ATOVAQUONE: 2,274 Adverse Event Reports & Safety Profile

Atovaquone and proguanil hydrochloride tablets (adult strength) and Atovaquone and proguanil hydrochloride pediatric tablets, for oral administration, contain a fixed-dose combination of the antimalarial agents atovaquone USP and proguanil hydrochloride USP. The chemical name of atovaquone USP is trans -2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone USP is a yellow crystalline solid that is freely soluble in N-methyl-2-pyrrolidone and in tetrahydrofuran; soluble in chloroform; sparingly soluble in acetone and dimethyl sulfoxide; slightly soluble in octanol, ethyl acetate, polyethylene glycol 200; very slightly soluble in 0.1N sodium hydroxide; insoluble in water. It has a molecular weight of 366.84 and the molecular formula C 22 H 19 ClO 3 . The compound has the following structural formula: The chemical name of proguanil hydrochloride USP is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride USP is a white crystalline powder slightly soluble in water, sparingly soluble in alcohol, practically insoluble in methylene chloride. It has a molecular weight of 290.22 g/mol and the molecular formula C 11 H 16 ClN 5

• HCl. The compound has the following structural formula: Each atovaquone and proguanil hydrochloride tablet (adult strength) contains 250 mg of atovaquone USP and 100 mg of proguanil hydrochloride USP and each atovaquone and proguanil hydrochloride pediatric tablets contains 62.5 mg of atovaquone USP and 25 mg of proguanil hydrochloride USP. The inactive ingredients in the tablet are colloidal silicon dioxide, ferric oxide red, hypromellose 2910, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, polyethylene glycol 400, polyethylene glycol 8000, povidone K30, sodium starch glycolate and titanium dioxide.

Atovaquone Chemical Structure

Proguanil HCl Chemical Structure

AND USAGE 1 INDICATIONS AND USAGE ------------------- INDICATIONS AND USAGE -------------------- Atovaquone oral suspension is a quinone antimicrobial drug indicated for: Prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents aged 13 years and older who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). ( 1.1) Treatment of mild-to-moderate PCP in adults and adolescents aged 13 years and older who cannot tolerate TMP-SMX . (1.2) Limitations of Use (1.3): Treatment of severe PCP (alveolar arterial oxygen diffusion gradient [(A-a)DO 2 ] > 45 mm Hg) with atovaquone has not been studied. The efficacy of atovaquone in subjects who are failing therapy with TMP-SMX has also not been studied.

1.1 Prevention of Pneumocystis jirovecii Pneumonia Atovaquone oral suspension is indicated for the prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents (aged 13 years and older) who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX).

1.2 Treatment of Mild-to-Moderate Pneumocystis jirovecii Pneumonia Atovaquone oral suspension is indicated for the acute oral treatment of mild-to-moderate PCP in adults and adolescents (aged 13 years and older) who cannot tolerate TMP-SMX.

1.3 Limitations of Use Clinical experience with atovaquone for the treatment of PCP has been limited to subjects with mild-to-moderate PCP (alveolar-arterial oxygen diffusion gradient [(A-a)DO 2 ] ≤ 45 mm Hg). Treatment of more severe episodes of PCP with atovaquone has not been studied. The efficacy of atovaquone in subjects who are failing therapy with TMP-SMX has also not been studied.

AND ADMINISTRATION 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.

• Atovaquone and proguanil hydrochloride tablets should be taken with food or a milky drink. Prophylaxis ( 2.1 ):
• Start prophylaxis 1 or 2 days before entering a malaria-endemic area and continue daily during the stay and for 7 days after return.
• Adults: One adult strength tablet per day.
• Pediatric Patients: Dosage based on body weight (see Table 1). Treatment ( 2.2 ):
• Adults: Four adult strength tablets as a single daily dose for 3 days.
• Pediatric Patients: Dosage based on body weight (see Table 2).

Renal

Impairment ( 2.3 ):

• Do not use for prophylaxis of malaria in patients with severe renal impairment.
• Use with caution for treatment of malaria in patients with severe renal impairment.

2.1 Prevention of Malaria Start prophylactic treatment with atovaquone and proguanil hydrochloride tablets 1 or 2 days before entering a malaria-endemic area and continue daily during the stay and for 7 days after return.

