Orlip

INSTRUCTION for medical use of the medicinal product ORLIP® (ORLIP®)

Composition:

active substance: orlistat;

1 capsule contains 120 mg of orlistat;

excipients: sodium starch glycolate, microcrystalline cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, talc.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: size № 2 capsules. Capsule color – cap – green, body – yellow. The contents of the capsules – white or almost white powder.

Pharmacotherapeutic group. Agents with peripheral mechanism of action used in the treatment of obesity. ATC code A08AB01.

Pharmacological properties.

Pharmacodynamics.

Orlistat is a potent and specific inhibitor of gastrointestinal lipases with prolonged action. Its therapeutic effect occurs in the lumen of the stomach and small intestine and involves the formation of covalent bonds with the active serine site of gastric and pancreatic lipase. The inactivated enzyme thus loses its ability to break down dietary fats entering in the form of triglycerides, thereby reducing absorption of free fatty acids and monoglycerides.

Pharmacokinetics.

Absorption

Studies involving volunteers with normal body weight and those with obesity have shown that systemic absorption of the drug is minimal. Eight hours after oral administration, unchanged orlistat was not detectable in blood plasma, indicating that its concentration is below 5 ng/mL.

Overall, after administration of therapeutic doses, unchanged orlistat was detected in blood plasma only sporadically, with very low concentrations (<10 ng/mL or 0.02 μmol). The absence of accumulation signs confirms minimal drug absorption.

Distribution

The volume of distribution cannot be determined because the drug is very poorly absorbed and lacks measurable systemic pharmacokinetics. In vitro, orlistat is more than 99% bound to plasma proteins (mainly lipoproteins and albumin). Minimal amounts of orlistat may penetrate into erythrocytes.

Metabolism

Based on data obtained from animal experiments, orlistat metabolism occurs primarily in the walls of the stomach and intestine. Approximately 42% of the minimal fraction of the drug that undergoes systemic absorption in obese patients consists of two main metabolites—M1 and M3.

Molecules M1 and M3 have an opened β-lactone ring and weakly inhibit lipase (1000 and 2500 times less, respectively, than orlistat). Considering their low inhibitory activity and low plasma concentrations (on average 26 ng/mL and 108 ng/mL, respectively) after administration of therapeutic doses, these metabolites are considered pharmacologically inactive.

Elimination

The main elimination route is excretion of the unabsorbed drug in feces. Approximately 97% of the administered dose was excreted in feces, of which 83% was unchanged orlistat.

Cumulative renal excretion of all substances structurally related to orlistat accounted for less than 2% of the administered dose. The time required for complete elimination of the drug from the body (via feces and urine) is 3–5 days. The elimination pathways of orlistat in volunteers with normal and excess body weight were found to be similar. Both orlistat and its metabolites M1 and M3 may undergo biliary excretion.

Clinical characteristics.

Indications.

Treatment in combination with a moderately hypocaloric diet in obese patients with a body mass index (BMI) ≥ 30 kg/m² or in patients with excess body weight (BMI ≥ 28 kg/m²), including those with obesity-related risk factors.

Treatment with orlistat should be discontinued after 12 weeks if there is no weight reduction of at least 5% compared to initial body weight.

Contraindications.

Chronic malabsorption syndrome, cholestasis, hypersensitivity to the active substance or to any of the other components of the medicinal product, breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Cyclosporine

When orlistat and cyclosporine are used concomitantly, decreased plasma concentrations of cyclosporine have been observed. This may lead to reduced immunosuppressive efficacy of cyclosporine. Therefore, concomitant administration with cyclosporine is not recommended (see section "Special precautions for use"). However, if concomitant use of orlistat and cyclosporine cannot be avoided, more frequent monitoring of cyclosporine plasma concentrations is recommended after initiation and discontinuation of orlistat in patients receiving cyclosporine. Cyclosporine plasma concentrations should be monitored until stabilization.

Acarbose

In the absence of pharmacokinetic interaction studies, concomitant use of orlistat and acarbose should be avoided.

Oral anticoagulants

When used concomitantly with orlistat, warfarin or other anticoagulants require monitoring of the international normalized ratio (INR).

Fat-soluble vitamins

Reduced absorption of fat-soluble vitamins A, D, E, and K has been observed during concomitant use with orlistat. In the majority of patients during clinical trials up to 4 full years of orlistat treatment, levels of vitamins A, D, E, K, and β-carotene remained within the normal range. To ensure adequate nutrition, patients on a weight-control diet should be advised to consume a diet rich in fruits and vegetables and to take multivitamin supplements. If multivitamins are recommended, they should be taken at least 2 hours after orlistat administration or at bedtime.

