Ritocom Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling.
PR Interval Prolongation, QT Interval Prolongation (see Precautions); Drug Interactions (see Precautions); Pancreatitis (see Precautions); Hepatotoxicity (see Precautions).
Because clinical trials are conducted under widely varying conditions, adverse reactions 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.
Adults - Clinical Trials Experience: The safety profile of lopinavir and ritonavir in adults is primarily based on 1555 HIV-1 infected patients in clinical trials.
The most common adverse reaction was diarrhea, which was generally of mild to moderate severity. In study 730, the incidence of diarrhea of any severity during 48 weeks of therapy was 60% in patients receiving lopinavir and ritonavir tablets once daily compared to 57% in patients receiving lopinavir and ritonavir tablets twice daily. More patients receiving lopinavir and ritonavir tablets once daily (14, 4.2%) had ongoing diarrhea at the time of discontinuation as compared to patients receiving lopinavir and ritonavir tablets twice daily (6, 1.8%). In study 730, discontinuations due to any adverse reaction were 4.8% in patients receiving lopinavir and ritonavir tablets once daily as compared to 3% in patients receiving lopinavir and ritonavir tablets twice daily. In study 863, discontinuations of randomized therapy due to adverse reactions were 3.4% in lopinavir and ritonavir-treated and 3.7% in nelfinavir-treated patients.
Treatment-emergent clinical adverse reactions of moderate or severe intensity in ≥2% of patients treated with combination therapy for up to 48 weeks (Study 863 and 730) and for up to 360 weeks (Study 720) are presented in Table 12 (treatment-naïve patients); and for up to 48 weeks (Study 888), 84 weeks (Study 957) and 144 weeks (Study 765) in Table 13 (protease inhibitor experienced patients). (See Table 12 and Table 13.)

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Less Common Adverse Reactions: Treatment-emergent adverse reactions occurring in less than 2% of adult patients receiving lopinavir and ritonavir in the clinical trials supporting approval and of at least moderate intensity are listed as follows by system organ class.
Blood and Lymphatic System Disorders: Anemia, leukopenia, lymphadenopathy, and splenomegaly.
Cardiac Disorders: Atrial fibrillation, atrioventricular block, myocardial infarction, palpitation.
Ear and Labyrinth Disorders: Hyperacusis, tinnitus, and vertigo.
Endocrine Disorders: Cushing's syndrome and hypothyroidism.
Eye Disorders: Eye disorder and visual disturbance.
Gastrointestinal Disorders: Abdominal distension, abdominal pain upper, constipation, dry mouth, enteritis, enterocolitis, enterocolitis hemorrhagic, eructation, esophagitis, fecal incontinence, gastric disorder, gastritis, gastroesophageal reflux disease, hemorrhoids, mouth ulceration, pancreatitis, periodontitis, stomach discomfort, and stomatitis.
General Disorders and Administration Site Conditions: Chest pain, cyst, drug interaction, edema, edema peripheral, face edema, fatigue, hypertrophy, and malaise.
Hepatobiliary Disorders: Cholangitis, cholecystitis, cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly, jaundice, and liver tenderness.
Immune System Disorders: Drug hypersensitivity, hypersensitivity, and immune reconstitution syndrome.
Infections and Infestations: Bacterial infection, cellulitis, folliculitis, furuncle, gastroenteritis, influenza, otitis media, perineal abscess, pharyngitis, rhinitis, sialoadenitis, sinusitis, and viral infection.
Investigations: Drug level increased, glucose tolerance decreased, and weight increased.
Metabolism and Nutrition Disorders: Decreased appetite, dehydration, diabetes mellitus, hypovitaminosis, increased appetite, lactic acidosis, lipomatosis, and obesity.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, arthropathy, back pain, muscular weakness, osteoarthritis, osteonecrosis, and pain in extremity.
Neoplasms Benign, Malignant and Unspecified (incl Cysts and Polyps): Benign neoplasm of skin, lipoma, and neoplasm.
Nervous System Disorders: Ageusia, amnesia, ataxia, cerebral infarction, convulsion, dizziness, dysgeusia, dyskinesia, encephalopathy, extrapyramidal disorder, facial palsy, hypertonia, migraine, neuropathy, neuropathy peripheral, somnolence, and tremor.
Psychiatric Disorders: Abnormal dreams, affect lability, agitation, anxiety, apathy, confusional state, nervousness, and thinking abnormal.
Renal and Urinary Disorders: Nephritis, nephrolithiasis, renal disorder, and urine abnormality.
Reproductive System and Breast Disorders: Breast enlargement, ejaculation disorder, erectile dysfunction, and gynecomastia.
Respiratory, Thoracic and Mediastinal Disorders: Asthma, cough, dyspnea, and pulmonary edema.
Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis acneiform, dermatitis allergic, dermatitis exfoliative, dry skin, eczema, hyperhidrosis, idiopathic capillaritis, nail disorder, pruritis, rash generalized, rash maculo-papular, seborrhea, skin discoloration, skin hypertrophy, skin striae, skin ulcer, and swelling face.
Vascular Disorders: Deep vein thrombosis, orthostatic hypotension, thrombophlebitis, varicose vein, and vasculitis.
Laboratory Abnormalities: The percentages of adult patients treated with combination therapy with Grade 3 to 4 laboratory abnormalities are presented in Table 14 (treatment-naïve patients) and Table 15 (treatment-experienced patients). (See Table 14 and Table 15.)

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Pediatric Patients - Clinical Trials Experience: Lopinavir and Ritonavir oral solution dosed up to 300/75 mg/m² has been studied in 100 pediatric patients 6 months to 12 years of age. The adverse reaction profile seen during Study 940 was similar to that for adult patients.
Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common adverse reactions of any severity reported in pediatric patients treated with combination therapy for up to 48 weeks in Study 940. A total of 8 patients experienced adverse reactions of moderate to severe intensity. The adverse reactions meeting these criteria and reported for the 8 subjects include: hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine aminotransferase increased, dry skin, rash, and dysgeusia. Rash was the only event of those listed that occurred in 2 or more subjects (N = 3).
Lopinavir and Ritonavir oral solution dosed at 300/75 mg/m² has been studied in 31 pediatric patients 14 days to 6 months of age. The adverse reaction profile in Study 1030 was similar to that observed in older children and adults. No adverse reaction was reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included decreased neutrophil count (N=3), anemia (N=2), high potassium (N=2), and low sodium (N=2).
Lopinavir and Ritonavir oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg/m² (without concomitant NNRTI) and 480/120 mg/m² (with concomitant NNRTI) have been studied in 26 pediatric patients 7 to 18 years of age in Study 1038. Patients also had saquinavir mesylate added to their regimen at Week 4. Rash (12%), blood cholesterol abnormal (12%) and blood triglycerides abnormal (12%) were the only adverse reactions reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included rash (N=3), blood triglycerides abnormal (N=3), and electrocardiogram QT prolonged (N=2). Both subjects with QT prolongation had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or pre-existing cardiac abnormalities.
Laboratory Abnormalities: The percentages of pediatric patients treated with combination therapy including lopinavir and ritonavir with Grade 3 to 4 laboratory abnormalities are presented in Table 16. (See Table 16.)

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Postmarketing Experience: The following adverse reactions have been reported during postmarketing use of lopinavir and ritonavir. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to lopinavir and ritonavir exposure.
Body as a Whole: Redistribution/accumulation of body fat has been reported (see Fat Redistribution under Precautions).
Cardiovascular: Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes (see PR and QT Interval Prolongation under Precautions).
Skin and Appendages: Stevens Johnson Syndrome and erythema multiforme.