Label: ATOVAQUONE AND PROGUANIL HYDROCHLORIDE tablet, film coated

Microbiology:

Pharmacokinetics:

Prevention of Malaria:

Atovaquone and proguanil hydrochloride tablets are indicated for the prophylaxis of P. falciparum malaria, including in areas where chloroquine resistance has been reported (see CLINICAL STUDIES).

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.

General:

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.

Elevated liver function tests and rare cases of hepatitis have been reported with prophylactic use of atovaquone and proguanil hydrochloride. A single case of hepatic failure requiring liver transplantation has also been reported with prophylactic use.

Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If atovaquone and proguanil hydrochloride is used in patients who are vomiting (see DOSAGE AND ADMINISTRATION), 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 atovaquone and proguanil hydrochloride. In the controlled clinical trials of atovaquone and proguanil hydrochloride, 15.3% of adults who were treated with atovaquone/proguanil received an antiemetic drug during that part of the trial when they received atovaquone/proguanil. Of these patients, 98.3% were successfully treated. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

Parasite relapse occurred commonly when P. vivax malaria was 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.

Information for Patients:

Patients should be instructed:

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to take atovaquone and proguanil hydrochloride tablets at the same time each day with food or a milky drink.

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to take a repeat dose of atovaquone and proguanil hydrochloride if vomiting occurs within 1 hour after dosing.

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to take a dose as soon as possible if a dose is missed, then return to their normal dosing schedule. However, if a dose is skipped, the patient should not double the next dose.

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that rare serious adverse events such as hepatitis, severe skin reactions, neurological, and hematological events have been reported when atovaquone and proguanil hydrochloride was used for the prophylaxis or treatment of malaria.

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to consult a healthcare professional regarding alternative forms of prophylaxis if prophylaxis with atovaquone and proguanil hydrochloride is prematurely discontinued for any reason.

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that protective clothing, insect repellants, and bednets are important components of malaria prophylaxis.

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that no chemoprophylactic regimen is 100% effective; therefore, patients should seek medical attention for any febrile illness that occurs during or after return from a malaria-endemic area and inform their healthcare professional that they may have been exposed to malaria.

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that falciparum malaria carries a higher risk of death and serious complications in pregnant women than in the general population. Pregnant women anticipating travel to malarious areas should discuss the risks and benefits of such travel with their physicians (see Pregnancy section).

Drug Interactions:

Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone. Parasitemia should be closely monitored in patients receiving tetracycline. 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.

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively. The concomitant administration of atovaquone and proguanil hydrochloride and rifampin or rifabutin is not recommended.

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, suitable coagulation tests should be closely monitored.

Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely.

Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Pregnancy:

Pregnancy Category C. 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 (see Information for Patients) in addition to antimalarials.

Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at maternal plasma concentrations up to 5 to 6.5 times the estimated human exposure during treatment of malaria. Following single-dose administration of 14C-labeled atovaquone to pregnant rats, concentrations of radiolabel in rat fetuses were 18% (mid-gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. In rabbits, atovaquone caused maternal toxicity at plasma concentrations that were approximately 0.6 to 1.3 times the estimated human exposure during treatment of malaria. 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. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations.

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 0.2-times the average human exposure based on AUC comparisons.) Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

The combination of atovaquone and proguanil hydrochloride was not teratogenic in rats at plasma concentrations up to 1.7 and 0.10 times, respectively, the estimated human exposure during treatment of malaria. In rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at plasma concentrations up to 0.34 and 0.82 times, respectively, the estimated human exposure during treatment of malaria.

While there are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women, atovaquone and proguanil hydrochloride may be used if the potential benefit justifies the potential risk to the fetus. The proguanil component of atovaquone and proguanil hydrochloride acts by inhibiting the parasitic dihydrofolate reductase (see CLINICAL PHARMACOLOGY: Microbiology: Mechanism of Action). However, there are no clinical data indicating that folate supplementation diminishes drug efficacy, and for women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements may be continued while taking atovaquone and proguanil hydrochloride.

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 atovaquone and proguanil hydrochloride is administered to a nursing mother.

Pediatric Use:

Geriatric Use:

Clinical studies of atovaquone and proguanil hydrochloride did not include sufficient numbers of subjects aged 65 and over 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 (see CLINICAL PHARMACOLOGY: Special Populations: Geriatrics), and the greater frequency of concomitant disease or other drug therapy.

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 atovaquone and proguanil hydrochloride. 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 atovaquone and proguanil hydrochloride.

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; a single case of hepatitis, cholestatis; failure requiring transplant has been reported.

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

Prevention of Malaria:

Prophylactic treatment with atovaquone and proguanil hydrochloride should be started 1 or 2 days before entering a malaria-endemic area and continued daily during the stay and for 7 days after return.

Treatment of Acute Malaria:

Patients with Renal Impairment:

Atovaquone and proguanil hydrochloride tablet should not be used for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min). Atovaquone and proguanil hydrochloride tablet may be used with caution for the treatment of malaria in patients with severe renal impairment (creatinine clearance <30 mL/min), only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure (see CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment). No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) and moderate (creatinine clearance 30 to 50 mL/min) renal impairment (see CLINICAL PHARMACOLOGY: Special Populations).

Patients with Hepatic Impairment:

No dosage adjustments are needed in patients with mild to moderate hepatic impairment. No studies have been conducted in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY: Special Populations: Hepatic Impairment).

