Relistor - instructions for use, dose, side effects, contraindications

Active substanceMethylnaltrexone bromideMethylnaltrexone bromide

Similar drugsTo uncover

Relistor

solution PC

Pfizer Inc. USA

Dosage form: & nbsp

hypodermic solution

Composition:

1 ml of solution contains

active substance: methylnaltrexone bromide 20 mg

Excipients: sodium chloride 6.5 mg, sodium calcium, edetate 0.4 mg, glycine hydrochloride 0.3 mg, hydrochloric acid to pH from 3.0 up to 5.0, sodium hydroxide to a pH of 3.0 to 5.0, water for injection to 1.0 ml.

Description:Transparent colorless or light yellow solution.

Pharmacotherapeutic group:antagonists of peripheral opioid receptors.

ATX: & nbsp

A.06.A.H.01 Methylnaltrexone bromide

Pharmacodynamics:

Methylnaltrexone bromide is a selective antagonist of opioid μ receptors (the inhibition constant is [Ki] = 28 nM). The activity of methylnaltrexone is 8 times lower relative to the kappa opioid receptor (Ki = 230 nM), and in relation to delta-opioid receptors, the affinity of methylnaltrexone is much lower. Methylnaltrexone has a limited ability to penetrate the blood-brain barrier, since it is a quaternary ammonium compound. In connection with this, methylnaltrexone functions as a p-opioid antagonist of peripheral action (for example, in the gastrointestinal tract (GI tract)), without affecting the analgesic effects mediated by opioids in the central nervous system.

Methylnaltrexone remains effective up to 4 months of admission.

Pharmacokinetics:

Suction

Methylnaltrexone is rapidly absorbed, the maximum concentration (C_max) is reached approximately 30 minutes after subcutaneous injection. With an increase in the dose from 0.15 mg / kg to 0.5 mg / kg, a proportional increase in C_max and the area under the "concentration-time" curve (AUC).

Dose (mg / kg)	Cmax (ng / ml)	AiC (ng-h / ml)
0,15	117±33	180±37
0,3	234±65	376±73
0,5	392±148	593±111

The absolute bioavailability of the dose of 0.30 mg / kg, administered subcutaneously, is 82 % compared with intravenous administration of the same dose.

Distribution

Methylnaltrexone undergoes a moderate distribution in tissues. The equilibrium volume of the distribution (V_ss) is approximately 1.1 l / kg. According to the data of equilibrium dialysis, methylnaltrexone binds to minimal amounts of human plasma proteins (from 11.0% to 15.3%).

Metabolism

In the human body, methylnaltrexone is slightly metabolized, which can be judged by the amount of methylnaltrexone metabolites found in the excreta. The main metabolic pathways are the conversion to isomers of methyl-6-naltrexol and methylnaltrexone sulfate.The methyl-6-naltrexol isomers have somewhat less antagonistic activity than the parent substance, and constitute approximately 8% of the plasma-related material related to the drug substance. Methylnaltrexone sulfate is an inactive metabolite and its plasma content is approximately 25 % from the material contained in the plasma, related to the drug substance. N- demethylation of methylnaltrexone with the formation of naltrexone, occurs in insignificant amounts, formed naltrexone is 0.06 % of the administered dose.

Excretion

Methylnaltrexone is excreted mainly unchanged. Approximately half of the dose is excreted by the kidneys and a slightly smaller portion through the intestine. Half-life (t1/ 2) is approximately 8 hours.

Use in special patient groups

Liver failure

When methylnaltrexone is used in patients with mild to moderate hepatic insufficiency (Child-Pugh classes A and B), no. significant change AUC and C_max. The change in the pharmacokinetics of methylnaltrexone in severe hepatic insufficiency has not been studied.

Renal insufficiency

Renal failure significantly affects the renal excretion of methylnaltrexone. ByAs the renal function decreases, the renal clearance of methylnaltrexone decreases.

It was found that in severe renal failure, a 8-9-fold decrease in methylnaltrexone clearance is observed, but this only leads to a 2-fold increase AUC methylnaltrexone. FROM_max does not change significantly.

Studies involving patients with terminal stage of renal failure requiring dialysis have not been conducted.

Elderly patients

There is a minimal effect of age on the efficacy and safety of methylnaltrexone. The average equilibrium values of C_max and AUC in elderly patients are respectively 545 ng / ml and 412 ng-h / ml, which is approximately 8.1% and 20% higher than the corresponding values for young patients. In this regard, dose adjustment in the treatment of elderly patients is not required.

