Prezista Side Effects

Please note - some side effects for Prezista 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 Prezista - for the Consumer

Prezista

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 Prezista:

Diarrhea; headache; mild stomach pain; nausea; vomiting.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); dark urine; eye pain, inflammation, or redness; fever; loss of appetite; mouth sores; muscle or joint pain; pale stools; red, swollen, blistered, or peeling skin; severe headache or dizziness; severe or persistent nausea, vomiting, or stomach or back pain; unusual drowsiness, tiredness, or weakness; yellowing of the skin or eyes.

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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Prezista Side Effects - for the Professional

Prezista

The overall safety profile of Prezista/ritonavir 800/100 mg once daily and Prezista/ritonavir 600/100 mg twice daily is based on clinical trials and post-marketing data, and is consistent with the data presented below.

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.

Due to the need for co-administration of Prezista with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

Clinical Trials Experience: Treatment-Naïve Adults

Study TMC114-C211

The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing Prezista/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-1-infected adult subjects. The total mean exposure for subjects in the Prezista/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 162.5 and 153.5 weeks, respectively.

The majority of the adverse drug reactions (ADRs) reported during treatment with Prezista/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to Prezista/ritonavir 800/100 mg once daily (≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the Prezista/ritonavir arm discontinued treatment due to ADRs.

ADRs to Prezista/ritonavir 800/100 mg once daily of at least moderate intensity (≥ Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult subjects are presented in Table 3 and subsequent text below the table.

Table 3: Selected Clinical Adverse Drug Reactions to Prezista/ritonavir 800/100 mg Once Daily* of at Least Moderate Intensity (≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects

	Randomized Study TMC114-C211
System Organ Class, Preferred Term, %	Prezista/ritonavir 800/100 mg once daily + TDF/FTC N = 343	lopinavir/ritonavir 800/200 mg per day + TDF/FTC N = 346
N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine
* Excluding laboratory abnormalities reported as ADRs
Gastrointestinal Disorders
Abdominal pain	6%	6%
Diarrhea	9%	16%
Nausea	4%	4%
Vomiting	2%	4%
General Disorders and Administration Site Conditions
Fatigue	< 1%	3%
Metabolism and Nutrition Disorders
Anorexia	2%	< 1%
Nervous System Disorders
Headache	7%	6%
Skin and Subcutaneous Tissue Disorders
Rash	6%	7%

Less Common Adverse Reactions

Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving Prezista/ritonavir 800/100 mg once daily are listed below by body system:

Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulence

General Disorders and Administration Site Conditions: asthenia

Hepatobiliary Disorders: acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity)

Immune System Disorders: (drug) hypersensitivity, immune reconstitution syndrome

Metabolism and Nutrition Disorders: diabetes mellitus

Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis

Psychiatric Disorders: abnormal dreams

Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson Syndrome, urticaria

Laboratory abnormalities:

Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with Prezista/ritonavir 800/100 mg once daily are presented in Table 4.

Table 4: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects*

		Randomized Study TMC114-C211
Laboratory Parameter Preferred Term, %	Limit	Prezista/ritonavir 800/100 mg once daily + TDF/FTC	lopinavir/ritonavir 800/200 mg per day + TDF/FTC
N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine
* Grade 4 data not applicable in Division of AIDS grading scale.
Biochemistry
Alanine Aminotransferase
Grade 2	> 2.5 to ≤ 5.0 X ULN	9%	9%
Grade 3	> 5.0 to ≤ 10.0 X ULN	3%	3%
Grade 4	> 10.0 X ULN	< 1%	3%
Aspartate Aminotransferase
Grade 2	> 2.5 to ≤ 5.0 X ULN	7%	10%
Grade 3	> 5.0 to ≤ 10.0 X ULN	4%	2%
Grade 4	> 10.0 X ULN	1%	3%
Alkaline Phosphatase
Grade 2	> 2.5 to ≤ 5.0 X ULN	1%	1%
Grade 3	> 5.0 to ≤ 10.0 X ULN	0%	< 1%
Grade 4	> 10.0 X ULN	0%	0%
Hyperbilirubinemia
Grade 2	> 1.5 to ≤ 2.5 X ULN	< 1%	5%
Grade 3	> 2.5 to ≤ 5.0 X ULN	< 1%	< 1%
Grade 4	> 5.0 X ULN	0%	0%
Triglycerides
Grade 2	5.65–8.48 mmol/L 500–750 mg/dL	3%	10%
Grade 3	8.49–13.56 mmol/L 751–1200 mg/dL	2%	5%
Grade 4	> 13.56 mmol/L > 1200 mg/dL	1%	1%
Total Cholesterol
Grade 2	6.20–7.77 mmol/L 240–300 mg/dL	23%	27%
Grade 3	> 7.77 mmol/L > 300 mg/dL	1%	5%
Low-Density Lipoprotein Cholesterol
Grade 2	4.13–4.90 mmol/L 160–190 mg/dL	14%	12%
Grade 3	≥ 4.91 mmol/L ≥ 191 mg/dL	9%	6%
Elevated Glucose Levels
Grade 2	6.95–13.88 mmol/L 126–250 mg/dL	11%	10%
Grade 3	13.89–27.75 mmol/L 251–500 mg/dL	1%	<1%
Grade 4	> 27.75 mmol/L > 500 mg/dL	0%	0%
Pancreatic Lipase
Grade 2	> 1.5 to ≤ 3.0 X ULN	3%	2%
Grade 3	> 3.0 to ≤ 5.0 X ULN	< 1%	1%
Grade 4	> 5.0 X ULN	0%	< 1%
Pancreatic Amylase
Grade 2	> 1.5 to ≤ 2.0 X ULN	5%	2%
Grade 3	> 2.0 to ≤ 5.0 X ULN	5%	4%
Grade 4	> 5.0 X ULN	0%	< 1%

