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
Nolvadex Side Effects, and Drug Interactions - Tamoxifen Citrate
Nolvadex Side Effects, and Drug Interactions - Tamoxifen Citrate
SIDE EFFECTS
Adverse reactions to tamoxifen citrate
are relatively mild and rarely severe enough to require discontinuation
of treatment in breast
cancer patients.
Continued clinical
studies have resulted in further information which better indicates
the incidence of adverse
reactions with tamoxifen citrate as compared to placebo.
Metastatic Breast Cancer
Increased bone and tumor
pain and, also, local
disease flare
have occurred, which are sometimes associated with a good tumor
response. Patients with increased bone
pain may require additional
analgesics. Patients with soft tissue disease
may have sudden increases in the size of preexisting lesions, sometimes
associated with marked erythema
within and surrounding the lesions and/or the development
of new lesions. When they occur, the bone
pain or disease flare
are seen shortly after starting tamoxifen citrate
and generally subside rapidly.
In patients treated with tamoxifen citrate
for metastatic breast
cancer, the most frequent adverse reaction
to tamoxifen citrate
is hot flashes.
Other adverse reactions which are seen infrequently are hypercalcemia,
peripheral edema, distaste for food, pruritus
vulvae, depression, dizziness, light-headedness, headache, hair
thinning and/or partial hair
loss, and vaginal dryness.
Premenopausal Women
TABLE 4 summarizes the incidence
of adverse reactions reported at a frequency of 2% or greater from
clinical trials (Ingle,
Pritchard, Buchanan) which compared tamoxifen citrate
therapy to ovarian ablation
in premenopausal patients with metastatic breast
cancer.
| TABLE 4 |
| |
Tamoxifen Citrate |
Ovarian Ablation |
| |
All Effects |
All Effects |
| |
% of Women |
% of Women |
| |
n = 104 |
n = 100 |
| Adverse Reactions* |
% |
% |
| Flush |
33 |
46 |
| Amenorrhea |
16 |
69 |
| Altered Menses |
13 |
5 |
| Oligomenorrhea |
9 |
1 |
| Bone Pain |
6 |
6 |
| Menstrual Disorder |
6 |
4 |
| Nausea |
5 |
4 |
| Cough/Coughing |
4 |
1 |
| Edema |
4 |
1 |
| Fatigue |
4 |
1 |
| Musculoskeletal Pain |
3 |
|
| Pain |
3 |
4 |
| Ovarian Cyst(s) |
3 |
2 |
| Depression |
2 |
2 |
| Abdominal Cramps |
1 |
2 |
| Anorexia |
1 |
2 |
| * Some women had more than one
adverse reaction. |
Male Breast Cancer
Tamoxifen citrate is
well tolerated in males with breast
cancer. Reports from the literature and case
reports suggest that the safety profile
of tamoxifen citrate
in males is similar to that seen in women. Loss of libido and impotence
have resulted in discontinuation of tamoxifen therapy in male patients.
Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone
and estrogen levels
were elevated. No significant
clinical changes were reported.
Adjuvant Breast Cancer
In the NSABP B-14 study, women with axillary node-negative breast
cancer were randomized to 5 years of tamoxifen citrate
20 mg/day or placebo
following primary surgery. The reported adverse effects are tabulated
in TABLE 5 (mean follow-up
of approximately 6.8 years) showing adverse events more common on
tamoxifen citrate than
on placebo. The incidence
of hot flashes (64% vs.
48%), vaginal discharge
(30% vs. 15%), and irregular menses
(25% vs. 19%) were higher with tamoxifen citrate
compared with placebo. All other adverse effects occurred with similar
frequency in the two treatment groups, with the exception of thrombotic
events, a higher incidence
was seen in tamoxifen citrate-treated patients (through 5 years,
1.7% vs. 0.4%). Two of the patients treated with tamoxifen citrate
who had thrombotic
events died.
| TABLE 5 NSABP B-14 Study |
| |
% of Women |
| |
Tamoxifen Citrate |
Placebo |
| Adverse Effect |
(n=1422) |
(n=1437) |
| Hot Flashes |
64 |
48 |
| Fluid Retention |
32 |
30 |
| Vaginal Discharge |
30 |
15 |
| Nausea |
26 |
24 |
| Irregular Menses |
25 |
19 |
| Weight Loss (>5%) |
23 |
18 |
| Skin Changes |
19 |
15 |
| Increased SGOT |
5 |
3 |
| Increased Bilirubin |
2 |
1 |
| Increased Creatinine |
2 |
1 |
| Thrombocytopenia* |
2 |
1 |
| Thrombotic Events |
|
|
0.8 |
0.2 |
|
|
0.5 |
0.2 |
|
|
0.4 |
0.0 |
| * Defined as a platelet
count of <100,000/mm3.
|
In the Eastern Cooperative Oncology Group (ECOG) adjuvant
breast cancer trial,
tamoxifen citrate or
placebo was administered
for 2 years to women following mastectomy. When compared to placebo,
tamoxifen citrate showed
a significantly higher incidence
of hot flashes (19% vs.
