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The safety of RESCRIPTOR Tablets alone and in combination with other therapies has been studied in approximately 6,000 patients receiving RESCRIPTOR. The majority of adverse events were of mild or moderate (i.e., ACTG Grade 1 or 2) intensity. The most frequently reported drug-related adverse event (i.e., events considered by the investigator to be related to the blinded study medication or events with an unknown or missing causal relationship to the blinded medication) among patients receiving RESCRIPTOR was skin rash (see Table 8 and PRECAUTIONS: Skin Rash).

Table 8: Percent of Patients With Treatment-Emergent Rash in Pivotal Trials (Studies 21 Part II and 13C)a

Percent of Patients With: Description of Rash Gradeb RESCRIPTOR 400 mg t.i.d.
(n = 412)
Control Group Patients
(n = 295)
Grade 1 rash Erythema, pruritus 69 (16.7%) 35 (11.9%)
Grade 2 rash Diffuse maculopapular rash, dry desquamation 59 (14.3%) 17 (5.8%)
Grade 3 rash Vesiculation, moist desquamation, ulceration 18 (4.4%) 0 (0.0%)
Grade 4 rash Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliative dermatitis 0 (0.0%) 0 (0.0%)
Rash of any grade   146 (35.4%) 52 (17.6%)
Treatment discontinuation as a result of rash   13 (3.2%) 1 (0.3%)
a Includes events reported regardless of causality.
b ACTG Toxicity Grading System; includes events reported as “rash,” “maculopapular rash,” and “urticaria.”

Adverse events of moderate to severe intensity reported by at least 5% of evaluable patients in any treatment group in the pivotal trials, which includes patients receiving RESCRIPTOR in combination with zidovudine and/or lamivudine in Study 21 Part II for up to 98 weeks and in combination with zidovudine and either lamivudine, didanosine, or zalcitabine in Study 13C for up to 72 weeks are summarized in Table 9.

Table 9: Treatment-Emergent Events Regardless of Causality, of Moderate-to-Severe or Life-Threatening Intensity Reported by at Least 5% of Evaluablea Patients in Any Treatment Group

Adverse Events Study 21 Part II Study 13C
Zidovudine + Lamivudine
(n = 123)
400 mg t.i.d. RESCRIPTOR + Zidovudine
(n = 123)
400 mg t.i.d. RESCRIPTOR + Zidovudine + Lamivudine
(n = 119)
Zidovudine + Didanosine, Zalcitabine, or Lamivudine
(n = 172)
400 mg t.i.d. RESCRIPTOR + Zidovudine + Didanosine, Zalcitabine, or Lamivudine
(n = 170)
% of pts. (n) % of pts. (n) % of pts. (n) % of pts. (n) % of pts. (n)
Body as a Whole
Abdominal pain, generalized 2.4 (3) 3.3 (4) 5.0 (6) 17 (3) 2.4 (4)
Asthenia/fatigue 16.3 (20) 15.4 (19) 16.0 (19) 8.1 (14) 5.3 (9)
Fever 2.4 (3) 1.6 (2) 3.4 (4) 6.4 (11) 7.1 (12)
Flu syndrome 4.9 (6) 7.3 (9) 5.0 (6) 5.2 (9) 2.4 (4)
Headache 14.6 (18) 12.2 (15) 16.8 (20) 12.8 (22) 11.2 (19)
Localized pain 4.9 (6) 5.7 (7) 5.0 (6) 2.9 (5) 1.8 (3)
Digestive
Diarrhea 8.1 (10) 2.4 (3) 4.2 (5) 8.1 (14) 5.9 (10)
Nausea 17.1 (21) 20.3 (25) 16.8 (20) 9.3 (16) 14.7 (25)
Vomiting 8.9 (11) 4.9 (6) 2.5 (3) 4.1 (7) 6.5 (11)
Nervous
Anxiety 1.6 (2) 2.4 (3) 6.7 (8) 4.1 (7) 3.5 (6)
Depressive symptoms 6.5 (8) 4.9 (6) 12.6 (15) 3.5 (6) 5.9 (10)
Insomnia 4.9 (6) 4.9 (6) 5.0 (6) 2.9 (5) 1.2 (2)
Respiratory
Bronchitis 4.1 (5) 6.5 (8) 6.7 (8) 3.5 (6) 3.5 (6)
Cough 9.8 (12) 4.1 (5) 5.0 (6) 5.2 (9) 3.5 (6)
Pharyngitis 6.5 (8) 1.6 (2) 5.0 (6) 4.1 (7) 3.5 (6)
Sinusitis 8.9 (11) 7.3 (9) 5.0 (6) 2.3 (4) 1.2 (2)
Upper respiratory infection 11.4 (14) 6.5 (8) 7.6 (9) 8.7 (15) 4.7 (8)
Skin
Rashes 3.3 (4) 19.5 (24) 13.4 (16) 7.6 (13) 18.8 (32)
aEvaluable patients in Study 21 Part II were those who received at least 1 dose of study medication and returned for at least 1 clinic study visit. Evaluable patients in Study 13C were those who received at least 1 dose of study medication.

Other Adverse Events in Phase II/III Studies: Other adverse events that occurred in patients receiving RESCRIPTOR (in combination treatment) in all Phase II and III studies, considered possibly related to treatment, and of at least ACTG Grade 2 in intensity are listed below by body system.

Body as a Whole: Abdominal cramps, abdominal distention, abdominal pain (localized), abscess, allergic reaction, chills, edema (generalized or localized), epidermal cyst, fever, infection, infection viral, lip edema, malaise, Mycobacterium tuberculosis infection, neck rigidity, sebaceous cyst, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).

