Pk-merz

Overdose

Deaths have been reported from overdose with PK-Merz (amantadine hydrochloride). The lowest reported acute lethal dose was 1 gram. Because some patients have attempted suicide by overdosing with amantadine, prescriptions should be written for the smallest quantity consistent with good patient management.

Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome - ARDS) have been reported; renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.

There is no specific antidote for an overdose of PK-Merz (amantadine hydrochloride). However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg doses in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported to be effective in the control of central nervous system toxicity caused by amantadine hydrochloride. For acute overdosing, general supportive measures should be employed along with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary, given intravenously. The pH of the urine has been reported to influence the excretion rate of PK-Merz (amantadine hydrochloride). Since the excretion rate of PK-Merz (amantadine hydrochloride) increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. The blood pressure, pulse, respiration and temperature should be monitored. The patient should be observed for hyperactivity and convulsions; if required, sedation, and anticonvulsant therapy should be administered. The patient should be observed for the possible development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and antihypotensive therapy should be given. Electrocardiographic monitoring may be required after ingestion, since malignant tachyarrhythmias can appear after overdose.

Care should be exercised when administering adrenergic agents, such as isoproterenol, to patients with a PK-Merz (amantadine hydrochloride) overdose, since the dopaminergic activity of PK-Merz (amantadine hydrochloride) has been reported to induce malignant arrhythmias.

The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of recent voiding, catheterization should be done.

Undesirable effects

The adverse reactions reported most frequently at the recommended dose of PK-Merz (amantadine hydrochloride) (5-10%) are: nausea, dizziness (lightheadedness), and insomnia.

Less frequently (1-5%) reported adverse reactions are: depression, anxiety and irritability, hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality, agitation, dry nose, diarrhea and fatigue.

Infrequently (0.1-1%) occurring adverse reactions are: congestive heart failure, psychosis, urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking abnormality, amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance, including punctate subepithelial or other corneal opacity, corneal edema, decreased visual acuity, sensitivity to light, and optic nerve palsy.

Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia, neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal ideation (see WARNINGS).

Other adverse reactions reported during postmarketing experience with PK-Merz (amantadine hydrochloride) usage include:

coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech;

cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia;

acute respiratory failure, pulmonary edema, and tachypnea;

dysphagia;

leukocytosis; agranulocytosis

keratitis and mydriasis;

pruritus and diaphoresis;

neuroleptic malignant syndrome (see WARNINGS), allergic reactions including anaphylactic reactions, edema, fever, pathological gambling, increased libido including hypersexuality, and impulse control symptoms.

elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and SGPT.

Pharmacodynamic properties

The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.

Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine required to inhibit by 50% the growth of virus (ED50) in tissue culture vary greatly (from 0.1 µg/mL to 25.0 µg/mL) depending upon the assay protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of 100 µg/mL.

Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative relationship between the in vitro sensitivity of influenza A variants to amantadine and the clinical response to therapy has not been established.

The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that PK-Merz (amantadine hydrochloride) may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (Ki = 10µM). Although amantadine has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation.

Special warnings and precautions for use

Deaths have been reported from overdose with PK-Merz (amantadine hydrochloride). The lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension (see OVERDOSAGE).

Suicide attempts, some of which have been fatal, have been reported in patients treated with PK-Merz (amantadine hydrochloride) , many of whom received short courses for influenza treatment or prophylaxis. The incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood. Suicide attempts and suicidal ideation have been reported in patients with and without prior history of psychiatric illness. PK-Merz (amantadine hydrochloride) can exacerbate mental problems in patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide may exhibit abnormal mental states which include disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, and somnolence or insomnia. Because of the possibility of serious adverse effects, caution should be observed when prescribing PK-Merz (amantadine hydrochloride) to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the benefit of treatment.

Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased seizure activity.

Patients receiving PK-Merz (amantadine hydrochloride) who note central nervous system effects or blurring of vision should be cautioned against driving or working in situations where alertness and adequate motor coordination are important.

Patients with a history of congestive heart failure or peripheral edema should be followed closely as there are patients who developed congestive heart failure while receiving PK-Merz (amantadine hydrochloride).

Patients with Parkinson's disease improving on PK-Merz (amantadine hydrochloride) should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis.

Because PK-Merz (amantadine hydrochloride) has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma.

PK-Merz (amantadine hydrochloride) should not be discontinued abruptly in patients with Parkinson's disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of PK-Merz (amantadine hydrochloride) should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.

Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of PK-Merz (amantadine hydrochloride) therapy. Therefore, patients should be observed carefully when the dosage of PK-Merz (amantadine hydrochloride) is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin.

The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.

Because PK-Merz (amantadine hydrochloride) is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of PK-Merz (amantadine hydrochloride) should be reduced in patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE AND ADMINISTRATION; Dosage for Impaired Renal Function).

Care should be exercised when administering PK-Merz (amantadine hydrochloride) to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving PK-Merz (amantadine hydrochloride) , though a specific relationship between the drug and such changes has not been established.

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using PK-Merz (amantadine hydrochloride) for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

The dose of PK-Merz (amantadine hydrochloride) may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering PK-Merz (amantadine hydrochloride) to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. PK-Merz (amantadine hydrochloride) has not been shown to prevent such complications.

Long-term in vivo animal studies designed to evaluate the carcinogenic potential of PK-Merz (amantadine hydrochloride) have not been performed. In several in vitro assays for gene mutation, PK-Merz (amantadine hydrochloride) did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract. Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140-550 mg/kg; estimated human equivalent doses of 11.7-45.8 mg/kg based on body surface area conversion).

The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, PK-Merz (amantadine hydrochloride) at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m2 basis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis); intermediate doses were not tested.

Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle.

The effect of amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7-14 of gestation, PK-Merz (amantadine hydrochloride) produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in which females were dosed on Days 7-14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a mg/m2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2 basis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well-controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy. PK-Merz (amantadine hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

PK-Merz (amantadine hydrochloride) is excreted in human milk. Use is not recommended in nursing mothers.

The safety and efficacy of PK-Merz (amantadine hydrochloride) in newborn infants and infants below the age of 1 year have not been established.

Because PK-Merz (amantadine hydrochloride) is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of PK-Merz (amantadine hydrochloride) should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of PK-Merz (amantadine hydrochloride) may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION).