A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Viread Side Effects, and Drug Interactions - Tenofovir disoproxil fumarate
Viread Side Effects, and Drug Interactions - Tenofovir disoproxil fumarate
SIDE EFFECTS
More than 1000 patients have been treated with VIREAD
alone or in combination with other antiretroviral medicinal products for
periods of 28 days to 143 weeks in Phase I-III clinical trials and a compassionate
access study.
Assessment of adverse reactions is based on two studies
(902 and 907) in which 653 treatment experienced patients received double-blind
treatment with VIREAD 300 mg (n=443) or placebo (n=210) for 24 weeks followed
by extended treatment with VIREAD.
Treatment-Related Adverse Events: The most common
adverse events that occurred in patients receiving VIREAD with other antiretroviral
agents in clinical trials were mild to moderate gastrointestinal events,
such as nausea, diarrhea, vomiting and flatulence. Less than 1% of patients
discontinued participation in the clinical studies due to gastrointestinal
adverse events.
A summary of treatment related adverse events is provided
in Table 6 below.
Table 6. Treatment-Related Adverse Events (Grades 1-4)
Reported in ³3% of VIREAD-Treated Patients
in the Pooled 902 - 907 Studies (0-24 weeks)
| |
VIREAD 300 mg
|
Placebo
|
|
Number of Patients Treated
|
443
|
210
|
|
Nausea
|
11%
|
10%
|
|
Diarrhea
|
9%
|
8%
|
|
Asthenia
|
8%
|
8%
|
|
Headache
|
6%
|
7%
|
|
Vomiting
|
5%
|
2%
|
|
Flatulence
|
4%
|
0%
|
|
Abdominal Pain
|
3%
|
3%
|
|
Anorexia
|
3%
|
1%
|
Laboratory Abnormalities: Laboratory abnormalities
observed in these studies occurred with similar frequency in the VIREAD
and placebo treated groups. A summary of Grade 3 and 4 laboratory abnormalities
is provided in Table 7 below.
Table 7: Grade 3/4 Laboratory Abnormalities Reported
in ³ 1% of VIREAD-Treated Patients in
the Pooled 902 - 907 Studies (0-24 weeks)
| |
VIREAD 300 mg
|
Placebo
|
|
Number of Patients Treated
|
443
|
210
|
|
Number of Patients with Grade 3 or 4 Laboratory
Abnormalities
|
117 (26%)
|
78 (37%)
|
|
Laboratory abnormalities
|
|
|
|
Triglyceride (>750 mg/dL)
|
37 (8%)
|
28 (13%)
|
|
Creatine kinase (>782 U/L)
|
53 (12%)
|
38 (18%)
|
|
Serum amylase (>175 U/L)
|
21 (5%)
|
14 (7%)
|
|
AST
|
|
|
|
(M; >180 U/L)
|
16 (4%)
|
6 (3%)
|
|
(F: >170 U/L)
|
|
|
|
Urine glucose (3+ or 4+)
|
12 (3%)
|
6 (3%)
|
|
ALT elevation
|
|
|
|
(M: >215 U/L)
|
10 (2%)
|
4 (2%)
|
|
(F: >170 U/L)
|
|
|
|
Serum glucose (>250 mg/dL)
|
8 (2%)
|
8 (4%)
|
|
Neutrophil (<650/mm3)
|
6 (1%)
|
3 (1%)
|
Observed During Clinical Practice
In addition to adverse events reported from clinical trials,
the following events have been identified during post-approval use of VIREAD.
Because they are reported voluntarily from a population of unknown size, estimates
of frequency cannot be made. These events have been chosen for inclusion due
to a combination of their seriousness, frequency of reporting or potential causal
connection to VIREAD.
