Pk-merz

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PK-MERZ (PK-MERZ®)

Composition:

Active substance: 1 tablet contains amantadine sulfate 100 mg;

Excipients:

Tablet core: lactose monohydrate, microcrystalline cellulose, potato starch, gelatin, povidone, sodium croscarmellose, talc, colloidal anhydrous silicon dioxide, magnesium stearate;

Tablet coating: talc, butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer (1:2:1), titanium dioxide (E 171), magnesium stearate, orange-yellow S (E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: orange-colored, round, biconvex, film-coated tablets with a score line on one side, odorless.

Pharmacotherapeutic group.

Antiparkinson agents. Dopaminergic agents. Adamantane derivatives. Amantadine.

ATC code N04BB01.

Pharmacological Properties

Pharmacodynamics

Amantadine has several pharmacological properties. It exerts an indirect agonist effect on striatal dopamine receptors. Animal studies have shown that amantadine increases extracellular dopamine concentration both by enhancing dopamine release and by blocking reuptake in presynaptic nerve cells. At therapeutic concentrations, amantadine inhibits NMDA receptor-mediated acetylcholine release and thus may exert an anticholinergic effect. Amantadine acts synergistically with L-dopa.

Pharmacokinetics

Amantadine is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Maximum plasma concentration is reached within 2–8 hours (tmax) after a single dose.

The highly soluble amantadine hydrochloride provides higher plasma concentrations than the less soluble amantadine sulfate, in which the peak plasma concentration (Cmax) occurs later than with the hydrochloride. A Cmax of 0.5 µg/mL is achieved after a single 250 mg oral dose of amantadine hydrochloride.

When administered at a dose of 200 mg/day, steady-state plasma concentrations are reached within 4–7 days, with plasma levels ranging from 400 to 900 ng/mL. After administration of 100 mg amantadine sulfate, Cmax is 0.15 µg/mL.

The total absorbed amount of active substance (AUC) is identical for both amantadine salts.

Plasma clearance has been determined to be equivalent to renal clearance and averages 17.7 ± 10 L/h in healthy adult volunteers. The volume of distribution (4.2 ± 1.9 L/kg) depends on age and is approximately 6 L/kg in adults.

The elimination half-life ranges from 10 to 30 hours, averaging 15 hours, and depends significantly on patient age. In elderly men (62–72 years), the half-life is 30 hours. In patients with renal impairment, the terminal plasma half-life may be considerably prolonged (up to 68 ± 10 hours).

Amantadine is approximately 67% bound to plasma proteins (in vitro), with about 33% remaining unbound in plasma. It crosses the blood-brain barrier via saturable transport systems.

It is excreted in urine almost entirely unchanged (90% of a single dose); a small amount is excreted in feces.

Amantadine has low dialyzability—approximately 5% removed per dialysis session.

Amantadine is not metabolized in the human body.

Clinical characteristics.

Indications.

Parkinson's disease: treatment of symptoms of Parkinson's disease such as rigidity, tremor, hypokinesia, and akinesia.

Extrapyramidal side effects of neuroleptics and other medicinal products: early dyskinesia, akathisia, and parkinsonism.

Contraindications.

The medicinal product must not be used in patients:

• with hypersensitivity to amantadine, orange-yellow S (E 110), or any other component of the product;
• with decompensated heart failure (NYHA class IV according to the classification developed by the New York Heart Association);
• with cardiomyopathy and myocarditis;
• with second- or third-degree atrioventricular block;
• with bradycardia (less than 55 beats/min);
• with prolonged QT interval (QTc > 420 ms according to Bazett's formula) or with prominent U-waves, or with congenital QT syndrome in family history;
• with severe ventricular arrhythmia, including chaotic polymorphic ventricular tachycardia;
• receiving concomitant treatment with budipine or other medicinal products that prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction");
• with reduced blood levels of potassium or magnesium;
• with epilepsy and other seizure disorders;
• with severe renal impairment;
• with peptic ulcer disease.

Special precautions.

Patients who are concurrently taking neuroleptics and the medicinal product PK-Merc are at risk of developing neuroleptic malignant syndrome if treatment with PK-Merc is suddenly discontinued.

Toxicity may occur in patients with renal impairment.

Extreme caution is required when prescribing the product to patients with organic brain syndrome or patients prone to seizures, as seizures may occur and pre-existing symptoms may be exacerbated (see sections "Dosage and administration" and "Side effects").

Patients with cardiovascular disorders require medical supervision during treatment with PK-Merc.

