Summary Of Exposure |
A) USES: Orlistat is used in the management of obesity by limiting the absorption of dietary fat.
B) PHARMACOLOGY: Orlistat, a reversible inhibitor of intestinal lipases, binds covalently with active serine residues of gastric and pancreatic lipases in the lumen of the stomach and intestine, making them unavailable to hydrolyze dietary triglycerides into absorbable fatty acids and monoglycerides. Because undigested triglycerides are not absorbed, a calorie deficit may occur, having a positive effect on weight control. Systemic absorption is minimal and is not needed for activity. A dose-dependent reduction in dietary fat absorption of up to approximately 30% is achieved with doses of 360 mg per day.
C) TOXICOLOGY: Systemic effects of orlistat are minimal due to its very low oral absorption.
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE
1) COMMON: Gastrointestinal adverse effects (dose-related), including soft/liquid stools, increased defecation, oily stools, flatulence, and fecal urgency or incontinence; reduction in serum levels of fat soluble vitamins, particularly vitamin E. OTHER EFFECTS: Nausea, vomiting, hemorrhoids, acute allergic reactions, elevated liver enzymes. Lichenoid drug eruption, myopathy, acute oxalate nephropathy, and depression have been reported in case reports; however, cause and effect relationships have not been established. In postmarketing evaluations, cases of severe liver injury, with hepatocellular necrosis or acute liver failure, have been rarely reported in patients who received orlistat. Causality could not be reliably established due to other medical conditions and concomitant use of other drugs that may have contributed to the development of liver injury in these patients.
F) WITH POISONING/EXPOSURE
1) OVERDOSE: Limited data. Inadvertent exposure is anticipated to be an extension of adverse events reported with therapeutic use. In a retrospective chart review of 92 children (5 years of age or less) with minor exposures (120 mg or less) to orlistat alone, most children developed no effects or only minor clinical events; no serious events occurred. A 28-month-old girl ingested an estimated 5160 mg of over-the-counter orlistat and remained asymptomatic.
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) MYOCARDIAL INFARCTION 1) WITH THERAPEUTIC USE a) Myocardial infarction was reported in one hyperlipidemic patient treated with doses of 180 mg daily (Tonstad et al, 1994). A direct causal relationship to orlistat was not established.
B) LACK OF EFFECT 1) WITH THERAPEUTIC USE a) Normal therapy with orlistat has NOT been associated with changes in blood pressure, heart rate, or electrocardiogram (Drent & van der Veen, 1993; Hussain et al, 1994; Guzelhan et al, 1994).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) DIARRHEA 1) WITH THERAPEUTIC USE a) Gastrointestinal adverse effects of oral orlistat, which appear to be dose-related, include soft/liquid stools, increased defecation, oily stools, abdominal pain, flatulence, and fecal urgency or incontinence. Up to 10% of patients on higher doses have discontinued orlistat therapy due to gastrointestinal effects. These effects are presumably related to inhibition of fat absorption. Other effects have included nausea, vomiting, and hemorrhoids (Prod Info XENICAL(R) oral capsules, 2010a; Hauptman et al, 1992; James et al, 1997; Tonstad et al, 1994; Sjostrom et al, 1998a; Reddy & Chow, 1998; Drent et al, 1995; Hartmann et al, 1993a). 1) Gastrointestinal tolerability appears to be inversely related to the amount of fat in the diet. Some patients on a diet containing 130 g of fat/day have been unable to tolerate doses as low as 25 mg 3 times daily, whereas doses as high as 1200 mg daily have been tolerated by others on a 45 g/day fat diet (Hauptman et al, 1992; Tonstad et al, 1994; Guzelhan et al, 1994; Hussain et al, 1994; Reitsma et al, 1994).