Clinical Trials Experience: Treatment-Experienced Adults

Study TMC114-C214

The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing Prezista/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-experienced HIV-1-infected adult subjects. The total mean exposure for subjects in the Prezista/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 80.7 and 76.4 weeks, respectively.

The majority of the ADRs reported during treatment with Prezista/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to Prezista/ritonavir 600/100 mg twice daily (≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the Prezista/ritonavir arm discontinued treatment due to ADRs.

ADRs to Prezista/ritonavir 600/100 mg twice daily of at least moderate intensity (≥ Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 5 and subsequent text below the table.

Table 5: Selected Clinical Adverse Drug Reactions to Prezista/ritonavir 600/100 mg Twice Daily* of at Least Moderate Intensity (≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects

	Randomized Study TMC114-C214
System Organ Class, Preferred Term, %	Prezista/ritonavir 600/100 mg twice daily + OBR N = 298	lopinavir/ritonavir 400/100 mg twice daily + OBR N = 297
N=total number of subjects per treatment group OBR = optimized background regimen
* Excluding laboratory abnormalities reported as ADRs
Gastrointestinal Disorders
Abdominal distension	2%	< 1%
Abdominal pain	6%	3%
Diarrhea	14%	20%
Dyspepsia	2%	1%
Nausea	7%	6%
Vomiting	5%	3%
General Disorders and Administration Site Conditions
Asthenia	3%	1%
Fatigue	2%	1%
Metabolism and Nutrition Disorders
Anorexia	2%	2%
Diabetes mellitus	2%	< 1%
Nervous System Disorders
Headache	3%	3%
Skin and Subcutaneous Tissue Disorders
Rash	7%	3%

Less Common Adverse Reactions

Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving Prezista/ritonavir 600/100 mg twice daily are listed below by body system:

Gastrointestinal Disorders: acute pancreatitis, flatulence

Musculoskeletal and Connective Tissue Disorders: myalgia

Psychiatric Disorders: abnormal dreams

Skin and Subcutaneous Tissue Disorders: pruritus, urticaria

Laboratory abnormalities:

Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with Prezista/ritonavir 600/100 mg twice daily are presented in Table 6.