In patients with Parkinson's disease, symptoms such as arterial hypotension, increased salivation, increased sweating, elevated body temperature, heat retention, edema, and depression are frequently observed. During treatment of such patients, special attention must be paid to adverse reactions and interactions of PK-Merc with other medicinal products.

An ophthalmological examination is required if symptoms of visual acuity loss or blurred vision occur, in order to rule out possible corneal edema. If corneal edema is diagnosed, PK-Merc must be discontinued. Corneal edema caused by PK-Merc usually resolves within one month after discontinuation of treatment.

Patients should inform their physician if they experience difficulty with urination.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of amantadine with other medicinal products that cause QT interval prolongation is contraindicated. These include:

• certain class IA antiarrhythmics (e.g., quinidine, disopyramide, procainamide) and class III (e.g., amiodarone, sotalol);
• certain neuroleptics (e.g., thioridazine, chlorpromazine, haloperidol, pimozide);
• certain tricyclic and tetracyclic antidepressants (e.g., amitriptyline);
• certain antihistamines (e.g., astemizole, terfenadine);
• certain macrolide antibiotics (e.g., erythromycin, clarithromycin);
• certain inhibitors of helicase (e.g., sparfloxacin);
• azole antifungals and other medicinal products such as budipine, halofantrine, cotrimoxazole, pentamidine, cisapride, and bepridil.

This list is not exhaustive. Before starting concomitant treatment with other medicinal products together with PK-Merc, the instructions for medical use must be carefully read regarding possible interactions of these medicinal products with amantadine, which may lead to QT interval prolongation.

The product may be used in combination with other antiparkinsonian agents. To avoid adverse effects (such as psychotic reactions), the dose of other agents or their combinations should be reduced.

No specific studies on the interaction of PK-Merc with other antiparkinsonian agents (e.g., levodopa, bromocriptine, trihexyphenidyl) or memantine have been conducted (refer to section "Side effects").

Concomitant use of PK-Merc with other medicinal products may result in the following interactions.

Anticholinergic agents. Enhanced adverse effects (confusion and hallucinations) of anticholinergic agents (e.g., trihexyphenidyl, benztropine, scopolamine, biperiden, orphenadrine, etc.).

Central nervous system (CNS) direct-acting sympathomimetics. Enhanced primary effect of amantadine.

Alcohol. Reduced alcohol tolerance.

Levodopa (antiparkinsonian agent). Mutual enhancement of therapeutic effect. Therefore, levodopa may be prescribed concomitantly with PK-Merc.

Memantine (anti-dementia agent). Memantine may enhance the effect and adverse effects of PK-Merc (see section "Special precautions for use"), therefore concomitant use with memantine should be avoided.

Diuretics. Concomitant use of diuretics such as triamterene/hydrochlorothiazide may lead to reduced plasma clearance of amantadine, resulting in toxic plasma concentrations. Therefore, concomitant use of this combination should be avoided.

Special precautions for use.

Special caution is required when administering the drug to patients:

• with psychoses;
• with impaired liver function;
• with thyrotoxicosis;
• with recurrent eczema;
• with prostatic hypertrophy;
• with narrow-angle glaucoma;
• with renal impairment (risk of amantadine accumulation due to impaired renal filtration; see sections "Dosage and administration" and "Special precautions for use");
• with agitation or confusion;
• with a history of delirium syndrome or exogenous psychosis;
• who are concurrently using memantine (see section "Interaction with other medicinal products and other types of interactions");
• who are concurrently using medicinal products affecting the central nervous system (see section "Interaction with other medicinal products and other types of interactions").

An ECG (50 mm/s) with manual determination of QT interval corrected for heart rate (QTc) according to Bazett should be performed before initiation of treatment and at 1 and 3 weeks after starting therapy. An ECG should also be performed prior to any subsequent dose increase and 2 weeks after such increase. Thereafter, ECG monitoring should be performed at least once a year. Treatment must not be initiated or should be discontinued if the baseline QTc value exceeds 420 ms, if QT interval increases by more than 60 ms during treatment, if QTc exceeds 480 ms, or if U-waves are observed on ECG.

Patients at risk of electrolyte imbalance due to, for example, diuretic therapy, frequent vomiting and/or diarrhea, patients receiving insulin during crisis situations, and patients with renal or anorexia-related disorders require laboratory monitoring and appropriate electrolyte replacement, especially potassium and magnesium.

If symptoms such as rapid heartbeat, dizziness, or fainting occur, treatment with PC-Merz must be discontinued immediately, and the patient should be observed for 24 hours for QT interval prolongation. If QT prolongation is not observed, treatment may be resumed, taking into account contraindications and interactions.

