Mepron Side Effects

Generic Name: atovaquone,atovaquone and proguanil hydrochloride

Please note - some side effects for Mepron may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Mepron - for the Consumer

Mepron

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Mepron:

Diarrhea; difficulty sleeping; dizziness; headache; increased cough; increased sweating; indigestion; loss of appetite; muscle pain; nausea; runny or stuffy nose; stomach pain; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Mepron:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest or throat; swelling of the mouth, face, lips, or tongue; unusual hoarseness); anxiety; change in the amount of urine produced; dark urine; depression; fever; flu-like symptoms; pale stools; red, swollen, blistered, or peeling skin; severe or persistent stomach pain; shortness of breath; unusual bruising or bleeding; white patches in the mouth; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Mepron Side Effects - for the Professional

Mepron

Because many patients who participated in clinical trials with Mepron had complications of advanced HIV disease, it was often difficult to distinguish adverse events caused by Mepron from those caused by underlying medical conditions. There were no life-threatening or fatal adverse experiences caused by Mepron.

PCP Prevention Studies

In the dapsone comparative study of Mepron Suspension, adverse experience data were collected only for treatment-limiting events. Among the entire population (n = 1,057), treatment-limiting events occurred at similar frequencies in patients treated with Mepron Suspension or dapsone (Table 6). Among patients who were taking neither dapsone nor atovaquone at enrollment (n = 487), treatment-limiting events occurred in 43% of patients treated with dapsone and 20% of patients treated with Mepron Suspension (P <0.001). In both populations, the type of treatment-limiting events differed between the 2 treatment arms. Hypersensitivity reactions (rash, fever, allergic reaction) and anemia were more common in patients treated with dapsone, while gastrointestinal events (nausea, diarrhea, and vomiting) were more common in patients treated with Mepron Suspension.

Table 6. Treatment-Limiting Adverse Experiences in the Dapsone Comparative PCP Prevention Study

Treatment-Limiting Adverse Experience	Percentage of Patients with Treatment-Limiting Adverse Experience
	All Patients		Patients Not Taking Either Drug at Enrollment
	Mepron 1,500 mg/day (n = 536)	Dapsone 100 mg/day (n = 521)	Mepron 1,500 mg/day (n = 238)	Dapsone 100 mg/day (n = 249)
Any event	24.4%	25.9%	20.2%	43.4%
Rash	6.3%	8.8%	7.6%	16.1%
Nausea	4.1%	0.6%	2.5%	0.8%
Diarrhea	3.2%	0.2%	2.1%	0.4%
Vomiting	2.2%	0.6%	1.3%	0.8%
Allergic reaction	1.1%	2.9%	0.8%	4.8%
Fever	0.6%	2.9%	0%	5.6%
Anemia	0%	1.5%	0%	2.0%

Table 7 summarizes the clinical adverse experiences reported by ≥20% of patients in any group in the aerosolized pentamidine comparative study of Mepron Suspension (n = 549), regardless of attribution. The incidence of adverse experiences at the recommended dose was similar to that seen with aerosolized pentamidine. Rash was the only individual adverse experience that occurred significantly more commonly in patients treated with both dosages of Mepron Suspension (39% to 46%) than in patients treated with aerosolized pentamidine (28%). Among patients treated with Mepron Suspension, there was no evidence of a dose-related increase in the incidence of adverse experiences. Treatment-limiting adverse experiences occurred less often in patients treated with aerosolized pentamidine (7%) than in patients treated with 1,500 mg Mepron Suspension once daily (25%, P ≤0.001) or 750 mg Mepron Suspension once daily (16%, P = 0.004). The most common adverse experiences requiring discontinuation of dosing in the group receiving 1,500 mg Mepron Suspension once daily were rash (6%), diarrhea (4%), and nausea (3%). The most common adverse experience requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%).

Table 7. Treatment-Emergent Adverse Experiences in the Aerosolized Pentamidine Comparative PCP Prevention Study

Treatment-Emergent Adverse Experience	Percentage of Patients with Treatment-Emergent Adverse Experience
	Mepron 1,500 mg/day (n = 175)	Mepron 750 mg/day (n = 188)	Aerosolized Pentamidine (n = 186)
Diarrhea	42%	42%	35%
Rash	39%	46%	28%
Headache	28%	31%	22%
Nausea	26%	32%	23%
Cough increased	25%	25%	31%
Fever	25%	31%	18%
Rhinitis	24%	18%	17%
Asthenia	22%	31%	31%
Infection	22%	18%	19%
Abdominal pain	20%	21%	20%
Dyspnea	15%	21%	16%
Vomiting	15%	22%	11%
Patients discontinuing therapy due to an adverse experience	25%	16%	7%
Patients reporting at least 1 adverse experience	98%	96%	89%

Other events occurring in ≥10% of the patients receiving the recommended dose of Mepron included sweating, flu syndrome, pain, sinusitis, pruritus, insomnia, depression, and myalgia. Bronchospasm occurred more frequently in patients receiving aerosolized pentamidine (11%) than in patients receiving Mepron 1,500 mg/day (4%) and Mepron 750 mg/day (2%).

Neither Mepron nor aerosolized pentamidine was associated with a substantial change from baseline values in any measured laboratory parameter, nor were there any significant differences in any measured laboratory parameter between Mepron and aerosolized pentamidine. Some patients had laboratory abnormalities considered serious by the investigator or that contributed to discontinuation of therapy.

PCP Treatment Studies

Table 8 summarizes all the clinical adverse experiences reported by ≥5% of the study population during the TMP-SMX comparative study of Mepron (n = 408), regardless of attribution. The incidence of adverse experiences with Mepron Suspension at the recommended dose was similar to that seen with the tablet formulation of atovaquone.

Table 8. Treatment-Emergent Adverse Experiences in the TMP-SMX Comparative PCP Treatment Study

	Percentage of Patients with Treatment-Emergent Adverse Experience
Treatment-Emergent Adverse Experience	Mepron (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%
Asthenia	8%	8%
Pruritus	5%	9%
Monilia, oral	5%	10%
Abdominal pain	4%	7%
Constipation	3%	17%
Dizziness	3%	8%
Patients discontinuing therapy due to an adverse experience	9%	24%
Patients reporting at least 1 adverse experience	63%	65%

Although an equal percentage of patients receiving Mepron and TMP-SMX reported at least 1 adverse experience, more patients receiving TMP-SMX required discontinuation of therapy due to an adverse event. Twenty-four percent of patients receiving TMP-SMX were prematurely discontinued from therapy due to an adverse experience versus 9% of patients receiving Mepron. Four percent of patients receiving Mepron had therapy discontinued due to development of rash. The majority of cases of rash among patients receiving Mepron were mild and did not require the discontinuation of dosing. The only other clinical adverse experience that led to premature discontinuation of dosing of Mepron by more than 1 patient was vomiting (<1%). The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (8%).

Laboratory test abnormalities reported for ≥5% of the study population during the treatment period are summarized in Table 9. Two percent of patients treated with Mepron and 7% of patients treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. In general, patients treated with Mepron developed fewer abnormalities in measures of hepatocellular function (ALT, AST, alkaline phosphatase) or amylase values than patients treated with TMP-SMX.

Table 9. Treatment-Emergent Laboratory Test Abnormalities in the TMP-SMX Comparative PCP Treatment Study

	Percentage of Patients Developing a Laboratory Test Abnormality
Laboratory Test Abnormality	Mepron	TMP-SMX
Anemia (Hgb<8.0 g/dL)	6%	7%
Neutropenia (ANC<750 cells/mm3)	3%	9%
Elevated ALT (>5 x ULN)	6%	16%
Elevated AST (>5 x ULN)	4%	14%
Elevated alkaline phosphatase (>2.5 x ULN)	8%	6%
Elevated amylase (>1.5 x ULN)	7%	12%
Hyponatremia (<0.96 x LLN)	7%	26%

ULN = upper limit of normal range.

LLN = lower limit of normal range.

Table 10 summarizes the clinical adverse experiences reported by ≥5% of the primary therapy study population (n = 144) during the comparative trial of Mepron and intravenous pentamidine, regardless of attribution. A slightly lower percentage of patients who received Mepron reported occurrence of adverse events than did those who received pentamidine (63% vs 72%). However, only 7% of patients discontinued treatment with Mepron due to adverse events, while 41% of patients who received pentamidine discontinued treatment for this reason (P <0.001). Of the 5 patients who discontinued therapy with Mepron, 3 reported rash (4%). Rash was not severe in any patient. No other reason for discontinuation of Mepron was cited more than once. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%).

Table 10. Treatment-Emergent Adverse Experiences in the Pentamidine Comparative PCP Treatment Study (Primary Therapy Group)

	Percentage of Patients with Treatment-Emergent Adverse Experience
Treatment-Emergent Adverse Experience	Mepron (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%
Abdominal pain	10%	11%
Pain	10%	10%
Sweat	10%	3%
Monilia, oral	10%	3%
Asthenia	8%	14%
Dizziness	8%	14%
Anxiety	7%	10%
Anorexia	7%	10%
Sinusitis	7%	6%
Dyspepsia	5%	10%
Rhinitis	5%	7%
Taste perversion	3%	13%
Hypoglycemia	1%	15%
Hypotension	1%	10%
Patients discontinuing therapy due to an adverse experience	7%	41%
Patients reporting at least 1 adverse experience	63%	72%

Laboratory test abnormalities reported in ≥5% of patients in the pentamidine comparative study are presented in Table 11. Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 patients who received Mepron. One patient (1%) had elevated creatinine and BUN levels and 1 patient (1%) had elevated amylase levels. Laboratory abnormalities were the sole or contributing factor in 14 patients who prematurely discontinued pentamidine therapy. In the 71 patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%), and leukopenia (4%).

Table 11. Treatment-Emergent Laboratory Test Abnormalities in the Pentamidine Comparative PCP Treatment Study

Laboratory Test	Percentage of Patients Developing a Laboratory Test Abnormality
Abnormality	Mepron	Pentamidine
Anemia (Hgb<8.0 g/dL)	4%	9%
Neutropenia (ANC<750 cells/mm3)	5%	9%
Hyponatremia (<0.96 x LLN)	10%	10%
Hyperkalemia (>1.18 x ULN)	0%	5%
Alkaline phosphatase (>2.5 x ULN)	5%	2%
Hyperglycemia (>1.8 x ULN)	9%	13%
Elevated AST (>5 x ULN)	0%	5%
Elevated amylase (>1.5 x ULN)	8%	4%
Elevated creatinine (>1.5 x ULN)	0%	7%

ULN = upper limit of normal range.

LLN = lower limit of normal range.

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of Mepron. 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 Mepron.

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

Rare cases of hepatitis, and one case of fatal liver failure have been reported with atovaquone usage.

Skin and Subcutaneous Tissue Disorders

Erythema multiforme, Stevens-Johnson syndrome, and skin desquamation have been reported in patients receiving multiple drug therapy including atovaquone.

Renal and Urinary Disorders

Acute renal impairment.

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Mepron Tablets

Because many patients who participated in clinical trials with Mepron had complications of advance HIV disease, it was often difficult to distinguish adverse events caused by Mepron from those caused by underlying medical conditions. There were no life-threatening or fatal adverse experiences caused by Mepron.

Table 4 summarizes all the clinical adverse experiences reported by ≥5% of the study population during the TMP-SMX comparative study of Mepron (n=408), regardless of attribution.

Although an equal percentage of patients receiving Mepron and TMP-SMX reported at least one adverse experience, more patients receiving TMP-SMX required discontinuation of therapy due to an adverse event. Nine percent of patients receiving Mepron were prematurely discontinued from therapy due to an adverse event versus 24% of patients receiving TMP-SMX. Four percent of patients receiving Mepron had therapy discontinued due to development of rash. The majority of cases of rash among patients receiving Mepron were mild and did not require the discontinuation of dosing. The only other clinical adverse experience that led to premature discontinuation of Mepron dosing by more than one patient was the development of vomiting (<1%). Twenty-four percent of patients receiving TMP-SMX were prematurely discontinued from therapy due to an adverse experience versus 9% of patients receiving Mepron. The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (8%).

Table 4 Treatment-Emergent Adverse Experiences in the TMP-SMX Comparative PCP Treatment Study

Treatment- Emergent Adverse Experience	Number of Patients with Treatment-Emergent Adverse Experience ((%) of Total)
	Mepron (n = 203)	TMP-SMX (n = 205)
Rash (including maculopapular)	47 (23%)	69 (34%)*
Nausea	43 (21%)	90 (44%)*
Diarrhea	39 (19%)	15 (7%)
Headache	33 (16%)	44 (22%)
Vomiting	29 (14%)	72 (35%)*
Fever	28 (14%)	52 (25%)*
Insomnia	20 (10%)	18 (9%)
Asthenia	17 (8%)	16 (8%)
Pruritus	11 (5%)	18 (9%)
Monilia, Oral	11 (5%)	21 (10%)
Abdominal Pain	9 (4%)	15 (7%)
Constipation	7 (3%)	35 (17%)*
Dizziness	7 (3%)	17 (8%)*
No. Patients Discontinuing Therapy due to an Adverse Experience	19 (9%)	50 (24%)*
No. Patients Reporting at least one Adverse Experience	127 (63%)	134 (65%)

