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elderly patients believed to develop parkinsonism neurologic fi ndings including muscle rigidity, AMANTADINE HYDROCHLORIDE
In six healthy volunteers, the ratio of amantadine in association with cerebral arteriosclerosis. In involuntary movements, altered consciousness; ORAL SOLUTION, USP
renal clearance to apparent oral plasma clearance the treatment of Parkinson's disease, Amantadine mental status changes; other disturbances such as was 0.79 ± 0.17 (mean ± SD). Hydrochloride Oral Solution USP is less effective autonomic dysfunction, tachycardia, tachypnea, than levodopa, (-)-3-(3,4-dihydroxyphenyl)-L- hyper- or hypotension; laboratory fi ndings such as The volume of distribution determined after the alanine, and its effi cacy in comparison with the creatine phosphokinase elevation, leukocytosis, intravenous administration of amantadine to 15 anticholinergic antiparkinson drugs has not yet been myoglobinuria, and increased serum myoglobin. healthy subjects was 3 to 8 L/kg, suggesting tissue Amantadine Hydrochloride is designated chemi- binding. Amantadine, after single oral 200 mg The early diagnosis of this condition is important cally as 1-adamantanamine hydrochloride. doses to 6 healthy young subjects and to 6 healthy Drug-Induced Extrapyramidal Reactions
for the appropriate management of these patients. elderly subjects, has been found in nasal mucus at Considering NMS as a possible diagnosis and mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± Amantadine Hydrochloride Oral Solution USP ruling out other acute illnesses (e.g., pneumonia, 0.26, and 0.39 ± 0.34 mcg/g at 1, 4, and 8 hours is indicated in the treatment of drug-induced systemic infection, etc.) is essential. This may after dosing, respectively. These concentrations extrapyramidal reactions. Although anticholinergic- be especially complex if the clinical presentation represented 31 ± 33%, 59 ± 61%, and 95 ± 86% of type side effects have been noted with Amantadine includes both serious medical illness and untreated the corresponding plasma amantadine concentra- Hydrochloride Oral Solution USP when used or inadequately treated extrapyramidal signs and Amantadine hydrochloride is a stable white or tions. Amantadine is approximately 67% bound in patients with drug-induced extrapyramidal symptoms (EPS). Other important considerations nearly white crystalline powder, freely soluble in to plasma proteins over a concentration range of reactions, there is a lower incidence of these side in the differential diagnosis include central anticho- water and soluble in alcohol and in chloroform. 0.1 to 2 mcg/mL. Following the administration of effects than that observed with the anticholinergic linergic toxicity, heat stroke, drug fever and primary amantadine 100 mg as a single dose, the mean ± SD antiparkinson drugs. central nervous system (CNS) pathology. Amantadine hydrochloride has pharmacological red blood cell to plasma ratio ranged from 2.7 ± 0.5 actions as both an anti-Parkinson and an antiviral in 6 healthy subjects to 1.4 ± 0.2 in 8 patients with The management of NMS should include: 1) renal insuffi ciency. Amantadine Hydrochloride Oral Solution USP is intensive symptomatic treatment and medical moni- contraindicated in patients with known hypersensi- toring, and 2) treatment of any concomitant serious Amantadine Hydrochloride Oral Solution USP The apparent oral plasma clearance of amantadine tivity to amantadine hydrochloride or to any of the medical problems for which specifi c treatments are contains 50 mg amantadine hydrochloride per 5 mL is reduced and the plasma half-life and plasma other ingredients in Amantadine Hydrochloride Oral available. Dopamine agonists, such as bromocrip- and the following inactive ingredients: artifi cial concentrations are increased in healthy elderly tine, and muscle relaxants, such as dantrolene are red-raspberry fl avor, citric acid, methylparaben, pro- individuals age 60 and older. After single dose often used in the treatment of NMS, however, pylparaben, propylene glycol, and sorbitol solution. administration of 25 to 75 mg to 7 healthy, elderly their effectiveness has not been demonstrated in male volunteers, the apparent plasma clearance of controlled studies. 