The safety of RESCRIPTOR Tablets alone and in combination with other therapies
hasbeen studied in approximately 6,000 patients receiving RESCRIPTOR. The majority
ofadverse 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)
| Percent of Patients with: |
Description of Rash Grade† |
RESCRIPTOR
400 m g TID
(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%) |
*Includes events reported regardless of causality
†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 Evaluable Patients in any Treatment Group
| |
Study 21 Part II |
Study 13C |
| Adverse Events |
ZDV + 3TC
(N = 123) |
400 mg tid RESC RESCRIPTOR+ ZDV
(N = 123) |
400 mg tid RESCRIPTOR + ZDV + 3TC
(N = 119) |
ZDV + ddI, ddC, or 3TC
(N = 172) |
400 mg tid RESCRIPTOR + ZDV + ddI, ddC or 3TC
(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) |
1.7 (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) |
| Vom iting |
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) |
| *Evaluable 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 that occurred in patients receiving RESCRIPTOR (in combination
treatment) in all phase II and III studies, and 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% ofpatients during Studies
21 Part II and 13C are summarized in Table 10. Markedlaboratory abnormalities
are defined as any Grade 3 or 4 abnormality found in patients atany time during
study.
Table 10. Marked Laboratory Abnormalities Reported by ≥ 2%
of Patients
| |
|
Study 21 Part II |
Study 13C |
| Adverse Events |
ToxicityLimit |
ZD V +3TC
N = 123 |
400 mg tid RESCRIPTOR + ZDV
N = 123 |
400 m g tid RESCRIPTOR + ZDV + 3TC
N = 119 |
ZDV + ddI, ddC or 3TC
N = 172 |
400 mg tid RESCRIPTOR + ZDV + ddI, ddC or 3TC
N = 170 |
| % pts. |
% pts. |
% pts. |
% pts. |
% 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 |
0.0 |
| N/A = not applicable because no predose values
were obtained for patients |