*P=<0.05

Laboratory test abnormalities reported for ≥5% of the study population during the treatment period are summarized in Table 5. Two percent of patients treated with Mepron and 7% of patients treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. In general, patients treated with Mepron developed fewer abnormalities in measures of hepatocellular function (ALT, AST, alkaline phosphatase) or amylase values than patients treat with TMP-SMX. Table 6 summarizes the clinical adverse experiences reported by ≥5% of the primary therapy study population (n=144) during the comparative trial of Mepron and intravenous pentamidine, regardless of attribution. A slightly lower percentage of patients who received Mepron reported occurrence of adverse events than did those who received pentamidine (63% vs. 72%). However, only 7% of patients discontinued treatment with Mepron due to adverse events while 41% of patients who received pentamidine discontinued treatment for this reason (P<0.001). Of the five patients who discontinued therapy with Mepron, three reported rash (4%). Rash was not severe in any patient. No other reason for discontinuation of Mepron was cited more than once. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%).

Table 5 Treatment-Emergent Laboratory Test Abnormalities in the TMP-SMX Comparative PCP Treatment Study

Laboratory Test Abnormality	Patients Developing a Laboratory Test Abnormality (%) of Total
	Mepron	TMP/SMX
Anemia (Hgb < 8.0 gm/dL)	6%	7%
Neutropenia (ANC <750 c/mm3	3%	9%
Elevated ALT (>5 X ULN)	6%	16%
Elevated AST (>5 X ULN)	4%	14%
Elevated Alkaline Phosphatase (>2.5 X ULN)	8%	6%
Elevated Amylase (>1.5 X ULN)	7%	12%
Hyponatremia (<0.96 X LLN)	7%	26%

ULN = upper limit of normal range

LLN = lower limit of normal range

Table 6 Treatment-Emergent Adverse Experiences in the Pentamidine Comparative PCP Treatment Study (Primary Therapy Group)

Treatment- Emergent Adverse Experience	Number of Patients with Treatment-Emergent Adverse Experience (%) of Total
	Mepron (n = 73)	TMP-SMX (n = 71)
Fever	29(40%)	18(25%)
Nausea	16(22%)	26(37%)
Rash	16(22%)	9(13%)
Diarrhea	15(21%)	22(31%)
Insomnia	14(19%)	10(14%)
Headache	13(18%)	20(28%)
Vomiting	10(14%)	12(17%)
Cough	10(14%)	1(1%)
Abdominal Pain	7(10%)	8(11%)
Pain	7(10%)	7(10%)
Sweat	7(10%)	2(3%)
Monilia, Oral	7(10%)	2(3%)
Asthenia	6(8%)	10(14%)
Dizziness	6(8%)	10(14%)
Anxiety	5(7%)	7(10%)
Anorexia	5(7%)	7(10%)
Sinusitis	5(7%)	4(6%)
Dyspepsia	4(5%)	7(10%)
Rhinitis	4(5%)	5(7%)
Taste Perversion	2(3%)	9(13%)*
Hypoglycemia	1(1%)	11(15%)*
Hypotension	1(1%)	7(10%)
No. Patients Discontinuing Therapy due to an Adverse Experience	5(7%)	29(41%)†
No. Patients Reporting at least one Adverse Experience	46(63%)	51(72%)

* P =< 0.05

†P = < 0.001

Laboratory test abnormalities reported in ≥5% of patients in the pentamidine comparative study are presented in Table 7. Laboratory abnormality was reported as the reason for discontinuation of treatment in two of 73 patients who received Mepron. One patient (1%) had elevated creatinine and BUN levels and one patient (1%) had elevated amylase levels. Laboratory abnormalities were the sole or contributing factor in 14 patients who prematurely discontinued pentamidine therapy. In the 71 patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%), and leucopenia (4%).

Table 7 Treatment-Emergent Laboratory Test Abnormalities in the Pentamidine Comparative PCP Treatment Study

Laboratory Test Abnormality	Patients Developing a Laboratory Test Abnormality (%) of Total)
	Mepron	Pentamidine
Anemia (Hgb < 8.0 gm/dL)	4%	9%
Neutropenia (ANC <750 cells/mm3)	5%	9%
Hyponatremia (<0.96 X LLN)	10%	10%
Hyperkalemia (>1.18 X ULN)	0%	5%
Alkaline Phosphatase (>2.5 X ULN)	5%	2%
Hyperglycemia (>1.8 X ULN)	9%	13%
Elevated AST (>5 X ULN)	0%	5%
Elevated Amylase (>1.5 X ULN)	8%	4%
Elevated Creatinine (>1.5 X ULN)	0%	7%

ULN = upper limit of normal range

LLN = lower limit of normal range

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Side Effects by Body System - for Healthcare Professionals

General

In PCP prevention studies comparing atovaquone to inhaled pentamidine, 16% to 25% of patients discontinued atovaquone and 7% discontinued pentamidine due to adverse events. Rash (6%), diarrhea (4%), and nausea (3%) were the most common reasons for discontinuing atovaquone, while bronchospasm (2%) was the most common reason for discontinuing pentamidine. In studies comparing atovaquone to dapsone, treatment-limiting hypersensitivity reactions were more frequent in the dapsone group (16.1%) and treatment-limiting gastrointestinal side effects were more common in the atovaquone group (up to 4.1%).

