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

Pharmacodynamics:The drug Duodope® is a gel containing a combination of active substances: levodopa and carbidopa monohydrate (4: 1 ratio), for long-term ishestinal administration to patients with severe Parkinson's disease with severe motor fluctuations and hyper / dyskinesia. Levodopa decarboxylated with the formation of dopamine in the brain, thereby reducing the severity of symptoms of Parkinson's disease. Carbidopa does not penetrate the blood-brain barrier and inhibits the extra-cerebral decarboxylation of levodopa, which leads to an increase in the amount of delivery of levodopa to the brain and its transformation into dopamine. When monotherapy with levodopa to achieve the desired effect, a much larger amount of the drug is needed compared to the combined use of levodopa with carbidopa. The intestinal administration of Duodope® reduces the severity of motor fluctuations and increases the duration of the control periods of voluntary movements in patients with severe Parkinson's disease who have been treated with levodopa preparations / an aromatic L-amino acid decarboxylase inhibitor (tableted forms) for many years.Reduction of the severity of motor fluctuations and hyper / dyskinesias is due to the maintenance of a stable equilibrium concentration of levodopa in the plasma in the therapeutic range. Reducing the severity of motor fluctuations and hyper / dyskinesia is often achieved already during the first day of treatment.

Pharmacokinetics:

Suction

Duodope® is administered via a probe placed directly into the duodenum or jejunum. Levodopa quickly and efficiently absorbed from the intestine through the amino acid transport system. Levodopa As part of Duodope®, it has the same bioavailability as levodopa in the composition of levodopa / carbidone preparations (tableted form 100/25 mg). Bioavailability of levodopa in the preparation of Duodope® is comparable with the bioavailability of levodopa in the composition of levodopa / carbidone preparations (in tableted form) and is 97%.

The preparation Duodopa significantly less expressed individual fluctuations in plasma concentration due to the fact that it is constantly introduced into the intestine and the rate of evacuation of gastric contents does not affect the rate of absorption.When using a high initial morning dose of Duodope®, the therapeutic concentration of levodopa in plasma is reached in 10-30 minutes.

Distribution

Carbidone (an inhibitor of decarboxylase aromatic L-amino acids), when used in combination with levodopa, increases bioavailability and reduces the clearance (C1) of levodopa. Levodopa has a relatively small volume of distribution (Vd). The distribution coefficient between erythrocytes and blood plasma for levodopa is approximately equal to unity. Levodopa binds to blood plasma proteins slightly (about 10-30%). Levodopa penetrates into the brain through a system of active transport of large neutral amino acids.

The degree of binding of carbidopa to plasma proteins is about 36%.

Metabolism and excretion

Levodopa is mainly excreted from the body through metabolism involving enzymes - decarboxylase of aromatic L-amino acids and catechol-O-methyl transferase. Other metabolic pathways are transamination and oxidation. Decarboxylation of levodopa to dopamine by decarboxylase of aromatic L-amino acids is the main pathway of enzymatic metabolism (when levodopa is used without enzyme inhibitors).O-methylation of levodopa by catechol-O-methyl transferase gives 3-O-methyldone. When levodopa is used with carbidopa, the elimination half-life (T1 / 2) of levodopa is approximately 1.5 hours. Carbidone is metabolized to two major metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These two metabolites are mainly excreted through the kidneys in unchanged form or in the form of glucuronide conjugates. Carbidonum in the unmodified form makes 30% from the general excretion with urine. T1 / 2 carbidopa is about 2 hours.

The relationship between pharmacokinetic and pharmacodynamics

The more stable the concentration of levodopa in plasma, the more stable the therapeutic effect. Since the effective dose for severe Parkinson's disease may be different, the dose should be selected individually, based on the clinical effect. With Duodopa®, there was no development of tolerance over time.

Indications:

The late stages of levodopa-sensitive Parkinson's disease with pronounced motor fluctuations and hyper / dyskinesia with insufficient effectiveness of other antiparkinsonian drugs.

Contraindications:

- Hypersensitivity to levodopa, carbidopa or any auxiliary components of Duodope® preparation.

- Closed-angle form of glaucoma.

- Severe hepatic / renal failure.

- Severe heart failure.

- Severe heart rhythm disturbances.

- Violation of cerebral circulation in an acute period.

- Simultaneous administration with nonselective MAO inhibitors and selective MAO type A inhibitors. It is necessary to discontinue the use of these drugs at least 2 weeks before the use of Duodope® (with the exception of selective MAO-B inhibitors (eg selegiline hydrochloride)).