2) Overall, at least one gastrointestinal adverse effect occurred in 73%, 80%, and 86% of patients receiving respective daily doses of 90 mg, 180 mg, and 360 mg (Tonstad et al, 1994).
b) INCIDENCE of adverse gastrointestinal effects in a clinical study of 657 orlistat-treated subjects are reported as follows (Davidson et al, 1999): 1) Flatus: 40.1%
2) Oily spotting: 32.7%
3) Fecal urgency: 29.7%
4) Fatty/oily stool 19.8%
5) Oily evacuation: 14.3%
6) Fecal incontinence: 11.8%
7) Increased defecation: 11.1%
2) WITH POISONING/EXPOSURE a) PEDIATRIC: In a retrospective chart review by the Texas Poison Center Network during 1999 through 2005, 92 orlistat alone exposures were identified in children 5 years of age or less. Of those cases, 4 children developed diarrhea and one child experienced vomiting (Forrester, 2008).
B) MALABSORPTION SYNDROME 1) WITH THERAPEUTIC USE a) Orlistat is capable of reducing absorption of fat-soluble vitamins, particularly vitamin E. Vitamin D levels have been significantly decreased only with higher doses of orlistat (120 mg 3 times daily), whereas vitamin A level reductions have not been statistically significant (Prod Info XENICAL(R) oral capsules, 2010a; Tonstad et al, 1994; Drent et al, 1995; Anon, 1996; James et al, 1997; Sjostrom et al, 1998a; Davidson et al, 1999).
C) PANCREATITIS 1) WITH THERAPEUTIC USE a) Pancreatitis has been observed during the postmarketing use of orlistat. However, a causal relationship or physiopathological mechanism between pancreatitis and orlistat use has not been established (Prod Info XENICAL(R) oral capsules, 2010a).
D) BILIARY CALCULUS 1) WITH THERAPEUTIC USE a) Significant weight loss can increase the risk of cholelithiasis. In a randomized clinical trial of orlistat use in the prevention of type 2 diabetes, cholelithiasis developed in 47 of 1649 (2.9%) patients treated with orlistat and 30 of 1655 (1.8%) patients in the placebo group. At similar amounts of weight loss, the incidence of cholelithiasis was similar for orlistat and placebo (Prod Info XENICAL(R) oral capsules, 2010a).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Increases in transaminases and alkaline phosphatase have been reported very rarely with the use of orlistat (Prod Info XENICAL(R) oral capsule, 2005).
B) HEPATIC FAILURE 1) WITH THERAPEUTIC USE a) In postmarketing evaluations, cases of severe liver injury, with hepatocellular necrosis or acute liver failure, have been rarely reported in patients who received orlistat (Prod Info XENICAL(R) oral capsules, 2010a). Following an international safety review, the United States (US) Food and Drug Administration identified 13 cases of severe liver injury with orlistat use (12 foreign reports with orlistat 120 mg and 1 US report with orlistat 60 mg) between April 1999 and August 2009. Liver injury resulted in transplantation in 3 patients and death in 2 patients. Causality could not be reliably established due to other medical conditions and concomitant use of other drugs that may have contributed to the development of liver injury in these patients (US Food and Drug Administration, 2010).
