ACTION AND MECHANISM

- [PANCREATIC LIPASE INHIBITOR], [ORAL LIPID ABSORPTION INHIBITOR]. 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 enzyme's active center 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 contained in food, which can lead to a reduction in energy intake of up to 200-300 kilocalories per day. In addition to acting on lipids, orlistat also prevents the absorption of fat-soluble vitamins A, D, E, and K.

SPECIAL WARNINGS

- This non-prescription medication is only authorized for overweight adults 18 years of age or older with a BMI of 28 kg/m2 or higher. If prescribed, 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 the height (in meters).

- Pay special attention to possible eating disorders.

- Diet and exercise should be part of your weight loss program, preferably beginning before starting orlistat treatment and continuing after it has ended.

- Before starting treatment with orlistat, any organic causes of obesity, such as untreated hypothyroidism, should be ruled out.

- In patients receiving anticoagulants, it is recommended to monitor the INR before, during, and after treatment with orlistat. Consult your physician before starting coadministration if you are using orlistat without a prescription. (See Interactions).

- Ciclosporin levels should be monitored in transplant patients, and if necessary, the dose should be increased or Neoral formulations used. Consult your doctor before starting coadministration if you are using orlistat without a prescription. (See Interactions).

- In patients receiving treatment with acarbose, the use of orlistat without a prescription is not recommended due to the absence of studies on pharmacokinetic interactions (See Interactions).

- Treatment with levothyroxine or antiepileptics should be monitored, and dosages should be adjusted. Consult your doctor before starting coadministration if you are using orlistat without a prescription. (See Interactions).

- Other treatments that require caution include oral contraceptives and amiodarone. (See Interactions.)

- The possibility of gastrointestinal adverse reactions (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 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 fat-soluble vitamins A, D, E, and K. If vitamin supplements are deemed necessary, they should be administered at least 2 hours after the orlistat dose or at bedtime. (See Interactions).

- Increased urinary oxalate excretion (hyperoxaluria) and oxalate nephropathy may occur, although rare; therefore, a doctor should be consulted before starting treatment in patients with kidney failure.

- While cases of serious hepatic adverse reactions continue to be evaluated, it is advisable to inform the patient 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.

SENIORS

The safety and efficacy of orlistat have not been evaluated in patients over 65 years of age, so its use is not recommended.

PATIENT ADVICE

- 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. The daily intake of fat, carbohydrates, and protein should be distributed among the three main meals. It is advisable to continue the diet after completing treatment.

- It is advisable to do regular physical exercise during and after the treatment.

- The prescribed doses should not be increased.

- Alcohol consumption should be avoided due to the large amount of calories it provides.

- Inform your doctor or pharmacist if you are taking anticoagulants, cyclosporine, acarbose, levothyroxine, antiepileptics, oral contraceptives, or amiodarone.

- In cases of severe diarrhea, patients using oral contraceptives should use an additional method of contraception.

- In cases of steatorrhea, antidiarrheals that reduce intestinal transit (loperamide) should not be used.

- If fat is not ingested at a meal, or if the patient skips a meal, the capsule corresponding to that meal will not be taken.

- Tell your doctor or pharmacist if you experience symptoms such as weakness, fatigue, fever, jaundice, or dark urine. These may indicate liver damage.

CONTRAINDICATIONS

- Hypersensitivity to any component of the medication.

- [INTESTINAL MALABSORPTION] Chronic. Orlistat decreases the absorption of lipids and fat-soluble vitamins, so in these patients it can cause malnutrition and increase the risk of steatorrhea.

- [CHOLESTASIS]. Orlistat decreases postprandial cholecystokinin concentrations by reducing the number of fatty acids present in the intestinal lumen. Although decreased gallbladder contractility has not been observed, it cannot be ruled out. Because orlistat may promote gallstone formation, its use is not recommended in patients with cholestasis.

- [ANOREXIA NERVOSA] and [BULIMIA]. Orlistat may be abused by patients with anorexia or bulimia nervosa. This medication should not be used in these patients.

- Treatment with cyclosporine, oral anticoagulants (acenocoumarol, warfarin), or acarbose. Co-administration of any of these drugs with orlistat EFP is considered contraindicated. (See Interactions, Precautions).

- Pregnancy.

PREGNANCY

Animal safety : In animal studies, no toxic effects on the mother or offspring have been observed using doses even higher than therapeutic doses.

Safety in humans : The use of orlistat is contraindicated during pregnancy, as weight loss offers no benefits to the mother and may be harmful to the fetus. Pregnant women are advised to maintain a slight weight gain (never lose weight) as a result of the physiological process that occurs during pregnancy. This gain should occur even in overweight and obese women. In the case of pregnancy, warn the mother of the negative consequences that weight loss may have on the fetus.

