These Highlights Do Not Include All The Information Needed To Use Stalevo Safely And Effectively. See Full Prescribing Information For Stalevo.

Entacapone

The most commonly observed adverse reactions (incidence at least 3% greater than placebo incidence) in the double-blind, carbidopa-levodopa-placebo-controlled trials of entacapone (N=1,003 patients) associated with the use of carbidopa-levodopa-entacapone alone and not seen at an equivalent frequency among the placebo-treated patients were: dyskinesia, diarrhea, nausea, hyperkinesia, abdominal pain, vomiting, dry mouth, and urine discoloration.

The treatment difference incidence for premature study discontinuation for entacapone with levodopa and dopa decarboxylase inhibitor in the double-blind, placebo-controlled trials was 5%. The treatment difference incidence for the most frequent causes of study discontinuation was 2% for diarrhea, and 1% for other specific adverse reactions including psychiatric reasons, dyskinesia/ hyperkinesia, nausea, or abdominal pain.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

[See USP Controlled Room Temperature.]

Dispense in tight container (USP).

Isoniazid may reduce the therapeutic effects of levodopa, a dose increase may be necessary.

The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Patients taking phenytoin with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Stalevo dosage should be increased as clinically needed in patients receiving phenytoin.

Stalevo is a combination of carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease.

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(α-hydrazino-(α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C₁₀H₁₄N₂O₄∙H₂O, and its structural formula is:

Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.

Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C₉H₁₁NO₄, and its structural formula is:

Entacapone, a COMT inhibitor, is a nitro-catechol-structured compound with a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C₁₄H₁₅N₃O₅ and its structural formula is:

Stalevo is supplied as tablets in 6 strengths:

Stalevo 50:12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone

Stalevo 75: 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone

Stalevo 100: 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone

Stalevo125: 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone

Stalevo 150: 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone

Stalevo 200: 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone

Inactive Ingredients: corn starch, croscarmellose sodium, glycerol 85%, hypromellose, magnesium stearate, mannitol, polysorbate 80, povidone, sucrose, red iron oxide, and titanium dioxide. Stalevo 50, Stalevo 100, and Stalevo 150 also contain yellow iron oxide.

Dyskinesia (involuntary movements) may occur or be exacerbated at lower dosages and sooner with Stalevo than with preparations containing only carbidopa and levodopa. The occurrence of dyskinesias may require dosage reduction.

In pivotal trials, the treatment difference incidence of dyskinesia was 10% and for carbidopa-levodopa plus 200 mg entacapone. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The treatment difference incidence of study withdrawal for dyskinesia was 1% for carbidopa-levodopa-entacapone.

The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by papaverine. Patients taking papaverine with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Stalevo dosage should be increased as clinically needed in patients receiving papaverine.

Iron salts or multi vitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa, carbidopa and entacapone and consequently reduce bioavailability of levodopa, carbidopa and entacapone.

Safety and effectiveness in pediatric patients have not been established.

Of the total number of subjects in clinical studies of Stalevo, 43.8% were 65 years old and over, while 7.2% were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients; however, greater sensitivity of some older individuals cannot be excluded.

Stalevo tablets have not been studied in Parkinson's disease patients or in healthy volunteers older than 75 years [see Clinical Pharmacology (12.3) ].

Cases of severe rhabdomyolysis have been reported with entacapone when used in combination with carbidopa and levodopa. Severe prolonged motor activity including dyskinesia may possibly account for rhabdomyolysis. Most of the cases were manifested by myalgia and increased values of creatine phosphokinase (CPK) and myoglobin. Some of the reactions also included fever and/or alteration of consciousness. It is also possible that rhabdomyolysis may be a result of the syndrome described in Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7) ].

Patients receiving nonselective MAO inhibitors and carbidopa, levodopa and entacapone may be at risk of increased adrenergic tone. Therefore, the use of Stalevo is contraindicated in patients receiving nonselective MAO inhibitors [see Contraindications (4) ].

Of the ingredients in Stalevo, levodopa is known to depress prolactin secretion and increase growth hormone levels.

The effectiveness of entacapone as an adjunct to levodopa in the treatment of Parkinson's disease was established in three 24-week multicenter, randomized, double-blind, placebo-controlled studies in patients with Parkinson's disease. In 2 of these studies (Studies 1 and 2), the patients' disease was "fluctuating", i.e., was characterized by documented periods of "On" (periods of relatively good functioning) and "Off" (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of these studies, patients were stabilized on levodopa for 2 weeks to 4 weeks.

There is limited experience using entacapone in patients who do not experience fluctuations.

In Studies 1 and 2, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of carbidopa/levodopa (up to 10 times daily, but patients averaged 4 doses to 6 doses per day). The double-blind portion of both studies was 6 months long. Patients periodically recorded the time spent in the "On" and "Off" states in home diaries throughout the duration of the trial. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the "On" state during an 18 hour diary recorded day (6 a.m. to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the "On" state.