b) CASE REPORT: A 35-year-old woman suffered subacute hepatic failure leading to liver transplantation after use of orlistat for moderate obesity. The patient had taken several anti-obesity drugs until January 1999; during that time, her liver enzymes were normal. In April 1999, she began receiving orlistat 120 mg/day (no other medications were coadministered). Three weeks later, laboratory results showed elevated serum concentrations of aspartate aminotransferase (AST 853 units/liter (L)); normal, less than 40), alanine aminotransferase (ALT 1016 units/L; normal, less than 40), and gamma glutamyl transferase (GGT 215; normal, less than 45); her prothrombin index was low (70%). Bilirubin levels were normal (1 mg/dL; normal less than 1.5), and autoimmune markers were negative. Orlistat was withdrawn. After 2 weeks, repeat tests showed AST 1132 units/L, ALT 1548 units/L, bilirubin 5.1 mg/dL, and prothrombin index 45%. On admission to a tertiary care center, similar tests indicated progression of liver failure (AST 1094 units/L, ALT 1400 units/L, bilirubin 9.5 mg/dL) and further reduction of prothrombin activity (30%). Her symptoms included ascites, hyponatremia, encephalopathy grade II, and ultrasound signs of liver atrophy. She was referred for liver transplantation, which occurred 28 days after admission. Massive necrosis was found in the excised liver. The authors believe there was a clear temporal association between orlistat therapy and the patient's development of liver failure (Montero et al, 2001).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) OXALATE NEPHROPATHY 1) WITH THERAPEUTIC USE a) A review of current studies suggests the use of orlistat can lead to oxalate nephropathy, stone formation, and deterioration in renal function, especially in patients with pre-existing renal disease. The inhibition of fat absorption may lead to an increased risk of stone formation due to hyperoxaluria. The effects of orlistat on the intestinal absorption of oxalate, including urinary levels of oxalate excretion in obese men and women were studied. Patients were randomly assigned to receive either orlistat for 6 months or no specific medication. Calcium, oxalate, and citrate levels were evaluated in a 24-hour urine collection from each patient. During a 3-month follow-up, a significant increase in oxalate excretion was noted in 61.8% (34/55) of patients receiving orlistat therapy (p = less than 0.05), and of these patients, 30 continued to have increased urinary excretion during a 6-month follow-up (p=0.001). Orlistat showed no marked effect on urinary citrate and calcium levels during both follow-up time frames (Ahmed, 2010).
b) CASE REPORT: A case report described acute oxalate nephropathy in a 66-year-old man 3 months after being initiated on orlistat 120 mg 3 times daily for obesity. The patient, who was also receiving biphasic insulin twice daily for type 2 diabetes, presented with repeated occurrences of hypoglycemia. Upon admission, his blood sugar level of 2.7 was normalized with oral glucose gel and IV 10% dextrose. Acute renal failure was demonstrated with a serum creatinine level of 405 micromol/L, which increased to 750 micromol/L over the next 2 days. Four months earlier, renal function was normal with an estimated GFR of 93 mL/min. Urinalysis was negative for blood and protein and an ultrasound showed normal kidneys. However, his urine microscopy showed amorphous crystals in moderate amounts. A renal biopsy showed signs of acute tubular necrosis. Interstitial edema separated the tubules with many containing oxalate crystals. He became increasingly acidotic and required dialysis 6 days after admission. It was postulated that his acute renal failure resulted from acute oxalate nephropathy due to calcium oxalate crystals precipitating within tubules. Hemodialysis was continued for 3 weeks after admission until the patient had an unexpected fatal cardiac arrest (Karamadoukis et al, 2009).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) LICHENOID DRUG ERUPTION 1) WITH THERAPEUTIC USE a) A case of lichenoid drug eruption occurred in a 42-year-old, clinically obese woman following orlistat monotherapy. Two years before, the patient had taken orlistat sporadically for 3 weeks only and 6 months prior to current presentation, she had taken orlistat 120 mg 3 times daily for 3 months. She presented with a 7-week history of itchy lesions on her vulva, feet, and axillae. Physical examination revealed small, flat-topped papules in both axillae, on the arches of the soles of the feet, and on the flexural surfaces of the wrists. The vulval lesions included white striae overlying purple papules on both the labia minora and labia majora. Presence of colloid bodies at the dermoepidermal junction and eosinophils in the papillary dermis, as evidenced in the biopsy sections, were consistent with a diagnosis of a lichenoid drug reaction. While the other lesions were asymptomatic and did not require treatment, the vulval lesions were treated with mometasone furoate 0.1% cream twice daily. This resulted in significant improvement with no clinical sign of a vulval lichenoid rash after 1 week of treatment. Subsequently, no new lesions were observed for 1 year after discontinuation of orlistat (Sergeant et al, 2006).
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Reproductive |
3.20.1) SUMMARY
A) Orlistat is classified as FDA pregnancy category X. No embryotoxicity or teratogenicity was reported in rats and rabbits given 23 and 47 times, respectively, the human dose. It is not known if orlistat is secreted in human milk.