Adults

One atovaquone and proguanil hydrochloride 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 Weight (kg) Atovaquone/ Proguanil HCl Total Daily Dose Dosage Regimen 11 to 20 62.5 mg/25 mg 1 Atovaquone and proguanil hydrochloride pediatric tablet daily 21 to 30 125 mg/50 mg 2 Atovaquone and proguanil hydrochloride pediatric tablets as a single daily dose 31 to 40 187.5 mg/75 mg 3 Atovaquone and proguanil hydrochloride pediatric tablets as a single daily dose > 40 250 mg/100 mg 1 Atovaquone and proguanil hydrochloride tablet (adult strength) as a single daily dose

2.2 Treatment of Acute Malaria Adults Four atovaquone and proguanil hydrochloride 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 Weight (kg) Atovaquone/ Proguanil HCl Total Daily Dose Dosage Regimen 5 to 8 125 mg/50 mg 2 Atovaquone and proguanil hydrochloride pediatric tablets daily for 3 consecutive days 9 to 10 187.5 mg/75 mg 3 Atovaquone and proguanil hydrochloride pediatric tablets daily for 3 consecutive days 11 to 20 250 mg/100 mg 1 Atovaquone and proguanil hydrochloride tablet (adult strength) daily for 3 consecutive days 21 to 30 500 mg/200 mg 2 Atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days 31 to 40 750 mg/300 mg 3 Atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days >40 1 g/400 mg 4 Atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days

2.3 Renal Impairment Do not use atovaquone and proguanil hydrochloride tablets for malaria prophylaxis in patients with severe renal impairment (creatinine clearance &lt; 30 mL/min) <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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 )].

4 CONTRAINDICATIONS

• Known serious hypersensitivity reactions to atovaquone or proguanil hydrochloride or any component of the formulation. ( 4.1 )
• Prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min). ( 4.2 )

4.1 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.

4.2 Severe Renal Impairment Atovaquone and proguanil hydrochloride is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance &lt;30 mL/min) because of pancytopenia in patients with severe renal impairment treated with proguanil <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )]</span>

REACTIONS 6 ADVERSE REACTIONS The following adverse reaction is discussed in another section of the labeling: Hepatotoxicity [see Warnings and Precautions (Section 5.2)].

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. Additionally, because many subjects who participated in clinical trials with atovaquone had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by atovaquone from those caused by underlying medical conditions.

Pcp

Prevention Trials In two clinical trials, atovaquone oral suspension was compared with dapsone or aerosolized pentamidine in HIV-1-infected adolescent (13 to 18 years) and adult subjects at risk of PCP (CD4 count < 200 cells/mm3 or a prior episode of PCP) and unable to tolerate TMP-SMX.

Dapsone Comparative

Trial: In the dapsone comparative trial (n = 1,057), the majority of subjects were white (64%), male (88%), and receiving prophylaxis for PCP at randomization (73%); the mean age was 38 years. Subjects received atovaquone oral suspension 1,500 mg once daily (n = 536) or dapsone 100 mg once daily (n = 521); median durations of exposure were 6.7 and 6.5 months, respectively. Adverse reaction data were collected only for adverse reactions requiring discontinuation of treatment, which occurred at similar frequencies in subjects treated with atovaquone oral suspension or dapsone (Table 1). Among subjects taking neither dapsone nor atovaquone at enrollment (n = 487), adverse reactions requiring discontinuation of treatment occurred in 43% of subjects treated with dapsone and 20% of subjects treated with atovaquone oral suspension. Gastrointestinal adverse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with atovaquone oral suspension (Table 1).

Table

1. Percentage (> 2%) of Subjects with Selected Adverse Reactions Requiring Discontinuation of Treatment in the Dapsone Comparative PCP Prevention Trial Adverse Reaction All Subjects Atovaquone Oral Suspension 1,500 mg/day (n = 536) % Dapsone 100 mg/day (n = 521) % Rash 6.3

8.8 Nausea 4.1

0.6 Diarrhea 3.2

0.2 Vomiting 2.2

0.6 Aerosolized Pentamidine Comparative Trial: In the aerosolized pentamidine comparative trial (n = 549), the majority of subjects were white (79%), male (92%), and were primary prophylaxis patients at enrollment (58%); the mean age was 38 years. Subjects received atovaquone oral suspension once daily at a dose of 750 mg (n = 188) or 1,500 mg (n = 175) or received aerosolized pentamidine 300 mg every 4 weeks (n = 186); the median durations of exposure were 6.2, 6, and 7.8 months, respectively.