In addition to the primary outcome measure, the amount of time spent in the "Off" state was evaluated, and patients were also evaluated by subparts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V and VI); an investigator's and patient's global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson's disease; and the change in daily carbidopa/levodopa dose.

In Study 1, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Study 1), all of whom received concomitant levodopa plus dopa decarboxylase inhibitor (either carbidopa/levodopa or benserazide/levodopa). In Study 2, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant carbidopa/levodopa.

The following tables (Table 4 and Table 5) display the results of these two studies:

Effects on "On" time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline.

Stalevo is contraindicated in patients:

• Taking nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine and tranylcypromine). These nonselective MAO inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo.
• With narrow-angle glaucoma.

The following adverse reactions are discussed in more detail in the Warnings and Precautions sections of labeling:

• Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1) ]
• Hypotension/Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.2) ]
• Dyskinesia [see Warnings and Precautions (5.3) ]
• Depression and suicidality [see Warnings and Precautions (5.4) ]
• Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.5) ]
• Impulse Control and/or Compulsive Behaviors [see Warnings and Precautions (5.6) ]
• Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7) ]
• Diarrhea and Colitis [see Warnings and Precautions (5.8) ]
• Rhabdomyolysis [see Warnings and Precautions (5.9) ]
• Peptic Ulcer Disease [see Warnings and Precautions (5.13) ]

• Drugs metabolized by COMT: use with caution (5.11,7.2)
• Anti-hypertensive agents: dose adjustment may be required (7.3)
• Tricyclic antidepressants: risk of hypertension and dyskinesia reported during concomitant use with carbidopa/levodopa (7.4)
• Dopamine D2 receptor antagonists, isoniazid, phenytoin, papaverine and iron salts: may reduce efficacy of Stalevo (7.5, 7.6, 7.7, 7.8, 7.9)
• Drugs that interfere with biliary excretion, glucuronidation and intestinal beta-glucuronidase: dose adjustment of Stalevo may be required (7.10)
• Drugs metabolized by CYP2C9 (e.g., coumadin): dose adjustment of Stalevo may be required; monitor INR when initiating Stalevo in patients on coumadin (7.11)

Renal impairment does not affect pharmacokinetics of entacapone. There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment [see Clinical Pharmacology (12.3) ].

The pharmacokinetics of Stalevo tablets has been studied in healthy subjects (age 45 years to 75 years). Overall, following administration of corresponding doses of levodopa, carbidopa and entacapone as Stalevo or as carbidopa and levodopa product plus Comtan (entacapone) tablets, the mean plasma concentrations of levodopa, carbidopa, and entacapone are comparable.

Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of Stalevo than with levodopa.

Stalevo may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.

Cases of falsely diagnosed pheochromocytoma in patients on carbidopa/levodopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on carbidopa/levodopa therapy.

The optimum daily dosage of Stalevo must be determined by careful titration in each patient.

Clinical experience with daily doses above 1,600 mg of entacapone is limited. The maximum recommended daily dose of Stalevo depends on the strength used. The maximum number of tablets to be used in a 24-hour period is less with the highest strength (Stalevo 200) than with lower strengths (see Table 1). Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 mg per day to 100 mg per day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.

Stalevo is indicated for the treatment of Parkinson's disease.

Stalevo can be used:

• To substitute (with equivalent strengths of each of the three components) carbidopa/levodopa and entacapone previously administered as individual products.
• To replace carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" and when they have been taking a total daily dose of levodopa of 600 mg or less and have not been experiencing dyskinesias.

Patients with hepatic impairment should be treated with caution [see Clinical Pharmacology (12.3) ]. As with levodopa, periodic evaluation of hepatic function is recommended during extended therapy.

In clinical trials of entacapone, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg of entacapone or placebo in combination with levodopa and dopa decarboxylase inhibitor, respectively. In patients treated with entacapone, 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 entacapone. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 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 entacapone treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of entacapone but recurred after retreatment with entacapone.

If prolonged diarrhea is suspected to be related to Stalevo, 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.

As with levodopa, treatment with Stalevo may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

The following adverse reactions described in this section are related to at least one of the components of Stalevo (i.e., levodopa, carbidopa, and/or entacapone) based upon the safety experience in clinical trials (especially pivotal trials) or in postmarketing reports.

Stalevo should be used as a substitute for patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. However, some patients who have been stabilized on a given dose of carbidopa/levodopa may be treated with Stalevo if a decision has been made to add entacapone (see below). Therapy should be individualized and adjusted according to the desired therapeutic response.

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 reactions may be related to the ergoline structure of these compounds, a possible causal role of nonergot derived drugs (e.g., entacapone, levodopa), which increase dopaminergic activity, has also been considered. 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 during its clinical development. Four cases of pulmonary fibrosis have been reported during clinical development of entacapone; 3 of these patients were also treated with pergolide and 1 with bromocriptine. The duration of treatment with entacapone ranged from 7 months to 17 months.

Symptomatic postural hypotension has occurred when carbidopa/levodopa was added to the treatment of patients receiving antihypertensive drugs. When starting therapy with Stalevo, dosage adjustment of antihypertensive drug may be required.

Each Stalevo tablet, provided in 6 single-dose strengths, contains carbidopa and levodopa in a 1:4 ratio and a 200 mg dose of entacapone. Stalevo (carbidopa, levodopa and entacapone) is supplied as film-coated tablets for oral administration in the following 6 strengths:

Stalevo 50 film-coated tablets containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone. The round, bi-convex shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 50" on one side.

Stalevo 75 film-coated tablets containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 75" on one side.

Stalevo 100 film-coated tablets containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 100" on one side.

Stalevo 125 film-coated tablets containing 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 125" on one side.

Stalevo 150 film-coated tablets containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone. The elongated-ellipse shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 150" on one side.

Stalevo 200 film-coated tablets containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone. The oval shaped tablets are dark brownish red, unscored, and embossed "LCE 200" on one side.

The following spontaneous reports of adverse events temporally associated with entacapone or Stalevo have been identified since market introduction and are not listed in Table 2. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to entacapone or Stalevo exposure.

Hepatitis with mainly cholestatic features has been reported.

Hospitalization is advised, and general supportive measures should be employed, along with immediate gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of entacapone in particular, by decreasing its absorption and reabsorption from the GI tract. Intravenous fluids should be administered judiciously and an adequate airway maintained.

Respiratory, circulatory and renal function should be monitored and appropriate supportive measures employed. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs, increasing the risk of drug interactions (especially catechol-structured drugs) should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Hemodialysis or hemoperfusion is unlikely to reduce entacapone levels due to its high binding to plasma proteins.

Pyridoxine is not effective in reversing the actions of Stalevo.

There have been reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa/levodopa.

• Pregnancy: based on animal data, may cause fetal harm (8.1)

All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or current psychoses should be treated with caution.

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment/total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in clinical practice.

Stalevo (carbidopa, levodopa and entacapone) is supplied as film-coated tablets for oral administration in the following six strengths:

Stalevo 50 film-coated tablets containing 12.5 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone.

The round, bi-convex shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 50" on one side.

Stalevo 75 film-coated tablets containing 18.75 mg of carbidopa, 75 mg of levodopa, and 200 mg of entacapone.

The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 75" on one side.

Stalevo 100 film-coated tablets containing 25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone.

The oval-shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 100" on one side.

Stalevo 125 film-coated tablets containing 31.25 mg of carbidopa, 125 mg of levodopa, and 200 mg of entacapone.

The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 125" on one side.

Stalevo 150 film-coated tablets containing 37.5 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone.

The elongated-ellipse shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 150" on one side.

Stalevo 200 film-coated tablets containing 50 mg of carbidopa, 200 mg of levodopa, and 200 mg of entacapone.

The oval shaped tablets are dark brownish red, unscored, and embossed "LCE 200" on one side.

Dopamine D2 receptor antagonists (e.g., metoclopramide, phenothiazines, butyrophenones, risperidone) may reduce the therapeutic effects of levodopa.

There are very few cases of overdose with levodopa reported in the published literature. Based on the available information, the acute symptoms of levodopa and dopa decarboxylase inhibitor overdose can be expected to arise from dopaminergic overstimulation. Doses of a few grams may result in CNS disturbances, with an increasing likelihood of cardiovascular disturbance (e.g., hypotension, tachycardia) and more severe psychiatric problems at higher doses. An isolated report of rhabdomyolysis and another of transient renal insufficiency suggest that levodopa overdose may give rise to systemic complications, secondary to dopaminergic overstimulation.

COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of entacapone may theoretically produce a 100% inhibition of the COMT enzyme in people, thereby preventing the O-methylation of endogenous and exogenous catechols.

In clinical trials, the highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 mcg per mL. The highest daily dose given to humans was 2,400 mg, administered in one study as 400 mg six times daily with carbidopa/levodopa for 14 days in 15 Parkinson's disease patients, and in another study as 800 mg three times daily for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 mcg per mL (at 45 min, compared to 1.0 mcg per mL and 1.2 mcg per mL with 200 mg entacapone at 45 min.). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2,000 mg entacapone have been administered as 200 mg 10 times daily with carbidopa/levodopa or benserazide/levodopa for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1,600 mg is limited.

Avoid interruption of Stalevo dosing because hyperpyrexia has been reported in patients who suddenly discontinue or reduce their use of levodopa [see Warnings and Precautions (5.7) ].

Do not split, crush or chew Stalevo tablets. Administer only one tablet at each dosing interval. All strengths of Stalevo contain 200 mg of entacapone. Combining multiple tablets or portions of tablets to achieve a higher levodopa dose may lead to an overdose of entacapone.

Administer Stalevo with or without food. However, a high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours [see Clinical Pharmacology (12.3) ].

