Xevoben xr: detailed information

Package leaflet: Information for the patient

Xevoben XR, 100 mg + 25 mg, prolonged-release capsules, hard
Levodopum + Benserazidum
Please read this leaflet carefully before taking this medicine, as it contains important information for you.

Keep this leaflet, as you may need to read it again.
If you have any further questions, please ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you personally. Do not pass it on to others. It may harm someone else even if their symptoms are the same as yours.
If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet

What Xevoben XR is and what it is used for
Important information before taking Xevoben XR
How to take Xevoben XR
Possible side effects
How to store Xevoben XR
Contents of the pack and other information

1. What Xevoben XR is and what it is used for

Xevoben XR is a medicine containing the active substances levodopa and benserazide.
The active substance levodopa is a precursor of dopamine, a substance naturally produced in the human body.
Insufficient levels of dopamine in certain areas of the brain are responsible for both Parkinson's disease and restless legs syndrome. This deficiency is compensated by the conversion of levodopa into dopamine.
The second active substance, benserazide, inhibits the breakdown of levodopa outside the brain and allows a lower dose of levodopa to be used.
The active substances levodopa and benserazide are released slowly over an extended period from a special pharmaceutical formulation (prolonged-release, hard capsules).

Xevoben XR is used:

in the treatment of Parkinson's disease (paralysis agitans, a disease characterized by tremor, slowness of movement, and muscle stiffness), when the patient is already being treated with levodopa in combination with benserazide or carbidopa in an immediate-release formulation;
in the treatment of idiopathic restless legs syndrome, when the patient is already being treated with levodopa in combination with benserazide or carbidopa in an immediate-release formulation;
in the treatment of restless legs syndrome associated with renal insufficiency requiring dialysis, when the patient is already being treated with levodopa in combination with benserazide or carbidopa in an immediate-release formulation.

Additional information for patients with Parkinson's disease
There is insufficient clinical experience with the use of Xevoben XR in patients who have not previously been treated with levodopa or in combination with other anti-parkinsonian medicines, or for long-term treatment.
Xevoben XR should not be used to treat symptoms resembling Parkinson's disease caused by certain medicines (drug-induced parkinsonism), or in Huntington's disease.

Additional information for patients with restless legs syndrome
There is insufficient clinical experience with the use of Xevoben XR in patients who have not previously been treated with levodopa in combination with benserazide in an immediate-release formulation.
Before starting treatment with levodopa and benserazide, your doctor will ensure that the symptoms of restless legs syndrome are not caused by iron deficiency. In such a case, iron deficiency should be treated with iron supplementation.

2. Important information before using Xevoben XR

When not to use Xevoben XR

if the patient is allergic to levodopa, benserazide, or any of the other ingredients of this medicine (listed in section 6);
in patients under 25 years of age (skeletal development must be complete);
in patients with severe disorders of specific hormone-producing organs, such as hyperthyroidism or significantly elevated blood cortisol levels (Cushing's syndrome), or with an adrenal gland tumour;
in patients with severe metabolic, liver, kidney or bone marrow disorders;
in patients with severe kidney disease not treated with dialysis (applies to patients with restless legs syndrome);
in patients with severe heart disease, such as serious problems with rapid heartbeat (tachycardia), severe cardiac arrhythmias or heart failure;
in patients with specific mental disorders (psychoses), whether or not of physical origin;
in patients concurrently taking antihypertensive medicines containing the active substance reserpine (see "Xevoben XR with other medicines");
in patients concurrently taking non-selective monoamine oxidase inhibitors (MAO inhibitors) (an antidepressant containing the active substance tranylcypromine) or a combination of a selective MAO-A inhibitor (an antidepressant containing the active substance moclobemide) with a selective MAO-B inhibitor (a medicine used in the treatment of Parkinson's disease containing the active substance selegiline or rasagiline) (see "Xevoben XR with other medicines");
in patients with high intraocular pressure (closed-angle glaucoma);
in pregnant women;
in women of childbearing potential who are not using effective contraception (see "Pregnancy and breastfeeding").

Warnings and precautions
Before starting treatment with Xevoben XR, discuss this with your doctor, pharmacist or nurse.
Hypersensitivity reactions may occur in predisposed individuals.
Caution should be exercised when using Xevoben XR in patients who experience excessive daytime fatigue or sudden, unexpected episodes of sleep during treatment with Xevoben XR. If this applies to the patient, consult a doctor (see "Driving and operating machinery").
Additional warning and precautions for patients with restless legs syndrome

if the patient has a more severe form of restless legs syndrome and requires a higher dose of Xevoben XR than that described in section 3, treatment with Xevoben XR should be discontinued if symptoms worsen or occur earlier in the day.