Dependence on sex

There were no significant differences in the pharmacokinetics of methylnaltrexone in patients of different sexes.

Dependence on body weight

It has been shown that the efficacy of methylnaltrexone, calculated per unit dose (mg / kg), increases with the patient's body weight.

Effect on cardiac repolarization

When applying a single dose of methylnaltrexone (0.15, 0.30 and 0.50 mg / kg) there is no longer lengthening of the intervals QT / QTc or signs of influence on secondary ECG parameters or the morphology of ECG waves.

Indications:Treatment of opioid-induced constipation in the late stages of the disease in patients receiving palliative care, with insufficient effectiveness of conventional laxatives.

Contraindications:

- hypersensitivity to the active substance or excipients of the drug;

- known or suspected mechanical gastrointestinal obstruction or symptoms an acute abdomen;

- severe hepatic impairment;

- terminal stage of renal failure requiring hemodialysis;

- pregnancy;

- children's age (under 18 years).

Carefully:

The use of methylnaltrexone bromide in the treatment of patients with colostomy, intraperitoneal catheter, active diverticulosis or fecal matter has not been studied.

Therefore, when using the drug Relistor in these patients, you need to be extra careful.

Do not use a Relistor to treat patients with constipation not associated with the use of opioids.

During postmarketing studies, cases of perforation of the gastrointestinal tract were reported in patients with conditions associated with local or widespread disruption of the structural integrity of the gastrointestinal wall (eg, cancer, peptic ulcer, pseudo-obstruction). In such cases, it is impossible to exclude the connection with the action of methylnaltrexone.

Pregnancy and lactation:

Experience with methylnaltrexone bromide in the treatment of pregnant women is not enough.

It is not known whether methylnaltrexone bromide with human milk. The decision to abolish breastfeeding or to cancel treatment with the drug Relistor should be taken, given the ratio of benefit and risk to the mother and child.

Dosing and Administration:

Only for the treatment of adults

The relistor should be used to stimulate rapid defecation if there is insufficient response to conventional laxatives.

The relistor is used no more often than once a day in the form of a subcutaneous injection. The interval between doses can be increased depending on the clinical effectiveness of the drug.

The use of two consecutive doses with a 24-hour interval is allowed only if there is no response (defecation) to the first dose.

The recommended dose is:

- for patients with a body weight of 38-62 kg: 8 mg (0.4 ml);

- for patients with a body weight of 62-114 kg: 12 mg (0.6 ml).

Patients with a body weight that does not meet the indicated intervals, the recommended dose is 0.15 mg / kg. The volume of injection for such patients should be calculated as follows:

dose (ml) = body weight of the patient (kg) x 0.0075.

After calculating the dose (ml) should be rounded to tenths of a milliliter.

Injections of the drug Relistor are recommended to be performed under the skin of the hips, abdomen or shoulder.

Injections of methylnaltrexone bromide can be performed independently of food intake. It is recommended that the injection site be changed at each new injection.

It is not recommended to perform injections on the areas of painful, reddened, denser skin or in the places of bruises.

Do not inject the Relistor into areas of the skin with scars or stretch marks.

Patients with renal insufficiency

Patients with severe renal failure (creatinine clearance less than 30 ml / min) need a dose reduction:

- for patients with a body weight of 62 to 114 kg, the dose is reduced from 12 mg to 8 mg (0.4 ml).

- for patients with body weight not corresponding to the range from 62 to 114 kg, the dose is reduced from 0.15 mg / kg to 0.075 mg / kg.

It is not recommended to apply the Relistor in patients with terminal stage of renal failure who are on dialysis.

Patients with hepatic insufficiency

In patients with mild or moderate hepatic insufficiency, dose adjustment is not required.

Elderly patients

Correction of the dose is not required.

Instructions for preparation for injection and injection

Do not use the reconstituted vial again, even if there are remnants of the drug.

If the drug is already syringed, but its use must be postponed, store the filled syringe at room temperature for a maximum of 24 hours.

Do not reuse the syringe or needle.

Stage 1. Preparation of materials for injection

1. Find a flat, clean and well-lit work surface.

2. Wash your hands with warm water and soap.

3. Prepare everything you need for the injection: a bottle with the drug Relistor, a syringe for hypodermic injections with a capacity of 1 ml, 2 tampons impregnated with alcohol, and a cotton ball or gauze.

4. Make sure that the solution in the vial is clear and colorless or light yellow, and does not contain visible particles.Do not use the solution if it is opaque or is not colorless or light yellow, or contains visible particles. In this case, consult a pharmacist, nurse or doctor.

Stage 2. Preparation of the syringe

1. Remove the protective cap from the vial.

2. Wipe the rubber stopper of the bottle with a swab impregnated with alcohol.

3. Pull in one go
Take the syringe from the work surface. While holding the cylinder of the spitz with one hand, remove the cap from the needle in one motion. Do not touch the needle or allow the needle to come into contact with other surfaces. Carefully pull the plunger of the syringe until the end of the plunger is at the line level corresponding to your dose.

4. Insert the needle at a right angle down into the center of the bottle stopper with the drug Relistor. Do not insert the needle at an angle so as not to break or bend the needle. You may experience a slight resistance as the needle passes through the plug. The needle should be inserted until you see the tip of the needle inside the vial.

5. Carefully press the plunger (air will pass into the bottle).
Note: If you use a syringe with a retractable needle from the delivery set, DO NOT ENTER THE AIR IN THE VARNISH COMPLETELY.After feeling the resistance, stop pressing the plunger. If the plunger passes the resistance, you will hear a click, which means that you have activated the protective mechanism and the needle disappears inside the syringe. In this case, the product should be discarded and begin the procedure first, using another vial and other syringes.

6. Turn the bottle upside down without removing the needle from the vial. While holding the syringe at eye level, make sure that the needle tip is always covered with liquid. Slowly pull the plunger down to the mark on the syringe corresponding to your dose.

7. While the needle will still be inside the vial with the drug Relistor, make sure there are no air bubbles in the syringe. Gently tap on the syringe so that the air bubbles rise to the top of the syringe. Slowly move the plunger upward, pushing out air bubbles. If you bring the solution back to the vial, slowly pull the plunger back to re-fill the syringe with the correct amount of solution.

8. Remove the syringe and needle from the bottle with the drug Relistor. Do not remove the needle from the syringe. Do not touch the needle or allow the needle to come into contact with other surfaces.The solution in the syringe should be used within 24

hours.

Stage 3. Selection and preparation of the injection site

1. Performing injections of the drug Relistor can be done under the skin of the thigh, abdomen and shoulder (if the injection is performed by another person).

Note: it is recommended to change the place with each injection. Try not to inject exactly at the same place that was used for injection earlier. It is not recommended to perform injections in areas of painful, reddened, denser skin or in places of bruises. Do not inject the Relistor into areas of the skin with scars or stretch marks.

2. Wipe the injection site with a swab dampened with alcohol. After this, do not touch this area before the injection. Wait until the skin dries, then perform the injection.

Step 4a. Performing an injection of a solution of the drug Relistor with a standard syringe and needle

1. While holding the filled syringe up with a needle, re-check the absence of air bubbles in the syringe. In the presence of bubbles, Caution tap on the syringe with your finger so that the air bubbles go up to the top of the syringe. Slowly lift the plunger to dislodge the air bubbles from the syringe.

2. Take the syringe with one hand, like a pencil. With your other hand, gently pinch the cleansed area of the skin and hold it firmly.

3. With a short quick movement, insert the needle into the skin at a slight angle (45 °).

4. After inserting the needle, release the skin fold and slowly press the plunger to insert the drug.

5. After emptying the syringe, quickly remove the needle from the skin at the same angle at which you injected the needle. There may be a slight bleeding at the injection site. You can squeeze the injection site with a cotton or gauze swab. Do not rub the injection site. If necessary, you can put a bandage on the injection site.

Step 4b. Performing an injection of a solution of the drug Relistor when used syringe with retractable needle from the delivery set

2. Take the syringe with one hand, like a pencil or a dart. With your other hand, gently pinch the cleansed area of the skin and hold it firmly.

3. With a short quick movement, insert the needle into the skin at a slight angle (45 °).

4. After inserting the needle, release the skin fold and slowly press the plunger to insert the drug.

5. After you hear a click, the needle will automatically be removed and closed with a cap. There may be a slight bleeding at the injection site. You can squeeze the injection site with a cotton or gauze swab. Do not rub the injection site. If necessary, you can put a bandage on the injection site.

Side effects:

Whenever subcutaneous injections of any medications, including Relistor, often occur at the injection site (for example, tingling, burning, pain, redness, swelling).

The most common adverse reactions to this medication included abdominal pain, nausea, diarrhea, and flatulence. In most cases, these reactions were mild or moderate. In each group that reflects the incidence of the side effect, these effects are listed in descending order of severity:

Very Frequent >=10%
Frequent >=1% <10%
Not frequent >=0,1% <1%
Rare >=0,01% <0,1%
Very rare <0,1%

From the nervous system

Frequent: dizziness.

From the gastrointestinal tract
Very frequent: abdominal pain, nausea, flatulence. Frequent: diarrhea.

From the skin

Frequent: hyperhidrosis.

Overdose:

Cases of overdose with the drug Relistor are not described.

After applying a dose of 0.64 mg / kg in the form of an intravenous bolus injection, orthostatic hypotension is noted.

When an overdose is necessary to control blood pressure and if orthostatic hypotension develops, you should inform the doctor about it. When the need for appropriate treatment.

Interaction:

Methylnaltrexone does not affect the pharmacokinetics of drugs metabolized with the participation of cytochrome P450 isoenzymes (CYP). Isozymes CYP only to a minimum extent participate in the metabolism of methylnaltrexone. Methylnaltrexone in vitro does not inhibit the activity of isoenzymes CYP1A2, CYP2B6, CYP2A6, CYP2C9, CYP2C19 and CYP3A4, but is a weak inhibitor of metabolism in the substrate model for isoenzyme CYP2D6. The subcutaneous dose of methylnaltrexone 0.3 mg / kg has no significant effect on the metabolism of dextromethorphan, which is a substrate for isoenzyme CYP2D6.

There is no significant relationship between the dose of non-narcotic analgesic at the time of treatment and the response to methylnaltrexone.In addition, there were no significant changes in the median daily dose of non-narcotic analgesic in patients receiving the Relistor.

With repeated use of cimetidine at a dose of 400 mg after a single admission of methylnaltrexone, a decrease in renal clearance of methylnaltrexone (from 31 l / h up to 18 l / h). However, this leads only to a slight decrease in system clearance (from 107 l / h to 95 l / h). As a consequence, a noticeable change AUC methylnaltrexone, in addition to Stach, before and after the administration of multiple doses of cimetidine, is not observed.

Incompatibility

Since compatibility studies have not been conducted, this drug should not be confused with other drugs.

Special instructions:

In case of severe or persistent diarrhea during the period of treatment, patients should be recommended to cancel treatment with Relistor and consult a doctor. 'Treatment with methylnaltrexone can lead to a quick stimulation of defecation (on average, for 30-60 minutes).

Methylnaltrexone was studied in studies, the duration of which did not exceed 4 months, and therefore this drug should be used only for a limited time.

A relistor should be used only in patients receiving palliative treatment. Patients should be advised to report to the doctor any cases - the appearance / impairment of the gastrointestinal function.

Since the Relistor is a peripheral antagonist of opioid receptors, it does not cause addiction or addiction.

Unused and the remaining product should be disposed of.

Effect on the ability to drive transp. cf. and fur:

Studies of the effect of the drug on the ability to drive and use mechanisms have not been conducted. Since methylnaltrexone is an opioid antagonist with an exceptionally peripheral effect, it is unlikely that the ability to do this will be affected. However, during the treatment period, dizziness may occur, which may affect the ability to drive vehicles and use mechanisms.

Form release / dosage:

For 0.6 ml of the drug in bottles of colorless optical glass type I (Hebrew F.), hermetically sealed with butyl rubber stoppers and rolled up with aluminum caps equipped with detachable plastic disks of the type "flip-off".

1 bottle along with the instruction for use is placed in a cardboard box or 1 bottle complete with 1 disposable syringe with a capacity of 1 ml with a built-in injection needle in a contour pack (blister) and 2 individually packed alcoholic napkins placed in plastic packaging and sealed with laminated paper.

For 2 or 7 plastic packages, together with the instructions for use are placed in a cardboard box.

Packaging:solution for subcutaneous administration, 20 mg / ml (vial) 0.6 ml x 1; 0.6 ml x 2/7 + (syringe) x 2/7 + (napkin) x 4/14

Storage conditions:

Store in a dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years. Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001071

Date of registration:27.10.2011

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

DSM Pharmaceuticals, Inc. USA

Representation: & nbspAQU-Service, Ltd.AQU-Service, Ltd.

Information update date: & nbsp14.01.2013

Illustrated instructions

Instructions

Relistor (Relistor)