Pc-merc

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PK-Merz (PК-Merz®)

Composition:

Active substance: amantadine sulfate;

1 vial (500 ml) contains amantadine sulfate 200 mg;

Excipients: water for injections, sodium chloride.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: colorless clear odorless solution.

Pharmacotherapeutic group.

Antiparkinson agents. ATC code N04B B01.

Pharmacological properties.

Pharmacodynamics.

Amantadine has various 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 thereby may exert an anticholinergic effect. Amantadine has a synergistic effect with L-dopa.

Pharmacokinetics.

Maximum plasma concentration is reached within 2–8 hours (tmax) after a single dose administration.

Amantadine hydrochloride, being more soluble, achieves higher plasma concentrations compared to the less soluble amantadine sulfate, for which peak plasma concentration (Cmax) occurs later than with hydrochloride. Cmax of 0.5 µg/mL is achieved after a single oral dose of 250 mg amantadine hydrochloride.

With administration of 200 mg/day, steady-state concentration is reached within 4–7 days, with plasma concentrations 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 salts of amantadine.

Plasma clearance has been determined to be identical to renal clearance and is 17.7 ± 10 L/hour in healthy adult volunteers.

The apparent volume of distribution (4.2 ± 1.9 L/kg) is age-dependent, reaching 6 L/kg in adults.

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

Following infusion of 200 mg amantadine sulfate, Cmax after 3 hours is 0.54 µg/mL. With treatment at a dose of 200 mg/day, average plasma concentration of 0.76 µg/mL is achieved at the end of infusion on day 6. Mean total clearance was calculated as 3.6 L/hour; plasma elimination half-life ranges from 7 to 23 hours, with a mean value of approximately 10 hours.

Amantadine is protein-bound in plasma by approximately 67% (in vitro); nearly 33% remains unbound in plasma. It penetrates the blood-brain barrier via saturable transport systems.

It is excreted in urine almost unchanged (90% of a single dose), with a minor amount excreted in feces.

Amantadine's dialyzability is low—approximately 5% per dialysis session.

Amantadine is not metabolized in the human body.

Clinical characteristics.

Indications.

• Intensive therapy and initial treatment of akinetic crisis in acute exacerbations of parkinsonism symptoms.
• For improving the ability to concentrate (vigilance) in post-comatose states of various etiologies under hospital conditions.

Contraindications.

• Hypersensitivity to amantadine or to any other components of the medicinal product;
• Decompensated heart failure (NYHA stage IV);
• Cardiomyopathy and myocarditis;
• Second- or third-degree atrioventricular block;
• Bradycardia (less than 55 beats/min);
• Prolonged QT interval (Bazett QTc >420 ms) or with prominent U-waves, or congenital QT syndrome in family history;
• Severe ventricular arrhythmia, including chaotic polymorphic ventricular tachycardia;
• Concomitant treatment with budipine or other medicinal products that prolong the QT interval (see section «Interaction with other medicinal products and other forms of interactions»);
• Low levels of potassium or magnesium in blood;
• Epilepsy and other seizure disorders;
• Severe renal impairment;
• Peptic ulcer disease.

Special precautions.

Patients who concurrently take neuroleptics and the medicinal product PK-Merz are at risk of developing neuroleptic malignant syndrome if PK-Merz is abruptly discontinued.

Toxicity may occur in patients with renal impairment.

Extreme caution is required when prescribing the medicinal product to patients with organic brain syndrome or those with epileptic seizures, as individual symptoms may be exacerbated.

Patients with known cardiovascular disorders should remain under continuous medical supervision during treatment with PK-Merz.

Patients with Parkinson’s disease often experience symptoms such as arterial hypotension, increased salivation, increased sweating, elevated body temperature, edema, and depression. For such patients, special attention should be paid to adverse reactions and interactions of PK-Merz with other medicinal products.

An ophthalmological examination is necessary as soon as symptoms of visual acuity loss or blurred vision appear, in order to exclude possible causes of corneal edema. If corneal edema is diagnosed, PK-Merz should be discontinued. Corneal edema caused by PK-Merz usually resolves after discontinuation of treatment within one month.

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

An infusion of 500 ml contains 77 mmol of sodium (1770 mg sodium). This should be taken into account for patients on a low-salt diet.

Interaction with other medicinal products and other forms of interactions.

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 antiarrhythmics (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 gyrase inhibitors (e.g., sparfloxacin);
• Azole antifungals and other medicinal products such as budipine, halofantrine, co-trimoxazole, pentamidine, cisapride, and bepridil.

Before starting concomitant use of other medicinal products with PK-Merz, the package leaflet should be carefully reviewed for possible interactions due to QT interval prolongation between drugs and amantadine. To avoid adverse reactions (such as psychotic reactions), the dose of other medicinal products or their combinations should be reduced.