There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment. Stalevo should be administered cautiously to patients with biliary obstruction or hepatic disease since biliary excretion appears to be the major route of excretion of entacapone and hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone [see Clinical Pharmacology (12.3) ].

Drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rate, arrhythmia, and/or increased blood pressure.

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 generally used for the treatment of Parkinson's disease and which increase central dopaminergic tone, including entacapone 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 Stalevo if a patient develops such urges while taking Stalevo [see Dosage and Administration (2.5), Warnings and Precautions (5.7) ].

Dopaminergic therapy in patients with Parkinson's disease has been associated with hallucinations. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with carbidopa, levodopa, entacapone and carbidopa, levodopa, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the carbidopa, levodopa, entacapone and carbidopa, levodopa, groups, respectively. Agitation occurred in 1% of patients treated with carbidopa, levodopa, entacapone and 0% treated with carbidopa, levodopa.

Cases of hyperpyrexia and confusion resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reduction or withdrawal of therapy with carbidopa, levodopa and entacapone. However, in some cases, hyperpyrexia and confusion were reported after initiation of treatment with entacapone. Hyperpyrexia and confusion are uncommon but they may be life-threatening with a variety of features, including hyperpyrexia/fever/hyperthermia, muscle rigidity, involuntary movements, altered consciousness/mental status changes, delirium, autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension, and abnormal laboratory findings (e.g., creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin).

If a patient needs to discontinue or reduce their daily dose of Stalevo, the dose should be decreased slowly, with supervision from a health care provider [see Dosage and Administration (2.5) ]. Specific methods for tapering entacapone have not been systematically evaluated.

The dosage of Stalevo should be adjusted as clinically needed in patients using other drugs metabolized via CYP2C9. An interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values on average by 13%. Cases of increased INR in patients concomitantly using warfarin have been reported during the post-approval use of entacapone. Thus, monitoring of INR is recommended when Stalevo treatment is initiated for patients receiving warfarin.

Reports of syncope were generally more frequent in patients in both treatment groups who had had a prior episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement). Hypotension, orthostatic hypotension, and syncope are observed in patients treated with drugs that increase central dopaminergic tone including Stalevo.

NDC 52427-805-01

Stalevo^® 50

carbidopa USP 12.5 mg

levodopa USP 50 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-809-01

Stalevo^® 75

carbidopa USP 18.75 mg

levodopa USP 75 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-816-01

Stalevo^® 100

carbidopa USP 25 mg

levodopa USP 100 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-827-01

Stalevo^® 125

carbidopa USP 31.25 mg

levodopa USP 125 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-834-01

Stalevo^® 150

carbidopa USP 37.5 mg

levodopa USP 150 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-842-01

Stalevo^® 200

carbidopa USP 50 mg

levodopa USP 200 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

Drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure [see Warnings and Precautions (5.10) ].

Anticholinergic agents, dopamine agonists, monoamine oxidase (MAO) - B inhibitors, amantadine, and other standard drugs for Parkinson's disease may be used concomitantly while Stalevo is being administered; however, dosage adjustments of the concomitant medication or Stalevo may be required.

Patients with Parkinson's disease treated with Stalevo or other carbidopa/levodopa products have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (including the operation of motor vehicles). Some of these episodes resulted in accidents. Although many of these patients reported somnolence while taking entacapone, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported to occur up to one year after initiation of treatment.

Somnolence was reported in 2% of patients taking entacapone and 0% in placebo in controlled trials. It is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with Stalevo.

Before initiating treatment with Stalevo, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase this risk such as use of concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Stalevo should ordinarily be discontinued [see Dosage and Administration (2.5) and Warnings and Precautions (5.7) ]. If the decision is made to continue Stalevo, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

There is no experience in transferring patients currently treated with extended release formulations of carbidopa/levodopa, or carbidopa/levodopa products that are not combined in a 1:4 ratio of carbidopa to levodopa.

Patients with a history of moderate or severe dyskinesias or taking more than 600 mg of the levodopa component per day are likely to require a reduction in their daily levodopa dose when entacapone is added. Because dose adjustment of the individual carbidopa or levodopa component is not possible with fixed-dose products, initially titrate patients to a dose that is tolerated and that meets their individual therapeutic need using a separate carbidopa/levodopa tablet (1:4 ratio) plus an entacapone tablet. Once the patient's individual dose of carbidopa/levodopa plus entacapone dose has been established using two separate tablets; switch the patient to a corresponding single tablet of Stalevo.

When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa either by decreasing the strength of Stalevo at each administration or by decreasing the frequency of administration by extending the time between doses.

Patients currently treated with entacapone 200 mg with each dose of non-extended release carbidopa/levodopa tablet, can switch to the corresponding strength of Stalevo containing the same amounts of levodopa and carbidopa. For example, patients receiving one tablet of carbidopa/levodopa 25 mg/100 mg and one tablet of entacapone 200 mg at each administration can switch to a single Stalevo 100 tablet (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone).

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).

