Numal

Prevention of Malaria

Numal® is indicated for the prophylaxis of Plasmodium falciparum malaria, including in areas where chloroquine resistance has been reported.

Treatment of Malaria

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

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.

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

Prevention of Malaria

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

Adults: One Numal 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

Treatment of Acute Malaria

Adults: Four Numal 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

Renal Impairment

Do not use Numal 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.

Hypersensitivity

Numal is 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.

Severe Renal Impairment

Numal 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Vomiting and Diarrhea

Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If Numal is used in patients who are vomiting, 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 Numal. 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.

Relapse of Infection

In mixed P. falciparum and Plasmodium vivax infections, P. vivax parasite relapse occurred commonly when patients were treated with Numal alone.

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

Hepatotoxicity

Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of Numal.

Severe or Complicated Malaria

Numal 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Atovaquone

A 24-month carcinogenicity study in CD rats was negative for neoplasms at doses up to 500 mg/kg/day corresponding to approximately 54 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. In CD-1 mice, a 24-month study showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested (50, 100, and 200 mg/kg/day) which correlated with at least 15 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.

Atovaquone did not impair fertility in male and female rats at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately 7.3 times the estimated human exposure during treatment of malaria based on AUC.

Proguanil

No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-1 mice at doses up to 16 mg/kg/day corresponding to 1.5 times the average human plasma exposure during prophylaxis of malaria based on AUC, and in Wistar Hannover rats at doses up 20 mg/kg/day corresponding to 1.1 times the average human plasma exposure during prophylaxis of malaria based on AUC.

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

A fertility study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.04-times the average human exposure during treatment of malaria based on AUC). Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Atovaquone

Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at doses up to 1,000 mg/kg/day corresponding to maternal plasma concentrations up to 7.3 times the estimated human exposure during treatment of malaria based on AUC. In rabbits, atovaquone caused adverse fetal effects and maternal toxicity at a dose of 1,200 mg/kg/day corresponding to plasma concentrations that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC. 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.

In a pre- and post-natal study in rats, atovaquone did not produce adverse effects in 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.

Proguanil

A pre- and post-natal study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 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 was not teratogenic in pregnant rats at atovaquone:proguanil hydrochloride (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 was not teratogenic or embryotoxic to rabbit fetuses at atovaquone:proguanil hydrochloride (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.

There are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women. Numal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 in addition to antimalarials.

The proguanil component of Numal acts by inhibiting the parasitic dihydrofolate reductase. However, there are no clinical data indicating that folate supplementation diminishes drug efficacy. For women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements may be continued while taking Numal.

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 Numal is administered to a nursing woman.

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 Numal have been established for the prophylaxis of malaria in controlled trials involving pediatric patients weighing 11 kg or more.

Treatment of Malaria

Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg. The efficacy and safety of Numal for the treatment of malaria have been established in controlled trials involving pediatric patients weighing 5 kg or more.

Geriatric Use

Clinical trials of Numal did not include sufficient numbers of subjects aged 65 years and older 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, and the greater frequency of concomitant disease or other drug therapy.

Renal Impairment

Do not use Numal 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.

Hepatic Impairment

No dosage adjustments are needed in patients with mild or moderate hepatic impairment. No trials have been conducted in patients with severe hepatic impairment.

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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

Non-immune travelers visiting a malaria-endemic area received Numal (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 Numal than an active comparator (Table 3). Fewer neuropsychiatric adverse experiences occurred in subjects who received Numal than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving Numal than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving Numal had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 3). Prophylaxis with Numal 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 Numal for Prophylaxis of P. falciparum Malaria

In a third active-controlled study, Numal (n = 110) was compared with chloroquine/proguanil (n = 111) for the prophylaxis of malaria in 221 non-immune pediatric patients (2 to 17 years of age). The mean duration of exposure was 23 days for Numal, 46 days for chloroquine, and 43 days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with Numal 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 Numal or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving Numal discontinued due to adverse events.

Treatment of Acute, Uncomplicated P. falciparum Malaria

In 7 controlled trials, 436 adolescents and adults received Numal 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 Numal.

In 2 controlled trials, 116 pediatric patients (weighing 11 to 40 kg) (mean age 7 years) received Numal for the treatment of malaria. The majority of subjects were black (72%); 28% were of other racial/ethnic groups, primarily Asian. 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 Numal 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 Numal, 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 Numal for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥ 5% of patients as an adverse experience attributable to Numal. 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 Numal. The frequency of these abnormalities varied substantially across trials of treatment and were not observed in the randomized portions of the prophylaxis trials.

One active-controlled trial evaluated the treatment of malaria in Thai adults (n = 182); the mean age of subjects was 26 years (range 15 to 63 years); 80% of subjects were male. Early elevations of ALT and AST occurred more frequently in patients treated with Numal (n = 91) compared to patients treated with an active control, mefloquine (n = 91). On Day 7, rates of elevated ALT and AST with Numal and mefloquine (for patients who had normal baseline levels of these clinical laboratory parameters) were ALT 26.7% vs. 15.6%; AST 16.9% vs. 8.6%, respectively. By Day 14 of this 28-day study, the frequency of transaminase elevations equalized across the 2 groups.

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of Numal. 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 Numal.

Blood and Lymphatic System Disorders: Neutropenia and anemia. Pancytopenia in patients with severe renal impairment treated with proguanil.

Immune System Disorders: Allergic reactions including anaphylaxis, angioedema, and urticaria, and vasculitis.

Nervous System Disorders: Seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established.

Gastrointestinal Disorders: Stomatitis.

Hepatobiliary Disorders: Elevated liver laboratory tests, hepatitis, cholestasis; hepatic failure requiring transplant has been reported.

Skin and Subcutaneous Tissue Disorders: Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome.

There is no information on overdoses of Numal substantially higher than the doses recommended for treatment.

There is no known antidote for atovaquone, and it is currently unknown if atovaquone is dialyzable. Overdoses up to 31,500 mg of atovaquone have been reported. In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose.

Overdoses of proguanil hydrochloride as large as 1,500 mg have been followed by complete recovery, and doses as high as 700 mg twice daily have been taken for over 2 weeks without serious toxicity. Adverse experiences occasionally associated with proguanil hydrochloride doses of 100 to 200 mg/day, such as epigastric discomfort and vomiting, would be likely to occur with overdose. There are also reports of reversible hair loss and scaling of the skin on the palms and/or soles, reversible aphthous ulceration, and hematologic side effects.

No trials of the pharmacodynamics of Numal have been conducted.

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%. Numal Tablets should be taken with food or a milky drink.

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 4.

Table 4: Apparent Clearance for Atovaquone and Proguanil in Patients as a Function of Body Weight

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

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 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.

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, 90% 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).

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 Numal 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.

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 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 to healthy subjects (Table 5). Also, the proguanil AUC and its elimination half-life 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 5). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment. The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of Numal have not been studied in patients with severe hepatic impairment.

Table 5: Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects With Mild and Moderate Hepatic Impairment Compared to Healthy Volunteers