3.20.2) TERATOGENICITY
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info XENICAL(R) oral capsules, 2012).
B) ANIMAL STUDIES 1) RATS AND RABBITS: No embryotoxicity or teratogenicity were reported in rats and rabbits administered orlistat at doses up to 800 mg/kg/day (23 and 47 times, respectively, the daily human dose on a mg/m(2) basis) (Prod Info XENICAL(R) oral capsules, 2012).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Orlistat has been classified as FDA pregnancy category X (Prod Info XENICAL(R) oral capsules, 2012).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info XENICAL(R) oral capsules, 2012).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) RATS: No effects on fertility were observed in rats given orlistat at 12 times the human dose (400 mg/kg/day), based on body surface area (Prod Info XENICAL(R) oral capsules, 2012)
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, the manufacturer does not report any carcinogenic potential. Breast neoplasms were reported in clinical trials; however, it is questionable whether the neoplasms were related to orlistat as they were detected within 6 months of the study initiation when minimal orlistat absorption occurs.
3.21.3) HUMAN STUDIES
A) BREAST CARCINOMA 1) In orlistat clinical trials, 9 cases of breast neoplasm were reported in patients receiving 360 mg per day, 1 case in those receiving 180 mg per day, and 1 case in the placebo group. It is doubtful that the neoplasms were related to orlistat since they were detected within 6 months of study initiation, and minimal absorption of the drug occurs (Cerulli et al, 1998; Anon, 1997).
3.21.4) ANIMAL STUDIES
A) LACK OF EFFECT 1) There was no evidence of carcinogenicity in rats or mice given orlistat doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively (38 and 46 times the human dose based on AUC versus time curve) (Prod Info XENICAL(R) oral capsules, 2009; McNeely & Benfield, 1998).
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Genotoxicity |
A) There was no evidence of mutagenicity or genotoxicity in the Ames test, a mammalian forward mutation assay, an in vitro clastogenesis assay in human lymphocytes, an unscheduled DNA synthesis assay in rat hepatocytes, or in vivo mouse micronucleus test (Prod Info XENICAL(R) oral capsules, 2009; McNeely & Benfield, 1998).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) DISORDER OF MUSCLE 1) WITH THERAPEUTIC USE a) CASE REPORT: A case report described development of myopathy in a 37-year-old man on chronic orlistat therapy. The patient presented with a 3-month history of diffuse muscle twitching and soreness in all muscle groups, including the face and neck, and mild exercise intolerance. The large muscles, including the calves, quadriceps, gluteals, biceps and triceps, were primarily affected; fasciculation-like twitching was present in multiple muscles. The patient, who was mildly obese, had been taking orlistat 120 mg 3 times daily with meals for 27 months prior to symptom onset. Electromyography (EMG) and nerve conduction studies did not reveal any abnormalities, and needle EMG examination of limb muscles was mostly normal. However, serum creatine kinase (CK) was 739 units/L (275% the upper limit of the normal (ULN)) at time of initial presentation. Subsequently, serum CK levels were consistently elevated ranging from just above the ULN to 9.4 times the ULN, and soreness and twitching worsened. The patient, who had continued taking orlistat, discontinued taking it approximately 7 months after initial presentation and tried multiple over-the-counter treatments to treat the symptoms. Over the next 2 years, while muscle twitches and myalgias persisted, there was a gradual improvement in exercise intolerance. One year later, the patient began taking coenzyme Q10 600 mg/day and, three months later, the twitching and myalgias decreased along with normalization of serum CK levels (Ringman & Mozaffar, 2008).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ACUTE ALLERGIC REACTION 1) WITH THERAPEUTIC USE a) Hypersensitivity reaction, including rash, pruritus, angioedema, urticaria, anaphylaxis, and bronchospasm, has been observed rarely following the use of orlistat during clinical trials or with the postmarketing use of the drug (Prod Info XENICAL(R) oral capsules, 2010a).
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