Table

2 summarizes the clinical adverse reactions reported by ≥ 20% of the subjects receiving either the 1,500 mg dose of atovaquone oral suspension or aerosolized pentamidine. Rash occurred more often in subjects treated with atovaquone oral suspension (46%) than in subjects treated with aerosolized pentamidine (28%). Treatment-limiting adverse reactions occurred in 25% of subjects treated with atovaquone oral suspension 1,500 mg once daily and in 7% of subjects treated with aerosolized pentamidine. The most frequent adverse reactions requiring discontinuation of dosing in the group receiving atovaquone oral suspension 1,500 mg once daily were rash (6%), diarrhea (4%), and nausea (3%). The most frequent adverse reaction requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%).

Table

2. Percentage (≥ 20%) of Subjects with Selected Adverse Reactions in the Aerosolized Pentamidine Comparative PCP Prevention Trial Adverse Reaction Atovaquone Oral Suspension 1,500 mg/day (n = 175) % Aerosolized Pentamidine (n = 186) % Diarrhea 42 35 Rash 39 28 Headache 28 22 Nausea 26 23 Fever 25 18 Rhinitis 24 17 Other reactions occurring in ≥10% of subjects receiving the recommended dose of atovaquone oral suspension (1,500 mg once daily) included vomiting, sweating, flu syndrome, sinusitis, pruritus, insomnia, depression, and myalgia.

Pcp

Treatment Trials Safety information is presented from 2 clinical efficacy trials of the atovaquone tablet formulation: 1) a randomized, double-blind trial comparing atovaquone tablets with MP-SMX in subjects with acquired immunodeficiency syndrome (AIDS) and mild-to- moderate PCP [(A-a)DO2] ≤ 45 mmHg and PaO2 ≥ 60 mmHg on room air; 2) a randomized, open-label trial comparing atovaquone tablets with intravenous (IV) pentamidine isethionate in subjects with mild-to-moderate PCP who could not tolerate trimethoprim or sulfa antimicrobials. TMP-SMX Comparative Trial: In the TMP-SMX comparative trial (n = 408), the majority of subjects were white (66%) and male (95%); the mean age was 36 years. Subjects received atovaquone 750 mg (three 250 mg tablets) 3 times daily for 21 days or TMP 320 mg plus SMX 1,600 mg 3 times daily for 21 days; median durations of exposure were 21 and 15 days, respectively.

Table

3 summarizes all clinical adverse reactions reported by ≥ 10% of the trial population regardless of attribution. Nine percent of subjects who received atovaquone and 24% of subjects who received TMP-SMX discontinued therapy due to an adverse reaction. Among the subjects who discontinued, 4% of subjects receiving atovaquone and 8% of subjects in the TMP-SMX group discontinued therapy due to rash. The incidence of adverse reactions with atovaquone oral suspension at the recommended dose (750 mg twice daily) was similar to that seen with the tablet formulation.

Table

3. Percentage (≥ 10%) of Subjects with Selected Adverse Reactions in the TMP-SMX Comparative PCP Treatment Trial Adverse Reaction Atovaquone Tablets (n = 203) % TMP-SMX (n = 205) % Rash (including maculopapular) 23 34 Nausea 21 44 Diarrhea 19 7 Headache 16 22 Vomiting 14 35 Fever 14 25 Insomnia 10 9 Two percent of subjects treated with atovaquone and 7% of subjects treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST.

Pentamidine Comparative

Trial: In the pentamidine comparative trial (n = 174), the majority of subjects in the primary therapy trial population (n = 145) were white (72%) and male (97%); the mean age was 37 years. Subjects received atovaquone 750 mg (three 250 mg tablets) 3 times daily for 21 days or a 3 mg to 4 mg/kg single pentamidine isethionate IV infusion daily for 21 days; the median durations of exposure were 21 and 14 days, respectively.

Table

4 summarizes the clinical adverse reactions reported by ≥ 10% of the primary therapy trial population regardless of attribution. Fewer subjects who received atovaquone reported adverse reactions than subjects who received pentamidine (63% vs. 72%). How- ever, only 7% of subjects discontinued treatment with atovaquone due to adverse reactions, while 41% of subjects who received pentamidine discontinued treatment for this reason. Of the 5 subjects who discontinued therapy with atovaquone, 3 reported rash (4%). Rash was not severe in any subject. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%).