Inform your doctor if you or your family members notice unusual behaviours resulting from an irresistible impulse, compulsion or obsessive performance of certain activities, harmful to the patient or others. These behaviours are known as impulse control disorders and may include gambling addiction, excessive eating or spending, increased sexual drive or intensified sexual thoughts and feelings. It may be necessary for the doctor to re-evaluate the ongoing treatment.
Regular medical monitoring is essential if:

the patient has previously had a heart attack;
the patient currently has irregular heartbeat, reduced blood flow to the coronary arteries or heart failure;
the patient has previously had gastrointestinal ulcers;
the patient has reduced bone strength;
the patient has open-angle glaucoma, as levodopa may theoretically increase intraocular pressure;
the patient has diabetes.

Additionally, liver and kidney function, cardiovascular function and blood counts should be monitored periodically.
Treatment with Xevoben XR may cause circulatory problems due to excessively low blood pressure (see section 4). These symptoms usually resolve or improve with a reduction in the dose of Xevoben XR. If the patient is elderly or is concurrently taking medicines used to treat high blood pressure or other medicines that may lower blood pressure, or if the patient has circulatory problems due to low blood pressure, the doctor will closely monitor the patient, especially at the beginning of treatment or during dose increases.
Therefore, regular visits scheduled by the doctor are essential.
Warning
Cognitive and behavioural disorders may occur in a small number of patients with Parkinson's disease, which may be related to taking Xevoben XR in much higher doses than required for the treatment of motor disorders, contrary to medical advice.
After many years of therapy with a medicine containing the same active substances as Xevoben XR, abrupt discontinuation of Xevoben XR may lead to withdrawal symptoms (known as malignant withdrawal syndrome of levodopa). Symptoms include very high fever, muscle rigidity and mental changes. In severe cases, excretion of muscle proteins in the urine (myoglobinuria), breakdown of muscle fibres (rhabdomyolysis), acute kidney failure or complete immobility may occur. These symptoms are potentially life-threatening. In such a case, contact your doctor immediately!
If the patient has a planned surgical procedure under general anaesthesia, treatment with a medicine containing levodopa/benserazide should be continued as long as possible up to the operation, except when anaesthesia involves halothane. For general anaesthesia using halothane, levodopa/benserazide-containing medicine should be discontinued 12–48 hours before the procedure due to the risk of blood pressure fluctuations and/or cardiac arrhythmias in patients concurrently receiving levodopa/benserazide and halothane. After the procedure, treatment can be resumed, gradually increasing the dose until the previously used dose is reached.
Note
Gastrointestinal disturbances such as dry mouth, nausea, vomiting or diarrhoea may occur, especially at the beginning of treatment (see section 4). These can be significantly reduced or eliminated by taking Xevoben XR with a small, low-protein meal (e.g., biscuits, crackers or similar), taking the medicine with liquid, or by gradually increasing the dose.
During long-term treatment and/or when using high doses, involuntary movements may occur (see section 4). These symptoms usually resolve or become less bothersome with dose reduction.
Patients with Parkinson's disease have an increased risk of developing melanoma compared to the general population. It is unclear whether this increased risk is due to Parkinson's disease itself or other factors, such as the use of levodopa in the treatment of Parkinson's disease. During treatment with Xevoben XR, patients should regularly examine their skin for suspicious changes and undergo periodic skin examinations by an appropriate specialist (e.g., a dermatologist).
Note for people around the patient
Treatment with Xevoben XR may lead to abnormally low mood (depression), especially if there is a previous predisposition to such symptoms (see section 4). However, depression may be one of the symptoms of Parkinson's disease or restless legs syndrome. Therefore, patients should be closely monitored for psychological changes to detect depression at an early stage. In such a case, contact your doctor.

Xevoben XR with other medicines
Tell your doctor or pharmacist about all medicines you are currently taking, have recently taken or plan to take.
Concurrent use of Xevoben XR with the following active substances or medicines may affect their action

medicines used to treat low blood pressure, circulatory disorders, irregular heartbeat, medicines inducing labour, or medicines used to treat lower airway spasms (called sympathomimetics), e.g., epinephrine, norepinephrine, isoproterenol or amphetamine. The effect of sympathomimetic medicines may be enhanced. Therefore, their concurrent use is not recommended. If concurrent use is necessary, the patient's cardiovascular system should be closely monitored, and the dose of the sympathomimetic medicine may need to be reduced.
medicines used to treat high blood pressure (called antihypertensives): the effect of the antihypertensive medicine may be enhanced, thereby increasing the risk of low blood pressure. Therefore, blood pressure should be monitored regularly (see above). If necessary, the doctor will adjust the dose of Xevoben XR and/or the antihypertensive medicine.

