ADVERSE REACTIONS
Adults
The safety of NORVIR alone and in combination with nucleoside reverse transcriptase inhibitors was studied in 1270 adult patients. Table 7 lists treatment-emergent adverse events (at least possibly related and of at least moderate intensity) that occurred in 2% or greater of adult patients receiving NORVIR alone or in combination with nucleoside reverse transcriptase inhibitors in Study 245 or Study 247 and in combination with saquinavir in study 462. In that study, 141 protease inhibitor-naive, HIV-infected patients with mean baseline CD4 of 300 cells/µL were randomized to one of four regimens of NORVIR + saquinavir, including NORVIR 400 mg twice-daily + saquinavir 400 mg twice-daily. Overall the most frequently reported clinical adverse events, other than asthenia, among adult patients receiving NORVIR were gastrointestinal and neurological disturbances including nausea, diarrhea, vomiting, anorexia, abdominal pain, taste perversion, and circumoral and peripheral paresthesias. Similar adverse event profiles were reported in adult patients receiving ritonavir in other trials.
Table 7. Percentage of Patients with Treatment-emergent Adverse Events1 of Moderate or Severe Intensity Occurring in ≥ 2% of Adult Patients Receiving NORVIR | Adverse Events | Study 245
Naive Patients2 | Study 247
Advanced Patients3 | Study 462
PI-Naive Patients4 |
| NORVIR + ZDV
n = 116 | NORVIR
n = 117 | ZDV
n = 119 | NORVIR
n = 541 | Placebo
n = 545 | NORVIR + Saquinavir n= 141 |
|
1 Includes those adverse events at least possibly related to study drug or of unknown relationship and excludes concurrent HIV conditions.
2 The median duration of treatment for patients randomized to regimens containing NORVIR in Study 245 was 9.1 months.
3 The median duration of treatment for patients randomized to regimens containing NORVIR in Study 247 was 9.4 months.
4 The median duration of treatment for patients in Study 462 was 48 weeks.
|
| Body as a Whole |
| Abdominal Pain | 5.2 | 6.0 | 5.9 | 8.3 | 5.1 | 2.1 |
| Asthenia | 28.4 | 10.3 | 11.8 | 15.3 | 6.4 | 16.3 |
| Fever | 1.7 | 0.9 | 1.7 | 5.0 | 2.4 | 0.7 |
| Headache | 7.8 | 6.0 | 6.7 | 6.5 | 5.7 | 4.3 |
| Malaise | 5.2 | 1.7 | 3.4 | 0.7 | 0.2 | 2.8 |
| Pain (unspecified) | 0.9 | 1.7 | 0.8 | 2.2 | 1.8 | 4.3 |
| Cardiovascular |
| Syncope | 0.9 | 1.7 | 0.8 | 0.6 | 0.0 | 2.1 |
| Vasodilation | 3.4 | 1.7 | 0.8 | 1.7 | 0.0 | 3.5 |
| Digestive |
| Anorexia | 8.6 | 1.7 | 4.2 | 7.8 | 4.2 | 4.3 |
| Constipation | 3.4 | 0.0 | 0.8 | 0.2 | 0.4 | 1.4 |
| Diarrhea | 25.0 | 15.4 | 2.5 | 23.3 | 7.9 | 22.7 |
| Dyspepsia | 2.6 | 0.0 | 1.7 | 5.9 | 1.5 | 0.7 |
| Fecal Incontinence | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 2.8 |
| Flatulence | 2.6 | 0.9 | 1.7 | 1.7 | 0.7 | 3.5 |
| Local Throat Irritation | 0.9 | 1.7 | 0.8 | 2.8 | 0.4 | 1.4 |
| Nausea | 46.6 | 25.6 | 26.1 | 29.8 | 8.4 | 18.4 |
| Vomiting | 23.3 | 13.7 | 12.6 | 17.4 | 4.4 | 7.1 |
| Metabolic and Nutritional |
| Weight Loss | 0.0 | 0.0 | 0.0 | 2.4 | 1.7 | 0.0 |
| Musculoskeletal |
| Arthralgia | 0.0 | 0.0 | 0.0 | 1.7 | 0.7 | 2.1 |
| Myalgia | 1.7 | 1.7 | 0.8 | 2.4 | 1.1 | 2.1 |
