AMANTADINE: 5,135 Adverse Event Reports & Safety Profile

DESCRIPTION Amantadine hydrochloride is designated chemically as 1-adamantanamine hydrochloride. Its molecular weight is 187.7 with a molecular formula C 10 H 17 N.HCl. It has the following structural formula: Amantadine hydrochloride, USP is a white or almost white, crystalline powder, freely soluble in water, ethanol and methanol; soluble in chloroform; sparingly soluble in methylene chloride; practically insoluble in ether. Amantadine hydrochloride has pharmacological actions as both an anti-Parkinson and an antiviral drug. Each amantadine hydrochloride capsule, USP intended for oral administration contains 100 mg of amantadine hydrochloride, USP. In addition, each capsule contains the following inactive ingredients: crosscarmellose sodium, ethyl cellulose, FD&C blue #1, FD&C red #40, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate and titanium dioxide. Each capsule is printed with white pharmaceutical ink which contains potassium hydroxide, shellac and titanium dioxide. Meets USP Dissolution Test 2 figure

INDICATIONS AND USAGE Amantadine Hydrochloride Oral Solution USP is indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus.

Amantadine Hydrochloride Oral

Solution USP is also indicated in the treatment of parkinsonism and drug-induced extrapyramidal reactions. Influenza A Prophylaxis Amantadine Hydrochloride Oral Solution USP is indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection.

Because Amantadine Hydrochloride Oral

Solution USP does not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically related viruses. Following vaccination during an influenza A outbreak, Amantadine Hydrochloride Oral Solution USP prophylaxis should be considered for the 2- to 4-week time period required to develop an antibody response. Influenza A Treatment Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP will avoid the development of influenza A virus pneumonitis or other complications in high risk patients. There is no clinical evidence indicating that Amantadine Hydrochloride Oral Solution USP is effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A v irus strains. The following points should be considered before initiating treatment or prophylaxis with Amantadine Hydrochloride Oral Solution USP: Amantadine Hydrochloride Oral Solution USP is not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Amantadine Hydrochloride Oral Solution USP. Parkinson's Disease/Syndrome Amantadine Hydrochloride Oral Solution USP is indicated in the treatment of idiopathic Parkinson's disease (Paralysis Agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication. It is indicated in those elderly patients believed to develop parkinsonism in association with cerebral arteriosclerosis. In the treatment of Parkinson's disease, Amantadine Hydrochloride Oral Solution USP is less effective than levodopa,(-)-3-(3,4dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic antiparkinson drugs has not yet been established. Drug-Induced Extrapyramidal Reactions Amantadine Hydrochloride Oral Solution USP is indicated in the treatment of drug-induced extrapyramidal reactions. Although anticholinergic-type side effects have been noted with Amantadine Hydrochloride Oral Solution USP when used in patients with drug-induced extrapyramidal reactions, there is a lower incidence of these side effects than that observed with the anticholinergic antiparkinson drugs.

DOSAGE AND ADMINISTRATION The dose of Amantadine Hydrochloride Oral Solution USP (Amantadine Hydrochloride, USP) may need reduction in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function (see Dosage for Impaired Renal Function ). Dosage for Prophylaxis and Treatment of Uncomplicated Influenza A Virus Illness Adult The adult daily dosage of Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP daily because of CNS or other toxicities.

Pediatric Patients

1 yr.-9 yrs. of age 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 The total daily dose is 200 mg given as one tablet of 100 mg (or two teaspoonfuls of syrup) twice a day.

The

100 mg daily dose has not been studied in this pediatric population. Therefore, there are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily dose in this patient population. 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.

Amantadine Hydrochloride Oral

Solution USP should be continued daily for at least 10 days following a known exposure.

If Amantadine Hydrochloride Oral

Solution USP 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, Amantadine Hydrochloride Oral Solution USP 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. Dosage for Parkinsonism Adult The usual dose of Amantadine Hydrochloride Oral Solution USP is 100 mg twice a day when used alone.

Amantadine Hydrochloride Oral

Solution USP has an onset of action usually within 48 hours. The initial dose of Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP.

When Amantadine Hydrochloride Oral

Solution USP or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit.

When Amantadine Hydrochloride Oral

Solution USP and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits.

Amantadine Hydrochloride Oral

Solution USP should be held constant at 100 mg daily or twice daily while the daily dose of levodopa is gradually increased to optimal benefit.