8% for placebo). The incidence
of all other adverse reactions was similar in the two treatment
groups with the exception of thrombocytopenia
where the incidence
for tamoxifen citrate was 10% vs. 3% for placebo, an observation
of borderline statistical
significance.
In other adjuvant
studies, Toronto and Nolvadex Adjuvant Trial Organization (NATO),
women received either tamoxifen citrate
or no therapy. In the Toronto
study, hot flashes were
observed in 29% for tamoxifen citrate
versus 1% in the untreated group. In
the NATO trial, hot flashes
and vaginal bleeding
were reported in 2.8% and 2.0% of women, respectively, for tamoxifen
citrate versus 0.2% for each in the untreated group.
Reduction in Breast Cancer Incidence in High Risk Women
In the NSABP P-1 Trial, there was an increase in five serious adverse
affects in the tamoxifen citrate
group: endometrial
cancer (33 cases in the
tamoxifen citrate group
vs. 14 in the placebo
group); pulmonary embolism (18 cases in the tamoxifen citrate
group vs. six in the placebo
group); deep vein thrombosis
(30 cases in the tamoxifen citrate
group vs. 19 in the placebo
group); stroke (34 cases
in the tamoxifen citrate
vs. 24 in the placebo
group); cataract formation
(540 cases in the tamoxifen citrate group vs. 483 in the placebo
group) and cataract
surgery (101 cases in the tamoxifen citrate
group vs. 63 in the placebo
group) (see WARNINGS and TABLE
2).
TABLE 6 presents the adverse events observed in NSABP P-1 by treatment
arm. Only adverse events more common on tamoxifen citrate
than placebo are shown.
| TABLE 6 NSABP P-1 Trial |
| All Adverse Events |
| |
% of Women |
| |
Tamoxifen Citrate |
Placebo |
| |
(n=6681) |
(n=6707) |
| Self Reported Symptoms |
N=6441* |
N=6469* |
|
|
80 |
68 |
|
|
55 |
35 |
|
|
23 |
22 |
| Laboratory Abnormalities |
N=6520† |
N=6535† |
|
|
0.7 |
0.3 |
| Adverse Effects |
N=6492‡ |
N=6484‡ |
| Other Toxicities |
|
|
11.6 |
10.8 |
|
|
6.0 |
5.1 |
|
|
4.4 |
3.2 |
|
|
5.2 |
4.4 |
|
|
5.6 |
4.7 |
|
|
2.5 |
2.1 |
| * Number with Quality of Life
Questionnaires. |
| † Number with Treatment Follow-up
Forms. |
| ‡ Number with Adverse Drug Reaction
Forms. |
In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving
tamoxifen citrate and placebo
therapy, respectively withdrew from the trial for medical reasons.
The following are the medical
reasons for withdrawing from tamoxifen citrate and placebo
therapy, respectively: Hot flashes (3.1% vs. 1.5%) and Vaginal Discharge
(0.5% vs. 0.1%).
In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving
tamoxifen citrate and placebo
therapy, respectively, withdrew for non-medical reasons.
On the NSABP P-1 trial, hot
flashes of any severity occurred in 68% of women on placebo
and in 80% of women on tamoxifen citrate. Severe hot flashes occurred
in 28% of women on placebo
and 45% of women on tamoxifen citrate. Vaginal discharge
occurred in 35% and 55% of women on placebo and tamoxifen citrate
respectively; and was severe in 4.5% and 12.3% respectively. There
was no difference in the incidence
of vaginal bleeding
between treatment arms.
Postmarketing Experience
Less frequently reported adverse reactions are vaginal
bleeding, vaginal discharge, menstrual irregularities and skin
rash. Usually these have not been of sufficient severity to require
dosage reduction
or discontinuation of treatment. Very rare reports of erythema
multiforme, Stevens-Johnson syndrome and bullous
pemphigoid have been
reported with tamoxifen citrate therapy.
DRUG INTERACTIONS
When tamoxifen citrate
is used in combination with coumarin-type anticoagulants, a significant
increase in anticoagulant
effect may occur. Where
such coadministration exists, careful monitoring of the patient's
prothrombin time
is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants
for any reason were ineligible for participation in the trial (see
CONTRAINDICATIONS).
There is an increased risk
of thromboembolic events occurring when cytotoxic agents are used
in combination with tamoxifen citrate.
Tamoxifen, N-desmethyl tamoxifen and 4-hydroxytamoxifen have been
found to be potent inhibitors
of hepatic cytochrome
p-450 mixed function
oxidases. The effect
of tamoxifen on metabolism
and excretion of other
antineoplastic drugs, such as cyclophosphamide
and other drugs that require mixed
function oxidases for activation, is not known.
One patient receiving
tamoxifen citrate with
concomitant phenobarbital
exhibited a steady state
serum level of tamoxifen
lower than that observed for other patients (i.e., 26 ng/ml
vs. mean value
of 122 ng/ml). However, the clinical
significance of this finding is not known.
Concomitant bromocriptine therapy has been shown to elevate serum
tamoxifen and N-desmethyl tamoxifen.
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