左旋多巴、卡比多巴、恩托卡朋三者的复方制剂stalevo最近已经在国外上市，用于治疗帕金森病的剂末效应，即一种长期用帕金森病药物后的药效衰退现象。该药现在有三种规格，即stalevo 50（左旋多巴/卡比多巴/恩托卡朋 50/12.5/200mg），stalevo100（左旋多巴/卡比多巴/恩托卡朋100/25/200mg），stalevo 150（左旋多巴/卡比多巴/恩托卡朋150/37.5/200mg）。stalevo的优势在于服用方便，尤其需要服用很多药物且吞咽有困难的帕金森病患者。大多数服用左旋多巴、卡比多巴标准片加恩托卡朋的患者可以直接切换到相对应的stalevo上去。对于服用左旋多巴、卡比多巴标准片但没有服用恩托卡朋的患者，应用stalevo即相当于增加了恩托卡朋。

 
Stalevo
Drug Descriptionfont sizeAAAStalevo® 50
Stalevo® 75
Stalevo® 100
Stalevo® 125
Stalevo® 150
Stalevo® 200

(carbidopa, levodopa and entacapone) Tablets
DRUG DESCRIPTION
Stalevo® (carbidopa, levodopa and entacapone) 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-(3,4dihydroxybenzene) propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is
Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), 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® (carbidopa, levodopa and entacapone) is supplied as tablets in six strengths: Stalevo® 50, containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone; Stalevo® 75, containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone; Stalevo® 100, containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone; Stalevo® 125, containing 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone; Stalevo® 150, containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone; Stalevo® 200, containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone.
The inactive ingredients of the Stalevo® tablet are 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.
INDICATIONS
Stalevo® (carbidopa, levodopa and entacapone) is indicated to treat patients with idiopathic Parkinson's disease:
1.To substitute (with equivalent strength of each of the three components) for immediate-release carbidopa/levodopa and entacapone previously administered as individual products.
2.To replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose “wearing-off” (only for patients taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias, see DOSAGE AND ADMINISTRATION).
DOSAGE AND ADMINISTRATION
Individual tablets should not be fractionated and only one tablet should be administered at each dosing interval.
Generally speaking, Stalevo® (carbidopa, levodopa and entacapone) 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).
The optimum daily dosage of Stalevo® must be determined by careful titration in each patient. Stalevo® tablets are available in six strengths, each in a 1:4 ratio of carbidopa to levodopa and combined with 200 mg of entacapone in a standard release formulation (Stalevo® 50 containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone; Stalevo® 75, containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone; Stalevo® 100 containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone; Stalevo® 125, containing 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone; Stalevo® 150 containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone; and Stalevo® 200 containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone).
Therapy should be individualized and adjusted according to the desired therapeutic response.
Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 mg to 100 mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.
Clinical experience with daily doses above 1600 mg of entacapone is limited. It is recommended that no more than one Stalevo® tablet be taken at each dosing administration.
Thus the maximum recommended daily dose of Stalevo® 50, Stalevo® 75, Stalevo® 100, Stalevo® 125 and Stalevo® 150, defined by the maximum daily dose of entacapone, is eight tablets per day. Because there is limited experience with total daily doses of carbidopa greater than 300mg, the maximum recommended daily dose of Stalevo® 200 is six tablets per day.
How to transfer patients taking carbidopa-levodopa preparations and Comtan® (entacapone) tablets to Stalevo® (carbidopa, levodopa and entacapone) tablets
There is no experience in transferring patients currently treated with formulations of carbidopa-levodopa other than immediate-release carbidopa-levodopa with a 1:4 ratio (controlledrelease formulations, or standard-release presentations with a 1:10 ratio of carbidopa-levodopa) and entacapone to Stalevo®.
Patients who are currently treated with Comtan 200 mg tablet with each dose of standard-release carbidopa-levodopa, can be directly switched to the corresponding strength of Stalevo® containing the same amounts of levodopa and carbidopa. For example, patients receiving one tablet of standard-release carbidopa-levodopa 25/100 mg and one tablet of Comtan 200 mg at each
administration can be switched to a single Stalevo® 100 tablet (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone).
How to transfer patients not currently treated with Comtan® (entacapone) tablets from carbidopa-levodopa to Stalevo® (carbidopa, levodopa and entacapone) tablets
In patients with Parkinson's disease who experience the signs and symptoms of end-of-dose “wearing-off” on their current standard-release carbidopa-levodopa treatment, clinical experience shows that patients with a history of moderate or severe dyskinesias or taking more than 600 mg of levodopa per day are likely to require a reduction in daily levodopa dose when entacapone is added to their treatment. Since dose adjustment of the individual components is impossible with fixed-dose products, it is recommended that patients first be titrated individually with a carbidopa-levodopa product (ratio 1:4) and an entacapone product, and then transferred to a corresponding dose of Stalevo® once the patient's status has stabilized.
In patients who take a total daily levodopa dose up to 600 mg, and who do not have dyskinesias, an attempt can be made to transfer to the corresponding daily dose of Stalevo®. Even in these patients, a reduction of carbidopa-levodopa or entacapone may be necessary however, the provider is reminded that this may not be possible with Stalevo®. Since entacapone prolongs and enhances the effects of levodopa, therapy should be individualized and adjusted if necessary according to the desired therapeutic response.
Maintenance of Stalevo® Treatment
Therapy should be individualized and adjusted for each patient according to the desired therapeutic response.
When less levodopa is required, the total daily dosage of carbidopa-levodopa should be reduced by either decreasing the strength of Stalevo® at each administration or by decreasing the frequency of administration by extending the time between doses.
When more levodopa is required, the next higher strength of Stalevo® should be taken and/or the frequency of doses should be increased, up to a maximum of 8 times daily of Stalevo® 50, Stalevo® 75, Stalevo® 100, Stalevo® 125 and Stalevo® 150
 and maximum of 6 times daily of Stalevo® 200.