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 Deaths have been reported from overdose with due to decline in renal function or other age related amantadine. The lowest reported acute lethal dose Because Amantadine Hydrochloride Oral Solution Mechanism of Action: Antiviral factors is not known. was 1 gram. Acute toxicity may be attributable to USP is mainly excreted in the urine, it accumulates The mechanism by which amantadine exerts its the anticholinergic effects of amantadine. Drug in the plasma and in the body when renal function antiviral activity is not clearly understood. It In a study of young healthy subjects (n=20), mean overdose has resulted in cardiac, respiratory, declines. Thus, the dose of Amantadine Hydro- appears to mainly prevent the release of infectious renal clearance of amantadine, normalized for body renal or central nervous system toxicity. Cardiac chloride Oral Solution USP should be reduced in viral nucleic acid into the host cell by interfering mass index, was 1.5 fold higher in males compared dysfunction includes arrhythmia, tachycardia and patients with renal impairment and in individuals with the function of the transmembrane domain of to females (p<0.032). hypertension (see OVERDOSAGE). Deaths who are 65 years of age or older (see DOSAGE the viral M2 protein. In certain cases, amantadine due to drug accumulation (overdose) have been AND ADMINISTRATION; Dosage for Impaired is also known to prevent virus assembly during Compared with otherwise healthy adult individuals, reported in patients with renal impairment, who Renal Function). virus replication. It does not appear to interfere the clearance of amantadine is signifi cantly reduced were prescribed higher than recommended doses with the immunogenicity of inactivated infl uenza A in adult patients with renal insuffi ciency. The of amantadine for their level of renal function (see elimination half-life increases two to three fold or DOSAGE AND ADMINISTRATION; Dosage of greater when creatinine clearance is less than 40 Impaired Renal Function and OVERDOSAGE). Care should be exercised when administering mL/min/1.73 m2 and averages eight days in patients Amantadine Hydrochloride Oral Solution USP to Amantadine inhibits the replication of infl uenza A on chronic maintenance hemodialysis. Amantadine patients with liver disease. Rare instances of revers- virus isolates from each of the subtypes, i.e., H1N1, is removed in negligible amounts by hemodialysis. ible elevation of liver enzymes have been reported H2N2 and H3N2. It has very little or no activity Suicide attempts, some of which have been in patients receiving Amantadine hydrochloride, against infl uenza B virus isolates. A quantitative The pH of the urine has been reported to infl uence fatal, have been reported in patients treated though a specifi c relationship between the drug and relationship between the in vitro susceptibility of the excretion rate of amantadine. Since the excre- with amantadine, many of whom received short such changes has not been established. infl uenza A virus to amantadine and the clinical tion rate of amantadine increases rapidly when the courses for infl uenza treatment or prophylaxis. The response to therapy has not been established in man. urine is acidic, the administration of urine acidify- incidence of suicide attempts is not known and the Impulse Control/Compulsive Behaviors
Sensitivity test results, expressed as the concentra- ing drugs may increase the elimination of the drug pathophysiologic mechanism is not understood. tion of amantadine required to inhibit by 50% the Suicide attempts and suicidal ideation have been Postmarketing reports suggest that patients treated growth of virus (ED ) in tissue culture vary greatly reported in patients with and without prior history with anti-Parkinson medications can experience (from 0.1 mcg/mL to 25 mcg/mL) depending upon INDICATIONS AND USAGE
of psychiatric illness. Amantadine Hydrochloride intense urges to gamble, increased sexual urges, the assay protocol used, size of virus inoculum, Amantadine Hydrochloride Oral Solution USP is Oral Solution USP can exacerbate mental problems intense urges to spend money uncontrollably, and isolates of infl uenza A virus strains tested, and the indicated for the prophylaxis and treatment of signs in patients with a history of psychiatric disorders other intense urges. Patients may be unable to cell type used. Host cells in tissue culture readily and symptoms of infection caused by various strains or substance abuse. Patients who attempt suicide control these urges while taking one or more of the tolerated amantadine up to a concentration of 100 of infl uenza A virus. Amantadine Hydrochloride may exhibit abnormal mental states which include medications that are generally used for the treatment Oral Solution USP is also indicated in the treatment disorientation, confusion, depression, personality of Parkinson's disease and that increase central of parkinsonism and drug-induced extrapyramidal changes, agitation, aggressive behavior, hallucina- dopaminergic tone, including Amantadine hydro- Drug Resistance tions, paranoia, other psychotic reactions, and som- chloride. In some cases, although not all, these Infl uenza A variants with reduced in vitro sensitivity nolence or insomnia. Because of the possibility of urges were reported to have stopped when the dose to amantadine have been isolated from epidemic Infl uenza A Prophylaxis