| Nervous |
| Anxiety | 0.9 | 0.0 | 0.8 | 1.7 | 0.9 | 2.1 |
| Circumoral Paresthesia | 5.2 | 3.4 | 0.0 | 6.7 | 0.4 | 6.4 |
| Confusion | 0.0 | 0.9 | 0.0 | 0.6 | 0.6 | 2.1 |
| Depression | 1.7 | 1.7 | 2.5 | 1.7 | 0.7 | 7.1 |
| Dizziness | 5.2 | 2.6 | 3.4 | 3.9 | 1.1 | 8.5 |
| Insomnia | 3.4 | 2.6 | 0.8 | 2.0 | 1.8 | 2.8 |
| Paresthesia | 5.2 | 2.6 | 0.0 | 3.0 | 0.4 | 2.1 |
| Peripheral Paresthesia | 0.0 | 6.0 | 0.8 | 5.0 | 1.1 | 5.7 |
| Somnolence | 2.6 | 2.6 | 0.0 | 2.4 | 0.2 | 0.0 |
| Thinking Abnormal | 2.6 | 0.0 | 0.8 | 0.9 | 0.4 | 0.7 |
| Respiratory |
| Pharyngitis | 0.9 | 2.6 | 0.0 | 0.4 | 0.4 | 1.4 |
| Skin and Appendages |
| Rash | 0.9 | 0.0 | 0.8 | 3.5 | 1.5 | 0.7 |
| Sweating | 3.4 | 2.6 | 1.7 | 1.7 | 1.1 | 2.8 |
| Special Senses |
| Taste Perversion | 17.2 | 11.1 | 8.4 | 7.0 | 2.2 | 5.0 |
| Urogenital |
| Nocturia | 0.0 | 0.0 | 0.0 | 0.2 | 0.0 | 2.8 |
Adverse events occurring in less than 2% of adult patients receiving NORVIR in all phase II/phase III studies and considered at least possibly related or of unknown relationship to treatment and of at least moderate intensity are listed below by body system.
Body as a Whole
Abdomen enlarged, accidental injury, allergic reaction, back pain, cachexia, chest pain, chills, facial edema, facial pain, flu syndrome, hormone level altered, hypothermia, kidney pain, neck pain, neck rigidity, pelvic pain, photosensitivity reaction, and substernal chest pain.
Cardiovascular System
Cardiovascular disorder, cerebral ischemia, cerebral venous thrombosis, hypertension, hypotension, migraine, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia and vasospasm.
Digestive System
Abnormal stools, bloody diarrhea, cheilitis, cholestatic jaundice, colitis, dry mouth, dysphagia, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gingivitis, hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, ileus, liver damage, melena, mouth ulcer, pancreatitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, tenesmus, thirst, tongue edema, and ulcerative colitis.
Endocrine System
Adrenal cortex insufficiency and diabetes mellitus.
Hemic and Lymphatic System
Acute myeloblastic leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, and thrombocytopenia.
Metabolic and Nutritional Disorders
Albuminuria, alcohol intolerance, avitaminosis, BUN increased, dehydration, edema, enzymatic abnormality, glycosuria, gout, hypercholesteremia, peripheral edema, and xanthomatosis.
Musculoskeletal System
Arthritis, arthrosis, bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps, muscle cramps, muscle weakness, myositis, and twitching.
Nervous System
Abnormal dreams, abnormal gait, agitation, amnesia, aphasia, ataxia, coma, convulsion, dementia, depersonalization, diplopia, emotional lability, euphoria, grand mal convulsion, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, libido decreased, manic reaction, nervousness, neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral neuropathy, peripheral sensory neuropathy, personality disorder, sleep disorder, speech disorder, stupor, subdural hematoma, tremor, urinary retention, vertigo, and vestibular disorder.