In patients with cardiac pacemakers, accurate determination of QT interval is not possible; therefore, the decision to use PC-Merz should be made individually after consultation with a cardiologist.

Additional use of amantadine for prevention and treatment of influenza A virus infection is not recommended due to the risk of overdose.

Amantadine treatment must not be stopped abruptly, as this may lead to worsening of Parkinson's disease, symptoms characteristic of neuroleptic malignant syndrome, and development of cognitive disorders such as catatonia, confusion, disorientation, deterioration of mental status, and delirium. Abrupt discontinuation of amantadine should be avoided in patients concurrently receiving neuroleptics due to the risk of neuroleptic-induced catatonia.

Suicidal ideation and suicide attempts have been reported in patients receiving amantadine. To prevent the emergence of suicidal thoughts and intentions, the drug should be prescribed at the lowest effective doses.

Peripheral edema may occur in some patients during prolonged use of the drug. This should be considered in patients with chronic heart failure.

The drug is contraindicated in patients with closed-angle glaucoma.

The colorant Orange-Yellow S (E 110) may cause allergic reactions.

The drug contains lactose and therefore should not be administered to patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Amantadine is contraindicated in pregnant women and women planning pregnancy.

The drug is contraindicated during breastfeeding, as it passes into breast milk. If treatment with the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Due to possible adverse reactions affecting the central nervous system, it is recommended to refrain from driving vehicles or operating machinery during treatment with this drug.

Dosage and Administration

The tablets should be taken with a small amount of liquid, preferably in the morning and during the day. The last daily dose should not be taken after 4:00 PM.

Single and Daily Doses

To prevent the potentially life-threatening adverse effect – polymorphic ventricular tachycardia – the above-mentioned warnings and contraindications must be observed.

Treatment of patients with Parkinson's syndrome and drug-induced movement disorders should be initiated gradually, with dosage adjustments based on therapeutic response.

Treatment should begin with an initial dose of 1 tablet (100 mg of amantadine sulfate) once daily for the first 4–7 days, followed by a weekly increase of 1 tablet per day until the effective therapeutic dose is reached.

The usual effective dose ranges from 1–3 tablets twice daily (200–600 mg of amantadine sulfate).

In elderly patients, particularly those with agitation, confusion, or delirium syndromes, a daily dose of 100 mg (1 tablet) is recommended. If this dose is ineffective, it may be cautiously increased under medical supervision to 200 mg daily.

When used in combination with other antiparkinsonian agents, the dosage should be individually adjusted.

For patients previously treated with amantadine, especially with amantadine sulfate injection solution, the initial oral dose should be higher.

In cases of acute worsening of parkinsonian symptoms during akinetic crisis, administration of amantadine sulfate solution for injection is required.

Patients with Renal Impairment

Dosages for patients with renal impairment must be adjusted according to glomerular filtration rate (GFR), as shown in the table:

* Achieved by taking alternately 1 tablet and 2 tablets of 100 mg amantadine sulfate.

Glomerular filtration rate (GFR) in men can be calculated using the following formula:

Clcr = (140 – age) × body weight,

72 × creatinine

where

Clcr – creatinine clearance in mL/min, and

creatinine – serum creatinine in mg/100 mL.

The creatinine clearance calculated by this formula (the corresponding value for women is approximately 85% of this value) can be equated to insulin clearance for determining GFR (120 mL/min for adults).

Amantadine is poorly dialyzed (approximately 5%).

Duration of treatment depends on the nature and severity of the disease and is determined by the physician. Patients must not discontinue treatment on their own.

Abrupt discontinuation of the drug should be avoided, as it may lead to exacerbation of extrapyramidal symptoms in patients with Parkinson's disease, including akinetic crisis; withdrawal effects may also manifest as delirium.

Children.

Experience with the use of the medicinal product in children is insufficient; therefore, it is not administered to this age group.

Overdose.

Multiple intoxications should always be considered, for example, ingestion of more than one drug for suicidal purposes.

Symptoms: Acute intoxication is characterized by nausea, vomiting, excessive excitation, tremor, ataxia, blurred vision, lethargy, depression, dysarthria, and convulsions; one case of cardiac arrhythmia has been reported. Neuromuscular disturbances, hyperreflexia, motor restlessness, extrapyramidal symptoms, torsional spasms, mydriasis, dysphagia, confusion, disorientation, delirium, myoclonus, dry mouth, hyperventilation, pulmonary edema, respiratory failure, respiratory distress syndrome, arterial hypertension, tachycardia, angina attack, cardiac arrest.