- Conditions in which adrenomimetics are contraindicated, for example, pheochromocytoma, hyperthyroidism and Cushing's syndrome.

- Breastfeeding period.

- Patients with suspected undiagnosed skin diseases or melanoma in the anamnesis (because levodopa can stimulate the development of malignant melanoma).

- Patients under the age of 18 years.

Carefully:

- Severe cardiovascular or pulmonary diseases.

- Bronchial asthma.

- Chronic open-angle glaucoma.

- Diseases of the kidneys, liver or endocrine system.

- Psychoses (current or in history), as well as peptic ulcer or a convulsive syndrome in an anamnesis.

- Joint reception with antipsychotics capable of blocking dopamine receptors (especially D2)

- Joint reception with drugs that can cause orthostatic hypotension (for example, ACE inhibitors, nitrates, diuretics, MAO inhibitors).

Pregnancy and lactation:

Pregnancy

There is insufficient data on the use of levodopa / carbidopa in pregnant women. The data obtained in animal studies revealed the developmental defects of the skeleton and internal organs of the fetus. Possible risk of use in humans is not known. In pregnancy, Duodope® can be used only after a thorough assessment of the risk-benefit relationship, when the benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding period

Levodopa is excreted in breast milk. There is information about the suppression of milk production during treatment with levodopa. Carbidopa is excreted in breast milk in animals, but it is not known whether it is excreted in human milk. The effect of levodopa / carbidopa on children is not known.During the application of Duodope®, breastfeeding should be discontinued.

Dosing and Administration:

The drug Duodope® is a gel for long-term intestinal application. The gel should be injected directly into the lumen of the duodenum or the upper part of the jejunum via a permanent duodenal probe installed by percutaneous endoscopic gastrostomy and consisting of the external abdominal and internal enteral parts. If for any reason percutaneous endoscopic gastrostomy can not be performed, it is possible to perform gastroejunostomy under X-ray control. Surgical support for transabdominal access and dose adjustment should be carried out together with neurologists.

To determine the effectiveness during the selection of the dose of Duodope® in patients with Parkinson's disease before using a permanent probe, a temporary naso-natural probe can be used. The dose of the drug should be selected individually for each patient until an optimal clinical effect is achieved,which consists in the maximum elongation of periods of functional control over voluntary movements due to the maximum reduction in episodes of motor control disorders with bradykinesia and dyskinesia.

At the initial stage Duodope® should be administered as a monotherapy. In the future, if necessary, you can simultaneously prescribe other drugs to treat Parkinson's disease. To administer Duodope®, only the special CADD®-Legacy 1400 pump must be used. The instructions for use are supplied with the pump.

Treatment with Duodope® using a permanent probe can be stopped at any time. To do this, you need to remove the probe and give the stoma at the site of its introduction to be tightened. Then it is necessary to continue treatment with the use of drugs (in oral dosage form), including those containing levodopa / carbidopa.

Dose selection

Long-term administration of the total daily dose of Duodope® is divided into 3 periods: the morning bolus dose, the constant maintenance dose and additional bolus doses. In all cases, individual dose adjustment is necessary.

Morning dose: The morning bolus dose of Duodope® is administered within 10-30 minutes to quickly reach the therapeutic concentration. The morning dose of Duodope® should be selected on the basis of the previous morning dose of levodopa by the patient. The total morning dose of Duodope® is usually 5-10 ml of gel, which corresponds to 100-200 mg of levodopa. The total morning dose of Duodope® should not exceed 15 ml of gel (300 mg of levodopa). The morning dose of Duodope® should be increased by 3 ml (the volume may vary depending on the probe used) gel to compensate for the dead volume of the probe. After the effective morning dose of Duodope® has been established, no further dose adjustment is required.

Permanent maintenance dose: The constant maintenance dose of Duodope® is selected individually. It should be in the range of 1-10 ml / h (20-200 mg levodopa / h) and usually is 2-6 ml / h (40-120 mg levodopa / h). In special cases, a higher dose of Duodope® may be needed. The maintenance dose of Duodope® is adjusted in increments of 0.1 ml / h (2 mg levodopa / h). The dose of Duodope® should be calculated on the basis of the previous dose of levodopa administered by the patient.After withdrawal of concomitant treatment, the dose of Duodope® should be adjusted.

