Action and mechanism Orlistat is a potent and specific inhibitor of gastric and pancreatic lipases, enzymes responsible for the hydrolysis of triglycerides. It acts in the lumen of the digestive tract, slowly binding to serine residues in the enzymes active site through a reversible covalent bond. By inhibiting the enzyme, it prevents the formation of fatty acids and monoglycerides, and their absorption. Orlistat can reduce the absorption of up to 30% of the lipids in food, which can lead to a reduction in energy intake of up to 200-300 kilocalories per day. In addition to its effect on lipids, orlistat also inhibits the absorption of fat-soluble vitamins A, D, E, and K. Pharmacokinetics Oral route: - Absorption: Oral absorption of orlistat is minimal. Following oral administration of 360 mg, plasma concentrations were not detectable (< 5 ng/ml). In animals, the oral bioavailability of orlistat has been shown to be less than 2%. - Distribution: In in vitro studies, the small amount of orlistat absorbed circulates in plasma bound to plasma proteins (99%), mainly albumin and lipoproteins. Minimal amounts may appear in erythrocytes. - Metabolism: Orlistat is likely metabolized primarily in the intestinal wall. In studies with obese patients, two main metabolites have been isolated in blood: M1, obtained by hydrolysis of the lactone ring at position 4, and M3, which is formed by the removal of an N-formylleucine from M1. These metabolites represent 42% of the total plasma concentration. They have no pharmacological activity. - Elimination: Orlistat is primarily eliminated in feces (97%), with 83% excreted unchanged. The absorbed fraction of orlistat is eliminated by renal excretion and bile. The elimination half-life is 1-2 hours, and the time required to eliminate all orlistat is 3-5 days. Pharmacokinetics in special situations: - Renal insufficiency: No studies have been conducted in patients with renal insufficiency. - Liver failure: No studies have been conducted in patients with liver failure. Instructions * EFP: - [OVERWEIGHT]. Weight loss in overweight adults (18 years or older) with a BMI greater than or equal to 28 kg/m2, associated with a low-fat, hypocaloric diet and exercise. Posology * MSP: - Adults, oral: 1 tablet every 8 hours. If no weight loss is observed after 12 weeks of treatment, it is recommended to consult a doctor and/or pharmacist, who will assess the need to discontinue orlistat. - Duration of treatment: Treatment should not be prolonged for periods longer than 6 months. - Children and adolescents under 18 years of age, oral: The safety and efficacy of orlistat have not been evaluated. Guidelines for proper administration Take immediately before, during, or at most one hour after meals. If you skip a meal or if your meal is fat-free, omit the dose of orlistat. Contraindications - Hypersensitivity to any component of the medication. - Chronic malabsorption syndrome. Orlistat decreases the absorption of lipids and fat-soluble vitamins, so in these patients it can cause malnutrition and increase the phenomena of steatorrhea. - [CHOLESTASIS]. Orlistat decreases postprandial cholecystokinin concentrations by reducing the number of fatty acids present in the intestinal lumen. Although decreases in gallbladder contractility have not been demonstrated, they cannot be ruled out. Since orlistat may promote gallstone formation, its use is not recommended in patients with cholestasis. - [ANOREXIA NERVOSA] and [BULIMIA NERVOSA]. Orlistat may be misused by patients with anorexia or bulimia nervosa. This medicine should not be used in these patients. - Treatment with cyclosporine, oral anticoagulants (acenocoumarol, warfarin), or acarbose. Concomitant administration of any of these drugs with orlistat EFP is considered contraindicated. (See Interactions, Precautions). - Pregnancy. Precautions - [RENAL INSUFFICIENCY], [KIDNEY STONES]. In some patients, orlistat may lead to increased urinary excretion of oxalates (hyperoxaluria) and oxalate nephropathy. A doctor should be consulted before starting orlistat EFP. - [TYPE 2 DIABETES MELLITUS]. Weight loss in obese patients with non-insulin-dependent diabetes was less than in obese patients without diabetes. Furthermore, with weight loss, diabetic patients may experience decreased insulin resistance, making closer blood glucose monitoring necessary and considering dosage adjustments (See Interactions). - [RECTORRHAGING]: Cases of rectal bleeding have been reported. In cases of severe and/or persistent symptoms, close clinical monitoring is advised. [HYPOTHYROIDISM]. Rare cases of hypothyroidism and/or impaired thyroid control have been reported in hypothyroid patients, possibly due to decreased absorption of iodine salts and/or levothyroxine. Monitor thyroid function in patients with hypothyroidism and consider the need to adjust the levothyroxine dose. Consult your doctor before starting concomitant administration if you are using orlistat EFP. (See Interactions). [NEPHROPATHY], [HYPOVOLEMIA]. The use of orlistat may be associated with increased urinary oxalate levels. Hyperoxaluria and oxalate nephropathy have been reported in patients with underlying chronic kidney disease and/or hypovolemia. Administer with caution to patients with a history of [HYPEROXALURIA] or [KIDNEY STONES] due to calcium oxalate. - [HIGH BLOOD PRESSURE]. Weight loss may be accompanied by an improvement in blood pressure, so patients on antihypertensive treatment may need an adjustment of their medication dosage. - [HYPERCHOLESTEROLEMIA]. Weight loss may be accompanied by an improvement in cholesterol levels, so in patients undergoing lipid-lowering treatment, a dose adjustment may be necessary. - Treatment with cyclosporine. Concomitant administration is not recommended; consult your doctor before starting concurrent administration if using orlistat EFP. (See Interactions, Contraindications). - Treatment with oral anticoagulants. Coagulation parameters (INR) should be monitored. A doctor should be consulted before starting concomitant administration if orlistat EFP is being used. (See Interactions, Contraindications). - Treatment with acarbose. The use of orlistat EFP is not recommended due to the lack of studies on pharmacokinetic interactions (See Interactions). - Treatment with antiepileptic drugs. Seizures have been reported in patients using both treatments. A doctor should be consulted before starting concomitant administration if orlistat EFP is being used. (See Interactions). - Treatment with amiodarone or oral hormonal contraceptives. Potential interactions between orlistat and these medications could have significant consequences, so caution is necessary. (See Interactions). - Fat-soluble vitamins. Orlistat may interfere with the intestinal absorption of vitamins A, D, E, and K. A diet rich in fruits and vegetables is recommended, and the need for vitamin supplements should be considered. If necessary, the doses of orlistat and these supplements should be spaced apart (See Interactions). Advice to the patient A nutritionally balanced, moderately low-calorie diet should be followed, with approximately 30% of calories coming from fat. A diet rich in fruits and vegetables is recommended. Daily intake of fat, carbohydrates, and protein should be distributed among the three main meals. It is advisable to continue this diet after the treatment has ended. - It is recommended to do regular physical exercise during and after treatment. - The prescribed doses should not be increased. - Alcohol consumption should be avoided due to the large number of calories it provides. - You should inform your doctor or pharmacist if you are being treated with anticoagulants, cyclosporine, acarbose, levothyroxine, antiepileptics, oral contraceptives or amiodarone. - In cases of severe diarrhea, patients using oral contraceptives should use an additional contraceptive method. - In cases of steatorrhea, antidiarrheals that decrease intestinal transit (loperamide) should not be used. - If no fat is ingested at a meal, or if the patient skips a meal, the capsule corresponding to that meal will not be taken. - You should inform your doctor or pharmacist if you experience symptoms such as weakness, fatigue, fever, jaundice, or dark urine. These could indicate liver damage. - In the case of orlistat EFP, it is not recommended to take two 27 mg tablets instead of one 60 mg capsule. The systemic absorption of the 27 mg tablets appears to be greater than that of the 60 mg capsules. Special warnings - This advertised medication is only authorized for adults aged 18 and over who are overweight (BMI of 28 kg/m2 or higher). With a medical prescription, in addition to being authorized for overweight (BMI 28-30 kg/m2), it can also be used for obesity (BMI > 30 kg/m2). - BMI is calculated by dividing body weight (in kg) by the square of height (in meters). - Pay special attention to possible eating disorders. - Diet and exercise should be part of the weight loss program, and should preferably begin before starting treatment with orlistat, and continue once it has ended. - Before starting treatment with orlistat, any organic cause of obesity, such as untreated hypothyroidism, should be ruled out. - In patients receiving anticoagulants, INR monitoring is recommended before, during, and after orlistat treatment. A doctor should be