Xenical Generic 60/120mg (Orlistat): for Obesity Management

Xenical generic (Orlistat) is a digestive lipase inhibitor applied for obesity management. Xenical works by reducing the absorption of food fats in the digestive tract.

Orlistat’s empirical formula is C29H53NO5, its molecular weight comprises 495.7. Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. It is a single diastereomeric molecule containing four chiral centers. Its structure is depicted below:

Orlistat is a crystalline powder of white to dingy white color. Orlistat is almost insoluble in water, easily soluble in chloroform, and well soluble in ethanol and methanol.

Xenical is presented for oral administration in the form of a turquoise hard-gelatin capsule that is imprinted with black. Every individual capsule includes a pellet formulation containing 120 mg of orlistat, the active ingredient, as well as several inactive ingredients such as sodium starch glycolate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and talc. The shell of the capsule contains gelatin, titanium dioxide, and FD&C Blue No. 2 with black printing ink including propylene glycol, pharmaceutical grade shellac, potassium hydroxide, strong ammonium solution, and black iron oxide.

Therapeutic Indications of Orlistat

Orlistat is indicated in combination with a mildly reduced-calorie diet to treat obese patients whose body mass index (BMI) is equal to or greater than 30 kg/m2, as well as overweight individuals (BMI ≥ 28 kg/m2) with accompanying risk factors. In other words, when considering treatment with Xenical BMI of 28 should be a minimal starting point.

Treatment with orlistat should be stopped following 12 weeks if a patient has been incapable of losing at least 5 % of his/her body mass as measured at the start of the treatment.

How It Works

Orlistat is a reversible inhibitor of lipases in the gastrointestinal tract. It blocks the action of lipase, an enzyme digesting fats in the intestines, and thus blocks about 30 percent of fat consumed with food. As a result, the body misses about one-third of the calories contained in the fat, and so weight loss occurs. Since the fat remains unabsorbed in the intestines, it gets eliminated from the body with the feces.

Because fat contains roughly twice as many calories per portion as carbohydrates and proteins, a patient taking Xenical can expect to subtract a substantial amount of calories consumed primarily shedding weight at a rate of 0 -1.5 kg per week. Studies of the prolonged use of Xenical show that patients who can tolerate Xenical intake can achieve a total weight loss that is almost 2.5 – 5 kg more than that achieved through diet and exercise alone.

Pharmacological characteristics

Pharmacokinetic characteristics

Absorption

Studies in obese and normal weight volunteers have indicated that the degree of absorption of orlistat in blood plasma was minimal. Eight hours following oral intake of orlistat, plasma concentrations of unchanged orlistat were non-measurable (< 5 ng/ml).

Generally, at therapeutic dosages, detection of unchanged orlistat in plasma was irregular and concentrations were very low (< 10 ng/ml or 0.02 µmol), without signs of buildup, which is coherent with minimal absorption. 

Distribution

Since orlistat is only minimally absorbed and has no distinct systemic pharmacokinetics, the volume of its distribution cannot be established. In vitro, orlistat is > 99 % bound to plasma proteins (albumin and lipoproteins). Orlistat partitions into erythrocytes only minimally.

Metabolism

It is highly likely that the metabolism of orlistat takes place largely within the gastrointestinal wall, as follows from animal studies data. As established in a study with obese patients, two key metabolites, M1 (4-member lactone ring hydrolyzed) along with M3 (M1 with N-formyl leucine side-chain cleaved), accounted for almost 42 % of the overall plasma concentration.

Both M1 and M3 have an open beta-lactone ring and thus a very meager lipase inhibitory activity (1,000 and 2,500 times weaker less than orlistat, respectively). Considering such a low inhibitory activity along with low plasma concentrations at therapeutic doses (average of 26 ng/ml and 108 ng/ml, correspondingly), these metabolites are viewed as pharmacologically insignificant.

Elimination

Fecal excretion of the unabsorbed medication was the main way of elimination, as studies in regular weight and obese subjects have indicated. Almost 97 % of the administered amount was excreted in feces and 83 % of that in the form of unchanged orlistat.

The aggregated renal excretion of orlistat-related materials was less than 2 % of the given dosage. The time to reach full excretion (urinary plus fecal) was 3 to 5 days. The disposition of the drug seemed to be similar between obese and normal-weight study participants. All three – M1, M3, and Orlistat,– are subject to biliary excretion.

Pharmacodynamical Characteristics

Pharmaco-therapeutic group: Peripherally acting antiobesity agent, ATC code: A08AB01.

Orlistat is a specific, long-acting and potent inhibitor of gastrointestinal lipases. Orlistat exercises its therapeutic action in the small intestine and the lumen of the stomach by creating a covalent bond with the active serine site of the pancreatic and gastric lipases. The disabled enzyme is thus inaccessible for hydrolyzing dietary fats consumed in form of triglycerides into absorbable monoglycerides and free fatty acids.