In PCP treatment studies, 9% of patients discontinued atovaquone due to side effects, compared to 24% of patients receiving sulfamethoxazole-trimethoprim. The most common reason for discontinuation in both treatment groups was rash (atovaquone, 4%; sulfamethoxazole-trimethoprim, 8%). In studies comparing intravenous pentamidine and atovaquone, 63% of patients in the atovaquone group and 72% of patients in the pentamidine group reported side effects. Treatment was discontinued in 7% of the atovaquone patients and 41% of the pentamidine patients due to adverse events; the most common reasons were rash (4%) in the atovaquone group and hypoglycemia (11%) and vomiting (9%) in the pentamidine group.

Gastrointestinal

Gastrointestinal side effects are among the most common and have included nausea (up to 40%), diarrhea (up to 42%), vomiting (up to 22%), abdominal pain (up to 21%), oral monilia (up to 10%), taste perversion (3%), and constipation (3%). The incidence of side effects was higher in patients in PCP treatment studies than in prevention studies. Seven percent of patients experience anorexia and 5% of patients experience dyspepsia, although these are difficult to attribute to the drug due to the serious underlying diseases in the patients who receive atovaquone. Hyperamylasemia has been reported in 8% of patients. Pancreatitis has also been reported during postmarketing experience.

Dermatologic

Dermatologic side effects have included rash (up to 46%), pruritus (greater than or equal to 10%), exfoliative dermatitis, photosensitivity, and toxic epidermal necrolysis. Erythema multiforme, Stevens-Johnson syndrome, and skin desquamation have been reported during postmarketing experience in patients receiving multiple drug treatment including atovaquone.

Hepatic

Hepatic side effects have included elevated ALT (greater than 5 times ULN, 6%), elevated AST (greater than 5 times ULN, 4%), elevated alkaline phosphatase (greater than 2.5 times ULN, up to 8%), and increased amylase (greater than 1.5 times ULN, up to 8%) in patients being treated for PCP. Therapy was discontinued in 2% of patients receiving atovaquone due to ALT/AST elevations, compared to 7% of patients being treated with sulfamethoxazole-trimethoprim. Hepatomegaly has also been reported. Rarely, hepatitis and at least one case of fatal liver failure have been reported during postmarketing experience.

Hematologic

Hematologic side effects have included anemia (up to 6%) and neutropenia (up to 5%), but may be due to underlying disease. Methemoglobinemia and thrombocytopenia have also been reported.

Metabolic

Metabolic side effects have included hyponatremia (up to 10%), hyperglycemia (9%), and hypoglycemia (1%).

Other

Other side effects have included fever (up to 40%), asthenia (up to 31%), flu syndrome (greater than or equal to 10%), pain (greater than or equal to 10%), infection (up to 22%), sweating (greater than or equal to 10%), and malaise, but some may be due to underlying disease. Fatigue, night sweats, and burning sensation of the tongue have also been reported.

Respiratory

Respiratory side effects have included dyspnea (up to 21%), increased cough (up to 25%), rhinitis (up to 24%), sinusitis (greater than or equal to 10%), bronchospasm (up to 4%), and pneumonia.

Nervous system

Nervous system side effects have included insomnia (up to 19%), dizziness (up to 8%), headache (up to 31%), anxiety (7%), and depression (greater than or equal to 10%).

Musculoskeletal

Musculoskeletal side effects have included myalgia (greater than or equal to 10%).

Hypersensitivity

Hypersensitivity reactions have included rash, erythema multiforme, exfoliative dermatitis, and allergic reactions (unspecified, up to 1.1%).

Renal

Renal side effects have included elevated creatinine (1%) and elevated BUN (1%). Acute renal impairment has been reported during postmarketing experience.

Cardiovascular

Cardiovascular side effects have included hypotension (1%).

Ocular

Ocular side effects have included vortex keratopathy during postmarketing experience.

Immunologic

Immunologic side effects have included hypersensitivity reactions including angioedema, bronchospasm, throat tightness, and urticaria during postmarketing experience.

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