Effects on fertility : Animal studies do not suggest harmful effects on fertility.

PHARMACOKINETICS

Oral route:

- Absorption: Oral absorption of orlistat is minimal. After oral administration of 360 mg, plasma concentrations were undetectable (<5 ng/ml). Oral bioavailability of orlistat has been shown to be less than 2% in animals.

- Distribution: In in vitro studies, the small amount of absorbed orlistat circulates in plasma bound to plasma proteins (99%), mainly albumin and lipoproteins. Minimal amounts may appear in erythrocytes.

- Metabolism: Orlistat may be primarily metabolized 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-formyl leucine from M1. These metabolites represent 42% of the total plasma concentration. They have no pharmacological activity.

- Elimination: Orlistat is eliminated primarily in feces (97%), with 83% remaining unchanged. The absorbed portion 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 impairment: No studies have been conducted in patients with renal impairment.

- Liver failure: No studies have been conducted in patients with liver failure.

INDICATIONS

"27 and 60 mg PRESENTATIONS":

- [OVERWEIGHT]. Weight loss in overweight adults (18 years of age or older), with a BMI greater than or equal to 28 kg/m2, associated with a low-calorie, low-fat diet and exercise.

INTERACTIONS

- Acarbose. In the absence of pharmacokinetic interaction studies, concomitant administration of orlistat with acarbose should be avoided.

- Amidarone. Possible decrease in amiodarone plasma levels; 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 effectiveness of oral contraceptives, as there have been some rare cases of unintended pregnancies. Therefore, the use of an additional method of contraception is recommended in cases of severe diarrhea.

- Anticoagulants (acenocoumarol, warfarin). There have been reports of orlistat administration resulting in a decrease in the INR in patients receiving warfarin. These effects could be due to decreased vitamin K absorption. It is recommended that orlistat be administered with caution in patients receiving anticoagulant therapy, with INR levels monitored, and a dosage adjustment of the anticoagulant may be necessary.

- Antidiabetics (including insulins). In obese patients with type 2 diabetes, a decrease in body weight caused by orlistat may be accompanied by a decrease in insulin resistance. Monitor blood glucose more frequently than usual and consider whether a dose reduction of antidiabetic agents is necessary.

- Antiepileptics (valproate, lamotrigine). Seizures have been reported in patients using both treatments concomitantly. Monitoring is recommended for changes in seizure frequency and/or severity. The patient should consult their physician before starting treatment with orlistat EFP.

- Antihypertensives (amlodipine, atenolol, enalapril, hydrochlorothiazide, or losartan). There have been some reports of increases in blood pressure in patients receiving these drugs when orlistat was coadministered. Caution is recommended when combining these drugs.

- Ciclosporin. Orlistat may decrease plasma concentrations of cyclosporin, with the consequent risk of losing its immunosuppressive effect. This effect could be due to possible interference with cyclosporin absorption, as it is a lipophilic substance. In principle, concomitant use is not recommended (especially if orlistat EFP is dispensed); if this combination is unavoidable, monitoring cyclosporin levels is recommended when starting and ending treatment with orlistat. This interaction appears to be less significant when cyclosporin is administered as a microemulsion (Neoral preparations) than when administered as an oily suspension.

- Lipid-lowering drugs. Weight loss may be accompanied by an improvement in cholesterol levels, so patients on lipid-lowering therapy may need to adjust their dosage.

- Levothyroxine. Risk of loss of therapeutic control in hypothyroid patients due to decreased levothyroxine activity. Orlistat appears to reduce its absorption. Interval administration should be at least 4 hours apart and thyroid function should be monitored, adjusting the levothyroxine dose. The patient should consult their physician 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 decreased stores of these vitamins are not usually observed, supplementation may occasionally be necessary. It is recommended to space the administration of these supplements and orlistat about two hours apart or to administer the supplements before going to sleep.

- Antiretrovirals: Possible reduction in oral absorption of the antiretroviral. Treatment with orlistat should only be initiated after careful consideration of the potential impact on the efficacy of antiretroviral therapy.

LACTATION

It is unknown whether orlistat is excreted in breast milk and whether this could have effects on the nursing infant. It is recommended that orlistat not be used by breastfeeding women.

The use of orlistat EFP is considered contraindicated in women who are breastfeeding.

CHILDREN

The safety and efficacy of orlistat in children and adolescents under 18 years of age have not been evaluated, so its use is not recommended.

RULES FOR CORRECT ADMINISTRATION

Take immediately before or during meals, or at most one hour after. If you skip a meal or if the meal is fat-free, you should skip the orlistat dose.