Treatment of Acute Malarial Infections:

In 3 phase II clinical trials, atovaquone alone, proguanil hydrochloride alone, and the combination of atovaquone and proguanil hydrochloride were evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum. Among 156 evaluable patients, the parasitological cure rate was 59/89 (66%) with atovaquone alone, 1/17 (6%) with proguanil hydrochloride alone, and 50/50 (100%) with the combination of atovaquone and proguanil hydrochloride.

Atovaquone and proguanil hydrochloride was evaluated for treatment of acute, uncomplicated malaria caused by P. falciparum in 8 phase III controlled clinical trials. Among 471 evaluable patients treated with the equivalent of 4 atovaquone and proguanil hydrochloride tablets once daily for 3 days, 464 had a sensitive response (elimination of parasitemia with no recurrent parasitemia during follow-up for 28 days) (see Table 5). Seven patients had a response of RI resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28 days after starting treatment). In these trials, the response to treatment with atovaquone and proguanil hydrochloride was similar to treatment with the comparator drug in 4 trials, and better than the response to treatment with the comparator drug in the other 4 trials.

The overall efficacy in 521 evaluable patients was 98.7% (Table 5).

Eighteen of 521 (3.5%) evaluable patients with acute falciparum malaria presented with a pretreatment serum creatinine greater than 2.0 mg/dL (range 2.1 to 4.3 mg/dL). All were successfully treated with atovaquone and proguanil hydrochloride and 17 of 18 (94.4%) had normal serum creatinine levels by day 7.

Data from a phase II trial of atovaquone conducted in Zambia suggested that approximately 40% of the study population in this country were HIV-infected patients. The enrollment criteria were similar for the phase III trial of atovaquone and proguanil hydrochloride conducted in Zambia and the results are presented in Table 5. Efficacy rates for atovaquone and proguanil hydrochloride in this study population were high and comparable to other populations studied.

The efficacy of atovaquone and proguanil hydrochloride in the treatment of the erythrocytic phase of nonfalciparum malaria was assessed in a small number of patients. Of the 23 patients in Thailand infected with P. vivax and treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg daily for 3 days, parasitemia cleared in 21 (91.3%) at 7 days. Parasite relapse occurred commonly when P. vivax malaria was treated with atovaquone and proguanil hydrochloride alone. Seven patients in Gabon with malaria due to P. ovale or P. malariae were treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg daily for 3 days. All 6 evaluable patients (3 with P. malariae, 2 with P. ovale, and 1 with mixed P. falciparum and P. ovale) were cured at 28 days. Relapsing malarias including P. vivax and P. ovale require additional treatment to prevent relapse.

Prevention of Malaria:

Atovaquone and proguanil hydrochloride was evaluated for prophylaxis of malaria in 5 clinical trials in malaria-endemic areas and in 3 active-controlled trials in non-immune travelers to malaria-endemic areas.

Three placebo-controlled studies of 10 to 12 weeks' duration were conducted among residents of malaria-endemic areas in Kenya, Zambia, and Gabon. Of a total of 669 randomized patients (including 264 pediatric patients 5 to 16 years of age), 103 were withdrawn for reasons other than falciparum malaria or drug-related adverse events. (Fifty-five percent of these were lost to follow-up and 45% were withdrawal for protocol violations). The results are listed in Table 6.

In another study, 330 Gabonese pediatric patients (weighing 13 to 40 kg, and aged 4 to 14 years) who had received successful open-label radical cure treatment with artesunate, were randomized to receive either atovaquone and proguanil hydrochloride (dosage based on body weight) or placebo in a double-blind fashion for 12 weeks. Blood smears were obtained weekly and any time malaria was suspected. Nineteen of the 165 children given atovaquone and proguanil hydrochloride and 18 of 165 patients given placebo withdrew from the study for reasons other than parasitemia (primary reason was lost to follow-up). In the per-protocol population, 1 out of 150 patients (<1%) who received atovaquone and proguanil hydrochloride developed P. falciparum parasitemia while receiving prophylaxis with atovaquone and proguanil hydrochloride compared with 31 (22%) of the 144 placebo recipients.

In a 10-week study in 175 South African subjects who moved into malaria-endemic areas and were given prophylaxis with 1 atovaquone and proguanil hydrochloride daily, parasitemia developed in 1 subject who missed several doses of medication. Since no placebo control was included, the incidence of malaria in this study was not known.

Two active-controlled studies were conducted in non-immune travelers who visited a malaria-endemic area. The mean duration of travel was 18 days (range 2 to 38 days). Of a total of 1,998 randomized patients who received atovaquone and proguanil hydrochloride or controlled drug, 24 discontinued from the study before follow-up evaluation 60 days after leaving the endemic area. Nine of these were lost to follow-up, 2 withdrew because of an adverse experience, and 13 were discontinued for other reasons. These studies were not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to P. falciparum malaria in both studies is unknown. The results are listed in Table 7.

A third randomized, open-label study was conducted which included 221 otherwise healthy pediatric patients (weighing ≥11 kg and 2 to 17 years of age) who were at risk of contracting malaria by traveling to an endemic area. The mean duration of travel was 15 days (range 1 to 30 days). Prophylaxis with atovaquone and proguanil hydrochloride (n = 110, dosage based on body weight) began 1 or 2 days before entering the endemic area and lasted until 7 days after leaving the area. A control group (n = 111) received prophylaxis with chloroquine/proguanil dosed according to WHO guidelines. No cases of malaria occurred in either group of children. However, the study was not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to P. falciparum malaria in this study is unknown.

In a malaria challenge study conducted in healthy US volunteers, atovaquone alone prevented malaria in 6 of 6 individuals, whereas 4 of 4 placebo-treated volunteers developed malaria.