Xenical Drug Information
Generic name: ORLISTAT
Intestinal Lipase Inhibitor [EPC]
Uses of Xenical
is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. XENICAL is indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m 2 or ≥27 kg/m 2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia). Table 1 illustrates body mass index (BMI) according to a variety of weights and heights.
The BMI is calculated by dividing weight in kilograms by height in meters squared. For example, a person who weighs 180 lbs and is 5 ' 5 " would have a BMI of 30. Table 1 Body Mass Index (BMI), kg/m 2 Conversion Factors: Weight in lbs ÷ 2.2 = weight in kilograms (kg) Height in inches × 0.0254 = height in meters (m) 1 foot = 12 inches XENICAL is a reversible inhibitor of gastrointestinal lipases indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. XENICAL is also indicated to reduce the risk for weight regain after prior weight loss.
Table 1
Dosage & Administration of Xenical
Recommended Dosing
The recommended dose of XENICAL is one 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal). The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of XENICAL can be omitted.
Because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition . The vitamin supplement should be taken at least 2 hours before or after the administration of XENICAL, such as at bedtime. For patients receiving both XENICAL and cyclosporine therapy, administer cyclosporine 3 hours after XENICAL. For patients receiving both XENICAL and levothyroxine therapy, administer levothyroxine and XENICAL at least 4 hours apart. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function.
Doses above 120 mg three times a day have not been shown to provide additional benefit. Based on fecal fat measurements, the effect of XENICAL is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.
Side Effects of Xenical
Clinical Trials
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 patients. Commonly Observed (based on first year and second year data) 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 2 Commonly Observed Adverse Events Adverse Event Year 1 Year 2 XENICAL Treatment designates XENICAL three times a day plus diet or placebo plus diet % Patients (N=1913) Placebo % Patients (N=1466) XENICAL % Patients (N=613) Placebo % Patients (N=524) Oily Spotting Oily discharge may be clear or have a coloration such as orange or brown. 26.6 1.3 4.4
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
Fecal Incontinence 7.7 0.9 1.8 0.2
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 XENICAL 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. Other Adverse Clinical Events 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 3 Other Treatment-Emergent Adverse Events From Seven Placebo-Controlled Clinical Trials Body System/Adverse Event Year 1 Year 2 XENICAL Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet % 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
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
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
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
Arthritis 5.4 4.8 – – Myalgia 4.2 3.3 – – Joint Disorder
2.3 2.2 – – Tendonitis – – 2.0
Central Nervous System Headache 30.6 27.6 – – Dizziness 5.2 5.0 –
– Body as a Whole Fatigue 7.2 6.4 3.1
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
Urinary System Urinary Tract Infection 7.5 7.3 5.9 4.8 Psychiatric Disorder Psychiatric
Anxiety 4.7 2.9 2.8
Depression – – 3.4 2.5 Hearing & Vestibular Disorders Otitis 4.3 3.4
2.9
Cardiovascular Disorders Pedal Edema – – 2.8 1.9 Table 4 illustrates the
percentage of adult patients on XENICAL and placebo who developed a low vitamin level on two or more consecutive visits during 1 and 2 years of therapy in studies in which patients were not previously receiving vitamin supplementation. Table 4 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values - First and Second Year) Placebo Treatment designates placebo plus diet or XENICAL plus diet XENICAL Vitamin A 1.0% 2.2% Vitamin D 6.6% 12.0% Vitamin E 1.0% 5.8% Beta-carotene 1.7% 6.1% Table 5 illustrates the percentage of adolescent patients on XENICAL and placebo who developed a low vitamin level on two or more consecutive visits during the 1-year study. Table 5 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Pediatric Patients With Normal Baseline Values All patients were treated with vitamin supplementation throughout the course of the study ) Placebo Treatment designates placebo plus diet or XENICAL plus diet XENICAL Vitamin A 0.0% 0.0% Vitamin D 0.7% 1.4% Vitamin E 0.0% 0.0% Beta-carotene 0.8% 1.5% 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.