POSOLOGY

"27 and 60 mg PRESENTATIONS":

- Adults, oral: 1 tablet every 8 hours. If no weight loss is observed after 12 weeks of treatment, it is recommended that you consult your doctor and/or pharmacist, who will assess the need to discontinue orlistat.

- Duration of treatment: Treatment should not be extended for periods exceeding 6 months.

PRECAUTIONS

- [KIDNEY FAILURE], [KIDNEY STONES]. In some patients, orlistat may cause increased urinary oxalate excretion (hyperoxaluria) and oxalate nephropathy. Consult your doctor before starting non-prescription orlistat.

- [TYPE 2 DIABETES MELLITUS]. Weight loss in obese patients with non-insulin-dependent diabetes was less than in obese patients without diabetes. Furthermore, when weight loss occurs, diabetic patients may experience a decrease in their insulin resistance, so closer monitoring of blood glucose levels is necessary and the need for dosage adjustments should be considered (See Interactions).

- [RECTAL BLEEDING]: 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 altered thyroid control have occurred 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 for levothyroxine dosage adjustment. Consult your physician before starting coadministration if orlistat is used without a prescription. (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 PRESSURE]. Weight loss may be accompanied by an improvement in blood pressure, so patients on antihypertensive treatment may need to adjust their medication dosage.

- [HYPERCHOLESTEROLEMIA]. Weight loss may be accompanied by an improvement in cholesterol levels, so a dose adjustment may be necessary in patients on lipid-lowering therapy.

- Treatment with cyclosporine. Coadministration is not recommended; consult your doctor before starting coadministration if you are using orlistat without a prescription. (See Interactions, Contraindications).

- Treatment with oral anticoagulants. Coagulation parameters (INR) should be monitored. Consult your physician before starting coadministration if you are using orlistat without a prescription. (See Interactions, Contraindications).

- Treatment with acarbose. Non-prescription use of orlistat is not recommended due to the lack of pharmacokinetic interaction studies (see Interactions).

- Treatment with antiepileptics. Seizures have been reported in patients using both treatments. Consult your doctor before starting coadministration if you are using orlistat without a prescription. (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, stagger the doses of orlistat and these supplements (See Interactions).

ADVERSE REACTIONS

Adverse reactions are primarily gastrointestinal in nature, and are usually frequent but transient. They are related to the inhibitory effect on fat absorption. Therefore, the incidence of these adverse reactions is higher in high-fat diets, so they can be reduced by reducing the amount of fat in the diet.

Adverse reactions are described according to each frequency interval, considering very frequent (>10%), frequent (1-10%), unfrequent (0.1-1%), rare (0.01-0.1%), very rare (<0.01%) or of unknown frequency (cannot be estimated from the available data).

- Gastrointestinal: Very common: [ABDOMINAL PAIN], [STEATORRHEA], faecal urgency, oily spotting, [DIARRHOEA], [FLATULENCE] and flatulence with faecal discharge, oily stools, loose stools. Common: Rectal pain, [FAECA INCONTINENCE], increased defecation, tooth and gum disorders. Frequency not known: [INTESTINAL DIVERTICULITIS], mild [RECTAL BLEEDING], [PANCREATITIS].

- Neurological/psychological: Very common: [HEADACHE]. Common: [ANXIETY].

- Genitourinary: Frequent: [GENITOURINARY INFECTION], [MENSTRUAL CYCLE DISORDERS]. Unknown frequency: [NEPHROPATHY] due to oxalate.

- Respiratory: Very common: [FLU], upper respiratory infections. Common: [RESPIRATORY INFECTION] lower respiratory infections.

- General: Frequent: [ASTHENIA].

- Allergic/dermatological: Frequency unknown: [HYPERSENSITIVITY REACTIONS], [PRURITUS], [SKIN RASHES], [URTICARIA], [ANGIOEDEMA], [BRONCHIAL SPASM], [ANAPHYLAXIS], bullous eruptions.

- Hepatobiliary: Unknown frequency: [HEPATITIS] which may be severe, [CHOLELITHIASIS], [PANCREATITIS], [ELEVATED TRANSAMINASES], [ELEVATED ALKALINE PHOSPHATASE].

- Metabolic: Very common: [HYPOGLYCEMIA] (occurred with a frequency >2% and with an incidence

> or = 1% over placebo in obese patients with type 2 diabetes).

- Hematological: Unknown frequency: [HYPOPROTHROMBINEMIA] and increased INR.

OVERDOSE

Symptoms: Following single doses of 800 mg or multiple doses of up to 400 mg/8 hours, no significant adverse effects have been observed. Based on human and animal studies, any systemic effects attributable to orlistat's ability to inhibit lipases should be rapidly reversible.

Treatment: In the event of a significant orlistat overdose, 24-hour patient monitoring is recommended. Treatment will be symptomatic.