Additional bolus doses: an additional dose of Duodope® should be selected individually, usually 0.5-2.0 ml. Additional bolus doses of Duodope® are administered if necessary in the event of hypokinesia during the day. In rare cases, a higher dose of Duodope® may be needed.

If the need for additional bolus doses of Duodopa® is more than 5 times a day, then an increase in the maintenance dose of Duodope® should be considered. After setting the initial dose of Duodope® for several weeks, small corrections of the morning bolus, supporting and additional bolus doses of Duodope® should be done.

Table 1. Determination of the total daily dose of Duodope®.

	Morning dose	Constant	Additional
		supportive	bolus doses:
		dose:
Start treatment (day 1)	Morning dose of the drug Duodopa® should settle for the morning an oral dose levodopa / carbidones (rape taken patient). Morning dose of Duodope® is calculated taking into account the recommended conversion factor. (cm. Table 2. Dependence of the morning oral dose levodopa / carbidopa and the morning dose of the drug Duodopa®).	Maintenance dose preparation Duodope® is adjusted from in a step of 0.1 ml / hr (2 mg of levodopa / h). Calculation example constant supporting dose: Constant maintenance dose (A mg) = total daytime oral dose (previously accepted patient) - morning dose; A mg: 20 mg / ml = B ml; Calculation of speed infusion during 16 hours: In ml: 16 h = C ml / h. With ml / h - 0.9 = D ml / hr (infusion rate).	Can be applied each hour. Beginning with doses of 1 ml.






Day 2 and	Morning dose of the drug	Support	Can be applied
ending	Duodope® can be	speed value	each hour.
period	adjusted for	infusion as in	Beginning with
dose titration	clinical	previous day.	doses of 1 ml.
(titration	effect on admission	The maintenance dose
usually	previous morning	preparation Duodope®
is	dose.	is adjusted from
4-7 days)		in a step of 0.1 ml / hr
		(2 mg of levodopa / h).
Period	After	Support	Can be applied
applications	effective morning	speed value	every 2 hours (with
stable	dose of Duodope®	infusion as in	necessity).
total daily	has been installed,	previous day.	The dose is usually
doses	further change		is from 0.5 ml
	dose is not required.		up to 2.0 ml.

Table 2. Dependence of the morning oral dose of levodopa / carbidopa and the morning dose of Duodopa®
Morning oral dose of levodopa / carbidopa	The dose percentage of Duodope®

0-200 mg	80%
201-399 mg	70%
> 400 mg	60%

Use of Duodope® at night

If there is a medical indication, Duodope® can be administered at night.

Monitoring of treatment: a sudden deterioration in the response to treatment with recurrent motor fluctuations can serve as an indication that the distal part of the probe has moved from the duodenum / jejunum to the stomach. The probe is transferred back to the duodenum / jejunum by a conductor under fluoroscopy control.

Application in children and adolescents

The drug Duodopa® is contraindicated for use in patients under the age of 18 years.

Application in elderly patients

There is extensive experience with the use of levodopa / carbidopa in elderly patients. The dosage recommendations given above include an analysis of the clinical data obtained in this category of patients.

Application in renal / hepatic insufficiency

There is no data on the pharmacokinetics of carbidopa and levodopa in patients with hepatic or renal insufficiency. Determination of efficacy and dose selection of Duodope® are based on achieving the optimal clinical effect in patients with Parkinson's disease, and it is not necessary to separately consider the effect of renal / hepatic insufficiency on the concentration of levodopa / carbidopa in blood plasma.

Interruption of treatment

If you need a sharp dose reduction or need to stop treatment with Duodope®, careful monitoring of the patient should be made, especially if he receives antipsychotics.

If suspected development of dementia or the establishment of such a diagnosis and increased risk of confusion, the maintenance of the pump should be provided by a specially trained personnel or guardian (for example, a close relative).

To use a drug cassette, it must be connected to a portable pump and a system connected to a nasoduodenal probe or a duodenal / neural probe in accordance with the instructions for use. Cassettes with the drug are for single use only and should not be used for more than 1 day (up to 16 hours), even if some of the drug remains. Do not use open cassettes again. At the end of the storage period, the gel may acquire a slightly yellowish color. This does not affect the concentration of the drug or the effectiveness of the treatment.

Side effects:

Adverse reactions, often observed with Duodope®

- Adverse reactions associated with the use of the drug - dyskinesia, nausea.

- Adverse reactions associated with percutaneous endoscopic gastrostomy - pain in the abdomen, complications associated with the introduction of the probe, excessive formation of granulation tissue, reddening of the skin at the site of the stoma, suppuration of the postoperative wound, postoperative discharge, pain at the site of stoma installation and reaction at the site of installation stoma.

Most of these adverse reactions were recorded after percutaneous endoscopic gastrostomy and were observed during the first 28 days. Adverse reactions associated with the use of the drug, percutaneous endoscopic gastrostomy and the use of a portable pump that arise after the start of the drug and are included, regardless of the cause, combined with adverse reactions that occur during post-registration follow-up of Duodope®.

Adverse reactions that often occur when using levodopa / carbidopa are the result of the central action of dopamine. The severity of these reactions can usually be reduced by lowering the dose of levodopa. Adverse reactions are given below, indicating the frequency (very often > 1/10, often > 1/100, according to <1/10, infrequently > 1/1000, but <1/100, rarely > 1/10000, but <1/1000, very rarely <1/10000).

Data of clinical trials and post-registration period

Adverse reactions associated with the use of Duodopa® (not including adverse reactions associated with percutaneous endoscopic gastrostomy and the use of a portable pump)
System of organs		Frequency of occurrence	Adverse Reactions
Violations of the blood and lymphatic		Often	Anemia.
systems		Infrequently	Leukopenia, thrombocytopenia.
Immune system disorders		Frequency unknown	Anaphylactic reactions.
Disorders from the gastrointestinal tract		Often	Nausea, constipation.
tract		Often	Vomiting, bloating, dyspepsia, flatulence, diarrhea, dryness of the oral mucosa, dysgeusia, dysphagia.
		Infrequently	Hyper secretion of saliva.
		Rarely	Bruxism, discoloration of saliva, burning mouth syndrome, hiccough.
Disorders from the metabolism and nutrition		Often	Decreased body weight.
Disorders from the metabolism and nutrition		Often	Weight gain, increased concentrations of amino acids (elevated concentrations of methylmalonic acid), decreased appetite, vitamin B6 deficiency, vitamin B12 deficiency, hyperhomocysteinemia.
Disorders from the nochek and urinary tract		Often	Urinary retention, involuntary urination.
		Infrequently	Chromaturia.
		Rarely	Priapism.
Disturbances from musculoskeletal and connective tissue		Often	Muscle spasms, pain in the neck.
Disturbances from the nervous system		Often	Dyskinesia, Parkinson's disease.
		Often	Polyneuropathy, dizziness, dystopia, the phenomenon of "on-off", paresthesia, fainting, headache, drowsiness, tremor, hypoesthesia.
		Infrequently	Ataxia, cramps, gait disturbance.
Disorders of the psyche		Often	Anxiety disorders, depression, insomnia.
Disorders of the psyche		Often	Unusual dreams, state stimulation, confusion, hallucinations, impulsive behavior, psychotic disorder, involuntary episodes of falling asleep, sleep disturbance.
		Often
		Infrequently	Completed suicide, dementia, disorientation, a state of euphoria, a sense of fear, increased sexual desire, nightmares, suicide attempts.
		Rarely	Pathological thinking.
Disturbances on the part of the organ of sight		Infrequently	Blepharospasm, diplopia, ocular ischemic neuropathy, blurred vision.
Disturbances from the respiratory system, chest and mediastinal organs		Often	Pain in the mouth and throat, shortness of breath, aspiration pneumonia.
		Infrequently	Pain in the thorax, dysphonia.
		Rarely	Abnormal breathing.
Disturbances from the skin and subcutaneous tissues	Often		Hyperhidrosis, contact dermatitis, peripheral edema, pruritus, rash.
	Infrequently		Alopecia, redness of the skin, hives.
	Rarely		Changing sweat color, malignant melanoma.
Heart Disease		Often	Arrhythmia.
Heart Disease		Infrequently	Feeling of rapid heart rate.
Vascular disorders		Often	Orthostatic hypotension.
		Often	Reduction of blood pressure, increased blood pressure.
		Infrequently	Phlebitis.
Laboratory and instrumental data		Often	An increase in the concentration of homocysteine in the blood, a decrease in the concentration of vitamin B6, a decrease in the concentration of vitamin B12.
General disorders and disorders at the site of administration		Often	Fatigue, pain in the place of installation of stoma, asthenia.
		Infrequently	Feeling of discomfort.
Trauma, intoxication and complications of manipulation		Often	Falls.

The analysis was performed in patients who received the Duodope® preparation or placebo gel through an inelastic probe after percutaneous endoscopic gastrostomy to ensure that adverse reactions associated with percutaneous endoscopic gastrostomy and the use of a portable pump were detected in all studies, regardless of the design of the study (double-blind or open).

Below are the side reactions associated with percutaneous endoscopic gastrostomy and the use of a portable pump.

Adverse reactions associated with percutaneous endoscopic gastrostomy and the use of a portable pump
System of organs	Frequency of occurrence	Adverse Reactions
Disorders from the gastrointestinal tract	Often	Pain in the abdomen.
tract	Often	Pneumoperitoneum, unpleasant sensations in the abdomen, peritonitis, pain in the upper abdomen.
Infectious and parasitic diseases	Often	Infection of the postoperative wound.
	Often	Cellulite in the place of installation of stoma, postoperative infection.
Trauma, intoxication and complications of manipulation	Often	Pain at the site of the stoma installation, redness of the skin at the site of the stoma installation, reactions at the site of the stoma installation, postoperative discharge.
	Often	Pain in the site of stoma installation, postoperative bleeding, complications associated with the installation of the gastrointestinal probe, postoperative discomfort, postoperative intestinal obstruction, postoperative complications.
Disturbances from the skin and subcutaneous tissues	Often	Excess formation of granulation tissue.
General disorders and disorders at the site of administration	Often	Difficulties with the introduction of the probe.
	Often	Probe shift, blockage of the probe.

There were reports of frequent adverse reactions associated with the complication of the installation of both the imanal probe and the naso-natural probe.

Adverse reactions with the use of the nazojunctional probe: pain in the mouth and pharynx, bloating, abdominal pain, abdominal discomfort, pain, throat irritation, gastrointestinal damage, esophageal bleeding, anxiety disorders, dysphagia, vomiting.

Adverse reactions with the use of an imanal probe: pain in the abdomen, abdominal discomfort, bloating, flatulence, pneumoperitoneum.

Other minor adverse reactions that were associated with a complication of the setting of both the imanal probe and the naso-natural probe: abdominal discomfort, upper abdominal pain, duodenal ulcer, duodenal ulcer, erosive duodenitis, erosive gastritis, gastrointestinal bleeding, peritonitis, pneumoperitoneum, ulcer of the small intestine.

The displacement of the probe into the cavity of the stomach leads to a relapse of motor fluctuations (due to the irregular evacuation of Duodope® from the stomach cavity to the intestine). The probe is transferred back to the duodenum by means of a conductor under the control of fluoroscopy.

Laboratory indicators

The following deviations from laboratory parameters were registered with levodopa / carbidopa preparations and, therefore, should be taken into account in the treatment of patients with Duodope®: increased activity of alkaline phosphatase, aspartate aminotransferase, alanine transaminase, lactate dehydrogenase; increased blood urea nitrogen concentrations, bilirubin, blood glucose, creatinine, uric acid; positive Coombs test result and reduced hemoglobin and hematocrit values. There were reports of urine in the urine of leukocytes, bacteria and blood.

The use of levodopa / carbidopa, and therefore Duodope®, can lead to a false positive result of rapid tests to detect ketones in the urine; this reaction does not change when urine is boiled.The use of glucose oxidase methods to investigate the presence of glucosuria can give false-negative results.

The following adverse reactions were observed with dopaminergic drugs and may be observed with Duodopa®:

- disorders of the blood and lymphatic system: agranulocytosis, hemolytic anemia;

- disorders of the nervous system: trism, malignant neuroleptic syndrome;

- violations of the organ of vision: Bernard-Horner's syndrome, mydriasis, cramp of the eye;

- disorders of the skin and subcutaneous tissues: angioedema, purpura Shenlaine-Genocha.

Overdose:Treatment of acute overdose of the preparation Duodope® basically coincides with the treatment of acute overdose of levodopa. However, in this situation pyridoxine ineffective. Regular ECG should be performed in connection with the risk of cardiac rhythm disturbances; if necessary, appropriate antiarrhythmic therapy is prescribed. It should be remembered about the possibility of drug interaction with other drugs that the patient was taking.Dialysis with an overdose of the drug to date has not been used, so its effectiveness is unknown.

Interaction:

Caution should be exercised while using Duodope® and the following preparations:

Antihypertensive drugs

When using a combination of levodopa and an inhibitor of dicarboxylase aromatic L-amino acids in patients who are already taking antihypertensive drugs, postural hypotension developed. You may need to adjust the dose of an antihypertensive drug.

Antidepressants

There are rare reports of such adverse reactions as an increase in blood pressure and dyskinesia that occurred when combined use of tricyclic antidepressants and levodopa / carbidopa preparations.

Anticholinergic drugs

Anticholinergic drugs can reduce the severity of tremor when combined with levodopa, but their combined use can enhance pathological involuntary movements. Anticholinergic drugs can reduce the severity of the effects of levodopa due to a slowing of its absorption.You may need to adjust the dose of Duodope®.

Inhibitors of catechol-O-methyltransferase (tolcapone, entacapone)

The combined use of COMT inhibitors (catechol-O-methyltransferase) and Duodope® can increase the bioavailability of levodopa. You may need to adjust the dose of Duodope®.

Preparations of iron

In the gastrointestinal tract levodopa can form chelate complexes with iron, which leads to a decrease in the absorption of levodopa.

Other medications

Dopamine receptor antagonists (some antipsychotics, eg phenothiazines, butyrophenones and risperidone, and antiemetics, for example, metoclopramide), benzodiazepines, isoniazid, phenytoin and papaverine can reduce the effectiveness of levodopa treatment. Patients taking these drugs with Duodope®. need careful monitoring for loss of therapeutic effectiveness.

It is possible to use Duodope® together with the recommended dose of MAO inhibitor, but only selective MAO inhibitor type B (eg selegiline hydrochloride).The combined use of selegiline and levodopa / carbidopa can lead to severe orthostatic hypotension.

Amantadine has a synergistic effect with levodopa and may exacerbate the severity of adverse reactions associated with this use. You may need to adjust the dose of Duodope®.

Sympathomimetics can increase the severity of adverse cardiovascular reactions associated with levodopa.

Due to levodopa competes with some amino acids for transport mechanisms, absorption of levodopa can worsen in patients whose diet is rich in proteins.

The effect of antacids on the bioavailability of Duodope® has not been studied.

Special instructions:

Before the introduction of a permanent nasode-duodenal probe, it is necessary to obtain positive clinical results of the trial application of Duodope® with the introduction through a temporary naso-natural probe.

The warnings and cautions below are for levodopa, and therefore apply to Duodope®.

The drug Duodope® is not recommended for the treatment of extrapyramidal reactions caused by other drugs.

In patients with a history of myocardial infarction and an atrial or ventricular arrhythmia, it is necessary to monitor cardiac function, especially in the initial period of dose selection.

In all patients receiving Duodope® treatment, it is necessary to carefully monitor the development of mental changes, depression with suicidal tendencies and other severe mental illnesses. Treatment of patients with psychoses, ongoing or in history, should be done with caution. It is necessary to carefully prescribe Duodopa ® together with antipsychotics that can block dopamine receptors (especially D2) - possibly reducing the antiparkinsonian effect or increasing the symptoms of the disease. Treatment Duodopa ® patients with chronic open-angle glaucoma should be carried out with caution, provided that the monitoring of intraocular pressure and its regular measurement.

The drug Duodopa® can cause orthostatic hypotension, therefore the drug should be administered with caution to patients taking other medications that cause orthostatic hypotension (eg, AIF inhibitors, nitrates, diuretics, MAO inhibitors).

In sharp cancellation antiparkinsonian drugs can occur neyrolepticheksky malignant syndrome (NMS) - a set of symptoms, including muscle rigidity, fever, mental changes (e.g., agitation, confusion, to whom), and also increase creatine phosphokinase activity in plasma. In rare cases, rhabdomyolysis and severe dyskinesia are observed in patients with Parkinson's disease within the ZNS. In this regard, with a sharp decrease in dose or withdrawal of a combination of levodopa / carbidopa, it is necessary to carefully monitor the patient's condition, especially if he takes antipsychotics. There have been reports of cases of gambling addiction occurs, increase libido and hypersexuality, and the inability to control these phenomena, in patients with Parkinson's disease who Dofaminomimetiki therapy was carried out, including levodopa / carbidopa (as well as drug Duodopa®.

