ADVERSE REACTIONS
Commonly Observed (based on first year and second year data - XENICAL 120 mg three times a day versus placebo):
Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events associated with the use of XENICAL in the seven double-blind, placebo-controlled clinical trials and are primarily a manifestation of the mechanism of action. (Commonly observed is defined as an incidence of ≥ 5% and an incidence in the XENICAL 120 mg group that is at least twice that of placebo.)
Table 11 Commonly Observed Adverse Events | Year 1 | Year 2 |
|---|
| Adverse Event | XENICAL
% Patients
(N=1913) | Placebo
% Patients
(N=1466) | XENICAL
% Patients
(N=613) | Placebo
% Patients
(N=524) |
|---|
| Oily Spotting | 26.6 | 1.3 | 4.4 | 0.2 |
| Flatus with Discharge | 23.9 | 1.4 | 2.1 | 0.2 |
| Fecal Urgency | 22.1 | 6.7 | 2.8 | 1.7 |
| Fatty/Oily Stool | 20.0 | 2.9 | 5.5 | 0.6 |
| Oily Evacuation | 11.9 | 0.8 | 2.3 | 0.2 |
| Increased Defecation | 10.8 | 4.1 | 2.6 | 0.8 |
| Fecal Incontinence | 7.7 | 0.9 | 1.8 | 0.2 |
These and other commonly observed adverse reactions were generally mild and transient, and they decreased during the second year of treatment. In general, the first occurrence of these events was within 3 months of starting therapy. Overall, approximately 50% of all episodes of GI adverse events associated with orlistat treatment lasted for less than 1 week, and a majority lasted for no more than 4 weeks. However, GI adverse events may occur in some individuals over a period of 6 months or longer.
Discontinuation of Treatment
In controlled clinical trials, 8.8% of patients treated with XENICAL discontinued treatment due to adverse events, compared with 5.0% of placebo-treated patients. For XENICAL, the most common adverse events resulting in discontinuation of treatment were gastrointestinal.
Incidence in Controlled Clinical Trials
The following table lists other treatment-emergent adverse events from seven multicenter, double-blind, placebo-controlled clinical trials that occurred at a frequency of ≥ 2% among patients treated with XENICAL 120 mg three times a day and with an incidence that was greater than placebo during year 1 and year 2, regardless of relationship to study medication.
Table 12 Other Treatment-Emergent Adverse Events From Seven Placebo-Controlled Clinical Trials | Year 1 | Year 2 |
|---|
| Body System/Adverse Event | XENICAL
% Patients
(N=1913) | Placebo
% Patients
(N=1466) | XENICAL
% Patients
(N=613) | Placebo
% Patients
(N=524) |
|---|
| – None reported at a frequency≥ 2% and greater than placebo |
| Gastrointestinal System | | | | |
| Abdominal Pain/Discomfort | 25.5 | 21.4 | – | – |
| Nausea | 8.1 | 7.3 | 3.6 | 2.7 |
| Infectious Diarrhea | 5.3 | 4.4 | – | – |
| Rectal Pain/Discomfort | 5.2 | 4.0 | 3.3 | 1.9 |
| Tooth Disorder | 4.3 | 3.1 | 2.9 | 2.3 |
| Gingival Disorder | 4.1 | 2.9 | 2.0 | 1.5 |
| Vomiting | 3.8 | 3.5 | – | – |
| Respiratory System | | | | |
| Influenza | 39.7 | 36.2 | – | – |
| Upper Respiratory Infection | 38.1 | 32.8 | 26.1 | 25.8 |
| Lower Respiratory Infection | 7.8 | 6.6 | – | – |
| Ear, Nose & Throat Symptoms | 2.0 | 1.6 | – | – |
| Musculoskeletal System | | | | |
| Back Pain | 13.9 | 12.1 | – | – |
| Pain Lower Extremities | – | – | 10.8 | 10.3 |
| Arthritis | 5.4 | 4.8 | – | – |
| Myalgia | 4.2 | 3.3 | – | – |
| Joint Disorder | 2.3 | 2.2 | – | – |
| Tendonitis | – | – | 2.0 | 1.9 |
| Central Nervous System | | | | |
| Headache | 30.6 | 27.6 | – | – |
| Dizziness | 5.2 | 5.0 | – | – |
| Body as a Whole | | | | |
| Fatigue | 7.2 | 6.4 | 3.1 | 1.7 |
| Sleep Disorder | 3.9 | 3.3 | – | – |
| Skin & Appendages | | | | |
| Rash | 4.3 | 4.0 | – | – |
| Dry Skin | 2.1 | 1.4 | – | – |
| Reproductive, Female | | | | |
| Menstrual Irregularity | 9.8 | 7.5 | – | – |
| Vaginitis | 3.8 | 3.6 | 2.6 | 1.9 |
| Urinary System | | | | |
| Urinary Tract Infection | 7.5 | 7.3 | 5.9 | 4.8 |
| Psychiatric Disorder | | | | |
| Psychiatric Anxiety | 4.7 | 2.9 | 2.8 | 2.1 |
| Depression | – | – | 3.4 | 2.5 |
| Hearing & Vestibular Disorders | | | | |
| Otitis | 4.3 | 3.4 | 2.9 | 2.5 |
| Cardiovascular Disorders | | | | |
| Pedal Edema | – | – | 2.8 | 1.9 |
In the 4-year XENDOS study, the general pattern of adverse events was similar to that reported for the 1- and 2-year studies with the total incidence of gastrointestinal-related adverse events occurring in year 1 decreasing each year over the 4-year period.
Other Clinical Studies or Postmarketing Surveillance
Rare cases of hypersensitivity have been reported with the use of XENICAL. Signs and symptoms have included pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption, increase in transaminases and in alkaline phosphatase, and exceptional cases of hepatitis that may be serious have been reported. No causal relationship or physiopathological mechanism between hepatitis and orlistat therapy has been established. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants. Hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine. Pancreatitis has been reported with the use of XENICAL in postmarketing surveillance. No causal relationship or physiopathological mechanism between pancreatitis and obesity therapy has been definitively established.
In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.
Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine (see WARNINGS).
Pediatric Patients
In clinical trials with XENICAL in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.
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