In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed. 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.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of XENICAL. 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 XENICAL exposure. Rare cases of increase in transaminases and in alkaline phosphatase and hepatitis that may be serious have been reported. There have been reports of hepatic failure observed with the use of XENICAL in postmarketing surveillance, with some of these cases resulting in liver transplant or death . 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 have been reported. Rare cases of leukocytoclastic vasculitis have been reported. Clinical signs include palpable purpura, maculopapular lesions, or bullous eruption.
Acute oxalate nephropathy after treatment with XENICAL has been reported in patients with or at risk for renal disease . 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. Lower gastrointestinal bleeding has been reported in patients treated with XENICAL. Most reports are nonserious; severe or persistent cases should be investigated further.
Warnings & Cautions for Xenical
Drug Interactions and Decreased Vitamin Absorption
XENICAL may interact with concomitant drugs including cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, and antiretroviral drugs. Data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Therefore, XENICAL and cyclosporine should not be simultaneously coadministered.
To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 hours before or after XENICAL in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered. Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene . In addition, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects.
The supplement should be taken once a day at least 2 hours before or after the administration of XENICAL, such as at bedtime. Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin may be required in some patients .
Liver Injury
There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with XENICAL, with some of these cases resulting in liver transplant or death. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain) while taking XENICAL. When these symptoms occur, XENICAL and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.
Oxalate Nephrolithiasis and Oxalate Nephropathy with Renal Failure Some patients may develop
increased levels of urinary oxalate following treatment with XENICAL. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing XENICAL to patients at increased risk for oxalate nephropathy, including patients with renal impairment and in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis. Discontinue XENICAL in patients who develop oxalate nephropathy.
Cholelithiasis Substantial weight loss can increase the risk of cholelithiasis.
In a clinical trial of XENICAL for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to XENICAL and 1.8% (30/1655) for patients randomized to placebo.
Miscellaneous Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing
XENICAL. Patients should be advised to adhere to dietary guidelines . Gastrointestinal events may increase when XENICAL is taken with a diet high in fat (>30% total daily calories from fat). The daily intake of fat should be distributed over three main meals. If XENICAL is taken with any one meal very high in fat, the possibility of gastrointestinal effects increases.
Drug Interactions with Xenical
Cyclosporine Data from a
XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. XENICAL and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of XENICAL .
Fat-soluble Vitamin Supplements and Analogues Data from a pharmacokinetic interaction study showed
that the absorption of beta-carotene supplement is reduced when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement. The effect of XENICAL on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time .
Levothyroxine Hypothyroidism has been reported in patients treated concomitantly with
XENICAL and levothyroxine postmarketing. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and XENICAL at least 4 hours apart .
Anticoagulants including Warfarin Vitamin K absorption may be decreased with
XENICAL. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with XENICAL and anticoagulants. Patients on chronic stable doses of warfarin or other anticoagulants who are prescribed XENICAL should be monitored closely for changes in coagulation parameters .
Amiodarone
A pharmacokinetic study, where amiodarone was orally administered during orlistat treatment, demonstrated a reduction in exposure to amiodarone and its metabolite, desethylamiodarone . A reduced therapeutic effect of amiodarone is possible. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied.
Antiepileptic Drugs Convulsions have been reported in patients treated concomitantly with orlistat
and antiepileptic drugs. Patients should be monitored for possible changes in the frequency and/or severity of convulsions.
Antiretroviral Drugs Loss of virological control has been reported in
HIV-infected patients taking orlistat concomitantly with antiretroviral drugs such as atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, and with the combinations lopinavir/ritonavir and emtricitabine/efavirenz/tenofovir disoproxil fumarate. The exact mechanism for this is unclear, but may include a drug-drug interaction that inhibits systemic absorption of the antiretroviral drug. HIV RNA levels should be frequently monitored in patients who take XENICAL while being treated for HIV infection.
If there is a confirmed increase in HIV viral load, XENICAL should be discontinued.
Pregnancy Safety for Xenical
Pregnancy Pregnancy Category X XENICAL is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus. Animal Data Reproduction studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity.
This dose is 23 and 47 times the daily human dose calculated on a body surface area (mg/m 2 ) basis for rats and rabbits, respectively.
Pediatric Use of Xenical
Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 have not been established. The safety and efficacy of XENICAL have been evaluated in obese adolescent patients aged 12 to 16 years. Use of XENICAL in this age group is supported by evidence from adequate and well-controlled studies of XENICAL in adults with additional data from a 54-week efficacy and safety study and a 21-day mineral balance study in obese adolescent patients aged 12 to 16 years.
Patients treated with XENICAL in the 54-week efficacy and safety study (64.8% female, 75% Caucasians, 18.8% Blacks, and 6.3% Other) had a mean reduction in BMI of 0.55 kg/m 2 compared with an average increase of 0.31 kg/m 2 in placebo-treated patients (p=0.001). In both adolescent studies, adverse effects were generally similar to those described in adults and included fatty/oily stool, oily spotting, and oily evacuation. In a subgroup of 152 XENICAL and 77 placebo patients from the 54-week study, changes in body composition measured by DEXA were similar in both treatment groups with the exception of fat mass, which was significantly reduced in patients treated with XENICAL compared to patients treated with placebo (-2.5 kg vs -0.6 kg, p=0.033). Because XENICAL can interfere with the absorption of fat-soluble vitamins, all patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. The vitamin supplement should be taken at least 2 hours before or after XENICAL . Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to those found in adults at the same dose level.
Daily fecal fat excretions were 27% and 7% of dietary intake in XENICAL and placebo treatment groups, respectively.
Contraindications for Xenical
is contraindicated in: Pregnancy Patients with chronic malabsorption syndrome Patients with cholestasis Patients with known hypersensitivity to XENICAL or to any component of this product Pregnancy Chronic malabsorption syndrome Cholestasis Known hypersensitivity to XENICAL or to any component of this product
Overdosage Information for Xenical
Single doses of 800 mg XENICAL and multiple doses of up to 400 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings. Should a significant overdose of XENICAL occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, systemic effects attributable to the lipase-inhibiting properties of XENICAL should be rapidly reversible.
Clinical Studies of Xenical
One-year Results: Weight Loss, Weight Maintenance, and Risk Factors Pooled data from
five clinical trials indicated that the overall mean weight loss from randomization to the end of 1 year of treatment in the intent-to-treat population was 13.4 lbs in the patients treated with XENICAL and 5.8 lbs in the placebo-treated patients. After 1 year of treatment, the mean percent weight loss difference between XENICAL-treated patients and placebo-treated patients was 3%. One thousand seventy two (69%) patients treated with XENICAL and 701 (63%) patients treated with placebo completed 1 year of treatment. Of the patients who completed 1 year of treatment, 57% of the patients treated with XENICAL (120 mg three times a day) and 31% of the placebo-treated patients lost at least 5% of their baseline body weight.
The percentages of patients achieving ≥5% and ≥10% weight loss after 1 year in five large multicenter studies for the intent-to-treat populations are presented in Table 6. Table 6 Percentage of Patients Losing ≥5% and ≥10% of Body Weight From Randomization After 1-Year Treatment Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet Study No. Intent-to-Treat Population Last observation carried forward ≥5% Weight Loss ≥10% Weight Loss XENICAL n Placebo n p-value XENICAL n Placebo n p-value The diet utilized during year 1 was a reduced-calorie diet. 14119B 35.5% 110 21.3% 108 0.021 16.4% 110 6.5% 108 0.022 14119C 54.8% 343 27.4% 340 <0.001 24.8% 343 8.2% 340 <0.001 14149 50.6% 241 26.3% 236 <0.001 22.8% 241 11.9% 236 0.02 14161 All studies, with the exception of 14161, were conducted at centers specialized in treating obesity and complications of obesity. Study 14161 was conducted with primary care physicians. 37.1% 210 16.0% 212 <0.001 19.5% 210 3.8% 212 <0.001 14185 42.6% 657 22.4% 223 <0.001 17.7% 657 9.9% 223 0.006 The relative changes in risk factors associated with obesity following 1 year of therapy with XENICAL and placebo are presented for the population as a whole and for the population with abnormal values at randomization.