consulted before starting concomitant administration if using over-the-counter orlistat. (See Interactions). Cyclosporine levels should be monitored in transplant patients, and if necessary, the dose should be increased or Neoral formulations used. A doctor should be consulted before starting concomitant administration if orlistat (prescription drug) is being used. (See Interactions). - In patients undergoing treatment with acarbose, the use of orlistat EFP is not recommended due to the absence of studies on pharmacokinetic interactions (See Interactions). - Treatment with levothyroxine or antiepileptic drugs should be monitored, and doses adjusted accordingly. A doctor should be consulted before starting concomitant administration if orlistat EFP is being used. (See Interactions). Other treatments that require caution include oral contraceptives and amiodarone. (See Interactions). The possibility of experiencing gastrointestinal side effects (abdominal pain, steatorrhea, flatulence) may increase if orlistat is taken with a high-fat diet (e.g., 2,000 kcal/day, >30% of calories from fat, equivalent to >67g of fat) or with a very high-fat meal. Daily fat intake should be distributed among the three main meals. - In addition to monitoring body weight, it may be advisable to measure blood lipids. Orlistat may interfere with the intestinal absorption of the fat-soluble vitamins A, D, E, and K. If vitamin supplementation is deemed necessary, it should be administered at least 2 hours after the orlistat dose or at bedtime. (See Interactions). - It is possible, although rare, that there may be increases in the excretion of oxalates in urine (hyperoxaluria) and oxalate nephropathy; therefore, a doctor should be consulted before starting treatment in patients with renal insufficiency. While cases of severe hepatic adverse reactions continue to be evaluated, it is advisable to inform patients that they should consult their doctor or pharmacist about possible symptoms that could be associated with the development of liver damage (weakness, fatigue, fever, jaundice, and dark urine). Other possible symptoms include abdominal pain, nausea, vomiting, light-colored stools, itching, and loss of appetite. Interactions - Acarbose. In the absence of studies on pharmacokinetic interactions, concomitant administration of orlistat with acarbose should be avoided. - Amidarone. A possible decrease in plasma levels of amiodarone may occur; patient monitoring is advisable. Consider the need to adjust the amiodarone dose. - Oral contraceptives. Although studies indicate no interaction between these medications, orlistat may indirectly reduce the availability of oral contraceptives, as there have been some isolated cases of unplanned pregnancies. Therefore, the use of an additional contraceptive method is recommended in cases of severe diarrhea. - Anticoagulants (acenocoumarol, warfarin). Some cases have been reported in which orlistat administration resulted in a decrease in INR in patients treated with warfarin. These effects could be due to decreased absorption of vitamin K. It is suggested that orlistat be administered with caution in patients undergoing anticoagulant therapy, monitoring INR levels, and that a dosage adjustment of the anticoagulant may be necessary. - Antidiabetic agents (including insulins). In obese patients with type 2 diabetes, weight loss caused by orlistat may be accompanied by a decrease in insulin resistance. Monitor blood glucose more frequently than usual and consider reducing the doses of antidiabetic agents. - Antiepileptic drugs (valproate, lamotrigine). Seizures have been reported in patients using both treatments concomitantly. Monitoring is recommended for changes in the frequency and/or severity of seizures. The patient should consult their doctor before starting treatment with orlistat EFP. - Antihypertensives (amlodipine, atenolol, enalapril, hydrochlorothiazide, or losartan). There are some cases in which increases in blood pressure have been described in patients whose blood pressure was controlled with these drugs when orlistat was administered concurrently. Caution is advised when combining these drugs. - Cyclosporine. Orlistat may decrease plasma concentrations of cyclosporine, with the consequent risk of loss of its immunosuppressive effect. This effect could be due to possible interference with the absorption of cyclosporine, as it is a lipophilic substance. In principle, concomitant use is not recommended (especially if orlistat is dispensed over-the-counter); if this combination is unavoidable, it is recommended to monitor cyclosporine levels at the beginning and end of orlistat treatment. This