Atovaquone and proguanil

Name: Atovaquone and proguanil

Proper Use of atovaquone and proguanil

Be sure to take atovaquone and proguanil at the same time each day.

Take atovaquone and proguanil with food or with a milky drink. This will help your body absorb the maximal amount of medicine.

If you vomit within 1 hour of taking atovaquone and proguanil, take the entire dose again as soon as your stomach can tolerate it.

If you or your child has trouble swallowing tablets, you may crush and mix atovaquone and proguanil with condensed milk just before taking it or giving it to your child.

Dosing

The dose of atovaquone and proguanil will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of atovaquone and proguanil. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For malaria prevention:
      • Adults—250 milligrams (mg) of atovaquone and 100 mg proguanil (1 adult strength tablet) per day, starting 1 to 2 days before entering malarial area and continuing for 7 days following return.
      • Children weighing 25 pounds (11 kilograms [kg]) or more—Dosage is according to weight and will be determined by your doctor.
      • Children weighing less than 25 pounds (11 kg)—Use and dose must be determined by your doctor.
    • For malaria treatment:
      • Adults—1 gram of atovaquone and 400 mg of proguanil (4 adult strength tablets) once daily as a single dose taken three days in a row.
      • Children weighing 11 pounds (5 kg) or more—Dosage is based on body weight and must be determined by your doctor.
      • Children weighing less than 11 pounds (5 kg)—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of atovaquone and proguanil, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Call your doctor or pharmacist for instructions.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Uses of Atovaquone and Proguanil

  • It is used to treat or prevent malaria.

What are some things I need to know or do while I take Atovaquone and Proguanil?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Liver problems have happened with atovaquone and proguanil. Sometimes, this has been very bad and has led to the need for a liver transplant or death. Liver problems may happen in people with or without liver disease. Talk with the doctor.
  • Other measures are needed along with this medicine including using screens, bed netting, insect repellent (10% to 35% DEET), and permethrin spray on clothing and nets. Avoid spraying most insect repellents on children. Lower evening and night-time outdoor activity.
  • If you are throwing up or have diarrhea, atovaquone and proguanil may not work as well. Talk with your doctor.
  • If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.
  • If you are 65 or older, use atovaquone and proguanil with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
  • If you are a pregnant woman and traveling to a malaria infested place, talk to your doctor about the risks first.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take atovaquone and proguanil or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to atovaquone and proguanil. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Contraindications

Hypersensitivity

Atovaquone and Proguanil hydrochloride 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

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), and Clinical Pharmacology (12.3)]

Adverse Reactions

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 the 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 Experiences in Active-Controlled Clinical Trials of Atovaquone and Proguanil hydrochloride for Prophylaxis of P. falciparum Malaria

Percent of Subjects With Adverse Experiencesa (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 (2 to 17 years of age). 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.

In 2 controlled trials, 116 pediatric patients (weighing 11 to 40 kg) (mean age 7 years) received Atovaquone and Proguanil hydrochloride 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 Atovaquone and Proguanil hydrochloride 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 Atovaquone and Proguanil hydrochloride, 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 Atovaquone and Proguanil hydrochloride for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥5% of patients as an adverse experience attributable to Atovaquone and Proguanil hydrochloride. 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 Atovaquone and Proguanil hydrochloride. 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 Atovaquone and Proguanil hydrochloride (n = 91) compared to patients treated with an active control, mefloquine (n = 91). On Day 7, rates of elevated ALT and AST with Atovaquone and Proguanil hydrochloride 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 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 anemia. Pancytopenia in patients with severe renal impairment treated with proguanil [see Contraindications (4.2)].

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

Contraindications

Hypersensitivity to atovaquone, proguanil, or any component of the formulation; prophylactic use in severe renal impairment (CrCl <30 mL/minute)

Dietary Considerations

Must be taken with food or milk-based drink.

Usual Adult Dose for Malaria

1 g atovaquone/400 mg proguanil (four adult strength tablets as a single dose) orally once a day for 3 consecutive days

Usual Pediatric Dose for Malaria Prophylaxis

Prophylactic treatment should start 1 or 2 days before entering a malaria-endemic area and continued daily during the stay and for 7 days after return.

11 to 20 kg ABW (actual body weight): 62.5 mg atovaquone/25 mg proguanil (one pediatric tablet) orally once a day

21 to 30 kg ABW: 125 mg atovaquone/50 mg proguanil (two pediatric tablets as a single dose) orally once a day

31 to 40 kg ABW: 187.5 mg atovaquone/75 mg proguanil (three pediatric tablets as a single dose) orally once a day

Greater than 40 kg ABW: 250 mg atovaquone/100 mg proguanil (one adult strength tablet) orally once a day

Precautions

Atovaquone-proguanil is contraindicated for use in the treatment prophylaxis of plasmodium falciparum malaria in patients with severe renal impairment (CrCl less than 30 mL/min).

Rarely, cases of anaphylaxis following treatment with atovaquone-proguanil have been reported.

Atovaquone-proguanil 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-proguanil. 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-proguanil is administered to 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.

Parasite relapse has occurred frequently when Plasmodium vivax was treated with atovaquone-proguanil alone.

In the event of recrudescent Plasmodium falciparum infections after treatment or failure of chemoprophylaxis with atovaquone-proguanil, patients should be treated with an alternative blood schizonticide.

Clinical studies of atovaquone-proguanil did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for elderly patients 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.

What side effects can this medication cause?

Atovaquone and proguanil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • nausea
  • vomiting
  • diarrhea
  • stomach pain
  • loss of appetite
  • headache
  • dizziness
  • cough
  • mouth sores

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

  • rash
  • hives
  • peeling or blistering skin
  • fever
  • swelling of the eyes, face, lips, tongue, throat, hands, feet, ankles or lower legs
  • difficulty breathing or swallowing
  • hoarseness or throat tightness
  • yellow eyes or skin, dark urine, loss of appetite, fatigue, or pain or discomfort in right upper stomach area

Atovaquone and proguanil may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

What other information should I know?

Keep all appointments with your doctor.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

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