When Amantadine Hydrochloride Oral

Solution USP 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 Amantadine Hydrochloride Oral Solution USP. Dosage for Drug-Induced Extrapyramidal Reactions Adult The usual dose of Amantadine Hydrochloride Oral Solution USP is 100 mg twice a day. Occasionally, patients whose responses are not optimal with Amantadine Hydrochloride Oral Solution USP at 200 mg daily may benefit from an increase up to 300 mg daily in divided doses. Dosage for Impaired Renal Function Depending upon creatinine clearance, the following dosage adjustments are recommended: CREATININE CLEARANCE DOSAGE Amantadine Hydrochloride Oral Solution USP (mL/min/1.73m 2 ) 30-50 200 mg 1 st day and 100 mg each day thereafter 15-29 200 mg 1 st day followed by 100 mg on alternate days <15 200 mg every 7 days The recommended dosage for patients on hemodialysis is 200 mg every 7 days.

GOCOVRI is contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m 2 ) [see Clinical Pharmacology ( 12.3 )]. GOCOVRI is contraindicated in patients with end-stage renal disease ( 4 )

REACTIONS The following serious adverse reactions are described in more detail elsewhere in the labeling: Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions ( 5.1 )] Suicidality and Depression [see Warnings and Precautions ( 5.2 )]

Hallucinations/Psychotic

Behavior [see Warnings and Precautions ( 5.3 )] Dizziness and Orthostatic Hypotension [see Warnings and Precautions ( 5.4 )] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions ( 5.5 )]

Corneal

Edema [see Warnings and Precautions ( 5.6 )]

Impulse Control/Compulsive

Behaviors [see Warnings and Precautions ( 5.7 )] The most commonly observed adverse reactions occurring at a frequency of >10% and greater than placebo were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Supernus Pharmaceuticals, Inc. at 1-833-223-2627 or FDA at 1-800-FDA-1088 or http://www/fda.gov/medwatch.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Placebo-Controlled Trials GOCOVRI was evaluated in two double-blind, placebo-controlled efficacy trials of similar design and population: Study 1 (123 patients) and Study 2 (75 patients) <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . The study population was approximately 56% male and 94% white, with a mean age of 65 years (age range from 34 years to 82 years). The mean duration of levodopa-induced dyskinesia was 4 years (range 0.1 to 14 years). Active treatment started at 137 mg once daily for one week, followed by a dose increase to 274 mg once daily. The treatment duration was 25 weeks for Study 1 and 13 weeks for Study 2. Of the 100 patients in the safety population described below, 39 patients were treated with GOCOVRI for 24 weeks. The safety data for these trials were pooled. The most common adverse reactions reported in &gt;10% of GOCOVRI-treated patients and more frequently than on placebo were: hallucinations, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. The overall rate of discontinuation because of adverse reactions for GOCOVRI-treated patients was 20%, compared to 8% for placebo-treated patients. Adverse reactions that led to treatment discontinuation in at least 2% of patients were hallucinations (8% GOCOVRI vs. 0% placebo), dry mouth (3% GOCOVRI vs. 0% placebo), peripheral edema (3% GOCOVRI vs. 0% placebo), blurred vision (GOCOVRI 3% vs. 0% placebo), postural dizziness and syncope (GOCOVRI 2% vs. 0% placebo), abnormal dreams (GOCOVRI 2% vs. 1% placebo), dysphagia (GOCOVRI 2% vs. 0% placebo), and gait disturbance (GOCOVRI 2% vs. 0% placebo).

Table

1: Adverse Reactions Reported for ≥3% of Patients Treated with 274 mg GOCOVRI in Study 1 and Study 2 (Pooled Analysis) a=Includes visual hallucinations and auditory hallucinations b=Includes anxiety and generalized anxiety c=Includes orthostatic hypotension, postural dizziness, syncope, presyncope, and hypotension d=The denominator is all male patients in the safety population randomized to GOCOVRI (n=54) or placebo (n=57)