While the relationship of these phenomena using dopaminergic not proved cancellation or reduction in dose of one or more drugs dofaminergichsskih caused cessation of these phenomena.Physicians should monitor the possible development of gambling, increased sexual desire and hypersexuality in patients with Parkinson's disease who are taking Duodope®. Doctors should consider reducing the dose or withdrawal of Duodope® if the patient develops these conditions. If general anesthesia is required, treatment with Duodope® can continue until then. While the patient is allowed to take liquids and medications inside. If it is necessary to temporarily stop the therapy, the drug intake can be resumed at the same dose, when it will be allowed to take the liquid. To avoid the development of dyskinesias against the background of taking levodopa, the dose of Duodope® can be reduced.

During prolonged therapy with Duodope®, periodic assessment of liver, kidney, hematopoietic and cardiovascular systems is recommended.

Duodope® contains hydrazine, a carbidopa degradation product, which may have genotoxicity and potentially oncogenic activity. The average daily dose of Duodope® is 100 ml, which corresponds to 2 g of levodopa and 0.5 g of carbidopa.The maximum daily dose is 200 ml. This corresponds to the intake of hydrazine in amounts reaching, on average, 4 mg per day; a maximum of 8 mg per day. The clinical significance of ingesting such amounts of hydrazine is not known.

Previous surgical intervention on the upper abdomen may cause difficulties in the installation of gastro- or ejnostomy.

There are separate reports of cases of occlusion of the probe and / or blockage of the intestine with the formation of bezoar, requiring replacement of the probe and, in rare cases, surgical intervention. Early symptoms of such conditions include abdominal pain, nausea and vomiting. In some cases, ulcers of the stomach and intestines were found. One of the risk factors for the formation of bezoar can be eating foods with a high fiber content (for example, asparagus).

Inadvertent treatment of the patient with a pump or probe can cause the development of complications. In this case, the patient should be assisted by a guardian (for example, a nurse or a close relative).

Monitoring of therapy: a sudden decrease in the effectiveness of the drug with the occurrence of motor fluctuations may indicate the movement of the distal part of the probe from the duodenum to the stomach.It is necessary to determine the location of the catheter by X-ray and return it to the duodenum under the radiological control.

A sudden or gradual increase in bradykinesia may indicate blockage of the device for any reason and needs to be studied.

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma, compared with the population as a whole. It is unclear whether an increased risk of melanoma develops with Parkinson's disease or other factors, such as the use of drugs to treat Parkinson's disease.

Thus, patients with Duodope® should monitor melanoma development on a regular basis. Periodic examinations of the skin should be performed properly by qualified specialists (eg dermatologists).

Complications observed in clinical trials include: bezoar, bowel obstruction, stoma erosion / ulcers, intestinal bleeding, intestinal ischemia, bowel obstruction, intestinal perforation, pancreatitis, peritonitis,pneumoperitoneum and postoperative wound infection. Pain in the abdomen may be a symptom of one of the complications listed above. Some complications can lead to serious consequences, including those requiring surgical intervention. Some complications can lead to death. Patients should notify their attending physician if they experience any of the above symptoms.

Effect on the ability to drive transp. cf. and fur:Levodona / carbidopa can cause dizziness and orthostatic hypotension, drowsiness and sudden falling asleep, so patients should be careful when driving and controlling the mechanisms. Patients treated with Duodope®, who are drowsy and / or have a sudden falling asleep, are advised not to drive or participate in activities in which impaired attention may expose them or others to the risk of serious injury or death (eg, management of mechanisms ) until. While these adverse reactions will not stop.

Form release / dosage:

Gel for intestinal administration, 20 mg / ml + 5 mg / ml.

Packaging:

For 100 ml of gel in a bag of PVC with a connection tube from PBX embedded in it at one end; the bag with the embedded tube sealed and placed in a solid cassette of transparent gray plastic, the connecting tube is passed through the hole in the top cover of the cassette (side) and fixed with special clips along the top cover of the cassette. The connecting tube is provided with a clip, a female Luer connection and a screw-on protective cap.

For 7 cassettes, the connecting tubes upwards together with the instruction for use are placed in a cardboard pack.

Storage conditions:At a temperature of 2 ° C to 8 ° C in a dark place. Keep out of the reach of children.

Shelf life:15 weeks. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003027

Date of registration:08.06.2015

The owner of the registration certificate:EbbVi Ltd.EbbVi Ltd. Russia

Manufacturer: & nbsp

FRESENIUS KABI NORGE, AS Norway

Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia

Information update date: & nbsp23.08.2015

Illustrated instructions

Instructions

Duodope® (Duodopa®)