Composition, form of production and packaging
Solution for administration of 1 ml
methylnaltrexone bromide 20 mg
0.6 ml - bottles of colorless glass type I (1) - packs cardboard.
0.6 ml - bottles (1) complete with 1 disposable syringe with built-in injection needle in contour pack (blister) and 2 individually packaged alcohol napkins - plastic packages (2) - cardboard packs.
0.6 ml - bottles (1) complete with 1 disposable syringe with built-in injection needle in contour pack (blister) and 2 individually packaged alcohol wipes - plastic packages (7) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
Methylnaltrexone bromide is a selective antagonist of opioid? -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 ОІ-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.
Methylnaltrexone is rapidly absorbed, C max is reached approximately 30 minutes after subcutaneous injection. When the dose is increased from 0.15 mg / kg to 0.5 mg / kg, a proportional increase in C max and AUC is noted.
Dose (mg / kg) Cmax (ng / ml) AUC (ng? H / ml)
0.15 117 В± 33 180 В± 37
0.3 234 В± 65 376 В± 73
0.5 392 В± 148 593 В± 111
The absolute bioavailability of the dose of 0.30 mg / kg administered subcutaneously is 82% compared to intravenous administration of the same dose.
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%).
In the human body, methylnaltrexone is slightly metabolized, as judged by the amount of methylnaltrexone metabolites found in the excreta. The main metabolic pathways are
conversion to isomers of methyl-6-naltrexol and methylnaltrexone sulfate. The isomers of methyl-6-naltrexol have slightly less antagonistic activity than the starting material, 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% of the plasma-related material related to the drug substance. N-demethylation of methylnaltrexone to form naltrexone. occurs in insignificant amounts, the resulting naltrexone is 0.06% of the administered dose.
Methylnaltrexone is excreted mainly unchanged. Approximately half of the dose is excreted by the kidneys and a slightly smaller portion through the intestine. The half-life (T 1/2 ) is approximately 8 hours.
When methylnaltrexone is used in patients with mild to moderate hepatic insufficiency (classes A and B according to the Child-Pugh classification), there is no significant change in AUC and C max . The change in the pharmacokinetics of methylnaltrexone in severe hepatic insufficiency has not been studied.
Renal failure significantly affects the renal excretion of methylnaltrexone. As the renal function decreases, the renal clearance of methylnaltrexone decreases. It was found that with severe renal failure, a 8-9-fold decrease in methylnaltrexone clearance is observed, but this only leads to a 2-fold increase in methylnaltrexone AUC.With MAX, it does not change significantly.
Studies involving patients with terminal stage of renal failure requiring dialysis have not been conducted.
There is a minimal effect of age on the efficacy and safety of methylnaltrexone. The average equilibrium values вЂ‹вЂ‹of C max and AUC in elderly patients are 545 ng / ml and 412 ng / h / ml, respectively, which is approximately 8.1% and 20% higher than the corresponding values вЂ‹вЂ‹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 prolongation of QT / QTc intervals or signs of influence on secondary ECG parameters or morphology of ECG waves.
- treatment of opioid-induced constipation in the late stages of the disease in patients receiving palliative care, with insufficient effectiveness of conventional laxatives.
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)? 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.
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 in it.
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 hypodermic syringe with a capacity of 1 ml, 2 tampons impregnated with alcohol, and a cotton ball or gauze.
4. Ensure that the solution in the vial is clear and colorless or light yellow, and contains no 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. 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 vial plug 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. Gently press the plunger (air will pass into the vial).
Note: If you are using a syringe with a retractable needle supplied, do not insert air into the vial 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. Without removing the needle from the vial, turn the bottle upside down. 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 is still inside the vial with the 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. You can inject the drug Relistor under the skin of the hip, abdomen and shoulder (if the injection is performed by another person).
Note: It is recommended that you change the location for 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 that there are no air bubbles in the syringe. In the presence of bubbles, gently tap on the syringe with your finger, so that air bubbles rise to the top of the syringe. Slowly lift the plunger to dislodge the air bubbles from the syringe. Take the syringe with one hand, like a pencil. With your other hand, gently pinch the cleansed area of вЂ‹вЂ‹the skin and hold it firmly.
With a short quick movement, insert the needle into the skin at a slight angle (45 В°).
4. After inserting the needle, release the skin fold and press the plunger slowly to insert the medication.
5. After emptying the syringe, quickly remove the needle from the skin at the same angle as the needle you inserted. 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 the solution of the Relistor product using a syringe with a retractable needle from the delivery set
1. While holding the filled syringe up with a needle, re-check that there are no air bubbles in the syringe. In the presence of bubbles, gently tap on the syringe with your finger, so that air bubbles rise to the top of the syringe. Slowly lift the plunger to displace the air bubbles from the syringe.
2. Take a syringe with one hand, like a pencil or a dart. With your other hand, gently pinch the cleansed area of вЂ‹вЂ‹the skin and hold it firmly.
3. Briefly insert the needle into the skin at a slight angle (45 В°).
4. After inserting the needle, release the skin fold and slowly press down on 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 press the injection site with a cotton or gauze tampon. Do not rub the injection site. If necessary, you can put a bandage on the injection site.
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% and <10%
Not frequent> 0.1% and <1%
Rare> 0.01% and <0.1%
Very rare <0.01%
From the nervous system
From the gastrointestinal tract
Very frequent: abdominal pain, nausea, flatulence.
From the skin
- hypersensitivity to the active substance or excipients of the drug;
- known or suspected mechanical obstruction of the gastrointestinal tract or symptoms of an acute abdomen;
severe hepatic impairment;
- terminal stage of renal failure requiring hemodialysis;
- Children's age (up to 18 years).
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 is excreted in 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.
APPLICATION FOR FUNCTIONS OF THE LIVER
Contraindicated in the terminal stage of renal failure, requiring hemodialysis.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated in severe hepatic insufficiency.
APPLICATION FOR CHILDREN
Contraindicated for children under 18 years.
APPLICATION IN ELDERLY PATIENTS
There is a minimal effect of age on the efficacy and safety of methylnaltrexone. Correction of dose in the treatment of elderly patients is not required.
In case of severe or persistent diarrhea during the period of treatment, patients should be recommended to cancel treatment with the drug Relistor and consult a doctor. Treatment with methylnaltrexone can lead to rapid 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.
It is recommended to advise patients to inform the doctor about any cases of 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.
Influence on ability to manage motor transport and use of mechanisms
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.
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.
If overdose is necessary to control blood pressure in the case of orthostatic hypotension should inform your doctor. If necessary prescribe appropriate treatment.
Methylnaltrexone has no effect on the pharmacokinetics of drugs metabolized by the participation of cytochrome P450 isoenzymes (CYP). CYP enzymes only minimally involved in the metabolism of methylnaltrexone. Methylnaltrexone In vitro activity is not ingibirust isozymes CYP1A2, CYP2B6, CYP2A6, CYP2C9, CYP2C19 and CYP3A4, but a weak inhibitor of the metabolism of the model substrate for the isoenzyme CYP2D6. Subcutaneous methylnaltrexone dose of 0.3 mg / kg had no significant effect on the metabolism of dextromethorphan, which is a substrate for the isoenzyme CYP2D6.
There was no significant correlation between the dose of narcotic analgesics at the start of treatment and the response to treatment metilnaltrsksonom. In addition, there was no significant change in median daily dose of narcotic analgesics in patients treated with Relistor.
Repeated application of cimetidine at a dose of 400 mg of methylnaltrexone following a single reception, there is a decrease renal clearance of methylnaltrexone (31 l / h to 18 l / h). However, this only leads to a slight decrease in systemic clearance (from 107 l / h to 95 l / h). As a result, a noticeable change in AUC of methylnaltrexone, in addition to C max , before and after administration of multiple doses of cimetidine is not observed.
Since compatibility studies were not carried out, the drug should not be mixed with other drugs.
TERMS OF RELEASE FROM PHARMACY
TERMS AND CONDITIONS OF STORAGE
Store in a dark place at a temperature not higher than 30 В° C. Keep out of the reach of children. Shelf life - 2 years.