PRECAUTIONS Hypotension, Orthostatic Hypotension, and Syncope Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and, therefore, might be expected to increase the occurrence of orthostatic hypotension. In controlled studies, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in both treatment groups who had an episode of documented hypotension. Hallucinations and Psychotic-Like Behavior Dopaminergic therapy in patients with Parkinson's disease has been associated with hallucinations. In clinical studies, hallucinations led to drug discontinuation and premature withdrawal in 0.8% and 0% of patients treated with 200 mg Comtan and placebo, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the 200 mg Comtan and placebo groups, respectively. Agitation occurred in 1% of patients treated with Comtan and 0% treated with placebo. Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during Comtan treatment or after starting or increasing the dose of Comtan. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. Abnormal thinking and behavior can cause paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Psychotic-like behaviors were also observed during the clinical development of Comtan. Patients with a major psychotic disorder should ordinarily not be treated with Comtan because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Comtan (see PRECAUTIONS). Impulse Control and 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 used for the treatment of Parkinson's disease and that increase central dopaminergic tone, including Comtan taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or 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 entacapone. Physicians should consider dose reduction or stopping Comtan if a patient develops such urges while taking Comtan. Diarrhea and Colitis In clinical studies, diarrhea developed in 60 of 603 (10%) and 16 of 400 (4%) of patients treated with 200 mg Comtan and placebo, respectively. In patients treated with Comtan, diarrhea was generally mild to moderate in severity (8.6%) but was regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of Comtan. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 weeks to 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment. Diarrhea may be associated with weight loss, dehydration, and hypokalemia. Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases, diarrhea has usually been moderate to severe, watery, and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when Comtan treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of Comtan but recurred after retreatment with Comtan. If prolonged diarrhea is suspected to be related to Comtan, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered. Dyskinesia Comtan may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled studies continued to experience frequent dyskinesia despite a reduction in their dose of levodopa. The incidence of dyskinesia was 25% for treatment with Comtan and 15% for placebo. The incidence of study withdrawal for dyskinesia was 1.5% for 200 mg Comtan and 0.8% for placebo. Other Events Reported With Dopaminergic Therapy The events listed below are events associated with the use of drugs that increase dopaminergic activity: Rhabdomyolysis Cases of severe rhabdomyolysis have been reported following the approval of Comtan. Although the reactions typically occurred while patients were treated with Comtan, the complicated nature of these cases makes it difficult to determine what role, if any, Comtan played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. Signs and symptoms include fever, alteration of consciousness, myalgia, increased values of creatine phosphokinase (CPK) and myoglobin. Hyperpyrexia and Confusion Cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) characterized by elevated temperature, muscular rigidity, altered consciousness, and elevated CPK have been reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs. In most of these cases, symptoms began after abrupt discontinuation of treatment with entacapone or reduction of its dose, or after the initiation of treatment with entacapone. The complicated nature of these cases makes it difficult to determine what role, if any, Comtan may have played in their pathogenesis. No cases have been reported following the abrupt withdrawal or dose reduction of entacapone treatment during clinical studies. Prescribers should exercise caution when discontinuing entacapone treatment. When considered necessary, withdrawal should proceed slowly. If the decision is made to discontinue treatment with Comtan, recommendations include monitoring the patient closely and adjusting other dopaminergic treatments as needed. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Tapering Comtan has not been systematically evaluated. Fibrotic Complications Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (e.g., entacapone) that increase dopaminergic activity can cause them is unknown. It should be noted that the expected incidence of fibrotic complications is so low that even if entacapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that it would have been detected in a cohort of the size exposed to entacapone. Four cases of pulmonary fibrosis were reported during clinical development of entacapone; three of these patients were also treated with pergolide and one with bromocriptine. The duration of treatment with entacapone ranged from 7 months to 17 months. 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 Comtan for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). Renal Toxicity In a 1-year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1,600 mg) caused an increased incidence of nephrotoxicity in male rats that was characterized by regenerative tubules, thickening of basement membranes, infiltration of mononuclear cells, and tubular protein casts. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although this toxicity could represent a species-specific effect, there is not yet evidence that this is so. Hepatic Impairment Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease compared to controls (see CLINICAL PHARMACOLOGY, Pharmacokinetics of Entacapone and DOSAGE AND ADMINISTRATION). Information for Patients Instruct patients to take Comtan only as prescribed. Inform patients that hallucinations and/or other psychotic-like behavior can occur. Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sweating. Hypotension may occur more frequently during initial therapy. Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially at the initiation of treatment with Comtan. Advise patients that they should neither drive a car nor operate other complex machinery until they have gained sufficient experience on Comtan to gauge whether or not it affects their mental and/or motor performance adversely. Warn patients about the possibility of sudden onset of sleep during daily activities, in some cases without awareness or warning signs, when they are taking dopaminergic agents, including Comtan. Because of the possible additive sedative effects, caution should be used when patients are taking other CNS depressants in combination with Comtan. Inform patients that nausea may occur, especially at the initiation of treatment with Comtan. Inform patients that diarrhea may occur with Comtan and it may have a delayed onset. Sometimes prolonged diarrhea may be caused by colitis (inflammation of the large intestine). Patients with diarrhea should drink fluids to maintain adequate hydration and monitor for weight loss. If diarrhea associated with Comtan is prolonged, discontinuing the drug is expected to lead to resolution, if diarrhea continues after stopping entacapone, further diagnostic investigations may be needed. Advise patients about the possibility of an increase in dyskinesia. Tell patients that treatment with entacapone may cause a change in the color of their urine (a brownish orange discoloration) that is not clinically relevant. In controlled studies, 10% of patients treated with Comtan reported urine discoloration compared to 0% of placebo patients. Although Comtan has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa and carbidopa, which is known to cause visceral and skeletal malformations in rabbits. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS, Pregnancy). Entacapone is excreted into maternal milk in rats. Because of the possibility that entacapone may be excreted into human maternal milk, advise patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant. Tell patients and family members to notify their healthcare practitioner if they notice that the patient develops unusual urges or behaviors. Laboratory Tests Comtan is a chelator of iron. The impact of entacapone on the body's iron stores is unknown; however, a tendency towards decreasing serum iron concentrations was noted in clinical studies. In a controlled clinical study, serum ferritin levels (as marker of iron deficiency and subclinical anemia) were not changed with entacapone compared to placebo after one year of treatment and there was no difference in rates of anemia or decreased hemoglobin levels. Special Populations Patients with hepatic impairment should be treated with caution (see INDICATIONS, DOSAGE AND ADMINISTRATION). Drug Interactions In vitro studies of human CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A only at very high concentrations (IC50 from 200 microM to over 1,000 microM; an oral 200 mg dose achieves a highest level of approximately 5 microM in people); these enzymes would therefore not be expected to be inhibited in clinical use. In an interaction study in healthy volunteers, entacapone did not significantly change the plasma levels of S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI90 11% to 26%], and the international normalized ratio (INR) values increased on average by 13% [CI90 6% to 19%]. Nevertheless, cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postapproval use of Comtan. Therefore, monitoring of INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Protein Binding Entacapone is highly protein bound (98%). In vitro studies have shown no binding displacement between entacapone and other highly bound drugs, such as warfarin, salicylic acid, phenylbutazone, and diazepam. Drugs Metabolized by Catechol-O-Methyltransferase (COMT) See WARNINGS. Hormone Levels Levodopa is known to depress prolactin secretion and increase growth hormone levels. Treatment with entacapone coadministered with levodopa and dopa decarboxylase inhibitor does not change these effects. Effect of Entacapone on the Metabolism of Other Drugs See WARNINGS regarding concomitant use of Comtan and non-selective MAO inhibitors. No interaction was noted with the MAO-B inhibitor selegiline in two multiple-dose interaction studies when entacapone was coadministered with a levodopa and dopa decarboxylase inhibitor (n = 29). More than 600 patients with Parkinson's disease in clinical studies have used selegiline in combination with entacapone and levodopa and dopa decarboxylase inhibitor. As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin, and chloramphenicol). No interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone without coadministered levodopa and dopa-decarboxylase inhibitor. Carcinogenesis Two-year carcinogenicity studies of entacapone were conducted in mice and rats. In mice, no increase in tumors was observed at oral doses of 100, 200 and 400 mg/kg/day. At the highest dose tested, plasma exposures (AUC) were 4 times higher than that in humans at the maximum recommended daily dose (MRDD) of 1,600 mg. In rats administered oral doses of 20, 90, or 400 mg/kg/day, an increased incidence of renal tubular adenomas and carcinomas was observed in males at the highest dose tested. Plasma AUCs at the higher dose not associated with increased renal tumors (90 mg/kg/day) were approximately 5 times that in humans at the MRDD of entacapone. The carcinogenic potential of entacapone administered in combination with levodopa and carbidopa has not been evaluated. Mutagenesis Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with levodopa and carbidopa, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test). Impairment of Fertility Entacapone did not impair fertility or general reproductive performance in rats treated with up to 700 mg/kg/day (plasma AUCs 28 times those in humans receiving the MRDD of 1,600 mg). Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg/kg/day of entacapone. Pregnancy In embryo-fetal development studies, entacapone was administered to pregnant animals throughout organogenesis at doses of up to 1,000 mg/kg/day in rats and 300 mg/kg/day in rabbits. Increased incidences of fetal variations were evident in litters from rats treated with the highest dose, in the absence of overt signs of maternal toxicity. The maternal plasma drug exposure (AUC) associated with this dose was approximately 34 times the estimated plasma exposure in humans receiving the maximum recommended daily dose (MRDD) of 1,600 mg. Increased frequencies of abortions, late and total resorptions, and decreased fetal weights were observed in the litters of rabbits treated with maternally toxic doses of 100 mg/kg/day (plasma AUCs 0.4 times those in humans receiving the MRDD) or greater. There was no evidence of teratogenicity in these studies. However, when entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, anophthalmia) was observed in the litters of dams treated with doses of 160 mg/kg/day (plasma AUCs 7 times those in humans receiving the MRDD) or greater, in the absence of maternal toxicity. Administration of up to 700 mg/kg/day (plasma AUCs 28 times those in humans receiving the MRDD) to female rats during the latter part of gestation and throughout lactation produced no evidence of developmental impairment in the offspring. Entacapone is always given concomitantly with levodopa and carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The teratogenic potential of entacapone in combination with levodopa and carbidopa was not assessed in animals. There is no experience from clinical studies regarding the use of Comtan in pregnant women. Therefore, Comtan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Women In animal studies, entacapone was excreted into maternal rat milk. It is not known whether entacapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when entacapone is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established.