Adverse

Reactions GOCOVRI 274 mg N=100 % Placebo N=98 % Psychiatric disorders Hallucinations a 21 3 Anxiety b 7 3 Insomnia 7 2 Depression/Depressed mood 6 1 Abnormal dreams 4 2 Confusional state 3 2 Nervous system disorders Dizziness 16 1 Headache 6 4 Dystonia 3 1 Gastrointestinal disorders Dry mouth 16 1 Constipation 13 3 Nausea 8 3 Vomiting 3 0 General disorders and administration site conditions Peripheral edema 16 1 Gait disturbance 3 0 Injury, poisoning and procedural complications Fall 13 7 Contusion 6 1 Infections and infestations Urinary tract infection 10 5 Skin and subcutaneous tissue disorders Livedo reticularis 6 0 Pigmentation disorder 3 0 Metabolism and nutrition disorders Decreased appetite 6 1 Vascular disorders Orthostatic hypotension c 13 1 Eye disorders Blurred vision 4 1 Cataract 3 1 Dry eye 3 0 Musculoskeletal and connective tissue disorders Joint swelling 3 0 Muscle spasms 3 0 Reproductive system and breast disorders Benign prostatic hyperplasia d 6 2 Respiratory, thoracic and mediastinal disorders Cough 3 0 Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and paranoia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. Difference in the Frequency of Adverse Reactions by Gender Adverse reactions reported more frequently in women treated with 274 mg of GOCOVRI (n=46), compared to men (n=54), were: dry mouth (22% women, 11% men), nausea (13% women, 4% men), livedo reticularis (13% women, 0% men), abnormal dreams (9% women, 0% men) and cataracts (7% women, 0% men). Men treated with 274 mg of GOCOVRI reported the following adverse reactions more frequently than women: dizziness (20% men, 11% women), peripheral edema (19% men, 11% women), anxiety (11% men, 2% women), orthostatic hypotension (7% men, 2% women) and gait disturbance (6% men, 0% women). Difference in the Frequency of Adverse Reactions by Age Hallucinations (visual or auditory) were reported in 31% of GOCOVRI-treated patients age 65 years and over (n=52), compared to 10% in patients below the age of 65 years (n=48). Falls were reported in 17% of GOCOVRI-treated patients age 65 and over, compared to 8% of patients below age 65. Orthostatic hypotension was reported in 8% of patients age 65 and over, compared to 2% of patients below age 65.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of GOCOVRI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System

Disorders: Seizure Vision: Corneal edema

AND PRECAUTIONS Falling Asleep During Activities of Daily Living : Advise patients prior to treatment; ordinarily discontinue if occurs ( 5.1 ) Suicidality and Depression : Monitor patients for depressed mood, depression, or suicidal ideation or behavior ( 5.2 )

Hallucinations/Psychotic

Behavior: Patients with major psychotic disorder should ordinarily not be treated with GOCOVRI; observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases ( 5.3 ) Dizziness and Orthostatic Hypotension : Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose ( 5.4 ) Withdrawal-Emergent Hyperpyrexia and Confusion : Avoid sudden discontinuation ( 5.5 )

Corneal

Edema : Monitor patients for new changes in vision, including blurred vision, with or without eye pain, or vision loss. Taper and discontinue if corneal edema occurs ( 5.6 )

Impulse Control/Compulsive

Behaviors : Ask patients about increased gambling urges, sexual urges, uncontrolled spending or other urges; consider dose reduction or discontinuation if occurs ( 5.7 )

5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated for Parkinson&apos;s disease have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported as adverse reactions in 4% of patients treated with GOCOVRI 274 mg and 1% for placebo. Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued. If a decision is made to continue GOCOVRI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living or daytime somnolence.

5.2 Suicidality and Depression In controlled clinical trials, suicidal ideation or suicide attempt was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients. Depression or depressed mood was reported in 6% of GOCOVRI-treated patients and 1% of placebo-treated patients. Confusional state was reported in 3% of GOCOVRI-treated patients and 2% of placebo-treated patients. Apathy was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients. Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

5.3 Hallucinations/Psychotic Behavior Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. In controlled trials, the incidence of patients who experienced visual hallucinations, auditory hallucinations, delusions, illusions, or paranoia was 25% in patients treated with GOCOVRI 274 mg, and 3% in placebo-treated patients. Hallucinations caused discontinuation of treatment in 8% of GOCOVRI-treated patients, and in 0% of placebo-treated patients. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation, and after dose increases.

5.4 Dizziness and Orthostatic Hypotension In controlled clinical trials, 29% of GOCOVRI-treated patients and 2% of placebo-treated patients experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension. In GOCOVRI-treated patients, 3% discontinued study treatment because of dizziness, postural dizziness, or syncope, compared to 0% of placebo-treated patients. Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Concomitant use of alcohol when using GOCOVRI is not recommended <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 )]</span>.

5.5 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson&apos;s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. It is recommended to avoid sudden discontinuation of GOCOVRI <span class="opacity-50 text-xs">[see Dosing Information ( 2.4 )]</span> .