Cardiovascular System: Abnormal cardiac rate and rhythm, cardiac insufficiency, cardiomyopathy, hypertension, migraine, pallor, peripheral vascular disorder, and postural hypotension.

Digestive System: Anorexia, bloody stool, colitis, constipation, decreased appetite, diarrhea (Clostridium difficile), diverticulitis, dry mouth, dyspepsia, dysphagia, enteritis at all levels, eructation, fecal incontinence, flatulence, gagging, gastroenteritis, gastroesophageal reflux, gastrointestinal bleeding, gastrointestinal disorder, gingivitis, gum hemorrhage, hepatomegaly, increased appetite, increased saliva, increased thirst, jaundice, mouth or tongue inflammation or ulcers, nonspecific hepatitis, oral/enteric moniliasis, pancreatitis, rectal disorder, sialadenitis, tooth abscess, and toothache.

Hemic and Lymphatic System: Adenopathy, bruising, eosinophilia, granulocytosis, leukopenia, pancytopenia, purpura, spleen disorder, thrombocytopenia, and prolonged prothrombin time.

Metabolic and Nutritional Disorders: Alcohol intolerance, amylase increased, bilirubinemia, hyperglycemia, hyperkalemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hyponatremia, hypophosphatemia, increased AST (SGOT), increased gamma glutamyl transpeptidase, increased lipase, increased serum alkaline phosphatase, increased serum creatinine, and weight increase or decrease.

Musculoskeletal System: Arthralgia or arthritis of single and multiple joints, bone disorder, bone pain, myalgia, tendon disorder, tenosynovitis, tetany, and vertigo.

Nervous System: Abnormal coordination, agitation, amnesia, change in dreams, cognitive impairment, confusion, decreased libido, disorientation, dizziness, emotional lability, euphoria, hallucination, hyperesthesia, hyperreflexia, hypertonia, hypesthesia, impaired concentration, manic symptoms, muscle cramp, nervousness, neuropathy, nystagmus, paralysis, paranoid symptoms, restlessness, sleep cycle disorder, somnolence, tingling, tremor, vertigo, and weakness.

Respiratory System: Chest congestion, dyspnea, epistaxis, hiccups, laryngismus, pneumonia, and rhinitis.

Skin and Appendages: Angioedema, dermal leukocytoclastic vasculitis, dermatitis, desquamation, diaphoresis, discolored skin, dry skin, erythema, erythema multiforme, folliculitis, fungal dermatitis, hair loss, herpes zoster or simplex, nail disorder, petechiae, non-application site pruritus, seborrhea, skin hypertrophy, skin disorder, skin nodule, Stevens-Johnson syndrome, urticaria, vesiculobullous rash, and wart.

Special Senses: Blepharitis, blurred vision, conjunctivitis, diplopia, dry eyes, ear pain, parosmia, otitis media, photophobia, taste perversion, and tinnitus.

Urogenital System: Amenorrhea, breast enlargement, calculi of the kidney, chromaturia, epididymitis, hematuria, hemospermia, impaired urination, impotence, kidney pain, metrorrhagia, nocturia, polyuria, proteinuria, testicular pain, urinary tract infection, and vaginal moniliasis.

Postmarketing Experience

Adverse event terms reported from postmarketing surveillance that were not reported in the Phase II and III trials are presented below.

Digestive System: Hepatic failure.

Hemic and Lymphatic System: Hemolytic anemia.

Musculoskeletal System: Rhabdomyolysis.

Urogenital System: Acute kidney failure.

Laboratory Abnormalities

Marked laboratory abnormalities observed in at least 2% of patients during Studies 21 Part II and 13C are summarized in Table 10. Marked laboratory abnormalities are defined as any Grade 3 or 4 abnormality found in patients at any time during study.

Table 10:Marked Laboratory Abnormalities Reported by ≥ 2% of Patients

Adverse Events/Toxicity Limits Study 21 Part II Study 13C
Zidovudine + Lamivudine
(n =123) % pts.
400 mg t.i.d. RESCRIPTOR + Zidovudine
(n =123) % pts.
400 mg t.i.d. RESCRIPTOR + Zidovudine + Lamivudine
(n = 119) % pts.
Zidovudine + Didanosine, Zalcitabine, or Lamivudine
(n = 172) % pts.
400 mg t.i.d. RESCRIPTOR + Zidovudine + Didanosine, Zalcitabine, or Lamivudine
(n = 170) % pts.
Hematology
Hemoglobin < 7 mg/dL 4.1 2.5 0.9 1.7 2.9
Neutrophils < 750/mm³ 5.7 4.9 3.4 10.4 7.6
Prothrombin time (PT) > 1.5 x ULN 0 0 1.7 2.9 2.4
Activated partial thromboplastin (APTT) > 2.33 x ULN 0 0.8 0 5.8 2.4
Chemistry
Alananine aminotransferase (ALT/SGPT) > 5 x ULN 2.5 4.1 5.1 3.5 4.1
Amylase > 2 x ULN 0.8 2.5 2.6 3.5 2.9
Aspartate aminotransferase (AST/SGOT) > 5 x ULN 1.6 2.5 3.4 3.5 2.3
Bilirubin > 2.5 x ULN 0.8 2.5 1.7 1.2 0
Gamma glutamyl transferase (GGT) > 5 x ULN N/A N/A N/A 4.1 1.8
Glucose (hypo/hyperglycemia) < 40 mg/dL > 250 mg/dL 4.1 0.8 1.7 1.2 0
N/A = not applicable because no predose values were obtained for patients.