serious adverse effects, caution should be observed was reduced or the medication was discontinued. strains in areas where adamantane derivatives are when prescribing Amantadine Hydrochloride Oral Because patients may not recognize these behaviors being used. Infl uenza viruses with reduced in vitro Amantadine Hydrochloride Oral Solution USP is Solution USP to patients being treated with drugs as abnormal it is important for prescribers to sensitivity have been shown to be transmissible and indicated for chemoprophylaxis against signs and having CNS effects, or for whom the potential risks specifi cally ask patients or their caregivers about the to cause typical infl uenza illness. The quantitative symptoms of infl uenza A virus infection. Because outweigh the benefi t of treatment. development of new or increased gambling urges, relationship between the in vitro sensitivity of Amantadine Hydrochloride Oral Solution USP does sexual urges, uncontrolled spending or other urges infl uenza A variants to amantadine and the clinical not completely prevent the host immune response CNS Effects
while being treated with Amantadine hydrochloride. response to therapy has not been established. to infl uenza A infection, individuals who take this Physicians should consider dose reduction or stop- drug may still develop immune responses to natural Patients with a history of epilepsy or other ping the medication if a patient develops such urges Mechanism of Action: Parkinson's Disease disease or vaccination and may be protected when "seizures" should be observed closely for possible while taking Amantadine hydrochloride. The mechanism of action of amantadine in the later exposed to antigenically related viruses. Fol- increased seizure activity. treatment of Parkinson's disease and drug-induced lowing vaccination during an infl uenza A outbreak, extrapyramidal reactions is not known. Data from Amantadine Hydrochloride Oral Solution USP Patients receiving Amantadine Hydrochloride Oral earlier animal studies suggest that Amantadine prophylaxis should be considered for the 2- to Solution USP who note central nervous system Epidemiological studies have shown that patients Hydrochloride Oral Solution USP may have direct 4-week time period required to develop an antibody effects or blurring of vision should be cautioned with Parkinson's disease have a higher risk (2- and indirect effects on dopamine neurons. More against driving or working in situations where alert- to approximately 6-fold higher) of developing recent studies have demonstrated that amantadine is ness and adequate motor coordination are important. melanoma than the general population. Whether a weak, non-competitive NMDA receptor antagonist Infl uenza A Treatment
the increased risk observed was due to Parkinson's (K =10 μM). Although amantadine has not been disease or other factors, such as drugs used to treat shown to possess direct anticholinergic activity in Amantadine Hydrochloride Oral Solution USP is Parkinson's disease, is unclear. animal studies, clinically, it exhibits anticholinergic- also indicated in the treatment of uncomplicated Patients with a history of congestive heart failure like side effects such as dry mouth, urinary reten- respiratory tract illness caused by infl uenza A virus or peripheral edema should be followed closely as For the reasons stated above, patients and providers tion, and constipation. strains especially when administered early in the there are patients who developed congestive heart are advised to monitor for melanomas frequently course of illness. There are no well-controlled clini- failure while receiving amantadine. and on a regular basis when using Amantadine cal studies demonstrating that treatment with Aman- Hydrochloride Oral Solution USP for any indica- tadine Hydrochloride Oral Solution USP will avoid Patients with Parkinson's disease improving on tion. Ideally, periodic skin examinations should be Amantadine Hydrochloride Oral Solution USP is the development of infl uenza A virus pneumonitis Amantadine Hydrochloride Oral Solution USP performed by appropriately qualifi ed individuals well absorbed orally. Maximum plasma concentra- or other complications in high risk patients. should resume normal activities gradually and (e.g., dermatologists). tions are directly related to dose for doses up to cautiously, consistent with other medical consid- 200 mg/day. Doses above 200 mg/day