Table 6: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects*

		Randomized Study TMC114-C214
Laboratory Parameter Preferred Term, %	Limit	Prezista/ritonavir 600/100 mg twice daily + OBR	lopinavir/ritonavir 400/100 mg twice daily + OBR
N=total number of subjects per treatment group OBR = optimized background regimen
* Grade 4 data not applicable in Division of AIDS grading scale
Biochemistry
Alanine Aminotransferase
Grade 2	> 2.5 to ≤ 5.0 X ULN	7%	5%
Grade 3	> 5.0 to ≤ 10.0 X ULN	2%	2%
Grade 4	> 10.0 X ULN	1%	2%
Aspartate Aminotransferase
Grade 2	> 2.5 to ≤ 5.0 X ULN	6%	6%
Grade 3	> 5.0 to ≤ 10.0 X ULN	2%	2%
Grade 4	> 10.0 X ULN	< 1%	2%
Alkaline Phosphatase
Grade 2	> 2.5 to ≤ 5.0 X ULN	< 1%	0%
Grade 3	> 5.0 to ≤ 10.0 X ULN	< 1%	< 1%
Grade 4	> 10.0 X ULN	0%	0%
Hyperbilirubinemia
Grade 2	> 1.5 to ≤ 2.5 X ULN	< 1%	2%
Grade 3	> 2.5 to ≤ 5.0 X ULN	< 1%	< 1%
Grade 4	> 5.0 X ULN	< 1%	0%
Triglycerides
Grade 2	5.65–8.48 mmol/L 500–750 mg/dL	10%	11%
Grade 3	8.49–13.56 mmol/L 751–1200 mg/dL	7%	10%
Grade 4	> 13.56 mmol/L > 1200 mg/dL	3%	6%
Total Cholesterol
Grade 2	6.20–7.77 mmol/L 240–300 mg/dL	25%	23%
Grade 3	> 7.77 mmol/L > 300 mg/dL	10%	14%
Low-Density Lipoprotein Cholesterol
Grade 2	4.13–4.90 mmol/L 160–190 mg/dL	14%	14%
Grade 3	≥ 4.91 mmol/L ≥ 191 mg/dL	8%	9%
Elevated Glucose Levels
Grade 2	6.95–13.88 mmol/L 126–250 mg/dL	10%	11%
Grade 3	13.89–27.75 mmol/L 251–500 mg/dL	1%	< 1%
Grade 4	> 27.75 mmol/L > 500 mg/dL	< 1%	0%
Pancreatic Lipase
Grade 2	> 1.5 to ≤ 3.0 X ULN	3%	4%
Grade 3	> 3.0 to ≤ 5.0 X ULN	2%	< 1%
Grade 4	> 5.0 X ULN	< 1%	0%
Pancreatic Amylase
Grade 2	> 1.5 to ≤ 2.0 X ULN	6%	7%
Grade 3	> 2.0 to ≤ 5.0 X ULN	7%	3%
Grade 4	> 5.0 X ULN	0%	0%

Serious ADRs

The following serious ADRs of at least moderate intensity (≥ Grade 2) occurred in the Phase 2b studies and Phase 3 studies with Prezista/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting.

Patients co-infected with hepatitis B and/or hepatitis C virus

In subjects co-infected with hepatitis B or C virus receiving Prezista/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving Prezista/ritonavir who were not co-infected, except for increased hepatic enzymes [see Warnings and Precautions (5.2)]. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection.

Clinical Trials Experience: Pediatric Patients

Prezista/ritonavir has been studied in 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg) in combination with other antiretroviral agents [see Use in Specific Populations (8.4) and Clinical Studies (14.4)].

Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults. ADRs to Prezista/ritonavir (all grades, ≥ 3%), excluding laboratory abnormalities reported as ADRs, were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%) and fatigue (3%).

Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%).

Postmarketing Experience

The following events have been identified during postmarketing use of Prezista. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Redistribution of body fat has been reported.

Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and Prezista/ritonavir) and toxic epidermal necrolysis have been reported [see Warnings and Precautions (5.3)].

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Side Effects by Body System - for Healthcare Professionals

General

The majority of side effects reported during treatment with darunavir plus ritonavir were mild in severity. The most common side effects of at least moderate intensity were diarrhea, nausea, vomiting, headache, rash, and abdominal pain. Adverse events led to discontinuation of darunavir in 2.3% and 4.7% of treatment-naive and treatment-experienced subjects, respectively, in randomized trials.

Gastrointestinal

Gastrointestinal side effects of at least moderate intensity have included diarrhea (up to 14%), nausea (up to 7%), vomiting (up to 5%), abdominal pain (up to 6%), anorexia (2%), abdominal distension (2%), dyspepsia (up to 2%), acute pancreatitis (less than 2%), and flatulence (less than 2%). Dry mouth and constipation have been reported.

Hepatic

Hepatic side effects of at least moderate intensity have included acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity; less than 2%) and increased hepatic enzyme. Hyperbilirubinemia (Grade 2: less than 1%; Grade 3: less than 1%; Grade 4: less than 1%), hypoalbuminemia, and elevated aspartate aminotransferase (Grade 2: up to 7%; Grade 3: up to 4%; Grade 4: up to 1%), alanine aminotransferase (Grade 2: up to 9%; Grade 3: up to 3%; Grade 4: up to 1%), alkaline phosphatase (Grade 2: up to 1%; Grade 3: less than 1%), and gamma glutamyl transferase have been reported. In patients receiving darunavir/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher in those coinfected with hepatitis B or C virus compared with patients who were not coinfected, with the exception of increased hepatic enzymes.

