Orlistat

When ATH:
A08AB01

Characteristic.

White or off-white crystalline powder. Practically insoluble in water, freely soluble in chloroform, slightly soluble in methanol and ethanol. It has no pK_a in physiological pH range.

Pharmacological action.
Inhibitory gastrointestinal lipase.

Application.

According to the Physician Desk Reference (2003), Orlistat is indicated for the treatment of obesity, incl. reduce and maintain body weight, in conjunction with a reduced-calorie diet. Orlistat is also shown to reduce the risk of re weight gain after initial reduction. Orlistat is indicated for patients with obesity body mass index (BMI, his calculation — see. "Cautions") ≥30 kg / m² or ≥27 kg / m² in the presence of other risk factors (diabetes, arterial hypertension, dyslipidaemia).

Contraindications.

Hypersensitivity, chronic malabsorption syndrome, cholestasis.

Restrictions apply.

Childhood (Safety and efficacy have not been established), hyperoxaluria history, nephrolithiasis (calcium oxalate stones).

Pregnancy and breast-feeding.

Adequate well-controlled studies of orlistat in pregnant women has not been. Since the animal data can not always predetermine response in humans, Orlistat is not recommended for use during pregnancy. Unknown, whether orlistat is secreted into breast milk, it should not be used in lactating women.

Side effects.

According to the double-blind, placebo-controlled clinical trials, patients, taking orlistat on 120 mg 3 twice a day by diet, during the first and second year of follow common (with frequency of ≥5%) and at least 2 times more likely, than placebo, observed side effects from the gastrointestinal tract, that reflect the mechanism of action of the drug. Next to the name contains the frequency of this side effect in the first / second year of observations in the orlistat group, in brackets - the same data in the placebo group.

From the digestive tract: oily discharge 26,6%/4,4% (1,3%/0,2%), bloating and gas emission 23,9%/2,1% (1,4%/0,2%), urgency to defecate 22,1%/2,8% (6,7%/1,7%), fatty / oily stool 20,0%/5,5% (2,9%/0,6%), oily stool 11,9%/2,3% (0,8%/0,2%), increased frequency of bowel movements 10,8%/2,6% (4,1%/0,8%), scatacratia 7,7%/1,8% (0,9%/0,2%).

These and other commonly observed adverse reactions were mostly moderate and transient, their frequency decreased in the second year of treatment. In general, the first episode of side effects observed during the 3 Months of therapy. Duration 50% all of gastrointestinal side effects, associated with treatment with orlistat, is less than 1 Sun, in most cases, no more than 4 Sun. However, side effects from the gastrointestinal tract, some patients may develop over 6 and more months of therapy.

In controlled clinical trials to stop treatment because of side effects have been forced 8,8% patients, prinimavshih orlistat, compared to 5,0% placebo. In the orlistat group most frequently interrupted treatment due to side effects from the gastrointestinal tract.

Seven multicentre, double-blind, placebo-controlled studies in patients, taking orlistat on 120 mg 3 twice a day in combination with a diet for 2 years, with a frequency ≥2% and greater than those of the placebo group (in combination with diet), The following side effects were noted. Next to the name contains the frequency of this side effect in the first / second year of observations in the orlistat group, in brackets - the same data in the placebo group (N means no reports of frequency characteristic ≥2% and exceeds the placebo).

From the nervous system and sensory organs: headache 30,6% / N (27,6%/N), dizziness 5,2% / N (5,0%/N), fatiguability 7,2%/3,1% (6,4%/1,7%), sleep disorders 3,9% / N (3,3%/N), anxiety 4,7%/2,8% (2,9%/2,1%), Depression N / 3,4% (N/2,5%).

From the respiratory system: upper respiratory tract infection 38,1%/26,1% (32,8%/25,8%), lower respiratory infections 7,8% / N (6,6%/N), symptoms of the ENT 2,0% / N (1,6%/N), otitis 4,3%/2,9% (3,4%/2,5%).

From the digestive tract: pain / abdominal discomfort 25,5% / N (21,4%/N), nausea 8,1%/3,6% (7,3%/2,7%), infectious diarrhea 5,3% / N (4,4%/N), pain / discomfort in the rectum 5,2%/3,3% (4,0%/1,9%), dental disease 4,3%/3,1% (2,9%/2,3%), gum disease 4,1%/2,0% (2,9%/1,5%), vomiting 3,8% / N (3,5%/N).

With the genitourinary system: irregular menstrual cycle 9.8%/N (7,5%/N), vaginitis 3,8%/2,6% (3,6%/1,9%), urinary tract infection 7,5%/5,9% (7,3%/4,8%).