Entacapone

The most commonly observed adverse reactions (incidence at least 3% greater than placebo incidence) in the double-blind, carbidopa-levodopa-placebo-controlled trials of entacapone (N=1,003 patients) associated with the use of carbidopa-levodopa-entacapone alone and not seen at an equivalent frequency among the placebo-treated patients were: dyskinesia, diarrhea, nausea, hyperkinesia, abdominal pain, vomiting, dry mouth, and urine discoloration.

The treatment difference incidence for premature study discontinuation for entacapone with levodopa and dopa decarboxylase inhibitor in the double-blind, placebo-controlled trials was 5%. The treatment difference incidence for the most frequent causes of study discontinuation was 2% for diarrhea, and 1% for other specific adverse reactions including psychiatric reasons, dyskinesia/ hyperkinesia, nausea, or abdominal pain.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

[See USP Controlled Room Temperature.]

Dispense in tight container (USP).

Isoniazid may reduce the therapeutic effects of levodopa, a dose increase may be necessary.

The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Patients taking phenytoin with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Stalevo dosage should be increased as clinically needed in patients receiving phenytoin.

Stalevo is a combination of carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease.

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(α-hydrazino-(α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C₁₀H₁₄N₂O₄∙H₂O, and its structural formula is:

Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.

Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C₉H₁₁NO₄, and its structural formula is:

Entacapone, a COMT inhibitor, is a nitro-catechol-structured compound with a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C₁₄H₁₅N₃O₅ and its structural formula is:

Stalevo is supplied as tablets in 6 strengths:

Stalevo 50:12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone

Stalevo 75: 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone

Stalevo 100: 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone

Stalevo125: 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone

Stalevo 150: 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone

Stalevo 200: 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone

Inactive Ingredients: corn starch, croscarmellose sodium, glycerol 85%, hypromellose, magnesium stearate, mannitol, polysorbate 80, povidone, sucrose, red iron oxide, and titanium dioxide. Stalevo 50, Stalevo 100, and Stalevo 150 also contain yellow iron oxide.

Dyskinesia (involuntary movements) may occur or be exacerbated at lower dosages and sooner with Stalevo than with preparations containing only carbidopa and levodopa. The occurrence of dyskinesias may require dosage reduction.

In pivotal trials, the treatment difference incidence of dyskinesia was 10% and for carbidopa-levodopa plus 200 mg entacapone. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The treatment difference incidence of study withdrawal for dyskinesia was 1% for carbidopa-levodopa-entacapone.

The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by papaverine. Patients taking papaverine with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Stalevo dosage should be increased as clinically needed in patients receiving papaverine.

Iron salts or multi vitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa, carbidopa and entacapone and consequently reduce bioavailability of levodopa, carbidopa and entacapone.

Safety and effectiveness in pediatric patients have not been established.

Of the total number of subjects in clinical studies of Stalevo, 43.8% were 65 years old and over, while 7.2% were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients; however, greater sensitivity of some older individuals cannot be excluded.

Stalevo tablets have not been studied in Parkinson's disease patients or in healthy volunteers older than 75 years [see Clinical Pharmacology (12.3) ].

Cases of severe rhabdomyolysis have been reported with entacapone when used in combination with carbidopa and levodopa. Severe prolonged motor activity including dyskinesia may possibly account for rhabdomyolysis. Most of the cases were manifested by myalgia and increased values of creatine phosphokinase (CPK) and myoglobin. Some of the reactions also included fever and/or alteration of consciousness. It is also possible that rhabdomyolysis may be a result of the syndrome described in Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7) ].

Patients receiving nonselective MAO inhibitors and carbidopa, levodopa and entacapone may be at risk of increased adrenergic tone. Therefore, the use of Stalevo is contraindicated in patients receiving nonselective MAO inhibitors [see Contraindications (4) ].

Of the ingredients in Stalevo, levodopa is known to depress prolactin secretion and increase growth hormone levels.

The effectiveness of entacapone as an adjunct to levodopa in the treatment of Parkinson's disease was established in three 24-week multicenter, randomized, double-blind, placebo-controlled studies in patients with Parkinson's disease. In 2 of these studies (Studies 1 and 2), the patients' disease was "fluctuating", i.e., was characterized by documented periods of "On" (periods of relatively good functioning) and "Off" (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of these studies, patients were stabilized on levodopa for 2 weeks to 4 weeks.

There is limited experience using entacapone in patients who do not experience fluctuations.

In Studies 1 and 2, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of carbidopa/levodopa (up to 10 times daily, but patients averaged 4 doses to 6 doses per day). The double-blind portion of both studies was 6 months long. Patients periodically recorded the time spent in the "On" and "Off" states in home diaries throughout the duration of the trial. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the "On" state during an 18 hour diary recorded day (6 a.m. to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the "On" state.

In addition to the primary outcome measure, the amount of time spent in the "Off" state was evaluated, and patients were also evaluated by subparts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V and VI); an investigator's and patient's global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson's disease; and the change in daily carbidopa/levodopa dose.