In several 2-year studies and one 4-year study, a low-calorie diet was used during therapy in both the Xenical orlistat and the placebo treatment groups.

Collective data from five 2-year studies with orlistat accompanied by a low-calorie diet indicated that 37 % of Xenical-treated patients and 19 % of placebo-treated patients shed at least 5 % of their original body weight after 12 weeks of therapy. Out of these, 49 % of Xenical patients and nearly 40 % of placebo patients managed to lose ≥ 10 % of their original body weight over one year. Vice versa, of patients who failed to show a loss of 5 % of their original body weight after 12 weeks of therapy, only 5 % of Xenical patients and as few as 2 % of placebo patients managed to lose ≥ 10 % of their original body weight over one year. In general, after one full year of therapy, the share of patients who managed to lose at least 10 % of their starting body weight was 20 % with Xenical 120 mg versus 8 % of placebo-treated patients. The mean difference in Xenical-enabled weight loss in comparison with placebo comprised 3.2 kg.

Numbers from the XENDOS clinical study conducted over the course of four years revealed that 60 % of Xenical-treated patients and 35 % of placebo-treated patients demonstrated a loss of at least 5 % of their original body weight after 12 weeks of therapy. Of these, 62 % of Xenical patients and 52 % of placebo patients managed to lose ≥ 10 % of their original body weight in one year. On the contrary, out of patients who failed to show a loss of 5 % of their original body weight after 12 weeks of therapy, only 5 % of Xenical patients and 4 % of placebo patients managed to lose ≥ 10 % of their initial body weight over the course of one year. After one year of therapy, 41 % of Xenical patients compared to 21 % of placebo patients lost ≥ 10 % of body weight with a mean difference in kilograms shed constituting 4.4 kg. After four years of therapy, 21 % of Xenical patients versus 10 % of placebo patients managed to lose ≥ 10 % of baseline body weight, with a mean difference in kilograms shed of 2.7 kg.

More patients on Xenical or placebo lost initial body weight of at least 5 % over the course of 12 weeks or 10 % over the course of one year in the XENDOS clinical trial than in the five 2-year trials. The reason for this variance is that the abovementioned five 2-year studies incorporated a 4-week diet as well as placebo introduction phase during which the trial participants shed on average 2.6 kg before starting treatment.

Results of the 4-year study also seemed to suggest that weight loss reached with Xenical delayed the advance of type 2 diabetes throughout the duration of the study (aggregated Xenical diabetes cases occurrences: 3.4% in the Xenical group versus 5.4% in the placebo group). Most diabetes instances originated from the subgroup of patients whose tolerance to glucose was impaired at baseline, which constituted 21 % of the randomized patients.

In a multi-location (Canada, US), double-blind, parallel-group, placebo-controlled trial, 539 obese teenage participants were randomized to get either 120 mg Xenical (n=357) or placebo (n=182) three times per day as an addition to a low-calorie diet and exercise for one full year. Both groups also received multivitamin supplements. The major endpoint was the alteration in body mass index (BMI) from the initial level to the end of the trial.

The results were significantly better in the Xenical group (0.86 kg/m2 difference in BMI of in favor of Xenical). 9.5 % of Xenical patients compared to 3.3 % of placebo patients lost ≥ 10 % of baseline body weight after 52 weeks, a mean difference constituting 2.6 kg in favor of Xenical. The side effects were similar to those experienced by adults. Yet, there was a baffling increase in the occurrence of bone fractures (6 % compared to 2.8 % in Xenical and placebo groups, respectively). Xenical benefits in this group are overshadowed by increased risk of bone fractures.

Preclinical Safety Information

Non-clinical information shows no specific hazards for humans as follows from standard studies of genotoxicity, toxicity to reproduction, repeated dose toxicity, and carcinogenic potential.

In several animal reproductive studies, no teratogenic actions were detected. No malformative consequences are expected in humans without any teratogenic effect in animals. Up to the present time, active ingredients accountable for malformations in humans have been proved teratogenic in animals when properly documented studies were performed in both species.

Method of Administration and Recommended Doses

Adults

The recommended dosage of Xenical is one 120 mg capsule consumed with a glass of water directly before, during or immediately after each major meal. If a meal is omitted or contains no fat, the dose of Xenical must not be taken.

It is advisable to stick to a diet rich in fruit and vegetables. In general, the Xenical diet should be mildly low-calorie and nutritionally balanced, with roughly 30% of calories coming from fat.

The daily consumption of fat, protein, and carbohydrate must be distributed among three main meals.

Xenical doses exceeding120 mg three times per day have not been proved to deliver further benefit.

The effect of Xenical marks an increase in fecal fat 24 to 48 hours afterward medicating. Upon withdrawal of treatment, fecal fat content typically returns to pre-therapy levels, during 48 to 72 hours. 

Other patient groups

The effect of orlistat in patients suffering from renal and/or hepatic impairment, as well as in elderly patients and children has not been intentionally studied.

Xenical is not intended for usage in children younger than 12 years of age.

Contraindications of Orlistat

Absolute contraindications

• Breast-feeding
• Hypersensitivity to the active ingredient or to any of other ingredients
• Chronic malabsorption syndrome
• Cholestasis
• Gallbladder disease

Relative contraindications

In organically-caused cases of obesity, for example, hypothyroidism, Xenical is contraindicated.

Since Xenical can result in weight loss, there is a chance for misuse on the part of some groups of individuals, such as those with bulimia or anorexia nervosa. Such patients should stay away from Xenical.

Because some patients may develop enlarged levels of urinary oxalate after treatment with Xenical, caution must be applied in patients with a history of kidney stones, calcium oxalate stones, as well as hyperoxaluria.

Only insufficient number of individuals aged 65 and older took part in clinical trials to establish the response in the patients. Hence, Xenical must be applied with caution in the elderly patients.

Special Warnings and Precautions for Use

In clinical studies, type II diabetic patients showed to lose less bodyweight with Xenical treatment than the non-diabetic patients. Antidiabetic therapy may need to be closely monitored during the Xenical treatment.

Co-administration of Xenical with an immunosuppressant drug cyclosporine is not recommended

The likelihood of developing gastrointestinal adverse reactions may grow when Xenical is taken with a high-fat diet (for instance, in a 2000 kcal/day diet, > 30% of calories coming from fat amounts to > 67 grams of fat). The daily consumption of fat must be distributed among three major meals. If Xenical is consumed with a meal with very high-fat content, the risk of gastrointestinal adverse effects may rise.

Instances of rectal hemorrhaging have been documented with Xenical. The prescribing doctors must further investigate in case of persistent and/or severe symptoms.

The usage of an extra contraceptive methods is suggested to counteract possible failure of oral contraception that might happen in cases of severe diarrhea.

The use of Xenical may be linked to oxalate nephropathy and hyperoxaluria leading occasionally to renal failure. Such a risk is bigger in patients with volume depletion and/or underlying chronic kidney disease.

In patients treated with oral anticoagulants concurrently, coagulation parameters must be monitored.

Rare incidence of hypothyroidism and/or curtailed control of hypothyroidism may happen. Although not proven, the mechanism may involve a reduced absorption of levothyroxine and/or iodine salts.

Antiepileptics patient: Xenical may destabilize anticonvulsant therapy by reducing the absorption of antiepileptic medicines (lamotrigine, valproate, etc), which may lead to seizures. Please speak to your doctor if you believe that the frequency and/or severity of the seizures have changed when taking antiepileptic drugs together with Xenical.

Antiretrovirals for HIV: Xenical may hypothetically decrease the absorption of antiretroviral medicines for HIV and could thus negatively impact the effectiveness of antiretroviral drugs for HIV.

There have been some reports of declined effectiveness of sedatives (benzodiazepines) and antidepressants antipsychotics (e.g. lithium) concurrent with the initiation of Xenical treatment in formerly well-controlled patients. Thus, Xenical treatment can only be started after meticulous consideration of the possible effect in these patients.

How Xenical Interacts with Other Drugs

Cyclosporine

A decline in cyclosporine plasma levels has been documented in selected cases when Xenical and cyclosporine were concurrently administered. This may lead to a reduced immunosuppressive efficiency. Thus, the combination is not advisable. Still, if such concurrent usage is unavoidable, more frequent checking of cyclosporine blood levels must be performed both after adding Xenical and upon withdrawal of Xenical in cyclosporine-treated individuals. Cyclosporine blood levels must be supervised until stabilized. 

Acarbose

The concurrent administration of Xenical and acarbose should be avoided given the lack of pharmacokinetic interaction research.

Oral anticoagulants

When anticoagulants, such as warfarin, are taken in combination with Xenical, international normalized ratio (INR) measures must be regularly examined.

Fat soluble food supplements

Treatment with Xenical may hypothetically weaken the absorption of some fat-soluble vitamins, such as A, D, E and K.

The majority of patients getting up to four years of treatment with Xenical in clinical trials had their vitamin A, D, E, K and beta-carotene levels staying within normal range. Patients on a weight observation diet who want to ensure adequate nutrition are advised to eat sufficient amounts of fruit and vegetables to improve their Xenical experience. If multivitamin supplements are recommended, they should better be taken at least two hours after the intake of Xenical or at bedtime.

Amiodarone

A minor decline in plasma concentration of amiodarone has been seen in a limited number of healthy study participants who took a dose of Xenical at the same time. In individuals undergoing amiodarone treatment, the clinical applicability of this effect remains unknown but might become clinically applicable in selected cases. In patients getting concurrent amiodarone treatment, reinforcement of ECG and clinical monitoring is demanded.

Fertility, Pregnancy, and Lactation

For Xenical, no clinical trials on exposed pregnancies have been conducted. Caution should be applied when prescribing Xenical to pregnant women.

Animal studies do not suggest direct or indirect detrimental effects regarding pregnancy, embryonal/ fetal development, parturition or perinatal development.

It is not identified whether Xenical is discharged into human milk. Thus, over the course of breastfeeding Xenical is contra-indicated.

Adverse Effects of Orlistat Generic

Undesirable reactions to Xenical are mainly gastrointestinal in nature. The frequency of adverse events declined with prolonged use of Xenical. Most undesirable effects are usually mild and tend to manifest themselves after intake of very fatty meals.

Adverse effects are detailed below by system organ class and frequency. Frequencies are described as:

• very common (≥10%),
• common (≥1% to <10%),
• uncommon (≥0,1% to <1%),
• rare (≥0,01% to <0,1%) and
• very rare (<0,01%) including isolated reports.

The following list of adverse effects that may be expected in the first year of therapy, is based on undesirable events that happened at a frequency of > 2 % as well as with an incidence ≥ 1 % above placebo in 1-year and 2-year clinical studies:

Nervous system disorders

• Very common: Headaches

Respiratory, thoracic and mediastinal (lung and airway) disorders

• Very common: Upper respiratory infection
• Common: Lower respiratory infection

Gastrointestinal disorders

Very common:

• Abdominal discomfort or pain
• Oily spotting from the rectum
• Flatulence
• Fatty/oily stool
• Flatus with discharge
• Liquid stool
• Fecal urgency
• Oily evacuation

Common:

• Rectal discomfort or pain
• Increased defecation
• Abdominal distension
• Increased quantity of bowel movements
• Soft stool
• Fecal incontinence
• Gingival disorder
• Tooth disorder

Renal and urinary disorders

• Common: Infections in urinary tract

Metabolism and nutrition disorders

• Very common: Hypoglycemia

General disorders

• Common: Fatigue

Psychiatric disorders

• Common: Anxiety

Reproductive system disorders

• Common: Menstrual irregularity

The ensuing list of adverse effects is based on spontaneous reports, and hence the frequency of the former remains undetermined:

Investigations

• Increase in alkaline phosphatase and liver transaminases;
• Declined prothrombin, increased INR and unstable anticoagulant treatment resulting in deterioration of hemostatic characteristics have been documented in patients receiving anticoagulants treatment in association with Xenical.

Gastrointestinal disorders

• Pancreatitis
• Diverticulitis
• Rectal bleeding

Immune system disorders

• Hypersensitivity (e.g. rash, angioedema, pruritus, urticaria, anaphylaxis, and bronchospasm)

Renal and urinary disorders

• Oxalate nephropathy potentially leading to renal failure

Skin disorders

• Bullous eruptions

Hepatobiliary disorders

• Cholelithiasis
• Serious cases of hepatitis. Some rare fatal cases or cases necessitating liver transplantation were reported.

Overdose cases

Single doses of 800 mg and up to three 400 mg doses of Xenical three times daily over the course of 15 days have been researched in normal weight and obese volunteers without substantial adverse Xenical results. Moreover, doses of 240 mg three timed per day have been given to obese patients over the course of 6 months. Most Xenical overdose cases reported had either no adverse effects or adverse effects similar to those documented with recommended doses.

Should a major overdose of Xenical happen, it is advised that the patient is monitored for 24 hours. As follows from human and animal research, any systemic effects that can be attributed to the lipase-inhibiting characteristics of Xenical should be quickly reversible.

How should I store Xenical?

• Store Xenical at temperatures 15°C to 30°C (59°F to 86°F).
• Keep Xenical out of the reach of young children.
• Store Xenical in a tightly sealed box.
• Dispose of Xenical after the expiration date.
• Safely throw away the remaining Xenical capsules that are outdated or no longer needed.

Disclaimer

The information uncovered in this article has been compiled with the educational purposes only. The team of authors provides the fact checking before posting any kind of information on this website. But the site’s administration does not guarantee correctness and/or update status of all contents in this article. This article can be taken as a guidance for self-treatment. Only licensed and professional healthcare specialist can diagnose and treat patients considering the personal symptoms in each particular case.