ADVERSE REACTIONS
Clinical Trials
The monthly formulation of LUPRON DEPOT 3.75 mg was utilized in controlled clinical trials that studied the drug in 166 endometriosis and 166 uterine fibroids patients. Adverse events reported in ≥ 5% of patients in either of these populations and thought to be potentially related to drug are noted in the following table.
Table 2 ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN ≥ 5% OF PATIENTS
| |
Endometriosis (2 Studies)
|
Uterine Fibroids (4 Studies)
|
| |
LUPRON DEPOT
3.75 mg
|
Danazol
|
Placebo
|
LUPRON DEPOT
3.75 mg
|
Placebo
|
| |
N=166
|
N=136
|
N=31
|
N=166
|
N=163
|
| |
N
|
(%)
|
N
|
(%)
|
N
|
(%)
|
N
|
(%)
|
N
|
(%)
|
| Body as a Whole |
|
|
|
|
|
|
|
|
|
|
| Asthenia |
5 |
(3) |
9 |
(7) |
0 |
(0) |
14 |
(8.4) |
8 |
(4.9) |
| General pain |
31 |
(19) |
22 |
(16) |
1 |
(3) |
14 |
(8.4) |
10 |
(6.1) |
| Headache* |
53 |
(32) |
30 |
(22) |
2 |
(6) |
43 |
(25.9) |
29 |
(17.8) |
| Cardiovascular System |
|
|
|
|
|
|
|
|
|
|
| Hot flashes/sweats* |
139 |
(84) |
77 |
(57) |
9 |
(29) |
121 |
(72.9) |
29 |
(17.8) |
| Gastrointestinal System |
|
|
|
|
|
|
|
|
|
|
| Nausea/vomiting |
21 |
(13) |
17 |
(13) |
1 |
(3) |
8 |
(4.8) |
6 |
(3.7) |
| GI disturbances* |
11 |
(7) |
8 |
(6) |
1 |
(3) |
5 |
(3.0) |
2 |
(1.2) |
| Metabolic and Nutritional Disorders |
|
|
|
|
|
|
|
|
|
|
| Edema |
12 |
(7) |
17 |
(13) |
1 |
(3) |
9 |
(5.4) |
2 |
(1.2) |
| Weight gain/loss |
22 |
(13) |
36 |
(26) |
0 |
(0) |
5 |
(3.0) |
2 |
(1.2) |
| Endocrine System |
|
|
|
|
|
|
|
|
|
|
| Acne |
17 |
(10) |
27 |
(20) |
0 |
(0) |
0 |
(0) |
0 |
(0) |
| Hirsutism |
2 |
(1) |
9 |
(7) |
1 |
(3) |
1 |
(0.6) |
0 |
(0) |
| Musculoskeletal System |
|
|
|
|
|
|
|
|
|
|
| Joint disorder* |
14 |
(8) |
11 |
(8) |
0 |
(0) |
13 |
(7.8) |
5 |
(3.1) |
| Myalgia* |
1 |
(1) |
7 |
(5) |
0 |
(0) |
1 |
(0.6) |
0 |
(0) |
| Nervous System |
|
|
|
|
|
|
|
|
|
|
| Decreased libido* |
19 |
(11) |
6 |
(4) |
0 |
(0) |
3 |
(1.8) |
0 |
(0) |
| Depression/emotional lability* |
36 |
(22) |
27 |
(20) |
1 |
(3) |
18 |
(10.8) |
7 |
(4.3) |
| Dizziness |
19 |
(11) |
4 |
(3) |
0 |
(0) |
3 |
(1.8) |
6 |
(3.7) |
| Nervousness* |
8 |
(5) |
11 |
(8) |
0 |
(0) |
8 |
(4.8) |
1 |
(0.6) |
| Neuromuscular disorders* |
11 |
(7) |
17 |
(13) |
0 |
(0) |
3 |
(1.8) |
0 |
(0) |
| Paresthesias |
12 |
(7) |
11 |
(8) |
0 |
(0) |
2 |
(1.2) |
1 |
(0.6) |
| Skin and Appendages |
|
|
|
|
|
|
|
|
|
|
| Skin reactions |
17 |
(10) |
20 |
(15) |
1 |
(3) |
5 |
(3.0) |
2 |
(1.2) |
| Urogenital System |
|
|
|
|
|
|
|
|
|
|
| Breast changes/tenderness/pain* |
10 |
(6) |
12 |
(9) |
0 |
(0) |
3 |
(1.8) |
7 |
(4.3) |
| Vaginitis* |
46 |
(28) |
23 |
(17) |
0 |
(0) |
19 |
(11.4) |
3 |
(1.8) |
| In these same studies, symptoms reported in < 5% of patients included: Body as a Whole - Body odor, Flu syndrome, Injection site reactions; Cardiovascular System - Palpitations, Syncope, Tachycardia; Digestive System - Appetite changes, Dry mouth, Thirst; Endocrine System - Androgen-like effects; Hemic and Lymphatic System - Ecchymosis, Lymphadenopathy; Nervous System - Anxiety*, Insomnia/Sleep disorders*, Delusions, Memory disorder, Personality disorder; Respiratory System - Rhinitis; Skin and Appendages - Alopecia, Hair disorder, Nail disorder; Special Senses - Conjunctivitis, Ophthalmologic disorders*, Taste perversion; Urogenital System - Dysuria*, Lactation, Menstrual disorders. |
| * = Possible effect of decreased estrogen. |
In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT, patients diagnosed with uterine fibroids received a higher dose (7.5 mg) of LUPRON DEPOT. Events seen with this dose that were thought to be potentially related to drug and were not seen at the lower dose included glossitis, hypesthesia, lactation, pyelonephritis, and urinary disorders. Generally, a higher incidence of hypoestrogenic effects was observed at the higher dose.
In a pharmacokinetic trial involving 20 healthy female subjects receiving LUPRON DEPOT–3 Month 11.25 mg, a few adverse events were reported with this formulation that were not reported previously. These included face edema, agitation, laryngitis, and ear pain.
In a Phase IV study involving endometriosis patients receiving LUPRON DEPOT 3.75 mg (N=20) or LUPRON DEPOT–3 Month 11.25 mg (N=21), similar adverse events were reported by the two groups of patients. In general the safety profiles of the two formulations were comparable in this study.
Table 3 lists the potentially drug-related adverse events observed in at least 5% of patients in any treatment group, during the first 6 months of treatment in the add-back clinical studies, in which patients were treated with monthly LUPRON DEPOT 3.75 mg with or without norethindrone acetate co-treatment.
Table 3 TREATMENT-RELATED ADVERSE EVENTS OCCURRING IN ≥ 5% OF PATIENTS
| |
Controlled Study
|
Open Label Study
|
| |
LD - Only*
N=51
|
LD/N†
N=55
|
LD/N†
N=136
|
|
Adverse Events
|
N
|
(%)
|
N
|
(%)
|
N
|
(%)
|
| Any Adverse Event |
50 |
(98) |
53 |
(96) |
126 |
(93) |
| Body as a Whole |
|
|
|
|
|
|
| Asthenia |
9 |
(18) |
10 |
(18) |
15 |
(11) |
| Headache/Migraine |
33 |
(65) |
28 |
(51) |
63 |
(46) |
| Injection Site Reaction |
1 |
(2) |
5 |
(9) |
4 |
(3) |
| Pain |
12 |
(24) |
16 |
(29) |
29 |
(21) |
| Cardiovascular System |
|
|
|
|
|
|
| Hot flashes/Sweats |
50 |
(98) |
48 |
(87) |
78 |
(57) |
| Digestive System |
|
|
|
|
|
|
| Altered Bowel Function |
7 |
(14) |
8 |
(15) |
14 |
(10) |
| Changes in Appetite |
2 |
(4) |
0 |
(0) |
8 |
(6) |
| GI Disturbance |
2 |
(4) |
4 |
(7) |
6 |
(4) |
| Nausea/Vomiting |
13 |
(25) |
16 |
(29) |
17 |
(13) |
| Metabolic and Nutritional Disorders |
|
|
|
|
|
|
| Edema |
0 |
(0) |
5 |
(9) |
9 |
(7) |
| Weight Changes |
6 |
(12) |
7 |
(13) |
6 |
(4) |
| Nervous System |
|
|
|
|
|
|
| Anxiety |
3 |
(6) |
0 |
(0) |
11 |
(8) |
| Depression/Emotional Lability |
16 |
(31) |
15 |
(27) |
46 |
(34) |
| Dizziness/Vertigo |
8 |
(16) |
6 |
(11) |
10 |
(7) |
| Insomnia/Sleep Disorder |
16 |
(31) |
7 |
(13) |
20 |
(15) |
| Libido Changes |
5 |
(10) |
2 |
(4) |
10 |
(7) |
| Memory Disorder |
3 |
(6) |
1 |
(2) |
6 |
(4) |
| Nervousness |
4 |
(8) |
2 |
(4) |
15 |
(11) |
| Neuromuscular Disorder |
1 |
(2) |
5 |
(9) |
4 |
(3) |
| Skin and Appendages |
|
|
|
|
|
|
| Alopecia |
0 |
(0) |
5 |
(9) |
4 |
(3) |
| Androgen-Like Effects |
2 |
(4) |
3 |
(5) |
24 |
(18) |
| Skin/Mucous Membrane Reaction |
2 |
(4) |
5 |
(9) |
15 |
(11) |
| Urogenital System |
|
|
|
|
|
|
| Breast Changes/Pain/Tenderness |
3 |
(6) |
7 |
(13) |
11 |
(8) |
| Menstrual Disorders |
1 |
(2) |
0 |
(0) |
7 |
(5) |
| Vaginitis |
10 |
(20) |
8 |
(15) |
11 |
(8) |
| * LD-Only = LUPRON DEPOT 3.75 mg |
| † LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg |
In the controlled clinical trial, 50 of 51 (98%) patients in the LD group (LUPRON DEPOT 3.75 mg) and 48 of 55 (87%) patients in the LD/N group (LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily) reported experiencing hot flashes on one or more occasions during treatment. During Month 6 of treatment, 32 of 37 (86%) patients in the LD group and 22 of 38 (58%) patients in the LD/N group reported having experienced hot flashes. The mean number of days on which hot flashes were reported during this month of treatment was 19 and 7 in the LD and LD/N treatment groups, respectively. The mean maximum number of hot flashes in a day during this month of treatment was 5.8 and 1.9 in the LD and LD/N treatment groups, respectively.