In Study 1, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Study 1), all of whom received concomitant levodopa plus dopa decarboxylase inhibitor (either carbidopa/levodopa or benserazide/levodopa). In Study 2, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant carbidopa/levodopa.

The following tables (Table 4 and Table 5) display the results of these two studies:

Effects on "On" time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline.

Stalevo is contraindicated in patients:

• Taking nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine and tranylcypromine). These nonselective MAO inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo.
• With narrow-angle glaucoma.

The following adverse reactions are discussed in more detail in the Warnings and Precautions sections of labeling:

• Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1) ]
• Hypotension/Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.2) ]
• Dyskinesia [see Warnings and Precautions (5.3) ]
• Depression and suicidality [see Warnings and Precautions (5.4) ]
• Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.5) ]
• Impulse Control and/or Compulsive Behaviors [see Warnings and Precautions (5.6) ]
• Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7) ]
• Diarrhea and Colitis [see Warnings and Precautions (5.8) ]
• Rhabdomyolysis [see Warnings and Precautions (5.9) ]
• Peptic Ulcer Disease [see Warnings and Precautions (5.13) ]

• Drugs metabolized by COMT: use with caution (5.11,7.2)
• Anti-hypertensive agents: dose adjustment may be required (7.3)
• Tricyclic antidepressants: risk of hypertension and dyskinesia reported during concomitant use with carbidopa/levodopa (7.4)
• Dopamine D2 receptor antagonists, isoniazid, phenytoin, papaverine and iron salts: may reduce efficacy of Stalevo (7.5, 7.6, 7.7, 7.8, 7.9)
• Drugs that interfere with biliary excretion, glucuronidation and intestinal beta-glucuronidase: dose adjustment of Stalevo may be required (7.10)
• Drugs metabolized by CYP2C9 (e.g., coumadin): dose adjustment of Stalevo may be required; monitor INR when initiating Stalevo in patients on coumadin (7.11)

Renal impairment does not affect pharmacokinetics of entacapone. There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment [see Clinical Pharmacology (12.3) ].

The pharmacokinetics of Stalevo tablets has been studied in healthy subjects (age 45 years to 75 years). Overall, following administration of corresponding doses of levodopa, carbidopa and entacapone as Stalevo or as carbidopa and levodopa product plus Comtan (entacapone) tablets, the mean plasma concentrations of levodopa, carbidopa, and entacapone are comparable.

Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of Stalevo than with levodopa.

Stalevo may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.

Cases of falsely diagnosed pheochromocytoma in patients on carbidopa/levodopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on carbidopa/levodopa therapy.

The optimum daily dosage of Stalevo must be determined by careful titration in each patient.

Clinical experience with daily doses above 1,600 mg of entacapone is limited. The maximum recommended daily dose of Stalevo depends on the strength used. The maximum number of tablets to be used in a 24-hour period is less with the highest strength (Stalevo 200) than with lower strengths (see Table 1). Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 mg per day to 100 mg per day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.

Stalevo is indicated for the treatment of Parkinson's disease.

Stalevo can be used:

• To substitute (with equivalent strengths of each of the three components) carbidopa/levodopa and entacapone previously administered as individual products.
• To replace carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" and when they have been taking a total daily dose of levodopa of 600 mg or less and have not been experiencing dyskinesias.

Patients with hepatic impairment should be treated with caution [see Clinical Pharmacology (12.3) ]. As with levodopa, periodic evaluation of hepatic function is recommended during extended therapy.

In clinical trials of entacapone, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg of entacapone or placebo in combination with levodopa and dopa decarboxylase inhibitor, respectively. In patients treated with entacapone, 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 entacapone. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 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 entacapone treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of entacapone but recurred after retreatment with entacapone.

If prolonged diarrhea is suspected to be related to Stalevo, 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.

As with levodopa, treatment with Stalevo may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

The following adverse reactions described in this section are related to at least one of the components of Stalevo (i.e., levodopa, carbidopa, and/or entacapone) based upon the safety experience in clinical trials (especially pivotal trials) or in postmarketing reports.

Stalevo should be used as a substitute for patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. However, some patients who have been stabilized on a given dose of carbidopa/levodopa may be treated with Stalevo if a decision has been made to add entacapone (see below). Therapy should be individualized and adjusted according to the desired therapeutic response.

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 reactions may be related to the ergoline structure of these compounds, a possible causal role of nonergot derived drugs (e.g., entacapone, levodopa), which increase dopaminergic activity, has also been considered. 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 during its clinical development. Four cases of pulmonary fibrosis have been reported during clinical development of entacapone; 3 of these patients were also treated with pergolide and 1 with bromocriptine. The duration of treatment with entacapone ranged from 7 months to 17 months.

Symptomatic postural hypotension has occurred when carbidopa/levodopa was added to the treatment of patients receiving antihypertensive drugs. When starting therapy with Stalevo, dosage adjustment of antihypertensive drug may be required.