may result There is no clinical evidence indicating that Aman- erations, such as the presence of osteoporosis or in a greater than proportional increase in maximum tadine Hydrochloride Oral Solution USP is effective phlebothrombosis. plasma concentrations. It is primarily excreted in the prophylaxis or treatment of viral respiratory The dose of Amantadine Hydrochloride Oral Solu- unchanged in the urine by glomerular fi ltration and tract illnesses other than those caused by infl uenza Because Amantadine Hydrochloride Oral Solution tion USP may need careful adjustment in patients tubular secretion. Eight metabolites of amantadine A virus strains. USP has anticholinergic effects and may cause with congestive heart failure, peripheral edema, or have been identifi ed in human urine. One metabo- mydriasis, it should not be given to patients with orthostatic hypotension. Care should be exercised lite, an N-acetylated compound, was quantifi ed The following points should be considered untreated angle closure glaucoma. when administering Amantadine Hydrochloride in human urine and accounted for 5 to 15% of the before initiating treatment or prophylaxis with Oral Solution USP to patients with a history of administered dose. Plasma acetylamantadine ac- Amantadine Hydrochloride Oral Solution USP: recurrent eczematoid rash, or to patients with counted for up to 80% of the concurrent amantadine Amantadine Hydrochloride Oral Solution USP psychosis or severe psychoneurosis not controlled plasma concentration in 5 of 12 healthy volunteers Amantadine Hydrochloride Oral Solution should not be discontinued abruptly in patients by chemotherapeutic agents. following the ingestion of a 200 mg dose of USP is not a substitute for early vaccination with Parkinson's disease since a few patients have amantadine. Acetylamantadine was not detected in on an annual basis as recommended by the experienced a parkinsonian crisis, i.e., a sudden Serious bacterial infections may begin with the plasma of the remaining seven volunteers. The Centers for Disease Control and Prevention marked clinical deterioration, when this medication infl uenza-like symptoms or may coexist with or oc- contribution of this metabolite to effi cacy or toxicity Advisory Committee on Immunization was suddenly stopped. The dose of anticholiner- cur as complications during the course of infl uenza. gic drugs or of Amantadine Hydrochloride Oral Amantadine Hydrochloride Oral Solution USP has Solution USP should be reduced if atropine-like not been shown to prevent such complications. There appears to be a relationship between plasma Infl uenza viruses change over time. Emer- effects appear when these drugs are used concur- amantadine concentrations and toxicity. As gence of resistance mutations could decrease rently. Abrupt discontinuation may also precipitate Information for Patients
concentration increases, toxicity seems to be more drug effectiveness. Other factors (for delirium, agitation, delusions, hallucinations, prevalent, however, absolute values of amantadine example, changes in viral virulence) might paranoid reaction, stupor, anxiety, depression and Patients should be advised of the following concentrations associated with adverse effects have also diminish clinical benefi t of antiviral not been fully defi ned.
drugs. Prescribers should consider available information on infl uenza drug susceptibility Neuroleptic Malignant Syndrome (NMS)
Blurry vision and/or impaired mental acuity may After oral administration of a single dose of 100 patterns and treatment effects when deciding mg amantadine hydrochloride oral solution to whether to use Amantadine Hydrochloride Sporadic cases of possible Neuroleptic Malignant fi ve healthy volunteers, the mean ± SD maximum Oral Solution USP.
Syndrome (NMS) have been reported in association Gradually increase physical activity as the symp- plasma concentration C was 0.24 ± 0.04 mcg/ with dose reduction or withdrawal of Amantadine toms of Parkinson's disease improve. mL and ranged from 0.18 to 0.28 mcg/mL. After 15 Hydrochloride Oral Solution USP therapy. There- days of amantadine 100 mg b.i.d., the C fore, patients should be observed carefully when the Avoid excessive alcohol usage, since it may ± 0.11 mcg/mL in four of the fi ve volunteers. Amantadine Hydrochloride Oral Solution USP is dosage of Amantadine Hydrochloride Oral Solution increase the potential for CNS effects such as diz- indicated in the treatment of idiopathic Parkinson's USP is reduced abruptly or discontinued, especially ziness, confusion, lightheadedness and orthostatic Plasma amantadine clearance ranged from 0.2 to disease (Paralysis Agitans), postencephalitic par- if the patient is receiving neuroleptics.