Amiodarone

A single study in a limited number of healthy volunteers observed a minor decrease in plasma levels of amiodarone when orlistat was administered concomitantly. The clinical significance of this finding in patients receiving amiodarone is unclear, but it may be clinically relevant in some cases. In patients receiving both orlistat and amiodarone, enhanced clinical and ECG monitoring is recommended.

There have been reports of seizures occurring during concomitant use of orlistat and antiepileptic agents (valproate, lamotrigine). A causal relationship has not been established; however, patients should be monitored for possible changes in frequency and/or severity of seizures.

Hypothyroidism and/or loss of control of hypothyroidism may rarely occur. The mechanism of this effect is not proven, but may involve reduced absorption of iodine salts and/or levothyroxine (see section "Special precautions for use").

There have been isolated reports of reduced efficacy of antiretroviral agents in HIV-infected patients, antidepressants, and antipsychotics (including lithium), coinciding with the initiation of orlistat therapy in patients with previously well-controlled conditions. Therefore, all potential consequences should be carefully evaluated in such patients before initiating orlistat treatment.

Absence of interaction

No interactions were observed in pharmacokinetic studies with amitriptyline, atorvastatin, biguanides, fibrates, fluoxetine, pravastatin, losartan, phentermine, digoxin, phenytoin, nifedipine administered as a gastrointestinal therapeutic system (nifedipine-GITS), or sustained-release nifedipine. The absence of these interactions has been demonstrated in dedicated drug interaction studies.

No interaction between orlistat and oral contraceptives was demonstrated in specific interaction studies. However, orlistat may indirectly reduce the availability of oral contraceptives, which could lead, in individual cases, to unintended pregnancy. Additional contraceptive methods are recommended in case of severe diarrhea.

Special precautions for use.

Treatment with orlistat may reduce the absorption of fat-soluble vitamins (A, D, E, and K). In most patients receiving orlistat in long-term studies lasting up to four years, levels of vitamins A, D, E, and K and beta-carotene remained within normal ranges. To ensure adequate nutrition, the use of multivitamin supplements should be considered.

In clinical trials, weight loss with orlistat was less pronounced in patients with type II diabetes mellitus than in patients without diabetes. During treatment with orlistat, therapy with antidiabetic medicinal products should be monitored.

Concomitant administration with cyclosporine is not recommended (see section "Interaction with other medicinal products and other forms of interactions").

Patients should be advised to follow dietary recommendations.

The likelihood of gastrointestinal adverse reactions may increase if orlistat is used with a diet high in fat (e.g., in a 2000 kcal/day diet, more than 30% of calories derived from fat, equivalent to approximately 67 g of fat). Daily fat intake should be distributed over three main meals.

Cases of rectal bleeding have been reported during orlistat use. If severe and/or persistent symptoms occur, further investigation is recommended.

Use of an additional contraceptive method is recommended to prevent potential failure of oral contraception that may occur in case of severe diarrhea.

Coagulation parameters should be monitored in patients receiving concomitant oral anticoagulants (see section "Interaction with other medicinal products and other forms of interactions").

Use of orlistat may be associated with hyperoxaluria and oxalate nephropathy, which sometimes may lead to renal failure. This risk is increased in patients with chronic kidney disease and/or reduced intravascular volume.

Hypothyroidism and/or loss of control of hypothyroidism may rarely occur. The mechanism of this phenomenon is not fully established, but may involve reduced absorption of iodine salts and/or levothyroxine (see section "Interaction with other medicinal products and other forms of interactions").

In patients with epilepsy, orlistat may disrupt anticonvulsant therapy by reducing absorption of antiepileptic drugs, potentially leading to seizures (see section "Interaction with other medicinal products and other forms of interactions").

Orlistat use may potentially reduce absorption of antiretroviral agents in HIV-infected patients and negatively affect the efficacy of antiretroviral therapy in HIV-infected patients (see section "Interaction with other medicinal products and other forms of interactions").

Use during pregnancy or breastfeeding.

There are no clinical data on the use of orlistat in pregnant women.

Animal studies have not shown any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. However, in the absence of clinical data, orlistat should not be prescribed to pregnant women.

Excretion of orlistat in human breast milk has not been studied; therefore, orlistat is contraindicated in women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of Administration and Dosage.

The recommended dose of orlistat for adults is one 120 mg capsule taken with water immediately before each main meal. If a meal is missed or contains no fat, the dose of orlistat may also be omitted.

Patients should follow a balanced, moderately hypocaloric diet containing approximately 30% of calories from fat. A diet rich in fruits and vegetables is recommended. The daily intake of fats, proteins, and carbohydrates should be distributed over three main meals.