Body as a whole: Asthenia
Gastrointestinal: Pancreatitis
Metabolic and nutritional: Hypophosphatemia, lactic acidosis
Nervous: Dizziness
Respiratory: Dyspnea
Skin: Rash
Urogenital: Increased creatinine, renal insufficiency, kidney
failure, Fanconi syndrome
DRUG INTERACTIONS
At concentrations substantially higher (~ 300-fold) than
those observed in vivo, tenofovir did not inhibit in vitro drug metabolism
mediated by any of the following human CYP450 isoforms: CYP3A4, CYP2D6,
CYP2C9 or CYP2E1. However, a small (6%) but statistically significant
reduction in metabolism of CYP1A substrate was observed. Based on the
results of in vitro experiments and the known elimination pathway of tenofovir,
the potential for CYP450 mediated interactions involving tenofovir with
other medicinal products is low. (See Pharmacokinetics)
Tenofovir is primarily excreted by the kidneys by a combination
of glomerular filtration and active tubular secretion. Co-administration
of VIREAD with drugs that are eliminated by active tubular secretion may
increase serum concentrations of either tenofovir or the co-administered
drug, due to competition for this elimination pathway. Drugs that decrease
renal function may also increase serum concentrations of tenofovir.
VIREAD has been evaluated in healthy volunteers in combination
with didanosine, lamivudine, indinavir, efavirenz, and lopinavir / ritonavir.
Tables 1 and 2 summarize pharmacokinetic effects of co-administered drug
on tenofovir pharmacokinetics and effects of tenofovir on the pharmacokinetics
of co-administered drug.
Table 1. Drug Interactions: Changes in Pharmacokinetic
Parameters for Tenofovir1 in the Presence of the Co-administered
Drug
|
Co-administered Drug
|
Dose of Co-administered Drug (mg)
|
N
|
% Change of Tenofovir Pharmacokinetic Parameters2
(90% CI)
|
|
Cmax
|
AUC
|
Cmin
|
|
Lamivudine
|
150 twice daily x 7 days
|
15
|
Û
|
Û
|
Û
|
|
Didanosine
Enteric coated
|
400 X 1
|
25
|
Û
|
Û
|
Û
|
|
Didanosine3
Buffered
|
250 or 400 once daily x 7 days
|
14
|
Û
|
Û
|
Û
|
|
Indinavir
|
800 three times daily x 7 days
|
13
|
14
( ¯ 3 to
33)
|
Û
|
Û
|
|
Lopinavir/ Ritonavir
|
400/100 twice daily x 14 days
|
21
|
31
( 12 to
53)
|
34
( 25 to
44)
|
29
( 11 to
48)
|
|
Efavirenz
|
600 once daily x 14 days
|
29
|
Û
|
Û
|
Û
|
1. Patients received VIREAD 300 mg once daily
2. Increase= ; Decrease=
¯ ; No Effect= Û
3. Buffered formulation
Table 2. Drug Interactions: Changes in Pharmacokinetic
Parameters for Co-administered Drug in the Presence of VIREAD 300 mg Once
Daily
|
Co-administered Drug
|
Dose of Coadmin-istered Drug (mg)
|
N
|
% Change of Co-administered Drug Pharmacokinetic Parameters1
(90% CI)
|
|
Cmax
|
AUC
|
Cmin
|
|
Lamivudine
|
150 twice daily x 7 days
|
15
|
¯ 24
(¯ 34 to ¯
12)
|
Û
|
Û
|
| Didanosine2 (enteric coated, without
food, see PRECAUTIONS) |
400 x 1
|
26
|
48
( 25 to
76)
|
48
( 31 to
67)
|
–
|
| Didanosine3 (enteric coated, with food,
see PRECAUTIONS) |
400 x 1
|
26
|
64
( 41 to
89)
|
60
( 44 to
79)
|
–
|
|
Didanosine2
buffered (see PRECAUTIONS)
|
250 or 400 once daily x 7 days
|
14
|
28
( 11 to
48)
|
44
( 31 to
59)
|
–
|
|
Indinavir
|
800 three times daily x 7 days
|
12
|
¯ 11
(¯ 30 to
12)
|
Û
|
Û
|
|
Lopinavir
|
Lopinavir/Ritonavir 400/100 twice daily x 14 days
|
21
|
¯ 15
( ¯ 23 to ¯
6)
|
¯ 15
( ¯ 22 to ¯
7)
|
Û
|
|
Ritonavir 400/100 twice
|
Lopinavir/Ritonavir daily x 14 days
|
21
|
¯ 28
(¯ 43 to ¯
9)
|
¯ 24
(¯ 33 to ¯
13)
|
7
( ¯ 22 to
37)
|
|
Efavirenz
|
600 once daily x 14 days
|
30
|
Û
|
Û
|
Û
|
1. Increase= ; Decrease=
¯ ; No Effect= Û
2. Buffered formulation
top