0.3 L/hr/kg after the administration of 5 mg to 25 kinsonism, and symptomatic parkinsonism which mg intravenous doses of amantadine to 15 healthy may follow injury to the nervous system by carbon NMS is an uncommon but life-threatening Avoid getting up suddenly from a sitting or lying monoxide intoxication. It is indicated in those syndrome characterized by fever or hyperthermia; position. If dizziness or lightheadedness occurs, notify physician. Notify physician if mood/mental changes, swelling amantadine during the fi rst trimester of pregnancy insomnia, anxiety, agitation, aggressive behavior, Dosage for Parkinsonism
of extremities, diffi culty urinating and/or shortness (100 mg P.O. for 7 days during the 6th and 7th hypertonia, hyperkinesia, ataxia, gait abnormality, of breath occur. week of gestation). Cardiovascular maldevelop- tremor, confusion, disorientation, depersonalization, ment (single ventricle with pulmonary atresia) was fear, delirium, hallucinations, psychotic reactions, The usual dose of Amantadine Hydrochloride Oral Do not take more medication than prescribed associated with maternal exposure to amantadine lethargy, somnolence and coma. Seizures may be Solution USP is 100 mg twice a day when used because of the risk of overdose. If there is no (100 mg/d) administered during the fi rst 2 weeks exacerbated in patients with prior history of seizure alone. Amantadine Hydrochloride Oral Solution improvement in a few days, or if medication ap- of pregnancy. Amantadine Hydrochloride Oral disorders. Hyperthermia has also been observed in USP has an onset of action usually within 48 hours. pears less effective after a few weeks, discuss with Solution USP should be used during pregnancy only cases where a drug overdose has occurred. if the potential benefi t justifi es the potential risk to The initial dose of Amantadine Hydrochloride Oral the embryo or fetus. There is no specifi c antidote for an overdose Solution USP is 100 mg daily for patients with Consult physician before discontinuing medication. of Amantadine Hydrochloride Oral Solution serious associated medical illnesses or who are USP. However, slowly administered intravenous receiving high doses of other antiparkinson drugs. Seek medical attention immediately if it is suspect- physostigmine in 1 and 2 mg doses in an adult2 at After one to several weeks at 100 mg once daily, ed that an overdose of medication has been taken. Amantadine Hydrochloride Oral Solution USP is 1- to 2-hour intervals and 0.5 mg doses in a child3 the dose may be increased to 100 mg twice daily, excreted in human milk. Use is not recommended at 5- to 10-minute intervals up to a maximum of 2 in nursing mothers. mg/hour have been reported to be effective in the control of central nervous system toxicity caused by Occasionally, patients whose responses are not opti- Careful observation is required when Amantadine amantadine hydrochloride. For acute overdosing, mal with Amantadine Hydrochloride Oral Solution Hydrochloride Oral Solution USP is adminis- general supportive measures should be employed USP at 200 mg daily may benefi t from an increase tered concurrently with central nervous system The safety and effi cacy of Amantadine Hydro- along with immediate gastric lavage or induction of up to 400 mg daily in divided doses. However, chloride Oral Solution USP in newborn infants emesis. Fluids should be forced, and if necessary, such patients should be supervised closely by their and infants below the age of 1 year have not been given intravenously. The pH of the urine has been Agents with anticholinergic properties may reported to infl uence the excretion rate of Amanta- potentiate the anticholinergic-like side effects of dine Hydrochloride Oral Solution USP. Since the Patients initially deriving benefi t from Amantadine Usage in the Elderly
excretion rate of Amantadine Hydrochloride Oral Hydrochloride Oral Solution USP not uncommonly Solution USP increases rapidly when the urine is experience a fall-off of effectiveness after a few Coadministration of thioridazine has been reported Because Amantadine Hydrochloride Oral Solution acidic, the administration of urine acidifying drugs months. Benefi t may be regained by increasing to worsen the tremor in elderly patients with Par- USP is primarily excreted in the urine, it accu- may increase the elimination of the drug from the the dose to 300 mg daily. Alternatively, temporary kinson's disease, however, it is not known if other mulates in the plasma and in the body when renal body. The blood pressure, pulse, respiration and discontinuation of Amantadine Hydrochloride phenothiazines