interaction appears to be less significant when cyclosporine is administered as a microemulsion (Neoral preparations) than when it is administered as an oil suspension. - Lipid-lowering drugs. Weight loss may be accompanied by an improvement in cholesterol levels, so in patients undergoing lipid-lowering treatment, it may be necessary to adjust the dose of this medication. - Levothyroxine. Risk of loss of therapeutic control in hypothyroid patients due to decreased levothyroxine activity. Orlistat appears to reduce its absorption. Space administration by at least 4 hours and monitor thyroid function, adjusting the levothyroxine dose accordingly. The patient should consult their doctor before starting treatment with orlistat EFP. - Fat-soluble vitamins (vitamins A, D, E, and K). Orlistat may interfere with the absorption of fat-soluble vitamins. Although decreases in the stores of these vitamins are not usually observed, supplementation may occasionally be necessary. It is recommended to separate the administration of these supplements from orlistat by about 2 hours or to administer the supplements before going to bed. Pregnancy FDA Pregnancy Category X. In animal studies, no toxic effects on the mother or offspring have been observed using doses even higher than therapeutic doses. The use of orlistat is contraindicated during pregnancy because weight loss offers no benefit to the mother and may be harmful to the fetus. Pregnant women are advised to gain a small amount of weight (never lose it), which is a natural consequence of the physiological process of pregnancy. This weight gain should occur even in overweight and obese women. In case of pregnancy, warn the mother of the negative consequences that weight loss can have on the fetus. Lactation It is unknown whether orlistat is excreted in breast milk and if this could have effects on the infant. It is recommended that orlistat not be used in breastfeeding women. The use of orlistat EFP is considered contraindicated in breastfeeding women. Children The safety and efficacy of orlistat in children and adolescents under 18 years of age have not been evaluated, therefore its use is not recommended. Seniors The safety and efficacy of orlistat have not been evaluated in patients over 65 years of age, therefore its use is not recommended. Adverse reactions Adverse reactions are primarily gastrointestinal in nature, and while they are frequent, they are usually transient. They are related to the inhibitory effect on fat absorption. Therefore, the incidence of these adverse reactions is higher with high-fat diets, and they can be reduced by decreasing the amount of fat in the diet. The following are described in decreasing order of severity within each frequency interval, considering very frequent (>10%), frequent (1-10%), infrequent (0.1-1%), or of unknown frequency (cannot be estimated from the available data, as they are data from spontaneous post-marketing notifications). - Gastrointestinal: Very common: abdominal pain, steatorrhea, fecal urgency, oily spotting, diarrhea, flatulence, and flatulence with fecal discharge, oily stool, and loose stools. Common: rectal pain, fecal incontinence, increased defecation, and dental and gum disorders. Frequency not known: diverticulitis, mild rectal bleeding, and pancreatitis. - Neurological/psychological: Very common: [HEADACHE]. Common: [ANXIETY]. - Genitourinary: Common: [GENITOURINARY INFECTION], [MENSTRUAL CYCLE DISORDERS]. Frequency unknown: [NEPHROPATHY] due to oxalate. - Respiratory: Very common: [FLU], upper respiratory infections. Common: [RESPIRATORY INFECTION] lower. - General: Frequent: [ASTHENIA]. - Allergic/dermatological: Frequency unknown: [HYPERSENSITIVITY REACTIONS], [PRURITUS], [EXANTHEMATOUS ERUPTIONS], [URTICARIA], [ANGIOEDEMA], [BRONCHOSPASM], [ANAPHYLAXIS], bullous eruptions. - Hepatobiliary: Frequency unknown: [HEPATITIS] which may be severe, [CHOLELITHIASIS], [PANCREATITIS], [INCREASE TRANSAMINASES], [INCREASE ALKALINE PHOSPHATASE]. - Metabolic: Very frequent: [HYPOGLYCEMIA] (occurred with a frequency >2% and with an incidence > or = 1% over placebo in obese patients with type 2 diabetes). - Hematological: Frequency unknown: [HYPOPROTHROMBINEMIA] and increased INR. Overdose Symptoms: Following administration of single doses of 800 mg or multiple doses of up to 400 mg every 8 hours, no significant adverse effects have been observed. According to studies in humans and animals, any systemic effects attributable to orlistats ability to inhibit lipases should be rapidly reversible. Treatment: In case of a significant orlistat overdose, 24-hour patient monitoring is recommended. Treatment will be symptomatic.