No specific interaction studies have been conducted on the concomitant use of PK-Merz with other antiparkinsonian agents (e.g., levodopa, bromocriptine, trihexyphenidyl) or memantine (see section «Adverse reactions»).

Concomitant use of PK-Merz and any of the following medicinal product groups or active ingredients may lead to the following interactions:

Anticholinergic agents

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

Central nervous system (CNS) direct-acting sympathomimetics

Enhancement of the primary action of amantadine.

Alcohol

Reduced alcohol tolerance.

Levodopa (antiparkinsonian agent)

Mutual enhancement of therapeutic effect. Therefore, levodopa may be prescribed concomitantly with PK-Merz.

Memantine (agent for dementia)

Memantine may enhance the action and adverse effects of PK-Merz (see section «Special precautions»).

Other medicinal products

Concomitant use of diuretics such as triamterene/hydrochlorothiazide may reduce amantadine plasma clearance, leading to the formation of a toxic plasma concentration. Therefore, concomitant use of this combination should be avoided.

Special precautions for use.

Particular caution should be exercised when administering the drug to patients with:

• hepatic dysfunction;
• thyrotoxicosis;
• recurrent eczema;
• prostatic hypertrophy;
• narrow-angle glaucoma;
• renal impairment (of varying severity; there is a risk of amantadine accumulation due to impaired renal filtration (see also section «Dosage and method of administration»);
• agitation or confusion;
• history of delirium syndrome or exogenous psychosis;
• concomitant treatment with memantine (see section «Interaction with other medicinal products and other forms of interaction»);
• concomitant use with medicinal products affecting the central nervous system (CNS) (see section «Interaction with other medicinal products and other forms of interaction»).

An ECG (50 mm/s) with manual measurement of QT interval corrected for heart rate (QTc) using Bazett's formula should be performed before initiating treatment, and again at 1 and 3 weeks after starting treatment. This ECG should also be repeated before any subsequent dose increase and 2 weeks after such increase. Thereafter, ECG monitoring should be performed at least once a year. Treatment should not be initiated or should be discontinued if the baseline QTc exceeds 420 ms, if QT prolongation increases by more than 60 ms during treatment, if QTc exceeds 480 ms during treatment with PK-Merz, solution for infusion, or in patients with visible U-waves. Adhering to the above precautions and considering contraindications can help prevent life-threatening adverse effects.

Patients at risk of electrolyte imbalance—for example, due to diuretic therapy, frequent vomiting and/or diarrhea, patients receiving insulin during crisis situations, or patients with renal or anorexia-related disorders—should undergo evaluation and monitoring of laboratory parameters, and receive appropriate electrolyte supplementation, particularly potassium and magnesium.

If symptoms such as rapid heartbeat, dizziness, or fainting occur, treatment with PK-Merz must be immediately discontinued and the patient should be monitored 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 PK-Merz should be made individually after consultation with a cardiologist.

Peripheral edema may occur in some patients during prolonged treatment. This should be taken into account in individuals with chronic heart failure.

Amantadine treatment should 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 possible risk of neuroleptic-induced catatonia.

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

Additional administration of amantadine for prophylaxis and treatment of influenza A virus is not advisable and should be avoided due to the risk of overdose.

Use during pregnancy or breastfeeding.

If amantadine is prescribed to a woman of childbearing potential, she should be instructed to consult her physician immediately if pregnancy is suspected or anticipated.

There are no data on placental transfer of the drug. Data on amantadine use in pregnant women are lacking. There have been reports of individual cases of normal deliveries, but also pregnancy complications and five cases of congenital defects (cardiovascular defects, limb abnormalities). In animal studies, amantadine demonstrated embryotoxic and teratogenic effects. The potential risk in humans is unknown. Therefore, amantadine should be used during pregnancy only if clearly necessary. If therapy is administered during the first trimester, ultrasound examination should be performed.

PK-Merz passes into breast milk. If amantadine therapy is absolutely necessary during breastfeeding, the infant must be closely monitored for possible drug-related symptoms (skin rashes, urinary retention, vomiting), and breastfeeding should be discontinued.

Amantadine is contraindicated in pregnant women and in women planning pregnancy.

The drug is contraindicated during breastfeeding because it passes into breast milk. If treatment is necessary, breastfeeding must be discontinued.

Ability to influence reaction speed when driving or operating machinery.

An effect on the ability to concentrate and adapt cannot be ruled out, especially when combined with other drugs used in the treatment of Parkinson's syndrome. At the beginning of treatment, the ability to drive or operate machinery may be impaired due to the disease itself. This impairment may be further exacerbated by concomitant alcohol use.