produce a similar response. function declines. Thus, the dose of Amantadine temperature should be monitored. The patient Oral Solution USP for several weeks, followed by Hydrochloride Oral Solution USP should be should be observed for hyperactivity and convul- reinitiation of the drug, may result in regaining Coadministration of Dyazide (triamterene/hy- reduced in patients with renal impairment and in sions; if required, sedation and anticonvulsant benefi t in some patients. A decision to use other drochlorothiazide) resulted in a higher plasma individuals who are 65 years of age or older. The therapy should be administered. The patient should antiparkinson drugs may be necessary. amantadine concentration in a 61-year-old man dose of Amantadine Hydrochloride Oral Solution be observed for the possible development of ar- receiving amantadine hydrochloride 100 mg TID USP may need reduction in patients with congestive rhythmias and hypotension; if required, appropriate Dosage for Concomitant Therapy
for Parkinson's disease.1 It is not known which heart failure, peripheral edema, or orthostatic hypo- antiarrhythmic and antihypotensive therapy should of the components of Dyazide contributed to the tension (see DOSAGE AND ADMINISTRATION). be given. Electrocardiographic monitoring may be Some patients who do not respond to anticholin- observation or if related drugs produce a similar required after ingestion, since malignant tachyar- ergic antiparkinson drugs may respond to Aman- rhythmias can appear after overdose. tadine Hydrochloride Oral Solution USP. When The adverse reactions reported most frequently (5 Amantadine Hydrochloride Oral Solution USP or Coadministration of quinine or quinidine with to 10%) at the recommended dose of Amantadine Care should be exercised when administering anticholinergic antiparkinson drugs are each used amantadine was shown to reduce the renal clearance Hydrochloride Oral Solution USP are: nausea, diz- adrenergic agents, such as isoproterenol, to patients with marginal benefi t, concomitant use may produce of amantadine by about 30%.
ziness (lightheadedness), and insomnia. with an Amantadine Hydrochloride Oral Solution additional benefi t. USP overdose, since the dopaminergic activity of The concurrent use of Amantadine Hydrochloride Less frequently (1 to 5%) reported adverse reactions Amantadine Hydrochloride Oral Solution USP has When Amantadine Hydrochloride Oral Solution Oral Solution USP with live attenuated infl uenza are: depression, anxiety and irritability, hallucina- been reported to induce malignant arrhythmias. USP and levodopa are initiated concurrently, the vaccine (LAIV) intranasal has not been evaluated. tions, confusion, anorexia, dry mouth, constipation, patient can exhibit rapid therapeutic benefi ts. However, because of the potential for interference ataxia, livedo reticularis, peripheral edema, The blood electrolytes, urine pH and urinary output Amantadine Hydrochloride Oral Solution USP between these products, LAIV should not be orthostatic hypotension, headache, somnolence, should be monitored. If there is no record of recent should be held constant at 100 mg daily or twice administered within 2 weeks before or 48 hours nervousness, dream abnormality, agitation, dry voiding, catheterization should be done. daily while the daily dose of levodopa is gradually after administration of Amantadine Hydrochloride nose, diarrhea and fatigue. increased to optimal benefi t. Oral Solution USP, unless medically indicated. The DOSAGE AND ADMINISTRATION
concern about possible interference arises from the Infrequently (0.1 to 1%) occurring adverse reactions The dose of Amantadine Hydrochloride Oral Solu- When Amantadine Hydrochloride Oral Solution potential for antiviral drugs to inhibit replication of are: congestive heart failure, psychosis, urinary tion USP may need reduction in patients with con- USP is added to optimal well-tolerated doses of live vaccine virus. Trivalent inactivated infl uenza retention, dyspnea, skin rash, vomiting, weakness, gestive heart failure, peripheral edema, orthostatic levodopa, additional benefi t may result, including vaccine can be administered at any time relative to slurred speech, euphoria, thinking abnormality, hypotension, or impaired renal function (see Dosage smoothing out the fl uctuations in improvement use of Amantadine Hydrochloride Oral Solution amnesia, hyperkinesia, hypertension, decreased for Impaired Renal Function). which sometimes occur in patients on levodopa libido, and visual disturbance, including punctate alone. Patients who require a reduction in their subepithelial or other corneal opacity, corneal usual dose of levodopa because of development of Carcinogenesis and Mutagenesis
edema, decreased visual acuity, sensitivity to light, Dosage for Prophylaxis and Treatment of Un-
side effects may possibly regain lost benefi t with and optic nerve palsy. complicated Infl uenza A Virus Illness
the addition of Amantadine Hydrochloride Oral Long-term in vivo animal studies designed to evaluate the carcinogenic potential of Amantadine Rare (less than 0.1%) occurring adverse reactions Hydrochloride Oral Solution USP have not been are: instances of convulsion, leukopenia, neutro- The adult daily dosage of Amantadine Hydrochlo- Dosage for Drug-Induced Extrapyramidal
performed. In several in vitro assays for gene penia, eczematoid dermatitis, oculogyric episodes, ride Oral Solution USP is 200 mg (four teaspoonfuls mutation, Amantadine Hydrochloride Oral Solution suicidal attempt, suicide, and suicidal ideation (see of oral solution) as a single daily dose. The daily USP did not increase the number of spontaneously dosage may be split into 100 mg (two teaspoonfuls observed mutations in four strains of Salmonella of oral solution) twice a day. If central nervous The usual dose of Amantadine Hydrochloride Oral typhimurium (Ames Test) or in a mammalian cell Other adverse reactions reported during postmarket- system effects develop in once-a-day dosage, a split Solution USP is 100 mg twice a day. Occasion- line (Chinese Hamster Ovary cells) when incuba- ing experience with Amantadine hydrochloride dosage schedule may reduce such complaints. In ally, patients whose responses are not optimal with tions were performed either with or without a liver persons 65 years of age or older, the daily dosage Amantadine Hydrochloride Oral Solution USP at metabolic activation extract. Further, there was no of Amantadine Hydrochloride Oral Solution USP 200 mg daily may benefi t from an increase up to evidence of chromosome damage observed in an 300 mg daily in divided doses. in vitro test using freshly derived and stimulated coma, stupor, delirium, hypokinesia, hypertonia, human peripheral blood lymphocytes (with and delusions, aggressive behavior, paranoid reaction, A 100 mg daily dose has also been shown in experi- Dosage for Impaired Renal Function
without metabolic activation) or in an in vivo mouse manic reaction, involuntary muscle contractions, mental challenge studies to be effective as prophy- bone marrow micronucleus test (140 to 550 mg/kg; gait abnormalities, paresthesia, EEG changes, and laxis in healthy adults who are not at high risk for Depending upon creatinine clearance, the following estimated human equivalent doses of 11.7 to 45.8 tremor. Abrupt discontinuation may also precipitate infl uenza-related complications. However, it has dosage adjustments are recommended: mg/kg based on body surface area conversion). delirium, agitation, delusions, hallucinations, not been demonstrated that a 100 mg daily dose is paranoid reaction, stupor, anxiety, depression and as effective as a 200 mg daily dose for prophylaxis, Impairment of Fertility
nor has the 100 mg daily dose been studied in the treatment of acute infl uenza illness. In recent clini- The effect of amantadine on fertility has not been cal trials, the incidence of central nervous system adequately tested, that is, in a study conducted cardiac arrest, arrhythmias including malignant (CNS) side effects associated with the 100 mg daily 200 mg 1st day and under Good Laboratory Practice (GLP) and ac- arrhythmias, hypotension, and tachycardia; dose was at or near the level of placebo. The 100 cording to current recommended methodology. In mg dose is recommended for persons who have each day thereafter a three litter, non-GLP, reproduction study in rats, demonstrated intolerance to 200 mg of Amantadine Amantadine hydrochloride at a dose of 32 mg/kg/ acute respiratory failure, pulmonary edema, and Hydrochloride Oral Solution USP daily because of day (equal to the maximum recommended human CNS or other toxicities. dose on a mg/m2 basis) administered to both males 100 mg on alternate and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/ 200 mg every 7 days kg/day (or 0.3 times the maximum recommended 1 yr. to 9 yrs. of age
human dose on a mg/m2 basis); intermediate doses The total daily dose should be calculated on the were not tested. leukocytosis, agranulocytosis; basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day), but The recommended dosage for patients on hemodi- not to exceed 150 mg per day. alysis is 200 mg every 7 days. Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor keratitis and mydriasis; 9 yrs. to 12 yrs. of age