The following medicines may affect the action of Xevoben XR
Reduced effect due to:

certain painkillers (opioids);
medicines used to treat high blood pressure containing the active substance reserpine. In this case, Xevoben XR should not be used (see above);
certain mood-lowering medicines (neuroleptics).

Enhanced effect and possible increase in adverse effects due to:

medicines containing the active substance selegiline (used in the treatment of Parkinson's disease).

Other possible interactions:

certain medicines used to treat depression (called MAO inhibitors): concurrent use of Xevoben XR and medicines containing tranylcypromine as the active substance may dangerously increase blood pressure. This situation may occur up to 2 weeks after stopping tranylcypromine treatment. Xevoben XR should not be used at that time (see above). Therefore, a 2-week interval should be maintained between stopping tranylcypromine and starting treatment with Xevoben XR. On the other hand, concurrent use of Xevoben XR with moclobemide, selegiline and rasagiline is considered safe.
concurrent use of Xevoben XR with domperidone may lead to increased blood levels of levodopa. Their concurrent administration may increase the risk of cardiac arrhythmias.

Concurrent use of Xevoben XR with other anti-parkinsonian medicines (e.g., dopamine agonists, amantadine, anticholinergics, selegiline, bromocriptine) is permitted.
However, it should be noted that not only the desired but also the undesirable effects of the medicine may be enhanced. The doctor may prescribe a reduced dose of Xevoben XR or the other medicine. If adjunctive therapy is initiated with a medicine containing entacapone, a reduction in the dose of Xevoben XR may also be necessary. Concurrent administration of Xevoben XR with medicines that neutralise gastric acid may lead to reduced absorption of the active substances it contains.
Changes in diagnostic laboratory tests
The following laboratory tests may be affected:

levodopa may influence laboratory test results for catecholamines, creatinine, uric acid and glucose (in glucosuria);
false-positive results may occur in ketone body tests performed using test strips (this reaction does not change when the urine sample is boiled);
false-negative results may occur in urine glucose tests determined using glucose oxidase;
false-positive results may occur in the Coombs test.

General anaesthesia using halothane
In cases of general anaesthesia requiring halothane, levodopa/benserazide-containing medicine should be discontinued 12–48 hours before the procedure due to the risk of blood pressure fluctuations and/or arrhythmias.
Xevoben XR with food and drink
Avoid eating high-protein meals immediately before taking Xevoben XR, as this may reduce the medicine's effectiveness.
Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.
A pregnancy test is recommended before starting treatment to exclude pregnancy.
Xevoben XR must not be used during pregnancy, as there are no available studies in pregnant women, and animal studies have shown harmful effects on the unborn offspring of both active substances contained in Xevoben XR. Women of childbearing potential must use an effective method of contraception during treatment with Xevoben XR. If, despite this, the patient becomes pregnant or suspects she may be pregnant, she should consult her doctor. The doctor will advise on how to discontinue treatment with Xevoben XR.
Breastfeeding must not be performed during treatment with Xevoben XR. If treatment with Xevoben XR is required, breastfeeding must be discontinued.
Driving and operating machinery
Xevoben XR may have a major influence on the ability to drive and operate machinery. In rare cases, treatment with Xevoben XR may cause excessive fatigue or sudden episodes of sleep. If this applies to the patient, driving and operating machinery should be avoided to prevent the risk of serious injury to the patient or others until excessive fatigue or sudden sleep attacks resolve.

3. How to use Xevoben XR

This medicine should always be used exactly as prescribed by your doctor. If in doubt, consult your doctor or pharmacist.
The number of extended-release capsules of Xevoben XR to be taken depends on the severity of the disease and the patient's tolerance to Xevoben XR. The most optimal dose for each patient is determined by gradually increasing the daily dose. Therefore, the dose prescribed to one patient may differ from that prescribed to another. Do not change the dose determined by your doctor without medical advice.