Table

4. Percentage (≥ 10%) of Subjects with Selected Adverse Reactions in the Pentamidine Comparative PCP Treatment Trial (Primary Therapy Group)

Adverse Reaction Atovaquone

Tablets (n = 73) % Pentamidine (n = 71) % Fever 40 25 Nausea 22 37 Rash 22 13 Diarrhea 21 31 Insomnia 19 14 Headache 18 28 Vomiting 14 17 Cough 14 1 Sweat 10 3 Monilia, oral 10 3 Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 subjects (3%) who received atovaquone, and in 14 of 71 subjects (20%) who received pentamidine. One subject (1%) receiving atovaquone had elevated creatinine and BUN levels and 1 subject (1%) had elevated amylase levels. In this trial, elevated levels of amylase occurred in subjects (8% versus 4%) receiving atovaquone tablets or pentamidine, respectively.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of atovaquone oral suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Methemoglobinemia, thrombocytopenia.

Immune System

Disorders: Hypersensitivity reactions including angioedema, bronchospasm, throat tightness, and urticaria.

Eye

Disorders: Vortex keratopathy.

Gastrointestinal

Disorders: Pancreatitis.

Hepatobiliary

Disorders: Hepatitis, fatal liver failure. Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome, and skin desquamation. Renal and Urinary Disorders: Acute renal impairment. -------------------- ADVERSE REACTIONS -------------------------- PCP Prevention: The most frequent adverse reactions (≥ 25% that required discontinuation) were diarrhea, rash, headache, nausea, and fever. (6.1 )

Pcp

Treatment: The most frequent adverse reactions (≥ 14% that required discontinuation) were rash (including maculopapular), nausea, diarrhea, headache, vomiting, and fever. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Kesin Pharma at 1-833-537-4679 or 1-888-235-2466 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. Additionally, because many subjects who participated in clinical trials with atovaquone had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by atovaquone from those caused by underlying medical conditions.

Pcp

Prevention Trials In 2 clinical trials, atovaquone oral suspension was compared with dapsone or aerosolized pentamidine in HIV-1–infected adolescent (13 to 18 years) and adult subjects at risk of PCP (CD4 count < 200 cells/mm 3 or a prior episode of PCP) and unable to tolerate TMP-SMX.

Dapsone Comparative

Trial: In the dapsone comparative trial (n = 1,057), the majority of subjects were white (64%), male (88%), and receiving prophylaxis for PCP at randomization (73%); the mean age was 38 years. Subjects received atovaquone oral suspension 1,500 mg once daily (n = 536) or dapsone 100 mg once daily (n = 521); median durations of exposure were 6.7 and 6.5 months, respectively. Adverse reaction data were collected only for adverse reactions requiring discontinuation of treatment, which occurred at similar frequencies in subjects treated with atovaquone oral suspension or dapsone (Table 1). Among subjects taking neither dapsone nor atovaquone at enrollment (n = 487), adverse reactions requiring discontinuation of treatment occurred in 43% of subjects treated with dapsone and 20% of subjects treated with atovaquone oral suspension. Gastrointestinal adverse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with atovaquone oral suspension (Table 1).

Table

1. Percentage (> 2%) of Subjects with Selected Adverse Reactions Requiring Discontinuation of Treatment in the Dapsone Comparative PCP Prevention Trial Adverse Reactions All Subjects Atovaquone Oral Suspension 1,500 mg/day (n = 536) % Dapsone 100 mg/day (n = 521) % Rash 6.3

8.8 Nausea 4.1

0.6 Diarrhea 3.2

0.2 Vomiting 2.2

0.6 Aerosolized Pentamidine Comparative Trial: In the aerosolized pentamidine comparative trial (n = 549), the majority of subjects were white (79%), male (92%), and were primary prophylaxis patients at enrollment (58%); the mean age was 38 years. Subjects received atovaquone oral suspension once daily at a dose of 750 mg (n = 188) or 1,500 mg (n = 175) or received aerosolized pentamidine 300 mg every 4 weeks (n = 186); the median durations of exposure were 6.2, 6, and 7.8 months, respectively.

