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adverse reactions
ADVERSE REACTIONS (SEE PRECAUTIONS ) The safety of FORTOVASE was studied in more than 500 patients who received the drug either alone or in combination with other antiretroviral agents. The majority of treatment-related adverse events were of mild intensity. The most frequently reported treatment-emergent adverse events among patients receiving FORTOVASE in combination with other antiretroviral agents were diarrhea, nausea, abdominal discomfort, and dyspepsia. Clinical adverse events of at least moderate intensity, which occurred in ≥2% of patients in studies NV15182 (an open-label, single-arm safety study) and NV15355 (an open-label randomized study comparing FORTOVASE and INVIRASE) are summarized in Table 7. The median duration of treatment in studies NV15182 and NV15355 were 52 and 18 weeks, respectively. In NV15182, more than 300 patients were on treatment for approximately 1 year. FORTOVASE did not appear to alter the pattern, frequency or severity of known major toxicities associated with the use of nucleoside analogues. Physicians should refer to the complete product information for other antiretroviral agents as appropriate for drug-associated adverse reactions to these other agents. Rare occurrences of the following serious adverse experiences have been reported during clinical trials of FORTOVASE and/or INVIRASE and were considered at least possibly related to use of study drugs: confusion, ataxia and weakness; seizures; headache; acute myeloblastic leukemia; hemolytic anemia; thrombocytopenia; thrombocytopenia and intracranial hemorrhage leading to death; attempted suicide; Stevens-Johnson syndrome; bullous skin eruption and polyarthritis; severe cutaneous reaction associated with increased liver function tests; isolated elevation of transaminases; exacerbation of chronic liver disease with Grade 4 elevated liver function tests, jaundice, ascites, and right and left upper quadrant abdominal pain; pancreatitis leading to death; intestinal obstruction; portal hypertension; thrombophlebitis; peripheral vasoconstriction; drug fever; nephrolithiasis; and acute renal insufficiency. Table 7 Percentage of Patients With Treatment-Emergent Adverse Events Includes adverse events at least possibly related to study drug or of unknown intensity and/or relationship to treatment (corresponding to ACTG Grade 2, 3 and 4). of at Least Moderate Intensity, Occurring in ≥2% of Patients NV15182 (48 weeks) NV15355 (48 weeks) Naive Patients ADVERSE EVENT FORTOVASE + TOC Antiretroviral Treatment of Choice. N=442 FORTOVASE+ 2 RTIs Reverse Transcriptase Inhibitor. N=90 Gastrointestinal Diarrhea 19.9 15.6 Nausea 10.6 13.3 Abdominal Discomfort 8.6 10.0 Dyspepsia 8.4 7.8 Flatulence 5.7 10.0 Vomiting 2.9 4.4 Abdoiminal Pain 2.3 4.4 Constipation – 3.3 Body as a Whole Fatigue 4.8 8.9 Appetite Decreased – 2.2 Chest Pain – 2.2 Central and Peripheral Nervous System Headaches 5.0 5.6 Psychiatric Disorders Depression 2.7 – Insomnia – 5.6 Anxiety – 2.2 Libido Disorder – 3.3 Special Senses Disorders Taste Alteration – 4.4 Musculoskeletal Disorders Pain – 3.3 Dermatological Disorders Eczema – – Rash – – Verruca – 2.2 Concomitant Therapy with Ritonavir Table 8 Grade 2, 3 and 4 Adverse Events (All Causality) Reported in ≥2% of Adult Patients in the MaxCmin 1 Study of FORTOVASE in Combination with Ritonavir 1000/100 mg bid FORTOVASE 1000 mg plus Ritonavir 100 mg bid (48 weeks) N=148 n(%=n/N) Endocrine Disorders Diabetes mellitus/hyperglycemia 4 (2.7) Lipodystrophy 8 (5.4) Gastrointestinal Disorders Nausea 16 (10.8) Vomiting 11 (7.4) Diarrhea 12 (8.1) Abdominal Pain 9 (6.1) Constipation 3 (2.0) General Disorders and Administration Site Conditions Fatigue 9 (6.1) Fever 5 (3.4) Musculoskeletal Disorders Back Pain 3 (2.0) Respiratory Disorders Pneumonia 8 (5.4) Bronchitis 4 (2.7) Influenza 4 (2.7) Sinusitis 4 (2.7) Dermatological Disorders Rash 5 (3.4) Pruritus 5 (3.4) Dry lips/skin 3 (2.0) Eczema 3 (2.0) Includes events with unknown relationship to study drug. Laboratory Abnormalities In the MaxCmin 1 study, Grade 3 and 4 thrombocytopenia (2.0% of patients) and anemia (2.0%) were observed with FORTOVASE in combination with ritonavir. At 48 weeks, other lab abnormalities included increased ALT, increased AST, increased GGT, hyperglycemia, hypertriglyceridemia, increased TSH, neutropenia, raised amylase, and increased LDH. Table 9 summarizes the percentage of patients with marked laboratory abnormalities in study NV15182 and NV15355 (median duration of treatment was 52 and 18 weeks, respectively). In study NV15182, by 48 weeks <1% of patients discontinued treatment due to laboratory abnormalities. In the safety study (NV15182), 27% to 33% of subjects experienced ≥1 grade shifts in ALT and AST during the 48-week study period. In 46% of such events, there was a single abnormal transaminase level with no evidence of persistently elevated enzyme values during the course of study. Only 3% to 4% of patients had ≥3 grade shifts in transaminase levels and less than 0.5% of patients had to discontinue the study for increased liver function test values. Table 9 Percentage of Patients with Marked Laboratory Abnormalities ACTG Grade 3 or above. NV15182 (48 weeks) NV15355 (48 weeks) Naive Patients FORTOVASE + TOC Antiretroviral Treatment of Choice. N=442 FORTOVASE + 2 RTIs Reverse Transcriptase Inhibitor. N=90 ND Not done. BIOCHEMISTRY Limit Alkaline Phosphatase (high) >5 × ULN ULN = Upper limit of normal range. 0.5 0.0 Calcium (high) >12.5 mg/dL 0.2 0.0 Creatine Kinase (high) >4 × ULN 7.8 6.0 Gamma GT (high) >5 × ULN 5.7 5.0 Glucose (low) <40 mg/dL 6.4 3.5 Glucose (high) >250 mg/dL 1.4 0.0 Phosphate (low) <1.5 mg/dL 0.5 1.0 Potassium (high) >6.5 mEq/L 2.7 3.5 Serum Amylase (high) >2 × ULN 1.9 ND SGOT (AST) (high) >5 × ULN 4.1 0.0 SGPT (ALT) (high) >5 × ULN 5.7 1.0 Sodium (high) >157 mEq/L 0.7 0.0 Sodium (low) <123 mEq/L 0.0 1.0 Total Bilirubin (high) >2.5 × ULN 1.6 0.0 Triglycerides (high) >750 mg/dL 0.0 2.0 HEMATOLOGY Hemoglobin (low) <7.0 gm/dL 0.7 1.0 Absolute Neutrophil Count (low) <750 mm 3 2.9 1.0 Platelets (low) <50,000 mm 3 0.9 0.0 Additional marked lab abnormalities have been observed with INVIRASE. These include: calcium (low), phosphate (low), potassium (low), sodium (low). Monotherapy and Combination Studies Other clinical adverse experiences of any intensity, at least remotely related to FORTOVASE and INVIRASE, including those in <2% of patients, are listed below by body system. Autonomic Nervous System Mouth dry, night sweats, sweating increased Body as a Whole Allergic reaction, anorexia, appetite decreased, appetite disturbances, asthenia, chest pain, edema, fever, intoxication, malaise, olfactory disorder, pain body, pain pelvic, retrosternal pain, shivering, trauma, wasting syndrome, weakness generalized, weight decrease, redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution ) Cardiovascular/Cerebrovascular Cyanosis, heart murmur, heart rate disorder, heart valve disorder, hypertension, hypotension, stroke, syncope, vein distended Central and Peripheral Nervous