Increasing the dose of orlistat beyond the recommended dose (120 mg three times daily) does not result in an enhanced therapeutic effect. Orlistat administration is associated with increased fat excretion in feces within 24–48 hours after drug administration. After discontinuation of treatment, fecal fat excretion usually returns to pre-orlistat levels within 48–72 hours.

The effect of orlistat has not been studied in patients with impaired kidney and/or liver function, as well as in children and elderly patients.

Children.

Clinical studies of orlistat in children have not been conducted. There are no appropriate indications for the use of orlistat in children.

Overdose.

In clinical trials, single doses of 800 mg orlistat or multiple doses of 400 mg three times daily for 15 days in individuals with normal body weight and in obese patients were not associated with significant adverse events. Additionally, in obese patients, experience exists with orlistat 240 mg three times daily for 6 months.

In most cases of orlistat overdose reported during post-marketing surveillance, either no adverse events were reported, or the adverse events were consistent with those observed during therapeutic use.

In the case of significant orlistat overdose, patient monitoring for 24 hours is recommended. Data from studies in volunteers and animals indicate that any systemic effect potentially related to the lipase-inhibiting properties of orlistat should resolve rapidly.

Adverse reactions.

Clinical trials

Orlistat adverse effects are mostly gastrointestinal and are due to its pharmacological action of inhibiting absorption of dietary fats. Their frequency increases with higher fat intake. Patients should be advised about the possibility of gastrointestinal adverse effects and the best ways to manage them, such as controlling the percentage of fat in the diet. Adherence to a low-fat diet reduces the likelihood of these adverse events and also helps patients manage and regulate fat intake.

Gastrointestinal adverse reactions are generally mild and transient. They usually occur early in treatment (within the first 3 months), and most patients experience only one episode. With continued orlistat treatment, the frequency of adverse reactions decreases.

The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), and very rare (<1/10000), including isolated cases. Within each group, adverse reactions are listed in order of decreasing severity.

Below are adverse reactions (first year of study) occurring at a frequency >2% and with an incidence ≥1% higher than with placebo in 1- and 2-year clinical trials.

From the nervous system: very common – headache.

From the respiratory system, thoracic organs and mediastinum: very common – upper respiratory tract infections; common – lower respiratory tract infections.

From the gastrointestinal system: very common – abdominal pain/discomfort, oily rectal discharge, passage of gas with discharge of oily spotting, urgent need for bowel movement, steatorrhea, flatulence, loose stools, oily evacuation, increased defecation frequency; common – rectal pain or discomfort, soft stools, fecal incontinence, bloating*, dental disorders, gingival disorders.

From the kidneys and urinary system: common – urinary tract infections.

Metabolism and nutritional disorders: very common – hypoglycemia*.

Infections and infestations: very common – influenza.

General disorders: common – weakness.

From the reproductive system and breast disorders: common – dysmenorrhea.

Psychiatric disorders: common – anxiety.

*Only specific adverse reactions occurring at a frequency >2% and with an incidence ≥1% higher than with placebo in patients with obesity and type II diabetes mellitus.

In 4-year clinical trials, the overall pattern of adverse events was similar to that reported in 1- and 2-year trials. The overall frequency of gastrointestinal adverse events observed during the first year decreased each year over the 4-year period.

Post-marketing experience (based on spontaneous reports, frequency unknown).

Laboratory tests: increased liver transaminase and alkaline phosphatase activity. When orlistat is co-administered with anticoagulants, cases of reduced prothrombin, increased international normalized ratio (INR), and anticoagulant treatment imbalance have been reported, leading to changes in hemostasis parameters.

From the gastrointestinal system: rectal bleeding, diverticulitis, pancreatitis.

From the skin and its appendages: bullous eruptions.

From the immune system: hypersensitivity reactions manifesting as pruritus, rash, urticaria, angioneurotic edema, bronchospasm, and anaphylaxis.

From the hepatobiliary system: cholelithiasis, hepatitis, which may be severe. Isolated cases of fatal outcomes or cases requiring liver transplantation have been reported.

From the kidneys and urinary system: hyperoxaluria, oxalate nephropathy, which may lead to impaired kidney function.

Seizures have been reported in patients concurrently receiving orlistat and antiepileptic drugs (see section "Interaction with other medicinal products and other forms of interaction").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep in the original packaging to protect from light, moisture, and in a place inaccessible to children.

Packaging. 10 capsules in a blister. 3 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. GM Pharmaceuticals Ltd.

Manufacturer's address and location of operations.

Rustavi Highway № 52, Tbilisi, Georgia