Treatment of Parkinson's disease symptoms
If your doctor has not advised otherwise, the treatment regimen is as follows:
The recommended starting dose is to maintain the previous morning dose of Xevoben in immediate-release formulation, followed by administration of Xevoben XR, extended-release capsules. The subsequent dosing regimen must be determined through careful dose titration.
If necessary, the dose of Xevoben XR, extended-release capsules, may be increased after 2–3 days by approximately 50% compared to the standard formulation of Xevoben, because Xevoben XR, extended-release capsules, result in lower blood concentrations of the active substances.
If prolonged effect of the medicine is required during the night, an additional 1–2 capsules of Xevoben XR, extended-release capsules, should be taken before bedtime, in addition to the established daily dose.
If the patient is using another medicine for Parkinson's disease, Xevoben XR, extended-release capsules, may be additionally administered. However, as soon as the patient's condition improves with Xevoben XR, the dose of the other medicine should be re-evaluated, reduced, and, if necessary, gradually discontinued.

Patients with hepatic or renal impairment
Dose adjustment of Xevoben XR is not necessary in patients with moderate hepatic impairment or mild to moderate renal impairment (creatinine clearance ≥30 mL/min).

Use in children and adolescents
Xevoben XR must not be used in children and adolescents under 25 years of age (see section 2).

Administration method
Oral use.
Xevoben XR should preferably be taken 30 minutes before a meal or 1 hour after a meal, swallowed with an adequate amount of liquid (preferably a glass of water), or taken with a small low-protein meal (e.g., biscuits, crackers, or similar). Extended-release capsules must always be swallowed whole.

Treatment duration
Xevoben XR replaces the neurotransmitter dopamine, which is insufficiently produced in the body. Therefore, treatment with Xevoben XR is long-term. At least 3 months of treatment may be required for the doctor to assess the therapy's effectiveness.

Treatment of restless legs syndrome (RLS) symptoms
The number of Xevoben XR capsules taken depends on the severity of restless legs syndrome. It may be necessary to determine the most optimal dose for the patient by gradually increasing the daily dose.

RLS with difficulty falling asleep
For patients experiencing difficulty falling asleep due to RLS, treatment with levodopa/benserazide in immediate-release formulation (e.g., Xevoben 100 mg + 25 mg tablets or Xevoben 200 mg + 50 mg tablets) should be initiated. The starting dose is 1 tablet of Xevoben taken one hour before bedtime. If symptoms do not improve, the dose may be increased to 2 tablets.

RLS with difficulty falling asleep and nocturnal sleep disturbances
For patients with RLS who experience both difficulty falling asleep and nocturnal sleep disturbances, a combination of Xevoben XR, extended-release capsules, and Xevoben 100 mg + 25 mg or 200 mg + 50 mg tablets should be used. Take 1 extended-release capsule together with 1 tablet of Xevoben 100 mg + 25 mg or ½ tablet of Xevoben 200 mg + 50 mg one hour before bedtime. If this does not sufficiently relieve symptoms during the second half of the night, the dose may be increased to 2 extended-release capsules.

Note
The maximum daily dose should not exceed 200–300 mg of levodopa and 50–75 mg of benserazide per day (equivalent to 2–3 capsules of Xevoben XR 100 mg + 25 mg) to avoid worsening of symptoms, spread to other body parts, or occurrence of RLS symptoms earlier in the day.
In such cases, further dose escalation should be avoided. Instead, the doctor should consider adjunctive therapy, dose reduction of Xevoben XR, or gradual discontinuation of Xevoben XR and replacement with another medicine.

Use in children and adolescents
Xevoben XR must not be used in children and adolescents under 25 years of age (see section 2).

Administration method
Oral use.
Swallow the entire capsule with an adequate amount of liquid (preferably a glass of water) or with a small low-protein meal (e.g., biscuits, crackers, or similar).

Treatment duration
Your doctor will inform you how long you should take Xevoben XR for the treatment of restless legs syndrome. Capsules are usually taken for a long time. Your doctor will regularly assess whether continued treatment with Xevoben XR is necessary.

If you feel the medicine's effect is too weak or too strong, consult your doctor or pharmacist.

Use of a higher than recommended dose of Xevoben XR
If you accidentally take twice the single dose, this will not affect further treatment; continue with the prescribed regimen.
If you take a significantly higher dose of Xevoben XR, symptoms listed in section 4 "Possible side effects" may occur. If life-threatening symptoms occur, contact your nearest doctor immediately!
Treatment involves general overdose management procedures, with special attention to monitoring cardiovascular parameters.
If a significantly higher dose of the extended-release formulation is taken, symptoms may be delayed due to the later absorption of active substances from the gastrointestinal tract.
Additionally, in case of ingestion of the extended-release formulation, measures should be taken to prevent further absorption of the medicine.

Missed dose of Xevoben XR
In Parkinson's disease
Do not take a double dose to make up for a missed capsule. If you miss a dose of Xevoben XR only once, continue with the prescribed treatment regimen.
However, remember that Xevoben XR is effective only when taken according to the treatment regimen prescribed by your doctor.