System Ataxia, cerebral hemorrhage, confusion, convulsions, dizziness, dysarthria, dysesthesia, hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling, myelopolyradiculoneuritis, neuropathy, numbness extremities, numbness face, paresis, paresthesis, peripheral neuropathy, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, spasms, tremor, unconsciousness Dermatological Acne, alopecia, chalazion, dermatitis, dermatitis seborrheic, erythema, folliculitis, furunculosis, hair changes, hot flushes, nail disorder, papillomatosis, papular rash, photosensitivity reaction, pigment changes skin, parasites external, pruritus, psoriasis, rash maculopapular, rash pruritic, red face, skin disorder, skin nodule, skin syndrome, skin ulceration, urticaria, verruca, xeroderma Endocrine/Metabolic Dehydration, diabetes mellitus, hyperglycemia, hypoglycemia, hypothyroidism, thirst, triglyceride increase, weight increase Gastrointestinal Abdominal distention, bowel movements frequent, buccal mucosa ulceration, canker sores oral, cheilitis, colic abdominal, dysphagia, esophageal ulceration, esophagitis, eructation, fecal incontinence, feces bloodstained, feces discolored, gastralgia, gastritis, gastroesophageal reflux, gastrointestinal inflammation, gingivitis, glossitis, hemorrhage rectum, hemorrhoids, infectious diarrhea, melena, painful defecation, parotid disorder, pruritus ani, pyrosis, salivary glands disorder, stomach upset, stomatitis, taste unpleasant, toothache, tooth disorder, ulcer gastrointestinal Hematologic Anemia, neutropenia, pancytopenia, splenomegaly Liver and Biliary Cholangitis sclerosing, cholelithiasis, hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, liver enzyme disorder, pancreatitis Musculoskeletal Arthralgia, arthritis, back pain, cramps leg, cramps muscle, lumbago, musculoskeletal disorders, myalgia, myopathy, pain facial, pain jaw, pain leg, pain musculoskeletal, stiffness, tissue changes Neoplasm Kaposi's sarcoma, tumor Platelet, Bleeding, Clotting Bleeding dermal, hemorrhage, microhemorrhages, thrombocytopenia Psychiatric Agitation, amnesia, anxiety attack, behavior disturbances, dreaming excessive, euphoria, hallucination, intellectual ability reduced, irritability, lethargy, overdose effect, psychic disorder, psychosis, somnolence, speech disorder Reproductive System Epididymitis, erectile impotence, impotence, menstrual disorder, menstrual irregularity, penis disorder, prostate enlarged, vaginal discharge Resistance Mechanism Abscess, angina tonsillaris, candidiasis, cellulitis, herpes simplex, herpes zoster, infection bacterial, infection mycotic, infection staphylococcal, infestation parasitic, influenza, lymphadenopathy, molluscum contagiosum, moniliasis Respiratory Asthma bronchial, bronchitis, cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary disease, respiratory disorder, rhinitis, rhinitis allergic atopic, sinusitis, upper respiratory tract infection Special Senses Blepharitis, conjunctivitis, cytomegalovirus retinitis, dry eye syndrome, earache, ear pressure, eye irritation, hearing decreased, otitis, taste unpleasant, tinnitus, visual disturbance, xerophthalmia Urinary System Micturition disorder, nocturia, renal calculus, renal colic, urinary tract bleeding, urinary tract infection Postmarketing Experience with INVIRASE and FORTOVASE Additional adverse events that have been observed during the postmarketing period are similar to those seen in clinical trials with INVIRASE and FORTOVASE and administration of INVIRASE and FORTOVASE in combination with ritonavir.