5.6 Corneal Edema Corneal edema has been reported in patients taking amantadine. Symptoms include sudden onset of blurry vision, or progressive vision loss, with or without eye pain. Corneal involvement is usually bilateral. Onset can occur from a few weeks to several years after starting amantadine. Resolution of symptoms typically begins within weeks of amantadine cessation. However, corneal grafts have been required in some patients when the condition is not recognized. Permanent damage can occur if amantadine is continued. Ask patients if their vision has changed and obtain ophthalmologic examinations to rule out corneal edema should vision changes occur after initiation of therapy with GOCOVRI. If corneal edema occurs, taper and discontinue GOCOVRI <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .

5.7 Impulse Control/Compulsive Behaviors Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including GOCOVRI, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with GOCOVRI. Consider dose reduction or stopping the medication if a patient develops such urges while taking GOCOVRI.

PRECAUTIONS Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP 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.

Neuroleptic Malignant

Syndrome (NMS) Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of Amantadine Hydrochloride Oral Solution USP therapy. Therefore, patients should be observed carefully when the dosage of Amantadine Hydrochloride Oral Solution USP 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. Renal disease Because Amantadine Hydrochloride Oral Solution USP is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of Amantadine Hydrochloride Oral Solution USP 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 ). Liver disease Care should be exercised when administering Amantadine Hydrochloride Oral Solution USP to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving Amantadine Hydrochloride Oral Solution USP, though a specific relationship between the drug and such changes has not been established.

Impulse Control/Compulsive

Behaviors Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are generally used for the treatment of Parkinson's disease and that increase central dopaminergic tone, including amantadine hydrochloride. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with amantadine hydrochloride. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking amantadine hydrochloride.

Melanoma

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 Amantadine Hydrochloride Oral Solution USP for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Other

The dose of Amantadine Hydrochloride Oral Solution USP may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering Amantadine Hydrochloride Oral Solution USP 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.

Amantadine Hydrochloride Oral

Solution USP has not been shown to prevent such complications. Information for Patients 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.

Drug Interactions

Careful observation is required when Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP (Amantadine Hydrochloride, USP) 100 mg TID for Parkinson's disease.1 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 Amantadine Hydrochloride Oral Solution USP 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 Amantadine Hydrochloride Oral Solution USP, 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 Amantadine Hydrochloride Oral Solution USP. Carcinogenesis and Mutagenesis Long-term in vivo animal studies designed to evaluate the carcinogenic potential of Amantadine Hydrochloride Oral Solution USP have not been performed. In several in vitro assays for gene mutation, Amantadine Hydrochloride Oral Solution USP 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). Impairment of Fertility 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, Amantadine Hydrochloride Oral Solution USP 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.

Pregnancy

Category C 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, Amantadine Hydrochloride Oral Solution USP 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.

Amantadine Hydrochloride Oral

Solution USP should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

Nursing Mothers Amantadine Hydrochloride Oral

Solution USP is excreted in human milk. Use is not recommended in nursing mothers.

Pediatric Use

The safety and efficacy of Amantadine Hydrochloride Oral Solution USP in newborn infants and infants below the age of 1 year have not been established. Usage in the Elderly Because Amantadine Hydrochloride Oral Solution USP is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of Amantadine Hydrochloride Oral Solution USP should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of Amantadine Hydrochloride Oral Solution USP may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION ).

Drug Interactions Careful observation is required when amantadine hydrochloride 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 amantadine hydrochloride (Amantadine Hydrochloride, USP) 100 mg TID for Parkinson’s disease. 1 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 amantadine hydrochloride 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 amantadine hydrochloride, 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 amantadine hydrochloride. Carcinogenesis and Mutagenesis Long-term in vivo animal studies designed to evaluate the carcinogenic potential of amantadine hydrochloride have not been performed. In several in vitro assays for gene mutation, 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 to 550 mg/kg; estimated human equivalent doses of 11.7 to 45.8 mg/kg based on body surface area conversion). Impairment of Fertility 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, amantadine hydrochloride at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m 2 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/m 2 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.

Pregnancy

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 to 14 of gestation, Symmetrel produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m 2 basis). In the non-GLP rat study in which females were dosed on Days 7 to 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/m 2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m 2 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. Amantadine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

Nursing Mothers

Amantadine hydrochloride is excreted in human milk. Use is not recommended in nursing mothers.

Pediatric Use

The safety and efficacy of amantadine hydrochloride in newborn infants and infants below the age of 1 year have not been established. Usage in the Elderly Because 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 amantadine hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of amantadine hydrochloride may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION ).