GI symptoms that occurred at least twice that of placebo in >= 5% of patients taking orlistat during double-blind, placebo-controlled clinical trials include flatulence with discharge (23.9% year 1; 4.4% year 2; placebo roughly 1%), fecal urgency (22.1% year 1; 2.8% year 2; placebo 6.7% year 1), fecal incontinence (7.7% year 1; 1.8% year 2; placebo < 1%), steatorrhea (20% year 1; 6% year 2; placebo 2.9% year 1), oily spotting (26.6% year 1; 4.4% year 2; placebo roughly 1%), oily evacuation (12% year 1; 2.3% year 2; placebo < 1%) and increased defecation (10.8% year 1; 2.6% year 2; placebo 4.1% year 1). These and other commonly observed adverse effects were usually mild to moderate with approximately 50% lasting for less than one week. At least 1 GI event occurred in 79% of patients in the orlistat group compared to 59% in the placebo group. During the first year of trials, the dropout rate due to adverse effects, primarily steatorrhea, was significantly higher for orlistat (9.1%) compared to placebo (4%) groups. Adverse effects decreased during the second year of study. Overall dropout rates due to adverse effects were similar for both groups over the 2 year period.[25613] Adverse gastrointestinal events associated with orlistat may increase with a diet containing greater than 30% of calories from fat. To prevent exacerbation of GI reactions, patients should adhere to the recommended diet plan while taking orlistat. Psyllium has been reported to be an effective fiber adjunct to reduce some of the GI side effects associated with orlistat.[25613] [27971]

The following adverse events occurred in >= 2% of patients taking orlistat during the first or second year of double-blind, placebo-controlled clinical trials (and at a percentage rate greater than placebo): abdominal pain (25.5 vs. 21.4% placebo); nausea/vomiting (8.1/3.1% vs. 7.3/3.5% placebo); dizziness (5.2 vs. 5% placebo); infectious diarrhea (5.3 vs. 4.4% placebo); rectal pain (5.2 vs. 4% placebo); gingival disorder (4.1 vs. 2.9% placebo); headache (31 vs. 28% placebo); influenza (39.7 vs. 36.2% placebo); general musculoskeletal pain, such as back pain (13.9 vs. 12.1% placebo), arthritis (5.4 vs. 4.8% placebo), and myalgia (4.2 vs. 3.3% placebo); menstrual irregularity (9.8 vs. 7.5% placebo); fatigue (7.2 vs. 6.4% placebo); pedal edema (2.8 vs. 1.9% placebo); anxiety/depression (2.8/3.4% vs. 2.1/2.5% placebo); rash (unspecified) (4.3 vs. 4% placebo); respiratory tract infection (46 vs. 40% placebo); otitis (4.3 vs. 3.4% placebo); urinary tract infection (5.9 vs. 4.8% placebo); vaginitis (2.6 vs. 1.9% placebo). 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.[27971]

Low serum levels of beta-carotene and vitamins A, D, and E were observed in a greater percentage of patients receiving orlistat compared to those taking placebo. Actual deficiencies due to hypovitaminosis may be prevented through the use of a daily multivitamin supplement that contains fat-soluble vitamins.[27971]

An increased risk of cholelithiasis has been associated with rapid and substantial weight loss. In a study investigating the use of orlistat in preventing type 2 diabetes, the rates of cholelithiasis were 2.9% (47/1649) for patients randomized to orlistat and 1.8% (30/1655) for patients randomized to placebo. The increased risk of cholelithiasis was not seen in orlistat trials not evaluating the prevention of type 2 diabetes.[27971] Nevertheless, clinicians should inform patients who take orlistat about this potential risk and instruct them to seek medical attention if they experience severe or prolonged abdominal pain and/or nausea and vomiting.