Population as a Whole The changes in metabolic, cardiovascular and anthropometric risk factors associated with obesity based on pooled data for five clinical studies, regardless of the patient's risk factor status at randomization, are presented in Table 7. One year of therapy with XENICAL resulted in relative improvement in several risk factors. Table 7 Mean Change in Risk Factors From Randomization Following 1-Year Treatment Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet Population as a Whole Risk Factor XENICAL 120 mg Intent-to-treat population at week 52, observed data based on pooled data from 5 studies Placebo Metabolic: Total Cholesterol -2.0% +5.0% LDL-Cholesterol -4.0% +5.0% HDL-Cholesterol +9.3% +12.8% LDL/HDL -0.37 -0.20 Triglycerides +1.34% +2.9% Fasting Glucose, mmol/L -0.04 +
Fasting Insulin, pmol/L -6.7 +5.2 Cardiovascular: Systolic Blood Pressure, mm Hg -1.01
+0.58 Diastolic Blood Pressure, mm Hg -1.19 +0.46 Anthropometric: Waist Circumference, cm -6.45 -4.04 Hip Circumference, cm -5.31 -2.96 Population With Abnormal Risk Factors at Randomization The changes from randomization following 1-year treatment in the population with abnormal lipid levels (LDL ≥130 mg/dL, LDL/HDL ≥3.5, HDL <35 mg/dL) were greater for XENICAL compared to placebo with respect to LDL-cholesterol (-7.83% vs +1.14%) and the LDL/HDL ratio (-0.64 vs -0.46). HDL increased in the placebo group by 20.1% and in the XENICAL group by 18.8%. In the population with abnormal blood pressure at baseline (systolic BP ≥140 mm Hg), the change in SBP from randomization to 1 year was greater for XENICAL (-10.89 mm Hg) than placebo (-5.07 mm Hg). For patients with a diastolic blood pressure ≥90 mm Hg, XENICAL patients decreased by -7.9 mm Hg while the placebo patients decreased by -5.5 mm Hg. Fasting insulin decreased more for XENICAL than placebo (-39 vs -16 pmol/L) from randomization to 1 year in the population with abnormal baseline values (≥120 pmol/L). A greater reduction in waist circumference for XENICAL vs placebo (-7.29 vs -4.53 cm) was observed in the population with abnormal baseline values (≥100 cm).
Effect on Weight Regain Three studies were designed to evaluate the effects
of XENICAL compared to placebo in reducing weight regain after a previous weight loss achieved following either diet alone (one study, 14302) or prior treatment with XENICAL (two studies, 14119C and 14185). The diet utilized during the 1-year weight regain portion of the studies was a weight-maintenance diet, rather than a weight-loss diet, and patients received less nutritional counseling than patients in weight-loss studies. For studies 14119C and 14185, patients' previous weight loss was due to 1 year of treatment with XENICAL in conjunction with a mildly hypocaloric diet. Study 14302 was conducted to evaluate the effects of 1 year of treatment with XENICAL on weight regain in patients who had lost 8% or more of their body weight in the previous 6 months on diet alone.
In study 14119C, patients treated with placebo regained 52% of the weight they had previously lost while the patients treated with XENICAL regained 26% of the weight they had previously lost (p<0.001). In study 14185, patients treated with placebo regained 63% of the weight they had previously lost while the patients treated with XENICAL regained 35% of the weight they had lost (p<0.001). In study 14302, patients treated with placebo regained 53% of the weight they had previously lost while the patients treated with XENICAL regained 32% of the weight that they had lost (p<0.001).