Table

2 summarizes the clinical adverse reactions reported by ≥ 20% of the subjects receiving either the 1,500 mg dose of atovaquone oral suspension or aerosolized pentamidine. Rash occurred more often in subjects treated with atovaquone oral suspension (46%) than in subjects treated with aerosolized pentamidine (28%). Treatment-limiting adverse reactions occurred in 25% of subjects treated with atovaquone oral suspension 1,500 mg once daily and in 7% of subjects treated with aerosolized pentamidine. The most frequent adverse reactions requiring discontinuation of dosing in the group receiving atovaquone oral suspension 1,500 mg once daily were rash (6%), diarrhea (4%), and nausea (3%). The most frequent adverse reaction requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%).

Table

2. Percentage (≥ 20%) of Subjects with Selected Adverse Reactions in the Aerosolized Pentamidine Comparative PCP Prevention Trial Adverse Reactions Atovaquone Oral Suspension 1,500 mg/day (n = 175) % Aerosolized Pentamidine (n = 186) % Diarrhea 42 35 Rash 39 28 Headache 28 22 Nausea 26 23 Fever 25 18 Rhinitis 24 17 Other reactions occurring in ≥ 10% of subjects receiving the recommended dose of atovaquone oral suspension (1,500 mg once daily) included vomiting, sweating, flu syndrome, sinusitis, pruritus, insomnia, depression, and myalgia.

Pcp

Treatment Trials Safety information is presented from 2 clinical efficacy trials of the atovaquone tablet formulation: 1) a randomized, double-blind trial comparing atovaquone tablets with TMP-SMX in subjects with acquired immunodeficiency syndrome (AIDS) and mild-to-moderate PCP [(A-a)DO 2 ] ≤ 45 mm Hg and PaO 2 ≥ 60 mm Hg on room air; 2) a randomized, open-label trial comparing atovaquone tablets with intravenous (IV) pentamidine isethionate in subjects with mild-to-moderate PCP who could not tolerate trimethoprim or sulfa antimicrobials. TMP-SMX Comparative Trial: In the TMP-SMX comparative trial (n = 408), the majority of subjects were white (66%) and male (95%); the mean age was 36 years. Subjects received atovaquone 750 mg (three 250 mg tablets) 3 times daily for 21 days or TMP 320 mg plus SMX 1,600 mg 3 times daily for 21 days; median durations of exposure were 21 and 15 days, respectively.

Table

3 summarizes all clinical adverse reactions reported by ≥ 10% of the trial population regardless of attribution. Nine percent of subjects who received atovaquone and 24% of subjects who received TMP-SMX discontinued therapy due to an adverse reaction. Among the subjects who discontinued, 4% of subjects receiving atovaquone and 8% of subjects in the TMP-SMX group discontinued therapy due to rash. The incidence of adverse reactions with atovaquone oral suspension at the recommended dose (750 mg twice daily) was similar to that seen with the tablet formulation.

Table

3. Percentage (≥ 10%) of Subjects with Selected Adverse Reactions in the TMP-SMX Comparative PCP Treatment Trial Adverse Reactions Atovaquone Tablets (n = 203) % TMP-SMX (n = 205) % Rash (including maculopapular) 23 34 Nausea 21 44 Diarrhea 19 7 Headache 16 22 Vomiting 14 35 Fever 14 25 Insomnia 10 9 Two percent of subjects treated with atovaquone and 7% of subjects treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST.

Pentamidine Comparative

Trial: In the pentamidine comparative trial (n = 174), the majority of subjects in the primary therapy trial population (n = 145) were white (72%) and male (97%); the mean age was 37 years. Subjects received atovaquone 750 mg (three 250 mg tablets) 3 times daily for 21 days or a 3 mg to 4 mg/kg single pentamidine isethionate IV infusion daily for 21 days; the median durations of exposure were 21 and 14 days, respectively.

Table

4 summarizes the clinical adverse reactions reported by ≥ 10% of the primary therapy trial population regardless of attribution. Fewer subjects who received atovaquone reported adverse reactions than subjects who received pentamidine (63% vs. 72%). However, only 7% of subjects discontinued treatment with atovaquone due to adverse reactions, while 41% of subjects who received pentamidine discontinued treatment for this reason. Of the 5 subjects who discontinued therapy with atovaquone, 3 reported rash (4%). Rash was not severe in any subject. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%).

