Symmetrel Information
Symmetrel (Amantadine) Description
Symmetrel (Amantadine) (Amantadine Hydrochloride, USP) is designated generically as amantadine hydrochloride and chemically as 1-adamantanamine hydrochloride.
Amantadine hydrochloride is a stable white or nearly white crystalline powder, freely soluble in water and soluble in alcohol and in chloroform.
Amantadine hydrochloride has pharmacological actions as both an anti-Parkinson and an antiviral drug.
Symmetrel (Amantadine) is available in tablets and syrup.
Each tablet intended for oral administration contains 100 mg amantadine hydrochloride and has the following inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6.
Symmetrel (Amantadine) syrup contains 50 mg of amantadine hydrochloride per 5 mL and has the following inactive ingredients: artificial raspberry flavor, citric acid, methylparaben, propylparaben, and sorbitol solution.
Symmetrel (Amantadine) Clinical Pharmacology
Symmetrel (Amantadine) is well absorbed orally. Maximum plasma concentrations are directly related to dose for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in maximum plasma concentrations. It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5-15% of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of amantadine. Acetylamantadine was not detected in the plasma of the remaining seven volunteers. The contribution of this metabolite to efficacy or toxicity is not known.
There appears to be a relationship between plasma amantadine concentrations and toxicity. As concentration increases, toxicity seems to be more prevalent, however, absolute values of amantadine concentrations associated with adverse effects have not been fully defined.
Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD maximum plasma concentration was 0.22 ± 0.03μg/mL (range: 0.18 to 0.32 μg/mL). The time to peak concentration was 3.3 ± 1.5 hours (range: 1.5 to 8.0 hours). The apparent oral clearance was 0.28 ± 0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25 hours). Across other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to 31 hours) in 19 healthy volunteers.
After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers, the mean ± SD maximum plasma concentration C was 0.24 ± 0.04 μg/mL and ranged from 0.18 to 0.28μg/mL. After 15 days of amantadine 100 mg b.i.d., the C was 0.47 ± 0.11 μg/mL in four of the five volunteers. The administration of amantadine tablets as a 200 mg single dose to 6 healthy subjects resulted in a C of 0.51 ± 0.14 μg/mL. Across studies, the time to C (T) averaged about 2 to 4 hours.
Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg intravenous doses of amantadine to 15 healthy volunteers.
In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma clearance was 0.79 ± 0.17 (mean ± SD).
The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal mucus at mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 μg/g at 1, 4, and 8 hours after dosing, respectively. These concentrations represented 31 ± 33%, 59 ± 61%, and 95 ± 86% of the corresponding plasma amantadine concentrations. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 μg/mL. Following the administration of amantadine 100 mg as a single dose, the mean ± SD red blood cell to plasma ratio ranged from 2.7 ± 0.5 in 6 healthy subjects to 1.4 ± 0.2 in 8 patients with renal insufficiency.
The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased in healthy elderly individuals age 60 and older. After single dose administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma clearance of amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life was 29 ± 7 hours (range 20 to 41 hours). Whether these changes are due to decline in renal function or other age related factors is not known.
In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for body mass index, was 1.5 fold higher in males compared to females (p
Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly reduced in adult patients with renal insufficiency. The elimination half-life increases two to three fold or greater when creatinine clearance is less than 40 mL/min/1.73 m and averages eight days in patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts by hemodialysis.
The pH of the urine has been reported to influence the excretion rate of Symmetrel (Amantadine) . Since the excretion rate of Symmetrel (Amantadine) increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body.
Symmetrel (Amantadine) Indications And Usage
Symmetrel (Amantadine) is indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Symmetrel (Amantadine) is also indicated in the treatment of parkinsonism and drug-induced extrapyramidal reactions.
Symmetrel (Amantadine) is also indicated in the treatment of uncomplicated respiratory tract illness caused by influenza A virus strains especially when administered early in the course of illness. There are no well-controlled clinical studies demonstrating that treatment with Symmetrel (Amantadine) will avoid the development of influenza A virus pneumonitis or other complications in high risk patients. There is no clinical evidence indicating that Symmetrel (Amantadine) is effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains.
The following points should be considered before initiating treatment or prophylaxis with Symmetrel (Amantadine) :
Symmetrel (Amantadine) Contraindications
Symmetrel (Amantadine) is contraindicated in patients with known hypersensitivity to amantadine hydrochloride or to any of the other ingredients in Symmetrel (Amantadine) .
Symmetrel (Amantadine) Warnings
Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased seizure activity.
Patients receiving Symmetrel (Amantadine) 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 Symmetrel (Amantadine) .
Patients with Parkinson’s disease improving on Symmetrel (Amantadine) should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis.
Because Symmetrel (Amantadine) has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma.
Symmetrel (Amantadine) Precautions
Symmetrel (Amantadine) 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 Symmetrel (Amantadine) 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 Symmetrel (Amantadine) therapy. Therefore, patients should be observed carefully when the dosage of Symmetrel (Amantadine) 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.
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 Symmetrel (Amantadine) for indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
The dose of Symmetrel (Amantadine) may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering Symmetrel (Amantadine) 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. Symmetrel (Amantadine) has not been shown to prevent such complications.
Patients should be advised of the following information:
Blurry vision and/or impaired mental acuity may occur.
Gradually increase physical activity as the symptoms of Parkinson’s disease improve.
Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness and orthostatic hypotension.
Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician.
Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur.
Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician.
Consult physician before discontinuing medication.
Seek medical attention immediately if it is suspected that an overdose of medication has been taken.
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease, including Symmetrel (Amantadine) . Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Symmetrel (Amantadine) . Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Symmetrel (Amantadine) . Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Symmetrel (Amantadine) .
Careful observation is required when Symmetrel (Amantadine) is administered concurrently with central nervous system stimulants.
Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine.
Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson’s disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine concentration in a 61-year-old man receiving Symmetrel (Amantadine) (Amantadine Hydrochloride, USP) 100 mg TID for Parkinson’s disease. It is not known which of the components of Dyazide contributed to the observation or if related drugs produce a similar response.
Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%.
The concurrent use of Symmetrel (Amantadine) with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of Symmetrel (Amantadine) , unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of Symmetrel (Amantadine) .
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, Symmetrel (Amantadine) 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 fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle.
Symmetrel (Amantadine) Adverse Reactions
The adverse reactions reported most frequently at the recommended dose of Symmetrel (Amantadine) (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 ).
Other adverse reactions reported during postmarketing experience with Symmetrel (Amantadine) usage include:
Symmetrel (Amantadine) Overdosage
Deaths have been reported from overdose with Symmetrel (Amantadine) . 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 Symmetrel (Amantadine) . However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult at 1- to 2-hour intervals and 0.5 mg doses in a child 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 Symmetrel (Amantadine) . Since the excretion rate of Symmetrel (Amantadine) 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 Symmetrel (Amantadine) overdose, since the dopaminergic activity of Symmetrel (Amantadine) 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.
Symmetrel (Amantadine) Dosage And Administration
The dose of Symmetrel (Amantadine) (Amantadine Hydrochloride, USP) may need reduction in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function (see ).
Adult
The adult daily dosage of Symmetrel (Amantadine) is 200 mg; two 100 mg tablets (or four teaspoonfuls of syrup) as a single daily dose. The daily dosage may be split into one tablet of 100 mg (or two teaspoonfuls of syrup) twice a day. If central nervous system effects develop in once-a-day dosage, a split dosage schedule may reduce such complaints. In persons 65 years of age or older, the daily dosage of Symmetrel (Amantadine) is 100 mg.
A 100 mg daily dose has also been shown in experimental challenge studies to be effective as prophylaxis in healthy adults who are not at high risk for influenza-related complications. However, it has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily dose for prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute influenza illness. In recent clinical trials, the incidence of central nervous system (CNS) side effects associated with the 100 mg daily dose was at or near the level of placebo. The 100 mg dose is recommended for persons who have demonstrated intolerance to 200 mg of Symmetrel (Amantadine) daily because of CNS or other toxicities.
Pediatric Patients The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day), but not to exceed 150 mg per day.
9 yrs.-12 yrs. of age
Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or after contact with individuals with influenza A virus respiratory tract illness.
Symmetrel (Amantadine) should be continued daily for at least 10 days following a known exposure. If Symmetrel (Amantadine) is used chemoprophylactically in conjunction with inactivated influenza A virus vaccine until protective antibody responses develop, then it should be administered for 2 to 4 weeks after the vaccine has been given. When inactivated influenza A virus vaccine is unavailable or contraindicated, Symmetrel (Amantadine) should be administered for the duration of known influenza A in the community because of repeated and unknown exposure.
Treatment of influenza A virus illness should be started as soon as possible, preferably within 24 to 48 hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after the disappearance of signs and symptoms.
Adult
The usual dose of Symmetrel (Amantadine) is 100 mg twice a day when used alone. Symmetrel (Amantadine) has an onset of action usually within 48 hours.
The initial dose of Symmetrel (Amantadine) is 100 mg daily for patients with serious associated medical illnesses or who are receiving high doses of other antiparkinson drugs. After one to several weeks at 100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary.
Occasionally, patients whose responses are not optimal with Symmetrel (Amantadine) at 200 mg daily may benefit from an increase up to 400 mg daily in divided doses. However, such patients should be supervised closely by their physicians.
Patients initially deriving benefit from Symmetrel (Amantadine) not uncommonly experience a fall-off of effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg daily. Alternatively, temporary discontinuation of Symmetrel (Amantadine) for several weeks, followed by reinitiation of the drug, may result in regaining benefit in some patients. A decision to use other antiparkinson drugs may be necessary.
Dosage for Concomitant Therapy
Some patients who do not respond to anticholinergic antiparkinson drugs may respond to Symmetrel (Amantadine) . When Symmetrel (Amantadine) or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit.
When Symmetrel (Amantadine) and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits. Symmetrel (Amantadine) should be held constant at 100 mg daily or twice daily while the daily dose of levodopa is gradually increased to optimal benefit.
When Symmetrel (Amantadine) is added to optimal well-tolerated doses of levodopa, additional benefit may result, including smoothing out the fluctuations in improvement which sometimes occur in patients on levodopa alone. Patients who require a reduction in their usual dose of levodopa because of development of side effects may possibly regain lost benefit with the addition of Symmetrel (Amantadine) .
Adult
The usual dose of Symmetrel (Amantadine) is 100 mg twice a day. Occasionally, patients whose responses are not optimal with Symmetrel (Amantadine) at 200 mg daily may benefit from an increase up to 300 mg daily in divided doses.
Depending upon creatinine clearance, the following dosage adjustments are recommended:
The recommended dosage for patients on hemodialysis is 200 mg every 7 days.
Symmetrel (Amantadine) How Supplied
Symmetrel (Amantadine) (Amantadine Hydrochloride, USP) is available in light orange, convex curved, triangular shaped 100 mg tablets with “Symmetrel (Amantadine) ” debossed on one side and plain on the other side as follows:
Bottles of 100 NDC 63481-108-70
As a clear, colorless syrup [each 5 mL (1 teaspoonful) contains 50 mg amantadine hydrochloride] in:
16 oz.(480 mL) bottles NDC63481-205-16
Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].
Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).
Symmetrel (Amantadine)