Each Stalevo tablet, provided in 6 single-dose strengths, contains carbidopa and levodopa in a 1:4 ratio and a 200 mg dose of entacapone. Stalevo (carbidopa, levodopa and entacapone) is supplied as film-coated tablets for oral administration in the following 6 strengths:

Stalevo 50 film-coated tablets containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone. The round, bi-convex shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 50" on one side.

Stalevo 75 film-coated tablets containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 75" on one side.

Stalevo 100 film-coated tablets containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 100" on one side.

Stalevo 125 film-coated tablets containing 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 125" on one side.

Stalevo 150 film-coated tablets containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone. The elongated-ellipse shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 150" on one side.

Stalevo 200 film-coated tablets containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone. The oval shaped tablets are dark brownish red, unscored, and embossed "LCE 200" on one side.

The following spontaneous reports of adverse events temporally associated with entacapone or Stalevo have been identified since market introduction and are not listed in Table 2. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to entacapone or Stalevo exposure.

Hepatitis with mainly cholestatic features has been reported.

Hospitalization is advised, and general supportive measures should be employed, along with immediate gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of entacapone in particular, by decreasing its absorption and reabsorption from the GI tract. Intravenous fluids should be administered judiciously and an adequate airway maintained.

Respiratory, circulatory and renal function should be monitored and appropriate supportive measures employed. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs, increasing the risk of drug interactions (especially catechol-structured drugs) should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Hemodialysis or hemoperfusion is unlikely to reduce entacapone levels due to its high binding to plasma proteins.

Pyridoxine is not effective in reversing the actions of Stalevo.

There have been reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa/levodopa.

• Pregnancy: based on animal data, may cause fetal harm (8.1)

All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or current psychoses should be treated with caution.

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment/total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in clinical practice.

Stalevo (carbidopa, levodopa and entacapone) is supplied as film-coated tablets for oral administration in the following six strengths:

Stalevo 50 film-coated tablets containing 12.5 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone.

The round, bi-convex shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 50" on one side.

Stalevo 75 film-coated tablets containing 18.75 mg of carbidopa, 75 mg of levodopa, and 200 mg of entacapone.

The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 75" on one side.

Stalevo 100 film-coated tablets containing 25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone.

The oval-shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 100" on one side.

Stalevo 125 film-coated tablets containing 31.25 mg of carbidopa, 125 mg of levodopa, and 200 mg of entacapone.

The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 125" on one side.

Stalevo 150 film-coated tablets containing 37.5 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone.

The elongated-ellipse shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 150" on one side.

Stalevo 200 film-coated tablets containing 50 mg of carbidopa, 200 mg of levodopa, and 200 mg of entacapone.

The oval shaped tablets are dark brownish red, unscored, and embossed "LCE 200" on one side.

Dopamine D2 receptor antagonists (e.g., metoclopramide, phenothiazines, butyrophenones, risperidone) may reduce the therapeutic effects of levodopa.

There are very few cases of overdose with levodopa reported in the published literature. Based on the available information, the acute symptoms of levodopa and dopa decarboxylase inhibitor overdose can be expected to arise from dopaminergic overstimulation. Doses of a few grams may result in CNS disturbances, with an increasing likelihood of cardiovascular disturbance (e.g., hypotension, tachycardia) and more severe psychiatric problems at higher doses. An isolated report of rhabdomyolysis and another of transient renal insufficiency suggest that levodopa overdose may give rise to systemic complications, secondary to dopaminergic overstimulation.

COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of entacapone may theoretically produce a 100% inhibition of the COMT enzyme in people, thereby preventing the O-methylation of endogenous and exogenous catechols.

In clinical trials, the highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 mcg per mL. The highest daily dose given to humans was 2,400 mg, administered in one study as 400 mg six times daily with carbidopa/levodopa for 14 days in 15 Parkinson's disease patients, and in another study as 800 mg three times daily for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 mcg per mL (at 45 min, compared to 1.0 mcg per mL and 1.2 mcg per mL with 200 mg entacapone at 45 min.). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2,000 mg entacapone have been administered as 200 mg 10 times daily with carbidopa/levodopa or benserazide/levodopa for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1,600 mg is limited.

Avoid interruption of Stalevo dosing because hyperpyrexia has been reported in patients who suddenly discontinue or reduce their use of levodopa [see Warnings and Precautions (5.7) ].

Do not split, crush or chew Stalevo tablets. Administer only one tablet at each dosing interval. All strengths of Stalevo contain 200 mg of entacapone. Combining multiple tablets or portions of tablets to achieve a higher levodopa dose may lead to an overdose of entacapone.

Administer Stalevo with or without food. However, a high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours [see Clinical Pharmacology (12.3) ].

There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment. Stalevo should be administered cautiously to patients with biliary obstruction or hepatic disease since biliary excretion appears to be the major route of excretion of entacapone and hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone [see Clinical Pharmacology (12.3) ].

Drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rate, arrhythmia, and/or increased blood pressure.

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 generally used for the treatment of Parkinson's disease and which increase central dopaminergic tone, including entacapone 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 Stalevo if a patient develops such urges while taking Stalevo [see Dosage and Administration (2.5), Warnings and Precautions (5.7) ].

Dopaminergic therapy in patients with Parkinson's disease has been associated with hallucinations. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with carbidopa, levodopa, entacapone and carbidopa, levodopa, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the carbidopa, levodopa, entacapone and carbidopa, levodopa, groups, respectively. Agitation occurred in 1% of patients treated with carbidopa, levodopa, entacapone and 0% treated with carbidopa, levodopa.

Cases of hyperpyrexia and confusion resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reduction or withdrawal of therapy with carbidopa, levodopa and entacapone. However, in some cases, hyperpyrexia and confusion were reported after initiation of treatment with entacapone. Hyperpyrexia and confusion are uncommon but they may be life-threatening with a variety of features, including hyperpyrexia/fever/hyperthermia, muscle rigidity, involuntary movements, altered consciousness/mental status changes, delirium, autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension, and abnormal laboratory findings (e.g., creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin).

If a patient needs to discontinue or reduce their daily dose of Stalevo, the dose should be decreased slowly, with supervision from a health care provider [see Dosage and Administration (2.5) ]. Specific methods for tapering entacapone have not been systematically evaluated.

The dosage of Stalevo should be adjusted as clinically needed in patients using other drugs metabolized via CYP2C9. An interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values on average by 13%. Cases of increased INR in patients concomitantly using warfarin have been reported during the post-approval use of entacapone. Thus, monitoring of INR is recommended when Stalevo treatment is initiated for patients receiving warfarin.

Reports of syncope were generally more frequent in patients in both treatment groups who had had a prior episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement). Hypotension, orthostatic hypotension, and syncope are observed in patients treated with drugs that increase central dopaminergic tone including Stalevo.

NDC 52427-805-01

Stalevo^® 50

carbidopa USP 12.5 mg

levodopa USP 50 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-809-01

Stalevo^® 75

carbidopa USP 18.75 mg

levodopa USP 75 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-816-01

Stalevo^® 100

carbidopa USP 25 mg

levodopa USP 100 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-827-01

Stalevo^® 125

carbidopa USP 31.25 mg

levodopa USP 125 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-834-01

Stalevo^® 150

carbidopa USP 37.5 mg

levodopa USP 150 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

NDC 52427-842-01

Stalevo^® 200

carbidopa USP 50 mg

levodopa USP 200 mg

and

entacapone 200 mg

Rx only

100 Tablets

Do not combine tablets to achieve a higher strength

tablet due to the risk of entacapone overdose.

Drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure [see Warnings and Precautions (5.10) ].

Anticholinergic agents, dopamine agonists, monoamine oxidase (MAO) - B inhibitors, amantadine, and other standard drugs for Parkinson's disease may be used concomitantly while Stalevo is being administered; however, dosage adjustments of the concomitant medication or Stalevo may be required.

Patients with Parkinson's disease treated with Stalevo or other carbidopa/levodopa products have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (including the operation of motor vehicles). Some of these episodes resulted in accidents. Although many of these patients reported somnolence while taking entacapone, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported to occur up to one year after initiation of treatment.

Somnolence was reported in 2% of patients taking entacapone and 0% in placebo in controlled trials. It is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with Stalevo.

Before initiating treatment with Stalevo, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase this risk such as use of concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Stalevo should ordinarily be discontinued [see Dosage and Administration (2.5) and Warnings and Precautions (5.7) ]. If the decision is made to continue Stalevo, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

There is no experience in transferring patients currently treated with extended release formulations of carbidopa/levodopa, or carbidopa/levodopa products that are not combined in a 1:4 ratio of carbidopa to levodopa.

Patients with a history of moderate or severe dyskinesias or taking more than 600 mg of the levodopa component per day are likely to require a reduction in their daily levodopa dose when entacapone is added. Because dose adjustment of the individual carbidopa or levodopa component is not possible with fixed-dose products, initially titrate patients to a dose that is tolerated and that meets their individual therapeutic need using a separate carbidopa/levodopa tablet (1:4 ratio) plus an entacapone tablet. Once the patient's individual dose of carbidopa/levodopa plus entacapone dose has been established using two separate tablets; switch the patient to a corresponding single tablet of Stalevo.

When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa either by decreasing the strength of Stalevo at each administration or by decreasing the frequency of administration by extending the time between doses.

Patients currently treated with entacapone 200 mg with each dose of non-extended release carbidopa/levodopa tablet, can switch to the corresponding strength of Stalevo containing the same amounts of levodopa and carbidopa. For example, patients receiving one tablet of carbidopa/levodopa 25 mg/100 mg and one tablet of entacapone 200 mg at each administration can switch to a single Stalevo 100 tablet (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone).

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).