Because amantadine hydrochloride is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older ( see DOSAGE AND ADMINISTRATION; Dosage for Impaired Renal Function).
Care should be exercised when administering amantadine hydrochloride to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine hydrochloride, though a specific relationship between the drug and such changes has not been established.
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.
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 for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
The dose of amantadine hydrochloride may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering amantadine hydrochloride to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine hydrochloride 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.
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 hydrochloride.
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 1 Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine hydrochloride concentration in a 61-year old man receiving amantadine hydrochloride 100 mg TID for Parkinson’s disease. 1 It is not known which of the components of 1 Dyazide contributed to the observation or if related drugs produce a similar response.
Coadministration of quinine or quinidine with amantadine hydrochloride was shown to reduce the renal clearance of amantadine hydrochloride 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.
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).
The effect of amantadine hydrochloride 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 hydrochloride 2 weeks prior to, and during the IVF cycle.
The effect of amantadine hydrochloride 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, amantadine hydrochloride produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/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 hydrochloride is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine hydrochloride 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 hydrochloride (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.
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