Two-year Results: Long-term Weight Control and Risk Factors
The treatment effects of XENICAL were examined for 2 years in four of the five 1-year weight management clinical studies previously discussed (see Table 6 ). At the end of year 1, the patients' diets were reviewed and changed where necessary. The diet prescribed in the second year was designed to maintain patient's current weight. XENICAL was shown to be more effective than placebo in long-term weight control in four large, multicenter, 2-year double-blind, placebo-controlled studies.
Pooled data from four clinical studies indicate that 74% of all patients treated with 120 mg three times a day of XENICAL and 76% of patients treated with placebo completed 2 years of the same therapy. Pooled data from four clinical studies indicate that the mean weight loss difference between XENICAL 120 mg three times a day and placebo treatment groups at year 2 in those patients who completed 1 year of treatment (ITT LOCF) was 3%. In the same studies cited in the One-year Results (see Table 6 ), the percentages of patients achieving a ≥5% and ≥10% weight loss after 2 years are shown in Table 8. Table 8 Percentage of Patients Losing ≥5% and ≥10% of Body Weight From Randomization After 2-Year Treatment Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet Study No. Intent-to-Treat Population Last observation carried forward ≥5% Weight Loss ≥10% Weight Loss XENICAL n Placebo n p-value XENICAL n Placebo n p-value The diet utilized during year 2 was designed for weight maintenance and not weight loss. 14119C 45.1% 133 23.6% 123 <0.001 24.8% 133 6.5% 123 <0.001 14149 43.3% 178 27.2% 158 0.002 18.0% 178 9.5% 158 0.025 14161 All studies, with the exception of 14161, were conducted at centers specializing in treating obesity or complications of obesity.
Study 14161 was conducted with primary care physicians. 25.0% 148 15.0% 113 0.049 16.9% 148 3.5% 113 0.001 14185 34.0% 147 27.9% 122 0.279 17.7% 147 11.5% 122 0.154 The relative changes in risk factors associated with obesity following 2 years of therapy were also assessed in the population as a whole and the population with abnormal risk factors at randomization. Population as a Whole The relative differences in risk factors between treatment with XENICAL and placebo were similar to the results following 1 year of therapy for total cholesterol, LDL-cholesterol, LDL/HDL ratio, triglycerides, fasting glucose, fasting insulin, diastolic blood pressure, waist circumference, and hip circumference. The relative differences between treatment groups for HDL cholesterol and systolic blood pressure were less than that observed in the year one results.
Population With Abnormal Risk Factors at Randomization The relative differences in risk factors between treatment with XENICAL and placebo were similar to the results following 1 year of therapy for LDL- and HDL-cholesterol, triglycerides, fasting insulin, diastolic blood pressure, and waist circumference. The relative differences between treatment groups for LDL/HDL ratio and isolated systolic blood pressure were less than that observed in the year one results.
Four-year Results: Long-term Weight Control and Risk Factors
In the 4-year double-blind, placebo-controlled XENDOS study, the effects of XENICAL in delaying the onset of type 2 diabetes and on body weight were compared to placebo in 3304 obese patients who had either normal or impaired glucose tolerance at baseline. Thirty-four percent of the 1655 patients who were randomized to the placebo group and 52% of the 1649 patients who were randomized to the XENICAL group completed the 4-year study. At the end of the study, the mean percent weight loss in the placebo group was -2.75% compared with -5.17% in the XENICAL group (p<0.001) (see Figure 2 ). Forty-five percent of the placebo patients and 73% of the XENICAL patients lost ≥5% of their baseline body weight, and 21% of the placebo patients and 41% of the XENICAL patients lost ≥10% of their baseline body weight following the first year of treatment.