Dosage and Administration.

Administer intravenously.

Treatment of patients with Parkinson's syndrome

In acute exacerbations of parkinsonian symptoms during akinetic crisis, an intravenous dose of 200 mg of amantadine sulfate should be administered 1–3 times daily. The infusion rate must not exceed 55 drops per minute, corresponding to an infusion time of approximately 3 hours.

Vigilance.

To improve vigilance in post-comatose states of various etiologies, treatment with a daily dose of 200 mg amantadine sulfate administered as a slow infusion (> 3 hours) may be performed initially for 3–5 days. Depending on the clinical picture, treatment may be prolonged, if possible, in oral form—up to 4 weeks at a dose of 200 mg amantadine sulfate per day.

Doses for patients with renal impairment.

Dosages for patients with renal impairment should be adjusted according to glomerular filtration rate (GFR), as shown in Table 1.

Table 1

* achieved by alternating administration of 100 mg and 200 mg of amantadine sulfate once each.

GFR can be approximately calculated using the following equation:

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 according to this formula applies exclusively to males (the corresponding value for females is 85% of this value) and can be equated to insulin clearance for determining GFR (120 mL/min for adults).

Amantadine is poorly dialyzed (approximately 5%).

The duration of treatment depends on the nature and severity of the disease and is determined by the physician. Patients should not discontinue treatment on their own.

Abrupt discontinuation of the drug should be avoided, as in patients with Parkinson's disease it may lead to worsening of extrapyramidal symptoms, which sometimes include akinetic crisis, and withdrawal effects may occasionally manifest as delirium.

Patients with reduced vigilance who continue treatment with tablets should not take the drug for longer than 4 weeks.

Children.

There are no data on the use of the drug in children; therefore, the drug should not be used in this age group.

Overdose.

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

Symptoms of overdose

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, dystonic spasms, dilated pupils, dysphagia, disorientation, 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.

An acute toxic psychosis in the form of confusion with visual hallucinations, sometimes including coma and myoclonus, has been observed after concomitant administration of amantadine and other antiparkinsonian drugs.

Treatment

There is no specific antidote or specific pharmacological treatment for overdose. In case of intoxication with the drug PK-Merz, additional intensive therapy is required. Therapeutic measures should include fluid administration and acidification of urine to accelerate elimination of the substance, possible sedation, anticonvulsant and antiarrhythmic measures (intravenous lidocaine).

For treatment of neurotoxic symptoms (such as those described above), intravenous administration of physostigmine at a dose of 1–2 mg every 2 hours in adults and 2 × 0.5 mg at 5–10 minute intervals up to a maximum dose of 2 mg in children may be attempted.

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

Close monitoring is recommended for patients predisposed to possible QT interval prolongation and factors contributing to the development of chaotic polymorphic ventricular tachycardia, such as electrolyte imbalances (particularly hypokalemia and hypomagnesemia) or bradycardia.

Adverse reactions.

The assessment of adverse effects is based on the following frequency indicators:

From the nervous system

Common: dizziness, motor disturbances.

Very rare: epileptic seizures, usually after treatment with doses exceeding the recommended ones; symptoms of myoclonia 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.

Psychiatric disorders

Common: sleep disturbances and psychomotor agitation.

In patients (particularly elderly patients) predisposed to psychiatric disorders, paranoid exogenous psychoses accompanied by visual hallucinations may occur. Such adverse reactions may occur more frequently when the drug is used concomitantly with other antiparkinsonian agents (e.g., levodopa, bromocriptine) or memantine.

Renal and urinary disorders

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

Disorders of the skin and subcutaneous tissue

Common: "livedo reticularis" accompanied by edema of the lower leg and ankle joint.

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

Gastrointestinal disorders

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

Cardiac disorders

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

Vascular disorders

Common: orthostatic dysregulation.

Eye disorders

Rare: blurred vision*.

Very rare: transient loss of vision*, increased photosensitivity, corneal lesions (subepithelial punctate opacities, which may be associated with superficial punctate keratitis), oculogyric crises, mydriasis.

Not known: corneal edema, which resolves after discontinuation of treatment.

*Ophthalmological examination is required as soon as symptoms of decreased visual acuity or blurred vision appear, in order to rule out possible causes of corneal edema (see section "Special precautions").

Blood and lymphatic system disorders

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

The above-mentioned adverse effects were reported less frequently after infusion therapy.

Immune system disorders

Very rare: anaphylactic reactions after infusion therapy.

Other: hypersensitivity reactions.

Shelf life.

5 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

500 ml of solution in a vial; 2 vials in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Merz Pharma GmbH & Co. KGaA.

Manufacturer's address and location of business operations.

Ludwigstrasse 22, 64354 Reinheim, Germany.