic impairment when compared with healthy subjects . 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 (Cmaxand AUC) and an increase in its elimination half‑life in subjects with mild hepatic impairment when compared with healthy volunteers . There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment. The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of atovaquone and proguanil hydrochloride have not been studied in patients with severe hepatic impairment.Table 3. Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects with Mild and Moderate Hepatic Impairment Compared with Healthy Volunteers ND = Not determined due to lack of quantifiable data.
aRatio of geometric means.
bMean difference.ParameterComparisonProguanilCycloguanilAUC(0-inf)a
mild:healthy
1.96 (1.51, 2.54)
0.32 (0.22, 0.45)
Cmaxa
mild:healthy
1.41 (1.16, 1.71)
0.35 (0.24, 0.50)
t1/2b
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
Cmaxa
moderate:healthy
0.97 (0.69, 1.36)
ND
t1/2b
moderate:healthy
1.46 (1.05, 2.05)
ND
Drug Interaction StudiesThere are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.
Atovaquone 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 atovaquone 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 atovaquone.Metoclopramide:Concomitant treatment with metoclopramide has been associated with decreased bioavailability of atovaquone.Indinavir:Concomitant administration of atovaquone (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 Cmaxof indinavir but resulted in a decrease in the Ctroughof indinavir (23% decrease [90% CI: 8%, 35%]).
• 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 Vomiting and DiarrheaAbsorption 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 .]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.• In mixedP. falciparumandPlasmodium vivaxinfection,P. vivaxrelapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone. ()5.2 Relapse of InfectionIn mixed
P. falciparumandPlasmodium vivaxinfections,P. vivaxparasite relapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone.In the event of recrudescent
P. falciparuminfections 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.• In the event of recrudescentP. falciparuminfections after treatment or prophylaxis failure, patients should be treated with a different blood schizonticide. ()5.2 Relapse of InfectionIn mixed
P. falciparumandPlasmodium vivaxinfections,P. vivaxparasite relapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone.In the event of recrudescent
P. falciparuminfections 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.• Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use. ()5.3 HepatotoxicityElevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of atovaquone and proguanil hydrochloride.
• 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. ()5.4 Severe or Complicated MalariaAtovaquone 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.