Respiratory System
Asthma, bronchitis, dyspnea, epistaxis, hiccup, hypoventilation, increased cough, interstitial pneumonia, larynx edema, lung disorder, rhinitis, and sinusitis.
Skin and Appendages
Acne, contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum, onychomycosis, pruritus, psoriasis, pustular rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, urticaria, and vesiculobullous rash.
Special Senses
Abnormal electro-oculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, ear pain, eye disorder, eye pain, hearing impairment, increased cerumen, iritis, parosmia, photophobia, taste loss, tinnitus, uveitis, visual field defect, and vitreous disorder.
Urogenital System
Acute kidney failure, breast pain, cystitis, dysuria, hematuria, impotence, kidney calculus, kidney failure, kidney function abnormal, kidney pain, menorrhagia, penis disorder, polyuria, urethritis, urinary frequency, urinary tract infection, and vaginitis.
Post-Marketing Experience
The following adverse events have been reported during post-marketing use of NORVIR. 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 NORVIR exposure.
Body as a Whole
Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.
Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
Redistribution/accumulation of body fat has been reported (see PRECAUTIONS - Fat Redistribution).
Cardiovascular System
First –degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported (See PRECAUTIONS – PR Interval Prolongation).
Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.
Endocrine System
Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate.
Hemic and Lymphatic System
There have been reports of increased bleeding in patients with hemophilia A or B (see PRECAUTIONS - Hemophilia).
Nervous System
There have been postmarketing reports of seizure. Also, see Cardiovascular System.
Laboratory Abnormalities
Table 8 shows the percentage of adult patients who developed marked laboratory abnormalities.
Table 8. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in > 3% of Patients Receiving NORVIR | | Study 245
Naive Patients | Study 247
Advanced Patients | Study 462PI-Naive Patients |
| Variable | Limit | NORVIR + ZDV | NORVIR | ZDV | NORVIR | Placebo | NORVIR + Saquinavir |
|
1 ULN = upper limit of the normal range.
- Indicates no events reported.
|
| Chemistry | High | | | | | | |
| Cholesterol | > 240 mg/dL | 30.7 | 44.8 | 9.3 | 36.5 | 8.0 | 65.2 |
| CPK | > 1000 IU/L | 9.6 | 12.1 | 11.0 | 9.1 | 6.3 | 9.9 |
| GGT | > 300 IU/L | 1.8 | 5.2 | 1.7 | 19.6 | 11.3 | 9.2 |
| SGOT (AST) | > 180 IU/L | 5.3 | 9.5 | 2.5 | 6.4 | 7.0 | 7.8 |
| SGPT (ALT) | > 215 IU/L | 5.3 | 7.8 | 3.4 | 8.5 | 4.4 | 9.2 |
| Triglycerides | > 800 mg/dL | 9.6 | 17.2 | 3.4 | 33.6 | 9.4 | 23.4 |
| Triglycerides | > 1500 mg/dL | 1.8 | 2.6 | - | 12.6 | 0.4 | 11.3 |
| Triglycerides Fasting | > 1500 mg/dL | 1.5 | 1.3 | - | 9.9 | 0.3 | - |
| Uric Acid | > 12 mg/dL | - | - | - | 3.8 | 0.2 | 1.4 |
| Hematology | Low | | | | | | |
| Hematocrit | < 30% | 2.6 | - | 0.8 | 17.3 | 22.0 | 0.7 |
| Hemoglobin | < 8.0 g/dL | 0.9 | - | - | 3.8 | 3.9 | - |
| Neutrophils | ≤ 0.5 x 109/L | - | - | - | 6.0 | 8.3 | - |
| RBC | < 3.0 x 1012/L | 1.8 | - | 5.9 | 18.6 | 24.4 | - |
| WBC | < 2.5 x 109/L | - | 0.9 | 6.8 | 36.9 | 59.4 | 3.5 |
Pediatrics
Treatment-Emergent Adverse Events
NORVIR has been studied in 265 pediatric patients> 1 month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients.
Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in ≥ 2% of pediatric patients enrolled in NORVIR clinical trials.
Laboratory Abnormalities
The following Grade 3-4 laboratory abnormalities occurred in > 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).
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