Following 4 years of treatment, 28% of the placebo patients and 45% of the XENICAL patients lost ≥5% of their baseline body weight and 10% of the placebo patients and 21% of the XENICAL patients lost ≥10% of their baseline body weight. After 4 years of treatment, the mean % difference in weight loss between XENICAL treated patients and placebo was 2.5%. Figure 2 Mean Change from Baseline Body Weight (Kgs) Over Time* *ITT LOCF study population The relative changes from baseline in risk factors associated with obesity following 4 years of therapy were assessed in the XENDOS study population (see Table 9 ). Table 9 Mean Change in Risk Factors From Randomization Following 4-Years Treatment Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet Risk Factor XENICAL 120 mg Intent-to-treat population Placebo Metabolic: Total Cholesterol -7.02% -2.03% LDL-Cholesterol -11.66% -3.85% HDL-Cholesterol +5.92% +7.01% LDL/HDL -0.53 -0.33 Triglycerides +3.64% +1.30 Fasting Glucose, mmol/L +0.12 +0.23 Fasting Insulin, pmol/L -24.93 -15.71 Cardiovascular: Systolic Blood Pressure, mm Hg -4.12 -2.60 Diastolic Blood Pressure, mm Hg -1.93 -0.87 Anthropometric: Waist Circumference, cm -5.78 -3.99 Figure 2 Onset of Type 2 Diabetes in Obese Patients In the XENDOS trial, in the overall population, XENICAL delayed the onset of type 2 diabetes such that at the end of four years of treatment the cumulative incidence rate of diabetes was 8.3% for the placebo group compared to 5.5% for the XENICAL group, p=0.01 (see Table 10 ). This finding was driven by a statistically-significant reduction in the incidence of developing type 2 diabetes in those patients who had impaired glucose tolerance at baseline ( Table 10 and Figure 3 ). XENICAL did not reduce the risk for the development of diabetes in patients with normal glucose tolerance at baseline. The effect of XENICAL to delay the onset of type 2 diabetes in obese patients with IGT is presumably due to weight loss, and not to any independent effects of the drug on glucose or insulin metabolism.
The effect of XENICAL on weight loss is adjunctive to diet and exercise. Table 10 Incidence Rate of Diabetes at Year 4 by OGTT Status at Baseline Based on patients with a baseline and at least one follow-up OGTT measurement, ITT LOCF study population. OGTT at Baseline Normal Impaired All Treatment Placebo XENICAL Placebo XENICAL Placebo XENICAL Number of patients 1148 1235 324 337 1472 1572 # pts developing diabetes 16 21 62 48 78 69 Life table rate Rate adjusted for dropouts 2.1% 1.7% 27.2% 18.7% 8.3% 5.5% Observed percent 1.4% 1.7% 19.1% 14.2% 5.3% 4.4% Absolute risk reduction Life table 0.4% 8.5% 2.8% Observed -0.3% 4.9% 0.9% Relative risk reduction Computed as (1- hazard ratio) 8% 42% 34% p-value 0.79 <0.01 0.01 Figure 3 Percentage of Patients Without Diabetes Over Time Figure 3
Study of Patients With Type 2 Diabetes
A 1-year double-blind, placebo-controlled study in type 2 diabetics (N=321) stabilized on sulfonylureas was conducted. Thirty percent of patients treated with XENICAL achieved at least a 5% or greater reduction in body weight from randomization compared to 13% of the placebo-treated patients (p<0.001). Table 11 describes the changes over 1 year of treatment with XENICAL compared to placebo, in sulfonylurea usage and dose reduction as well as in hemoglobin HbA1c, fasting glucose, and insulin. Table 11 Mean Changes in Body Weight and Glycemic Control From Randomization Following 1-Year Treatment in Patients With Type 2 Diabetes XENICAL 120 mg Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet (n=162) Placebo (n=159) Statistical Significance Statistical significance based on intent-to-treat population, last observation carried forward. % patients who discontinued dose of oral sulfonylurea 11.7% 7.5% Statistically significant (p≤0.05) based on intent-to-treat, last observation carried forward ns nonsignificant, p>0.05 % patients who decreased dose of oral sulfonylurea 31.5% 21.4% Average reduction in sulfonylurea medication dose -22.8% -9.1% Body weight change (lbs) -8.9 -
HbA1c -0.18% +0.28% Fasting glucose, mmol/L -0.02 +0.54 Fasting insulin, pmol/L -19.68
-18.02 ns In addition, XENICAL (n=162) compared to placebo (n=159) was associated with significant lowering for total cholesterol (-1.0% vs +9.0%, p≤0.05), LDL-cholesterol (-3.0% vs +10.0%, p≤0.05), LDL/HDL ratio (-0.26 vs -0.02, p≤0.05) and triglycerides (+2.54% vs +16.2%, p≤0.05), respectively. For HDL cholesterol, there was a +6.49% increase on XENICAL and +8.6% increase on placebo, p>0.05. Systolic blood pressure increased by +0.61 mm Hg on XENICAL and increased by +4.33 mm Hg on placebo, p>0.05. Diastolic blood pressure decreased by -0.47 mm Hg for XENICAL and by -0.5 mm Hg for placebo, p>0.05.