Table

4. Percentage (≥ 10%) of Subjects with Selected Adverse Reactions in the Pentamidine Comparative PCP Treatment Trial (Primary Therapy Group)

Adverse Reactions Atovaquone

Tablets (n = 73) % Pentamidine (n = 71) % Fever 40 25 Nausea 22 37 Rash 22 13 Diarrhea 21 31 Insomnia 19 14 Headache 18 28 Vomiting 14 17 Cough 14 1 Sweat 10 3 Monilia, oral 10 3 Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 subjects (3%) who received atovaquone, and in 14 of 71 subjects (20%) who received pentamidine. One subject (1%) receiving atovaquone had elevated creatinine and BUN levels and 1 subject (1%) had elevated amylase levels. In this trial, elevated levels of amylase occurred in subjects (8% versus 4%) receiving atovaquone tablets or pentamidine, respectively.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of atovaquone oral suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders Methemoglobinemia, thrombocytopenia.

Immune System Disorders

Hypersensitivity reactions including angioedema, bronchospasm, throat tightness, and urticaria.

Eye Disorders

Vortex keratopathy.

Gastrointestinal Disorders

Pancreatitis.

Hepatobiliary Disorders

Hepatitis, fatal liver failure. Skin and Subcutaneous Tissue Disorders Erythema multiforme, Stevens-Johnson syndrome, and skin desquamation. Renal and Urinary Disorders Acute renal impairment.

AND PRECAUTIONS

• 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 tablets 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 )
• Atovaquone and proguanil hydrochloride tablets have 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 )

5.1 Vomiting and Diarrhea Absorption 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span>. Vomiting occurred in up to 19% of pediatric patients given treatment doses of atovaquone and proguanil hydrochloride tablets. 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 tablets alone. In the event of recrudescent P. falciparum infections 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.

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 tablets.

5.4 Severe or Complicated Malaria Atovaquone and proguanil hydrochloride tablets have 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.

INTERACTIONS 7 DRUG INTERACTIONS

7.1 Rifampin/Rifabutin Concomitant administration of rifampin or rifabutin and atovaquone oral suspension is known to reduce atovaquone concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (Section 12.3)]</span>. Concomitant administration of atovaquone oral suspension and rifampin or rifabutin is not recommended.

7.2 Tetracycline Concomitant administration of tetracycline and atovaquone oral suspension has been associated with a reduction in plasma concen- trations of atovaquone <span class="opacity-50 text-xs">[see Clinical Pharmacology (Section 12.3)]</span> . Caution should be used when prescribing tetracycline concomitant- ly with atovaquone oral suspension. Monitor patients for potential loss of efficacy of atovaquone if coadministration is necessary.

7.3 Metoclopramide Metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available <span class="opacity-50 text-xs">[see Clinical Pharmacology (Section 12.3)]</span>.

7.4 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (Section 12.3)]</span>. Caution should be exercised when prescribing atovaquone oral suspension with indinavir due to the decrease in trough concentrations of indinavir. Monitor patients for potential loss of efficacy of indinavir if coadministration with atovaquone oral suspension is necessary. -------------------- DRUG INTERACTIONS ------------------------ Concomitant administration of rifampin or rifabutin reduces atovaquone concentrations; concomitant use with atovaquone oral suspension is not recommended. (7.1) Concomitant administration of tetracycline reduces atovaquone concentrations; use caution when co-administering. Monitor patients for potential loss of efficacy of atovaquone if co-administration of tetracycline is necessary. (7.2) Concomitant administration with metoclopramide reduces atovaquone concentrations; administer concomitantly only if other antiemetics are not available. (7.3) Concomitant administration of indinavir reduces indinavir trough concentrations; use caution when co-administering. Monitor patients for potential loss of efficacy of indinavir if co-administration is necessary. (7.4)

7.1 Rifampin/Rifabutin Concomitant administration of rifampin or rifabutin and atovaquone oral suspension is known to reduce atovaquone concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Concomitant administration of atovaquone oral suspension and rifampin or rifabutin is not recommended.

7.2 Tetracycline Concomitant administration of tetracycline and atovaquone oral suspension has been associated with a reduction in plasma concentrations of atovaquone <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Caution should be used when prescribing tetracycline concomitantly with atovaquone oral suspension. Monitor patients for potential loss of efficacy of atovaquone if co-administration is necessary.

7.3 Metoclopramide Metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

7.4 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3)]</span>. Caution should be exercised when prescribing atovaquone oral suspension with indinavir due to the decrease in trough concentrations of indinavir. Monitor patients for potential loss of efficacy of indinavir if co-administration with atovaquone oral suspension is necessary.