Changes in Bone Density
In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids (three months of therapy) were treated with LUPRON DEPOT 3.75 mg. In endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3.2% at six months compared with the pretreatment value. Clinical studies demonstrate that concurrent hormonal therapy (norethindrone acetate 5 mg daily) and calcium supplementation is effective in significantly reducing the loss of bone mineral density that occurs with LUPRON treatment, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis. LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in two clinical trials. The results from this regimen were similar in both studies. LUPRON DEPOT 3.75 mg was used as a control group in one study. The bone mineral density data of the lumbar spine from these two studies are presented in Table 4.
Table 4 MEAN PERCENT CHANGE FROM BASELINE IN BONE MINERAL DENSITY OF LUMBAR SPINE
| |
LUPRON DEPOT 3.75 mg
|
LUPRON DEPOT 3.75 mg plus
norethindrone acetate 5 mg daily
|
| |
Controlled Study
|
Controlled Study
|
Open Label Study
|
| |
N
|
Change
(Mean, 95% CI)
#
|
N
|
Change
(Mean, 95% CI)
#
|
N
|
Change
(Mean, 95% CI)
#
|
| Week 24* |
41 |
-3.2% (-3.8, -2.6) |
42 |
-0.3% (-0.8, 0.3) |
115 |
-0.2% (-0.6, 0.2) |
| Week 52† |
29 |
-6.3% (-7.1, -5.4) |
32 |
-1.0% (-1.9, -0.1) |
84 |
-1.1% (-1.6, -0.5) |
| * Includes on-treatment measurements that fell within 2-252 days after the first day of treatment. |
| † Includes on-treatment measurements >252 days after the first day of treatment. |
|
# 95% CI: 95% Confidence Interval |
In the Phase IV, six-month pharmacokinetic/pharmacodynamic study in endometriosis patients who were treated with LUPRON DEPOT 3.75 mg or LUPRON DEPOT–3 Month 11.25 mg, vertebral bone density measured by DEXA decreased compared with baseline by an average of 3.0% and 2.8% at six months for the two groups, respectively.
When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid patients, vertebral trabecular bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean decrease of 2.7% compared with baseline. Six months after discontinuation of therapy, a trend toward recovery was observed. Use of LUPRON DEPOT for longer than three months (uterine fibroids) or six months (endometriosis) or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss and is not recommended.
Changes in Laboratory Values During Treatment
Liver Enzymes
Three percent of uterine fibroid patients treated with LUPRON DEPOT 3.75 mg, manifested posttreatment transaminase values that were at least twice the baseline value and above the upper limit of the normal range. None of the laboratory increases were associated with clinical symptoms.
In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT or GGT. Five of the 6 increases were observed beyond 6 months of treatment. None were associated with an elevated bilirubin concentration.
Lipids
Triglycerides were increased above the upper limit of normal in 12% of the endometriosis patients who received LUPRON DEPOT 3.75 mg and in 32% of the subjects receiving LUPRON DEPOT–3 Month 11.25 mg.