Glucose Tolerance in Obese Patients Two-year studies that included oral glucose tolerance
tests were conducted in obese patients not previously diagnosed or treated for type 2 diabetes and whose baseline oral glucose tolerance test (OGTT) status at randomization was either normal, impaired, or diabetic. The progression from a normal OGTT at randomization to a diabetic or impaired OGTT following 2 years of treatment with XENICAL (n=251) or placebo (n=207) were compared. Following treatment with XENICAL, 0.0% and 7.2% of the patients progressed from normal to diabetic and normal to impaired, respectively, compared to 1.9% and 12.6% of the placebo treatment group, respectively.
In patients found to have an impaired OGTT at randomization, the percent of patients improving to normal or deteriorating to diabetic status following 1 and 2 years of treatment with XENICAL compared to placebo are presented. After 1 year of treatment, 45.8% of the placebo patients and 73% of the XENICAL patients had a normal oral glucose tolerance test while 10.4% of the placebo patients and 2.6% of the XENICAL patients became diabetic. After 2 years of treatment, 50% of the placebo patients and 71.7% of the XENICAL patients had a normal oral glucose tolerance test while 7.5% of placebo patients were found to be diabetic and 1.7% of XENICAL patients were found to be diabetic after treatment.
Pediatric Clinical Studies
The effects of XENICAL on body mass index (BMI) and weight loss were assessed in a 54-week multicenter, double-blind, placebo-controlled study in 539 obese adolescents (357 receiving XENICAL 120 mg three times a day, 182 receiving placebo), aged 12 to 16 years. All study participants had a baseline BMI that was 2 units greater than the US weighted mean for the 95 th percentile based on age and gender. Body mass index was the primary efficacy parameter because it takes into account changes in height and body weight, which occur in growing children.
During the study, all patients were instructed to take a multivitamin containing fat-soluble vitamins at least 2 hours before or after ingestion of XENICAL. Patients were also maintained on a well-balanced, reduced-calorie diet that was intended to provide 30% of calories from fat. In addition, all patients were placed on a behavior modification program and offered exercise counseling. Approximately 65% of patients in each treatment group completed the study.
Following one year of treatment, BMI decreased by an average of 0.55 kg/m 2 in the XENICAL-treated patients and increased by an average of 0.31 kg/m 2 in the placebo-treated patients (p=0.001). The percentages of patients achieving ≥5% and ≥10% reduction in BMI and body weight after 52 weeks of treatment for the intent-to-treat population are presented in Table 12. Table 12 Percentages of Patients with ≥5% and ≥10% Decrease in Body Mass Index and Body Weight After 1-Year Treatment Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet (Protocol NM16189) Intent-to-Treat Population Last observation carried forward ≥5% Decrease ≥10% Decrease XENICAL n Placebo n XENICAL n Placebo n BMI 26.5% 347 15.7% 178 13.3% 347 4.5% 178 Body Weight 19.0% 348 11.7% 180 9.5% 348 3.3% 180
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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