On the part of the musculoskeletal system: back pain 13,9% / N (12,1%/N), pain in the lower extremities N / 10,8% (N/10,3%), arthritis 5.4%/N (4,8%/N), myalgia 4,2% / N (3,3%/N), dysfunction of the joints 2,3% / N (2,2%/N), tendonitis N/2.0% (N/1,9%).

For the skin: rash 4,3% / N (4,0%/N), xeroderma 2,1% / N (1,4%/N).

Other: Flu 39,7% / N (36,2%/N), swelling of feet N / 2,8% (N/1,9%).

There are rare reports of hypersensitivity reactions to orlistat, including itching, rash, krapivnicu, angioneurotic edema and anaphylaxis.

Cooperation.

Orlistat not affecting farmakokinetiku pravastatin, alcohol, digoksina (assigned in a single dose) and phenytoin (assigned in a single dose 300 mg), on the bioavailability of nifedipine (sustained release tablets), ovulatory-suppressive activity of oral contraceptives, farmakokinetiku (both R-, and S-enantiomer) and pharmacodynamics (prothrombin time and factor VII levels) varfarina. Alcohol did not affect the pharmacodynamics (fat excretion in feces) and systemic exposure of orlistat.

According to preliminary information, while the use of orlistat and cyclosporine levels in the plasma of the last drops (orlistat and cyclosporine should not be taken simultaneously; to reduce the possibility of drug interactions Cyclosporine should be taken at 2 hours before or after 2 h after administration orlistata). Orlistat reduces the absorption of beta-carotene, contained in food supplements, on 30% and it inhibits the absorption of vitamin E (in the form of tocopherol acetate) approximately 60%. Effect of orlistat on the absorption of vitamin D, A, contained additives, date unknown. Although the level of carboxylated osteocalcin, Marker dietary intake of vitamin K, while taking orlistat has not changed, those taking orlistat people reveal a tendency to decrease in the content of vitamin K.

Overdose.

Single dose 800 mg orlistata or his repeated dose to 400 mg 3 twice a day for 15 days people with normal body weight and obesity was not accompanied by significant side effects.

If you found a significant overdose of orlistat, You should monitor the patient during 24 no. According to studies in animals and humans, systemic effects, related properties of orlistat lipazingibiruyuschimi, should be rapidly reversible.

Dosing and Administration.

Inside, with each main meal, containing fats, during meals or no later than, than 1 hours after meals, by 120 mg 3 once a day. Allowed to pass orlistat, if there was a missed meal or food does not contain fat.

Precautions.

Before the appointment of orlistat should exclude organic causes of obesity, such as hypothyroidism. At the time of treatment is recommended a balanced low-calorie diet, wherein the fats provide less than 30% calories. The probability of side effects from the gastrointestinal tract is increased by a high content of fat in food (more 30% daily calories). The daily intake of fats, carbohydrate and protein should be distributed between the three main meals. Because orlistat reduces the absorption of certain fat-soluble vitamins, to ensure an adequate intake of their patients must take multivitamin preparations, containing liposoluble vitamins. Besides, vitamin D, and beta-carotene in obese patients may be lower, than humans, nonobese. Multivitamins should be 2 hours before or after 2 h after administration orlistata, such as before going to bed. Orlistat doses, exceeding 120 mg 3 once a day, It does not provide an additional effect. Patients, odnovremenno prinimayushtih orlistat and cyclosporine, It requires more frequent monitoring of cyclosporine plasma.

Patients, did not receive prophylactic vitamin supplements, when two or more consecutive visits to the doctor during the first and second years of treatment with orlistat was recorded a decrease in plasma levels of vitamins in the following percentage of cases (Data given in parentheses in the placebo group): Vitamin A 2,2% (1,0%), vitamin D 12,0% (6,6%), Vitamin E 5,8% (1,0%), beta-carotene 6,1% (1,7%). In some patients having a background of orlistat can increase urinary oxalate. As with other drugs for weight reduction, in some groups of patients (such as anorexia nervosa or bulimia) there is a possibility of abuse of orlistat.

Since the absorption of vitamin K while taking orlistat may decrease, patients, receiving orlistat against the backdrop of a long continuous use of warfarin, should closely monitor the parameters of blood coagulation.

Induction orlistat weight loss may be associated with improved metabolic control of diabetes, which will require reducing the dose of oral hypoglycemic agents (sulfonylurea derivatives, metformin, etc..) or insulin.

Cautions.

The degree of obesity was evaluated by body mass index (BMI), which is calculated by the formula: BMI = M/P², where M is the mass of the body, kg; P-growth, m.

Cooperation