In rare cases, leukocytoclastic vasculitis has been reported during post-marketing use of orlistat, with clinical signs including palpable purpura, maculopapular rash, or bullous rash or eruption. Rare post-marketing cases of hypersensitivity reactions have been reported with the use of orlistat. Signs and symptoms have included pruritus, rash (unspecified), urticaria, angioedema, bronchospasm, and anaphylactoid reactions.[27971]

Cases of elevated hepatic enzymes, increased alkaline phosphatase, exceptional cases of hepatitis, severe liver injury with hepatic necrosis, and acute hepatic failure have been reported during post-marketing use of orlistat. In addition, in August, 2009, the FDA announced that it was reviewing reports of liver-related adverse events associated with the use of prescription and over-the-counter orlistat; after a comprehensive review, the FDA identified 13 total reports of severe liver injury with orlistat. Of the 13 cases, 2 patients died from hepatic failure and 3 patients required liver transplantation. No definite association between liver injury and orlistat has been established. At this time, the FDA advises that healthcare professionals weigh the benefits of weight loss with orlistat against the potential risks when determining if orlistat is appropriate for patients. Patients should report signs and symptoms of liver injury to their health care provider immediately.[40642] [27971]

Post-marketing cases 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. In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.[27971]

During post-marketing surveillance, cases of pancreatitis have been reported with the use of orlistat. No causal relationships or plausible mechanisms have been identified to account for this effect in weight-loss therapy.[27971]

During post-marketing surveillance, hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine. Patients treated with orlistat and levothyroxine should be monitored for changes in thyroid function; orlistat may interfere with the absorption of levothyroxine from the gastrointestinal tract. Administer levothyroxine and orlistat at least 4 hours apart.[27971]

During post marketing surveillance of orlistat therapy, seizures have been reported in patients treated concomitantly with orlistat and anticonvulsant drugs. Patients should be monitored for changes in the frequency or severity of seizures.[27971]

Orlistat reduces the absorption of vitamin D and may lead to vitamin D deficiency. Patients should be monitored and supplemented with vitamin D when necessary.[63388]

Postmarketing reports of acute oxalate nephropathy and hyperoxaluria have occurred in patients with or at risk for renal disease following treatment with orlistat. As these reports are made voluntarily, the frequency and causal relationship to orlistat exposure is not established.[27971]

Orlistat has been shown to decrease nutrient and vitamin absorption; therefore, orlistat is contraindicated for use in patients with chronic malabsorption syndrome. Because orlistat 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 supplement should be taken at least 2 hours before or after orlistat. Orlistat may interact with concomitant drugs, and the clinician is advised to review drug interactions.[27971] [60877]

Orlistat is contraindicated for use in individuals with cholestasis; patients with a history of gallbladder disease should consult a healthcare provider before use.[27971] [60877] Substantial weight loss can increase the risk of cholelithiasis or gallbladder disease. In a clinical trial of orlistat, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to orlistat and 1.8% (30/1655) for patients randomized to placebo. The long-term effects on gallstone formation have not been determined; orlistat use does not appear to influence gallbladder motility.[27971] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, close monitoring for cholelithiasis is recommended in patients undergoing weight loss therapy, regardless of modality. Effective preventative measures for obese patients at risk for cholelithiasis include a slower rate of weight loss, increasing/including some dietary fat in the diet (assuming the patient has been on a very low-calorie diet containing little or no fat), or administration of ursodeoxycholic acid. The AACE/ACE Obesity Guidelines also recommend monitoring for pancreatitis due to a proven association between pancreatitis and obesity and reports of pancreatitis occurring in patients receiving orlistat. The drug should be withheld if pancreatitis occurs or the patient has a previous history of pancreatitis.[62881]

Carefully consider the risk: benefit ratio of using orlistat in patients with hepatic disease. There have been rare postmarketing reports of serious liver injury, hepatotoxicity, and hepatocellular necrosis in patients treated with orlistat by prescription or without a prescription, with some of these cases resulting in acute hepatic failure, liver transplant, or death. Some of these reports involved patients with other potential risks for liver injury. 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 orlistat. When these symptoms occur, orlistat and other suspect medications should be discontinued immediately and liver function tests (LFTs), including ALT and AST levels, obtained.[27971] [40642] [60877] Orlistat may be best avoided in patients with hepatitis treated with antiretroviral drugs. Loss of virological control has been reported in non-hepatitis patients treated with antiretroviral drugs for human immunodeficiency virus (HIV), and some of these same medications may be used for patients infected with hepatitis or with co-infection with hepatitis.[27971] [60877] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, all weight loss medications should be used cautiously in patients with hepatic impairment and should be avoided in severe hepatic impairment (i.e., Child-Pugh score greater than 9).[62881]

Use prescription orlistat with caution in patients receiving antiretroviral therapy for human immunodeficiency virus (HIV) infection. Patients with HIV infection should consult with their health care professional before non-prescription use of orlistat. Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with antiretroviral drugs. The exact mechanism for this is unclear but may include inhibition of systemic absorption of the antiretroviral drug. If orlistat use is necessary, frequently monitor the patient's HIV RNA levels. If a confirmed increase in HIV viral load occurs, then orlistat should be discontinued.[27971] [60877]