Hematologic

Hematologic side effects have included decreased white blood cell count, lymphocytes, total absolute neutrophil count, and platelets; increased partial thromboplastin time and plasma prothrombin time; and anemia. Hematologic side effects associated with protease inhibitors have included spontaneous bleeding in patients with hemophilia A and B. In many of the reported cases, treatment with protease inhibitors was continued or restarted and some patients required additional factor VIII. A causal relationship between protease inhibitor therapy and these episodes has not been established.

Metabolic

Metabolic side effects of at least moderate intensity have included diabetes mellitus (up to 2%), hypercholesterolemia, hyperglycemia, hypertriglyceridemia, increased low density lipoprotein, and increased pancreatic enzyme. Elevated pancreatic lipase (Grade 2: 3%; Grade 3: up to 2%; Grade 4: less than 1%), pancreatic amylase (Grade 2: up to 6%; Grade 3: up to 7%), glucose levels (Grade 2: up to 11%; Grade 3: up to 1%; Grade 4: less than 1%), total cholesterol (Grade 2: up to 25%; Grade 3: up to 10%), triglycerides (Grade 2: up to 10%; Grade 3: up to 7%; Grade 4: up to 3%), and low-density lipoprotein cholesterol (Grade 2: 14%; Grade 3: up to 9%) have been reported. Hypoglycemia, hyperuricemia, decreased bicarbonate, hypocalcemia, hyponatremia, hypernatremia, hyperlipidemia, decreased appetite, obesity, fat redistribution, hyponatremia, polydipsia, decreased weight, and lipodystrophy have also been reported. Redistribution of body fat has been reported during postmarketing experience.

Nervous system

Nervous system side effects of at least moderate intensity have included headache (up to 7%). Peripheral neuropathy, hypoesthesia, paresthesia, somnolence, transient ischemic attack, insomnia, dizziness, and progressive multifocal leukoencephalopathy have been reported.

Psychiatric

Psychiatric side effects of at least moderate intensity have included abnormal dreams (less than 2%). Memory impairment, confusion state, disorientation, irritability, altered mood, nightmare, and anxiety have been reported.

Musculoskeletal

Musculoskeletal side effects of at least moderate intensity have included myalgia and osteonecrosis in less than 2% of patients. Arthralgia, pain in extremities, osteopenia, and osteoporosis have been reported. Rarely, rhabdomyolysis has been reported during postmarketing experience.

Cardiovascular

Cardiovascular side effects have included myocardial infarction, tachycardia, and hypertension.

Other

Other side effects of at least moderate intensity have included asthenia (up to 3%) and fatigue (up to 2%). Vertigo, pyrexia, rigors, hyperthermia, peripheral edema, and herpes simplex infection have been reported.

Renal

Renal side effects have included acute renal failure, renal insufficiency, nephrolithiasis, and polyuria.

Respiratory

Respiratory side effects have included nasopharyngitis, dyspnea, cough, hiccups, pneumonia, and upper respiratory tract infection.

Dermatologic

Dermatologic side effects of at least moderate intensity have included rash (up to 7%), and angioedema, pruritus, urticaria, and Stevens-Johnson syndrome in less than 2% of patients. Folliculitis, lipoatrophy, night sweats, allergic dermatitis, eczema, toxic skin eruption, alopecia, dermatitis medicamentosa, hyperhidrosis, skin inflammation, maculopapular rash, and erythema multiforme have been reported. Severe skin reactions (in some cases accompanied by fever and/or elevations of transaminases) have been reported during clinical development programs. Rarely, toxic epidermal necrolysis has been reported during postmarketing experience.

Endocrine

Endocrine side effects have included gynecomastia.

Genitourinary

Genitourinary side effects have included acute renal failure, renal insufficiency, nephrolithiasis, polyuria, and gynecomastia.

Immunologic

Immunologic side effects of at least moderate intensity have included immune reconstitution syndrome (less than 2%).

Hypersensitivity

Hypersensitivity side effects of at least moderate intensity have included drug hypersensitivity (less than 2%). Facial edema has been reported.

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