Of those endometriosis and uterine fibroid patients whose pretreatment cholesterol values were in the normal range, mean change following therapy was +16 mg/dL to +17 mg/dL in endometriosis patients and +11 mg/dL to +29 mg/dL in uterine fibroid patients. In the endometriosis treated patients, increases from the pretreatment values were statistically significant (p<0.03). There was essentially no increase in the LDL/HDL ratio in patients from either population receiving LUPRON DEPOT 3.75 mg.
In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily were evaluated for 12 months of treatment. LUPRON DEPOT 3.75 mg was used as a control group in one study. Percent changes from baseline for serum lipids and percentages of patients with serum lipid values outside of the normal range in the two studies are summarized in the tables below.
Table 5 SERUM LIPIDS: MEAN PERCENT CHANGES FROM BASELINE VALUES AT TREATMENT WEEK 24
| |
LUPRON DEPOT 3.75 mg
|
LUPRON DEPOT 3.75 mg
plus norethindrone acetate 5 mg daily
|
| |
Controlled Study
(n=39)
|
Controlled Study
(n=41)
|
Open Label Study
(n=117)
|
| |
Baseline
Value* |
Wk 24
% Change |
Baseline
Value* |
Wk 24
% Change |
Baseline
Value* |
Wk 24
% Change |
| Total Cholesterol |
170.5 |
9.2% |
179.3 |
0.2% |
181.2 |
2.8% |
| HDL Cholesterol |
52.4 |
7.4% |
51.8 |
-18.8% |
51.0 |
-14.6% |
| LDL Cholesterol |
96.6 |
10.9% |
101.5 |
14.1% |
109.1 |
13.1% |
| LDL/HDL Ratio |
2.0† |
5.0% |
2.1† |
43.4% |
2.3† |
39.4% |
| Triglycerides |
107.8 |
17.5% |
130.2 |
9.5% |
105.4 |
13.8% |
| * mg/dL |
| † ratio |
Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from patients with follow up data returned to pretreatment values.
Table 6 PERCENTAGE OF PATIENTS WITH SERUM LIPID VALUES OUTSIDE OF THE NORMAL RANGE
| |
LUPRON DEPOT 3.75 mg
|
LUPRON DEPOT 3.75 mg
plus norethindrone acetate 5 mg daily
|
| |
Controlled Study
(n=39)
|
Controlled Study
(n=41)
|
Open Label Study
(n=117)
|
| |
Wk 0 |
Wk 24* |
Wk 0 |
Wk 24* |
Wk 0 |
Wk 24* |
Total Cholesterol (>240 mg/dL)
|
15% |
23% |
15% |
20% |
6% |
7% |
HDL Cholesterol (<40 mg/dL)
|
15% |
10% |
15% |
44% |
15% |
41% |
LDL Cholesterol (>160 mg/dL)
|
0% |
8% |
5% |
7% |
9% |
11% |
LDL/HDL Ratio (>4.0)
|
0% |
3% |
2% |
15% |
7% |
21% |
Triglycerides (>200 mg/dL)
|
13% |
13% |
12% |
10% |
5% |
9% |
| * Includes all patients regardless of baseline value. |
Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are recognized risk factors for cardiovascular disease. The long-term significance of the observed treatment-related changes in serum lipids in women with endometriosis is unknown. Therefore assessment of cardiovascular risk factors should be considered prior to initiation of concurrent treatment with LUPRON and norethindrone acetate.
Chemistry
Slight to moderate mean increases were noted for glucose, uric acid, BUN, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorus. None of these increases were clinically significant. In the hormonal add-back studies LUPRON DEPOT in combination with norethindrone acetate was associated with elevations of GGT and SGPT in 6% to 7% of patients.
Postmarketing
The following adverse reactions have been identified during postapproval use of LUPRON DEPOT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
During postmarketing surveillance with other dosage forms and in the same and/or different populations, the following adverse events were reported. Like other drugs in this class, mood swings, including depression, have been reported. There have been rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of development or worsening of depression during treatment with LUPRON.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Symptoms consistent with fibromyalgia (eg: joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.
Other events reported are:
Hepato-biliary disorder: Rarely reported serious liver injury
Injury, poisoning and procedural complications: Spinal fracture
Investigations: Decreased WBC
Musculoskeletal and Connective tissue disorder: Tenosynovitis-like symptoms
Nervous System Disorder: Convulsion, peripheral neuropathy, paralysis
Vascular Disorder: Hypotension
Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.
Pituitary apoplexy
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in the same and different patient populations.
|