In restless legs syndrome
Do not take a double dose to make up for a missed dose. If you miss a dose of Xevoben XR only once, continue with the prescribed treatment regimen.
However, remember that Xevoben XR is effective only when taken according to the treatment regimen prescribed by your doctor.

Stopping Xevoben XR
Consult your doctor if any adverse effects occur. Your doctor will discuss with you other available treatment options and whether alternative therapies are available.
Do not stop taking Xevoben XR on your own, as symptoms may return.
If you have any further questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone experiences them.
The frequency of adverse reactions during treatment with Xevoben XR is unknown.
Possible adverse reactions:

Nasopharyngitis, bronchitis, infections with fever.
Decreased number of platelets, white and red blood cells.
Reduced appetite.
Cognitive disturbances and behavioural disorders following intake of doses higher than recommended for Xevoben XR (see section 2).
Confusional state, pathologically lowered mood (depression), which may be one of the clinical symptoms of Parkinson's disease or restless legs syndrome (see section 2, "Advice for people around the patient"), inner restlessness, anxiety, sensory hallucinations, delusions, distorted sense of time.
The patient may experience inability to resist impulses, urges or compulsions to perform actions that may be harmful to the patient or others, which may include:
gambling addiction, despite serious personal or family consequences,
altered or increased sexual interest and behaviour of significance to the patient or others, e.g. activities related to increased sexual drive,
compulsive, uncontrolled spending or compulsive buying,
binge eating (consuming large amounts of food in a short time) or compulsive eating (eating more food than normal and more than needed to satisfy hunger).

You should inform the doctor if the patient shows any of these behaviours, so that ways of managing or reducing these symptoms can be discussed.

Loss of taste sensation, taste disturbances, involuntary movements resulting from long-term treatment and (or) high doses of the medicine (see section 2), fatigue, excessive daytime tiredness, sudden sleep attacks (see section 2, "Warnings and precautions"), dizziness, headache, dry mouth.
Irregular heart rhythm.
Low blood pressure causing dizziness and fainting (see section 2).
Nausea, vomiting, diarrhoea, especially at the beginning of treatment (see section 2), change in colour of saliva, tongue, teeth and oral mucosa.
Increased transaminase activity, increased alkaline phosphatase activity, increased gamma-glutamyltransferase activity.
Skin hypersensitivity reactions such as itching and rash.
Increased blood urea concentration, change in urine colour (urine usually becomes red-tinged and darkens upon standing).
Psychiatric disorders such as inner restlessness, anxiety, sleep disturbances, sensory hallucinations, delusions, distorted sense of time, especially in elderly patients or in patients with a history of predisposition to such disorders.

Additional adverse reactions in patients with Parkinson's disease

marked disturbances in motor coordination after prolonged treatment;
sleep disturbances.

Additional adverse reactions in patients with restless legs syndrome

worsening or shift of symptom onset to the afternoon or early evening with prolonged treatment and (or) high doses of the medicine (see section 3, heading "Warning");
sleep disturbances unrelated to restless legs syndrome.

Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions not listed
in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions
can be reported directly to the Department of Monitoring of Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Xevoben XR

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label or carton after:
EXP. The expiry date refers to the last day of the stated month.
There are no special requirements regarding the storage temperature of the medicine. Keep the bottle
tightly closed to protect it from moisture.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Xevoben XR contains

The active substances are levodopa and benserazide. One prolonged-release hard capsule contains 100 mg levodopa + 25 mg benserazide (in the form of hydrochloride).
Other components: capsule contents: hypromellose, hydrogenated vegetable oil (derived from cottonseed), calcium hydrogen phosphate, povidone K30, mannitol, talc, magnesium stearate.
Capsule shell: gelatin (E 141), titanium dioxide (E 171), yellow iron oxide (E 172), indigo carmine (E 132).

What Xevoben XR looks like and contents of the pack
Hard, opaque gelatin capsules of size "1" with a dark green cap and light blue body, filled with white to off-white fine powder.
Xevoben XR is available in orange, type III glass bottles with a PE cap containing a desiccant, packed in a cardboard box containing 20, 30, 50, 60 or 100 prolonged-release hard capsules.
Marketing Authorisation Holder
Farmak International Sp. z o.o.
ul. Koszykowa 65
00-667 Warsaw
tel.: +48 22 822 93 06
e-mail: [email protected]

Manufacturer/Importer
Farmak International Sp. z o.o.
ul. Chełmżyńska 249
04-458 Warsaw

This medicinal product is authorised in the Member States of the European Economic Area:
Poland: Xevoben XR