Monitor renal function when prescribing orlistat to patients at risk for renal impairment and use with caution in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis. Some patients may develop increased levels of urinary oxalate following treatment with orlistat, and cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Patients taking orlistat who present with urinary tract pain or with difficulty passing urine may need to be evaluated for the presence of kidney stones. Orlistat should be discontinued in patients who develop oxalate nephropathy.[27971] [60877] The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines do not recommend use in patients with a history or risk factors for oxalate nephropathy. AACE/ACE Obesity Guidelines consider orlistat a weight reduction option for obese patients with mild to moderate renal impairment (i.e., CrCl 30 to 79 mL/minute). Patients with severe renal disease or impairment (CrCl less than 30 mL/minute) should be monitored closely for oxalate nephropathy if orlistat is used. Orlistat can also be considered in selected patients with end-stage renal failure with a high level of caution.[62881]

Patients who have undergone an organ transplant must not take nonprescription orlistat, as use may cause interference with medications that prevent transplant rejection. Such patients should use orlistat under prescription only. Prescription use of orlistat should be carefully monitored in such patients. Data from an orlistat and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma concentrations when the drugs are coadministered. Doses of orlistat and cyclosporine must be separated to limit this interaction. More frequent monitoring of cyclosporine concentrations should be considered.[27971] [60877]

Organic causes of obesity, such as hypothyroidism, should be ruled out prior to prescribing orlistat, and should be treated as per clinical standards of care. Patients treated for hypothyroidism should be aware that orlistat can inhibit the proper absorption of thyroid hormones such as levothyroxine, and doses should be separated to help limit interactions. Thyroid function should be monitored routinely in such patients to ensure euthyroidism is maintained as weight loss efforts are continued.[27971] [60877]

Use caution when orlistat is used in patients with a concurrent seizure disorder. Patients with a seizure disorder should not use the nonprescription product without healthcare provider approval and monitoring. During postmarketing surveillance of orlistat therapy, seizures have been reported in patients treated concomitantly with orlistat and anticonvulsant drugs, presumably due to an interaction with antiepileptic medications. Review potential drug interactions. Patients should be monitored for possible changes in the frequency and/or severity of convulsions.[27971] [60877] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, orlistat is a preferred weight loss medication in patients with a seizure disorder; many other drugs indicated for weight reduction carry a potential for seizure risk.[62881]

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. Patients with diabetes should be advised to continue to routinely monitor blood glucose and report any changes in blood glucose control to their healthcare provider.[27971] [60877] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications should be considered as an adjunct to lifestyle therapy in all patients with type 2 diabetes mellitus as needed for weight loss sufficient to improve glycemic control, lipids, and blood pressure. During controlled trial evaluation of orlistat as an adjunct to lifestyle therapy versus lifestyle therapy alone for diabetes prevention, a greater weight loss and more profound reductions in incident diabetes occurred with orlistat plus lifestyle therapy than lifestyle therapy alone.[62881]

Patients who are underweight or who suffer from malnutrition should not use orlistat.[27971] [60877] [62881] Adherence to dietary intake instructions is important in patients taking orlistat. Educate treated patients on the importance of maintaining a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. Generally, the daily intake of fat, carbohydrate, and protein should be distributed over 3 main meals.[27971] [60877] Patients taking orlistat for weight loss or maintenance should be strongly encouraged to take a daily multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because orlistat has been shown to reduce the absorption of some fat-soluble vitamins (A, D, E, K) and beta-carotene. Also, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects. The multivitamin supplement should be taken once a day at least 2 hours before or after the administration of orlistat, such as at bedtime.[27971] [60877] There are insufficient data on the use of orlistat following bariatric surgery.[62881] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, orlistat can be a treatment option along with non-medication interventions (i.e., behavioral/lifestyle program, psychotherapy) in overweight or obese patients with binge eating disorder (BED).[62881] Patients with eating disorders such as anorexia nervosa or bulimia nervosa should not use weight loss medications. The AACE/ACE Obesity Guidelines also consider orlistat a treatment option in obese patients with a substance abuse disorder, including alcoholism, as the drug does not have an addiction or abuse potential.[62881]

Nonprescription self-use of orlistat is not advised in patients receiving anticoagulant therapy with warfarin; patients are encouraged to discuss the use and receive approval from their health care professionals before using orlistat for weight loss. Vitamin K absorption may be decreased with the use of orlistat. Reports of decreased prothrombin, increased INR, and unbalanced anticoagulant therapy resulting in a change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and warfarin. More frequent monitoring of the INR or other parameters may be needed in such patients.[27971] [60877]

According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, orlistat is a preferred weight loss medication for obese patients with existing hypertension, established coronary artery disease, or cardiac arrhythmias; the drug is not associated with adverse cardiovascular effects and does not increase blood pressure or heart rate.[62881] Some trials with orlistat have demonstrated reduction in cardiovascular risk factors, such as lipid profiles and waist circumference in addition to weight reduction.[25613] [25615] Data are insufficient regarding the benefits of the use of orlistat in obese patients with heart failure; the AACE/ACE Obesity Guidelines recommend caution.[62881]

According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, orlistat may be considered for patients with obesity and depression; however, monitor all patients undergoing weight loss therapy for mood disorders, depression, and suicidal ideation. Evidence assessing safety and efficacy of weight loss medications in patients with a psychotic disorder (e.g., schizophrenia) is insufficient, and the AACE/ACE Obesity Guidelines recommend caution. Patients receiving an antipsychotic should be treated with structured lifestyle modifications to promote weight loss and weight gain prevention; the AACE/ACE Obesity Guidelines suggest that metformin may be beneficial for modest weight loss and metabolic improvements in patients receiving an antipsychotic.[62881]

Clinical studies of orlistat for weight reduction did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger adults.[27971] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, there are limited data on the use of orlistat for weight reduction in geriatric patients and extra caution is advisable in this population. Geriatric patients selected for weight loss therapy should have structured lifestyle interventions including reduced calorie meal plans and exercise, clear health-related goals including diabetes prevention in high-risk patients with pre-diabetes, blood pressure reduction, and improvements in osteoarthritis, mobility, and physical functioning. Overweight or obese elderly patients being considered for a weight loss medication should be evaluated for osteopenia and sarcopenia.[62881]

Orlistat is contraindicated for use during pregnancy because weight loss offers no potential benefit to a pregnant woman and weight loss, coupled with reduced absorption of fat-soluble vitamins (A, D, E, K) 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 and the need to provide appropriate nutrition to the developing fetus. 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.[27971] Pregnant women must also avoid nonprescription use of the drug.[60877] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications must not be used during pregnancy. The AACE/ACE Obesity Guidelines recommend that women of childbearing potential receiving orlistat use adequate contraception and discontinue orlistat if pregnancy occurs.[62881]

The manufacturer recommends caution when administering orlistat to a breast-feeding woman; nonprescription use should be avoided. The minimal systemic bioavailability of orlistat suggests that the drug is not expressed in breast milk; however, it is not known with certainty if orlistat is present in human milk.[27971] [60877] It is not known if the effects of orlistat on maternal availability of fat-soluble vitamins would affect breast milk quality or quantity. Women who are breast-feeding should be encouraged to take proper vitamin supplementation as suggested by orlistat product labeling to avoid deficiencies of fat-soluble vitamins. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, the use of orlistat in breast-feeding women is generally not recommended.[62881]

The safety and efficacy of orlistat have not been evaluated in children less than 12 years of age; do not give to infants. Because orlistat may reduce the absorption of certain nutrients essential for proper growth and development, use in children under 12 years of age has not been advised. Use of orlistat in adolescents 12 years and older should be in conjunction with a healthcare professional's approval and prescription. Monitor weight and growth, and, ensure the use of a properly selected multivitamin supplement daily.[27971] Nonprescription use is not advised in pediatric patients as the nonprescription product has been approved only for use in overweight adults.[60877] In pediatric patients 12 years and older, pharmacotherapy is usually reserved for pediatric patients with a BMI at the 95th percentile or more or meeting the adult BMI recommendations for use. Reserve medication therapy for overweight children (BMI 85th to 94th percentile) in those with significant, severe comorbidities who have not responded to lifestyle modification.[58571] [63035] Orlistat can reduce BMI and weight and reduces the risk for weight regain in chronic use; however, in pediatric patients, adherence at meals (e.g., school days, etc.) and side effects may be problematic.[27971] [62880] [62881] [58571] [63035]