Systemic glucocorticosteroid use may result in the following:
- Hypercorticism and Adrenal Suppression [see WARNINGS AND PRECAUTIONS]
- Symptoms of steroid withdrawal in those patients transferring from Systemic Glucocorticosteroid Therapy [see WARNINGS AND PRECAUTIONS]
- Immunosuppression [see WARNINGS AND PRECAUTIONS]
- Increased Systemic Glucocorticosteroid Susceptibilty [see WARNINGS AND PRECAUTIONS]
- Other Glucocorticosteroid Effects [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice
The safety of ENTOCORT EC was evaluated in 651 patients in five short-term, active disease state studies. They ranged in age from 17 to 74 (mean 35), 40% were male and 97% were white, 2.6% were greater than or equal to 65 years of age. Five hundred and twenty patients were treated with ENTOCORT EC 9 mg (total daily dose). The most common adverse reactions reported were headache, respiratory infection, nausea, and symptoms of hypercorticism. Clinical studies have shown that the frequency of glucocorticosteroidassociated adverse reactions was substantially reduced with ENTOCORT EC capsules compared with prednisolone at therapeutically equivalent doses. Adverse reactions occurring in greater than or equal to 5% of the patients are listed in Table 1:
Table 1 : Adverse Reactions Occurring in greater than or equal to 5% of the Patients in any treated group
|Adverse Reaction||ENTOCORT EC 9 mg
|Prednisolone 40 mg
|Respiratory Infection||55 (11)||7(7)||20(14)||5(6)|
|*This drug is not approved for the treatment of Crohn's disease in the United States.|
The safety of ENTOCORT EC was evaluated in 233 patients in four long-term clinical trials (52 weeks). A total of 145 patients were treated with ENTOCORT EC 6 mg. A total of 8% of ENTOCORT EC patients discontinued treatment due to adverse reactions compared with 10% in the placebo group. The adverse reaction profile in long-term treatment of Crohn's disease was similar to that of short-term treatment with ENTOCORT EC 9 mg in active Crohn's disease.
In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% of the 6 mg ENTOCORT EC patients and are not listed in (Table 1) or by body system below: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).
Adverse reactions, occurring in patients treated with ENTOCORT EC 9 mg (total daily dose) in short-term active disease state studies and/or ENTOCORT EC 6 mg (total daily dose) long-term, with an incidence less than 5% and greater than placebo are listed below by system organ class:
Blood and lymphatic system disorders: leukocytosis
Cardiac disorders: palpitation, tachycardia, Eye disorders: eye abnormality, vision abnormal
General disorders and administration site conditions: asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, fever
Gastrointestinal disorders: anus disorder, Crohn's disease aggravated, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder
Infections and infestations: Ear infection-not otherwise specified, bronchitis, abscess, rhinitis, urinary tract infection, thrush
Investigations: c-reactive protein increased, weight increased
Metabolism and nutrition disorders: appetite increased, hypokalemia
Musculoskeletal and connective tissue disorders: arthritis, cramps, myalgia
Nervous system disorders: hyperkinesia, parasthesia, tremor, vertigo, dizziness, somnolence, amnesia
Psychiatric disorders: agitation, confusion, insomnia, nervousness, sleep disorder
Renal and urinary disorders: dysuria, micturition frequency, nocturia
Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder
Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder
Skin and subcutaneous tissue disorders: acne, alopecia, dermatitis, eczema, skin disorder, sweating increased, purpura
Vascular disorders: flushing, hypertension
Table 2 displays the frequency and incidence of signs/symptoms of hypercorticism by active questioning of patients in short-term clinical trials.
Table 2 : Summary and Incidence of Signs/Symptoms of Hypercorticism in Short-Term Studies
|Signs/Symptom||ENTOCORT EC 9 mg
|Prednisolone Taper 40 mg
|Acne||63 (15)||14 (13)||33 (23) *|
|Bruising Easily||63 (15)||12 (11)||13 (9)|
|Moon Face||46 (11)||4 (4)||53 (37) *|
|Swollen Ankles||32 (7)||6 (6)||13 (9)|
|Hirsutism†||22 (5)||2 (2)||5 (3)|
|Buffalo Hump||6 (1)||2 (2)||5 (3)|
|Skin Striae||4 (1)||2 (2)||0 (0)|
|* Statistically significantly different from ENTOCORT EC 9 mg
† Adverse reaction dictionary included term hair growth increased, local and hair growth increased, general.
Table 3 displays the frequency and incidence of signs/symptoms of hypercorticism by active questioning of patients in long-term clinical trials.
Table 3 : Summary and Incidence of Symptoms of Hypercorticism in Long-Term Studies
|Signs/Symptom||ENTOCORT EC 3 mg
|ENTOCORT EC 6 mg
|Bruising easily||4 (5)||15 (10)||5 (4)|
|Acne||4 (5)||14(10)||3 (2)|
|Moon face||3 (3)||6 (4)||0|
|Hirsutism||2 (2)||5 (3)||1 (1)|
|Swollen ankles||2 (2)||3(2)||3(2)|
|Buffalo hump||1 (1)||1 (1)||0|
|Skin striae||2 (2)||0||0|
The incidence of signs/symptoms of hypercorticism as described above in long-term clinical trials was similar to that seen in the short-term clinical trials.
A randomized, open, parallel-group multicenter safety study specifically compared the effect of ENTOCORT EC (less than 9 mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with ENTOCORT EC than with prednisolone in steroid-naïve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of symptoms associated with hypercorticism was significantly higher with prednisolone treatment.
Clinical Laboratory Test Findings
The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to ENTOCORT EC, were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, C-reactive protein increased, and adrenal insufficiency.
The following adverse reactions have been reported during post-approval use of ENTOCORT EC. 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.
Immune System Disorders: Anaphylactic reactions
Nervous System Disorders: Benign intracranial hypertension
Psychiatric Disorders: Mood swings