Renal function impairment may occur, including increased blood urea nitrogen and decreased creatinine clearance, urinary retention.

Acute toxic psychosis characterized by confusion with visual hallucinations, sometimes including coma and myoclonus, has been observed after concomitant intake of amantadine and other antiparkinsonian agents.

Treatment. No specific recommendations exist. There is no known antidote. In case of intoxication with the drug PK-Merz, induce vomiting and/or perform gastric lavage. In life-threatening intoxication, resuscitation measures are required. Therapeutic measures should be taken, including fluid administration and urinary acidification to accelerate elimination of the substance, sedation, anticonvulsant and antiarrhythmic measures.

For treatment of the neurotoxic symptoms described above, intravenous administration of physostigmine at a dose of 1–2 mg every 2 hours for adults and 2 × 0.5 mg at 5–10 minute intervals up to a maximum dose of 2 mg for children may be used.

Due to the low dialyzability of amantadine (5%), hemodialysis is not recommended.

Particular close monitoring is recommended for patients at risk of QT interval prolongation and development of chaotic polymorphic ventricular tachycardia, for example due to electrolyte imbalance (particularly hypokalemia and hypomagnesemia) or risk of bradycardia.

Side effects.

Side effects are classified by frequency:

From the nervous system side:

Common: motor disorders.

Uncommon: dizziness, orthostatic disturbances.

Rare: blurred vision.

Very rare: epileptic seizures, usually after treatment with doses exceeding the recommended ones; symptoms of myoclonus and peripheral neuropathy; anxiety, headache, somnolence, insomnia, weakness, fever, ataxia, slurred speech, impaired concentration, irritability, depression, myalgia, paresthesia, confusion, disorientation, tremor, dyskinesia, stupor, suicidal thoughts and ideation, malignant neuroleptic syndrome, delirium, hypomanic or manic state, hallucinations, nightmares.

From the mental side:

Common: sleep disturbances, motor and mental agitation.

In patients (particularly elderly) predisposed to psychiatric disorders, paranoid exogenous psychoses accompanied by visual hallucinations may occur. Such adverse effects may occur more frequently when tablets are taken in combination with other antiparkinsonian agents (such as levodopa, bromocriptine) or memantine.

From the kidneys and urinary system side:

Common: urinary retention in patients with prostate hyperplasia, urinary incontinence, changes in libido.

From the skin and subcutaneous tissue side:

Very rare: increased photosensitivity, skin rashes, pruritus, excessive sweating, eczematous dermatitis.

Common: "livedo reticularis" (mottled skin), with edema in the lower leg and ankle joint area.

From the gastrointestinal tract side:

Uncommon: anorexia, vomiting, constipation, diarrhea, reversible increase in liver enzyme activity.

Common: nausea, dry mouth.

From the cardiac side:

Very rare: cardiac arrhythmia (ventricular tachycardia, ventricular fibrillation, chaotic polymorphic ventricular tachycardia, and QT interval prolongation), orthostatic hypotension, tachycardia, peripheral edema, heart failure. Most of these reactions were caused by overdose, concomitant use of certain medications, or other factors (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Cardiac arrhythmia with tachycardia.

From the vascular system side:

Common: orthostatic dysregulation.

From the eye side:

Rare: blurred vision*.

Very rare: temporary loss of vision*, increased light sensitivity, corneal lesions (punctate subepithelial opacities, possibly associated with superficial punctate keratitis), corneal epithelial edema, decreased visual acuity, oculogyric crises, mydriasis.

Unknown: corneal edema, which resolves after discontinuation of treatment.

From the blood and lymphatic system side:

Very rare: hematological adverse reactions such as leukopenia and thrombocytopenia.

From the musculoskeletal and connective tissue side: rhabdomyolysis may occur. Patients should be carefully monitored. If symptoms such as myalgia, feelings of weakness, elevated levels of creatine kinase (creatine phosphokinase), or increased myoglobin levels in blood and urine are observed, the use of this medicinal product should be discontinued and appropriate measures taken. In addition, caution is advised due to the potential risk of acute renal failure as a consequence of rhabdomyolysis.

*An ophthalmological examination should be performed as soon as symptoms of decreased visual acuity or blurred vision appear, in order to rule out possible corneal edema (see section "Special precautions").

Shelf life. 5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 tablets per blister; 3 or 9 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Merz Pharma GmbH & Co. KGaA.

Manufacturer's address and place of business.

Ludwigstrasse 22, 64354 Reinheim, Germany.