How Supplied
ingested amantadine 2 weeks prior to, and during The total daily dose is 200 mg given as 100 mg Amantadine Hydrochloride Oral Solution USP is Skin and Appendages
(two teaspoonfuls of oral solution) twice a day. available as a clear, colorless, raspberry fl avored pruritus and diaphoresis; The 100 mg daily dose has not been studied in this oral solution [each 5 mL (1 teaspoonful) contains 50 pediatric population. Therefore, there are no data mg amantadine hydrochloride] in: Effects: Pregnancy Category C
which demonstrate that this dose is as effective as neuroleptic malignant syndrome (see WARNINGS), or is safer than the 200 mg daily dose in this patient 16 oz. (473 mL) bottles NDC 46287-015-01 The effect of amantadine on embryofetal and allergic reactions including anaphylactic reactions, peri-postnatal development has not been adequately edema and fever; Store at 20°-25° C (68°-77° F); excursions permit- tested, that is, in studies conducted under Good Prophylactic dosing should be started in anticipa- ted to 15°-30° C (59°-86° F) [See USP Controlled Laboratory Practice (GLP) and according to current tion of an infl uenza A outbreak and before or after Room Temperature] recommended methodology. However, in two non- elevated: CPK, BUN, serum creatinine, alkaline contact with individuals with infl uenza A virus GLP studies in rats in which females were dosed phosphatase, LDH, bilirubin, GGT, SGOT, and respiratory tract illness. from 5 days prior to mating to Day 6 of gestation Dispense in a tight container as defi ned in the USP, or on Days 7 to 14 of gestation, Amantadine hydro- Amantadine Hydrochloride Oral Solution USP with a child-resistant closure (as required). chloride produced increases in embryonic death at should be continued daily for at least 10 days fol- an oral dose of 100 mg/kg (or 3 times the maximum Deaths have been reported from overdose with lowing a known exposure. If Amantadine Hydro- recommended human dose on a mg/m2 basis). In Amantadine hydrochloride. The lowest reported chloride Oral Solution USP is used chemoprophy- the non-GLP rat study in which females were dosed acute lethal dose was 1 gram. Because some lactically in conjunction with inactivated infl uenza 1 W.W. Wilson and A.H. Rajput, Amantadine-Dya- on Days 7 to 14 of gestation, there was a marked patients have attempted suicide by overdosing with A virus vaccine until protective antibody responses zide Interaction, Can. Med. Assoc. J. 129:974-975, increase in severe visceral and skeletal malforma- amantadine, prescriptions should be written for develop, then it should be administered for 2 to tions at oral doses of 50 and 100 mg/kg (or 1.5 and the smallest quantity consistent with good patient 4 weeks after the vaccine has been given. When 2 D.F. Casey, N. Engl. J. Med. 298:516, 1978.
3 times, respectively, the maximum recommended inactivated infl uenza A virus vaccine is unavailable 3 C.D. Berkowitz, J. Pediatr. 95:144, 1979. human dose on a mg/m2 basis). The no-effect dose or contraindicated, Amantadine Hydrochloride for teratogenicity was 37 mg/kg (equal to the maxi- Acute toxicity may be attributable to the anticho- Oral Solution USP should be administered for the mum recommended human dose on a mg/m2 basis). linergic effects of amantadine. Drug overdose has duration of known infl uenza A in the community The safety margins reported may not accurately resulted in cardiac, respiratory, renal or central because of repeated and unknown exposure. refl ect the risk considering the questionable quality nervous system toxicity. Cardiac dysfunction of the study on which they are based. There are no includes arrhythmia, tachycardia and hypertension. Treatment of infl uenza A virus illness should be adequate and well-controlled studies in pregnant Pulmonary edema and respiratory distress (includ- started as soon as possible, preferably within 24 to CMP Pharma, Inc. women. Human data regarding teratogenicity after ing adult respiratory distress syndrome – ARDS) 48 hours after onset of signs and symptoms, and maternal use of amantadine is scarce. have been reported; renal dysfunction including should be continued for 24 to 48 hours after the Farmville, North Carolina 27828 increased BUN, decreased creatinine clearance disappearance of signs and symptoms. Tetralogy of Fallot and tibial hemimelia (normal and renal insuffi ciency can occur. Central nervous Revised January 2015 karyotype) occurred in an infant exposed to system effects that have been reported include Copyright CMP Pharma, Inc. 2015

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