Addition of Other Antiparkinsonian Medications
Standard drugs for Parkinson's disease may be used concomitantly while Stalevo® is being administered, although dosage adjustments may be required.

Interruption of Therapy
Sporadic cases of a symptom complex resembling Neuroleptic Malignant Syndrome (NMS) have been associated with dose reductions and withdrawal of levodopa preparations. Patients should be observed carefully if abrupt reduction or discontinuation of Stalevo® is required, especially if the patient is receiving neuroleptics. (See WARNINGS.)

If general anesthesia is required, Stalevo® may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the patient should be observed for symptoms resembling NMS, and the usual daily dosage may be administered as soon as the patient is able to take oral medication.

Special Populations
Patients With Impaired Hepatic Function
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. However, these studies were conducted with single-dose entacapone without levodopa/dopa decarboxylase inhibitor coadministration, and therefore the effects of liver disease on the kinetics of chronically administered entacapone have not been evaluated (see CLINICAL PHARMACOLOGY, Pharmacokinetics of Entacapone).
HOW SUPPLIED
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.

HDPE bottle of 100 tablets.....................................NDC 0078-0407-05
HDPE bottle of 250 tablets.....................................NDC 0078-0407-28

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.

HDPE bottle of 100 tablets......................................NDC 0078-0544-05

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.

HDPE bottle of 100 tablets.....................................NDC 0078-0408-05
HDPE bottle of 250 tablets.....................................NDC 0078-0408-28

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.

HDPE bottle of 100 tablets.....................................NDC 0078-0545-05

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.

HDPE bottle of 100 tablets......................................NDC 0078-0409-05
HDPE bottle of 250 tablets......................................NDC 0078-0409-28

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.

HDPE bottle of 100 tablets.....................................NDC 0078-0527-05

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

[see USP Controlled Room Temperature.]

Dispense in tight container (USP).

APRIL 2008. Manufactured by: Orion Corporation ORION PHARMA Orionintie 1, FIN-02200 Espoo, Finland. Marketed by: Novartis Pharmaceuticals Corporation East Hanover , New Jersey 07936.
SIDE EFFECTS
Carbidopa-levodopa
The most common adverse reactions reported with carbidopa-levodopa have included dyskinesias, such as choreiform, dystonic, and other involuntary movements and nausea.

The following other adverse reactions have been reported with carbidopa-levodopa

Body as a Whole: Chest pain, asthenia.

Cardiovascular: Cardiac irregularities, hypotension, orthostatic effects including orthostatic hypotension, hypertension, syncope, phlebitis, palpitation.

Gastrointestinal: Dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations.

Hematologic: Agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia.

Hypersensitivity: Angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like reactions).

Musculoskeletal: Back pain, shoulder pain, muscle cramps.

Nervous System/Psychiatric: Psychotic episodes including delusions, hallucinations, and paranoid ideation, neuroleptic malignant syndrome (see WARNINGS), bradykinetic episodes (“on-off” phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, increased libido. Convulsions also have occurred; however, a causal relationship with carbidopa-levodopa has not been established.

Respiratory: Dyspnea, upper respiratory infection.

Skin: Rash, increased sweating, alopecia, dark sweat.

Urogenital: Urinary tract infection, urinary frequency, dark urine.

Laboratory Tests: Decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, bilirubin, blood urea nitrogen (BUN), Coombs' test; elevated serum glucose; white blood cells, bacteria, and blood in the urine.

Other adverse reactions that have been reported with levodopa alone and with various carbidopa-levodopa formulations, and may occur with Stalevo® (carbidopa, levodopa and entacapone) are:

Body as a Whole: Abdominal pain and distress, fatigue.

Cardiovascular: Myocardial infarction.

Gastrointestinal: Gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups.

Metabolic: Edema, weight gain, weight loss.

Musculoskeletal: Leg pain.

Nervous System/Psychiatric: Ataxia, extrapyramidal disorder, failing, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased tremor, numbness, muscle twitching, activation of latent Horner's syndrome, peripheral neuropathy.

Respiratory: Pharyngeal pain, cough.

Skin: Malignant melanoma (see also CONTRAINDICATIONS), flushing.

Special Senses: Oculogyric crisis, diplopia, blurred vision, dilated pupils.

Urogenital: Urinary retention, urinary incontinence, priapism.

Miscellaneous: Bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation.

Laboratory Tests: Decreased white blood cell count and serum potassium; increased serum creatinine and uric acid; protein and glucose in urine.

Entacapone
The most commonly observed adverse events ( > 5%) in the double-blind, placebo-controlled trials of entacapone (N=1003) associated with the use of entacapone alone and not seen at an equivalent frequency among the placebo-treated patients were: dyskinesia/hyperkinesia, nausea, urine discoloration, diarrhea, and abdominal pain.

Approximately 14% of the 603 patients given entacapone in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared to 9% of the 400 patients who received placebo. The most frequent causes of discontinuation in decreasing order are: psychiatric reasons (2% vs. 1%), diarrhea (2% vs. 0%), dyskinesia/hyperkinesia (2% vs. 1%), nausea (2% vs. 1%), abdominal pain (1% vs. 0%), and aggravation of Parkinson's disease symptoms (1% vs. 1%).
Adverse Event Incidence in Controlled Clinical Studies of Entacapone
Table 5 lists treatment emergent adverse events that occurred in at least 1% of patients treated with entacapone participating in the double-blind, placebo-controlled studies and that were numerically
more common in the entacapone group, compared to placebo. In these studies, either entacapone or placebo was added to carbidopa-levodopa (or benserazide-levodopa).
Hyperkinesia 10 5
Hypokinesia 9 8
Dizziness 8 6
SPECIAL SENSES, OTHER DISORDERS
Taste Perversion 1 0
PSYCHIATRIC DISORDERS
Anxiety 2 1
Somnolence 2 0
Agitation 1 0
GASTROINTESTINAL SYSTEM DISORDERS
Nausea 14 8
Diarrhea 10 4
Abdominal Pain 8 4
Constipation 6 4
Vomiting 4 1
Mouth Dry 3 0
Dyspepsia 2 1
Flatulence 2 0
Gastritis 1 0
Gastrointestinal Disorders NOS 1 0
RESPIRATORY SYSTEM DISORDERS
Dyspnea 3 1
PLATELET, BLEEDING & CLOTTING DISORDERS
Purpura 2 1
URINARY SYSTEM DISORDERS
Urine Discoloration 10 0
BODY AS A WHOLE - GENERAL DISORDERS
Back Pain 4 2
Fatigue 6 4
Asthenia 2 1
RESISTANCE MECHANISM DISORDERS
Infection Bacterial 1 0
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures do, however, provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse events observed in the population studied.
Effects of Gender and Age on Adverse ReactionsNo differences were noted in the rate of adverse events attributable to entacapone alone by age or gender.
Drug Abuse And DependenceControlled substance class: Stalevo® (carbidopa, levodopa and entacapone) is not a controlled substance.
Physical and psychological dependence: Stalevo® has not been systematically studied, in animal or humans, for its potential for abuse, tolerance or physical dependence. In premarketing clinical experience, carbidopa-levodopa did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior. However, there are rare postmarketing reports of abuse and dependence of medications containing levodopa. In general, these reports consist of patients taking increasing doses of medication in order to achieve a euphoric state.
DRUG INTERACTIONSCaution should be exercised when the following drugs are administered concomitantly with Stalevo®.
Anti-hypertensive agentsSymptomatic postural hypotension has occurred when carbidopa-levodopa was added to the treatment of patients receiving antihypertensive drugs. Therefore, when therapy with Stalevo® is started, dosage adjustment of the antihypertensive drug may be required.
MAO inhibitorsFor patients receiving nonselective MAO inhibitors, see CONTRAINDICATIONS. Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone.
Tricyclic antidepressantsThere have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazidDopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa.
Phenytoin and papaverineThe beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with carbidopa-levodopa should be carefully observed for loss of therapeutic response.
Iron saltsIron salts may reduce the bioavailability of levodopa, carbidopa and entacapone. The clinical relevance is unclear.
MetoclopramideAlthough metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.
Drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase (probenecid, cholestyramine, erythromycin, rifampicin, ampicillin and chloramphenicol)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).
PyridoxineStalevo® can be given to patients receiving supplemental pyridoxine. Oral coadministration of 10-25 mg of pyridoxine hydrochloride (vitamin B6) with levodopa may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine; therefore, Stalevo® can be given to patients receiving supplemental pyridoxine.
Effect of levodopa and carbidopa in Stalevo® on the metabolism of other drugsInhibition or induction effect of levodopa and carbidopa has not been investigated.
Effect of entacapone in Stalevo® on the metabolism of other drugsEntacapone is unlikely to inhibit the metabolism of other drugs that are metabolized by major P450s including CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. 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 to over 1000 μM; an oral 200 mg dose achieves a highest level of approximately 5 μM in people); these enzymes would therefore not be expected to be inhibited in clinical use. However, no information is available regarding the induction effect from entacapone.
Drugs that are highly protein bound (such as warfarin, salicylic acid, phenylbutazone, and diazepam)Levodopa Levodopa is bound to plasma protein only to a minor extent (about 10%-30%).
Carbidopa Carbidopa is approximately 36% bound to plasma protein.
Entacapone 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.
Hormone LevelsOf the ingredients in Stalevo®, levodopa is known to depress prolactin secretion and increase growth hormone levels.
WARNINGSThe addition of carbidopa to levodopa reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa. Because carbidopa as well as entacapone permits more levodopa to reach the brain and more dopamine to be formed, certain adverse CNS effects, e.g., dyskinesia (involuntary movements) may occur at lower dosages and sooner with levodopa preparations containing carbidopa and entacapone than with levodopa alone.
The occurrence of dyskinesias may require dosage reduction (see PRECAUTIONS, Dyskinesia).
Stalevo® (carbidopa, levodopa and entacapone) may cause mental disturbances. These reactions are thought to be due to increased brain dopamine following administration of
levodopa. 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.
Stalevo® should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering Stalevo® to patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients, cardiac function should be monitored carefully during the period of initial dosage adjustment, in a facility with provisions for intensive cardiac care.
As with levodopa, treatment with Stalevo® may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.
Neuroleptic Malignant Syndrome (NMS)Sporadic cases of a symptom complex resembling NMS have been reported in association with dose reductions or withdrawal of therapy with carbidopa-levodopa. Therefore, patients should be observed carefully when the dosage of Stalevo® is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin have been reported.
The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.
Drugs Metabolized By Catechol-O-Methyltransferase (COMT)When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa/dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively.
Therefore, 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.
Ventricular tachycardia was noted in one 32-year-old healthy male volunteer in an interaction study after epinephrine infusion and oral entacapone administration. Treatment with propranolol was required. A causal relationship to entacapone administration appears probable but cannot be attributed with certainty.
PRECAUTIONSGeneralAs with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with Stalevo® (carbidopa, levodopa and entacapone) provided the intraocular pressure is well controlled and the patient is monitored carefully for changes in intraocular pressure during therapy.
Hypotension/SyncopeIn the large controlled trials of entacapone, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients treated also with levodopa/dopa decarboxylase inhibitor, 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 (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement).
DiarrheaIn 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/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 4-12 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.
HallucinationsDopaminergic therapy in Parkinson's disease patients has been associated with hallucinations. In clinical trials of entacapone, hallucinations developed in approximately 4.0% of patients treated with 200 mg entacapone or placebo in combination with levodopa/dopa decarboxylase inhibitor. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with 200 mg entacapone and placebo, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the 200 mg entacapone and placebo groups, respectively.
DyskinesiaEntacapone may potentiate the dopaminergic side effects of levodopa and may therefore cause and/or exacerbate preexisting dyskinesia. 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 rates of withdrawal for dyskinesia were 1.5% and 0.8% for 200 mg entacapone and placebo, respectively.
Other Events Reported With Dopaminergic TherapyThe events listed below are rare events known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists.
Rhabdomyolysis: Cases of severe rhabdomyolysis have been reported with entacapone when used in combination with levodopa. The complicated nature of these cases makes it impossible to determine what role, if any, entacapone played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. One case, however, included fever and alteration of consciousness. It is therefore possible that the rhabdomyolysis may be a result of the syndrome described in Hyperpyrexia and Confusion (see PRECAUTIONS, Other Events Reported With Dopaminergic Therapy).
Hyperpyrexia and Confusion: Cases of a symptom complex resembling the neuroleptic malignant syndrome 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. No cases have been reported following the abrupt withdrawal or dose reduction of entacapone treatment during clinical studies.
Prescribers should exercise caution when discontinuing carbidopa, levodopa and entacapone combination treatment. When considered necessary, withdrawal should proceed slowly. If a decision is made to discontinue treatment with Stalevo®, 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 entacapone 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, levodopa) 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 7-17 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 Stalevo for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).
Renal ToxicityIn a one-year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1600 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 ImpairmentPatients 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, and DOSAGE AND ADMINISTRATION).
Biliary ObstructionCaution should be exercised when administering Stalevo® to patients with biliary obstruction, as entacapone is excreted mostly via the bile.
Laboratory TestsAbnormalities 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.
Entacapone 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 trials. 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.
CarcinogenesisIn a two-year bioassay of carbidopa-levodopa, no evidence of carcinogenicity was found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa.
Two-year carcinogenicity studies of entacapone were conducted in mice and rats. Rats were treated once daily by oral gavage with entacapone doses of 20, 90, or 400 mg/kg. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose of entacapone. Plasma exposures (AUC) associated with this dose were approximately 20 times higher than estimated plasma exposures of humans receiving the maximum recommended daily dose of entacapone (MRDD = 1600 mg). Mice were treated once daily by oral gavage with doses of 20, 100 or 600 mg/kg of entacapone (0.05, 0.3, and two times the MRDD for humans on a mg/m² basis). Because of a high incidence of premature mortality in mice receiving the highest dose of entacapone, the mouse study is not an adequate assessment of carcinogenicity. Although no treatment related tumors were observed in animals receiving the lower doses, the carcinogenic potential of entacapone has not been fully evaluated. The carcinogenic potential of entacapone administered in combination with carbidopa-levodopa has not been evaluated.
MutagenesisCarbidopa was positive in the Ames test in the presence and absence of metabolic activation, was mutagenic in the in vitro mouse lymphoma/thymidine kinase assay in the absence of metabolic activation, and was negative in the in vivo mouse micronucleus test.
Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma/thymidine kinase 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 carbidopa-levodopa, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test).
Impairment of FertilityIn reproduction studies with carbidopa-levodopa, no effects on fertility were found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa.
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). Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg/kg/day of entacapone.
PregnancyPregnancy Category CCarbidopa-levodopa caused both visceral and skeletal malformations in rabbits at all doses and ratios of carbidopa-levodopa tested, which ranged from 10 times/5 times the maximum recommended human dose of carbidopa-levodopa to 20 times/10 times the maximum recommended human dose of carbidopa-levodopa. There was a decrease in the number of live pups delivered by rats receiving approximately two times the maximum recommended human dose of carbidopa and approximately five times the maximum recommended human dose of levodopa during organogenesis. No teratogenic effects were observed in mice receiving up to 20 times the maximum recommended human dose of carbidopa-levodopa.
It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal.
In embryo-fetal development studies, entacapone was administered to pregnant
FONT> animals throughout organogenesis at doses of up to 1000 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 1600 mg. Increased frequencies of abortions and late/total resorptions and decreased fetal weights were observed in the litters of rabbits treated with maternotoxic 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 seven times those in humans receiving the MRDD) or greater, in the absence of maternotoxicity. 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.
There is no experience from clinical studies regarding the use of Stalevo® in pregnant women. Therefore, Stalevo® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing WomenIn animal studies, carbidopa and entacapone were excreted into maternal rat milk. It is not known whether entacapone or carbidopa-levodopa are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Stalevo® is administered to a nursing woman.
Pediatric UseSafety and effectiveness in pediatric patients have not been established.
OVERDOSE
Management of acute overdosage with Stalevo® (carbidopa, levodopa and entacapone) is the same as management of acute overdosage with levodopa and entacapone. Pyridoxine is not effective in reversing the actions of Stalevo®.
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/reabsorption from the GI tract. Intravenous fluids should be administered judiciously and an adequate airway maintained.
The adequacy of the respiratory, circulatory and renal systems should be carefully 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.
There are very few cases of overdosage with levodopa reported in the published literature. Based on the limited available information, the acute symptoms of levodopa/dopa decarboxylase inhibitor overdosage 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 overdosage may give rise to systemic complications, secondary to dopaminergic overstimulation.
There have been no reported cases of either accidental or intentional overdose with entacapone tablets. However, 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.
The highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 μg/mL. The highest daily dose given to humans was 2400 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 t.i.d. for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 μg/mL (at 45 min., compared to 1.0 and 1.2 μg/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 2000 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 1600 mg is limited.
The range of lethal plasma concentrations of entacapone based on animal data was 80-130 μg/mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses.
CONTRAINDICATIONS
Stalevo® (carbidopa, levodopa and entacapone) tablets are contraindicated in patients who have demonstrated hypersensitivity to any component (carbidopa, levodopa, or entacapone) of the drug or its excipients.
Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of entacapone and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. As with carbidopa-levodopa, nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with Stalevo®. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo®. Stalevo® may be administered concomitantly with the manufacturer's recommended dose of MAO inhibitors with selectivity for MAO type B (e.g., selegiline HCl). (See PRECAUTIONS: DRUG INTERACTIONS.)
Stalevo® is contraindicated in patients with narrow-angle glaucoma.
Because levodopa may activate malignant melanoma, Stalevo® should not be used in patients with suspicious, undiagnosed skin lesions or a history of melanoma.
FONT> animals throughout organogenesis at doses of up to 1000 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 1600 mg. Increased frequencies of abortions and late/total resorptions and decreased fetal weights were observed in the litters of rabbits treated with maternotoxic 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 seven times those in humans receiving the MRDD) or greater, in the absence of maternotoxicity. 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.
There is no experience from clinical studies regarding the use of Stalevo® in pregnant women. Therefore, Stalevo® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing WomenIn animal studies, carbidopa and entacapone were excreted into maternal rat milk. It is not known whether entacapone or carbidopa-levodopa are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Stalevo® is administered to a nursing woman.
Pediatric UseSafety and effectiveness in pediatric patients have not been established.
OVERDOSE
Management of acute overdosage with Stalevo® (carbidopa, levodopa and entacapone) is the same as management of acute overdosage with levodopa and entacapone. Pyridoxine is not effective in reversing the actions of Stalevo®.
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/reabsorption from the GI tract. Intravenous fluids should be administered judiciously and an adequate airway maintained.
The adequacy of the respiratory, circulatory and renal systems should be carefully 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.
There are very few cases of overdosage with levodopa reported in the published literature. Based on the limited available information, the acute symptoms of levodopa/dopa decarboxylase inhibitor overdosage 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 overdosage may give rise to systemic complications, secondary to dopaminergic overstimulation.
There have been no reported cases of either accidental or intentional overdose with entacapone tablets. However, 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.
The highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 μg/mL. The highest daily dose given to humans was 2400 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 t.i.d. for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 μg/mL (at 45 min., compared to 1.0 and 1.2 μg/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 2000 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 1600 mg is limited.
The range of lethal plasma concentrations of entacapone based on animal data was 80-130 μg/mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses.
CONTRAINDICATIONS
Stalevo® (carbidopa, levodopa and entacapone) tablets are contraindicated in patients who have demonstrated hypersensitivity to any component (carbidopa, levodopa, or entacapone) of the drug or its excipients.
Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of entacapone and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. As with carbidopa-levodopa, nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with Stalevo®. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo®. Stalevo® may be administered concomitantly with the manufacturer's recommended dose of MAO inhibitors with selectivity for MAO type B (e.g., selegiline HCl). (See PRECAUTIONS: DRUG INTERACTIONS.)Stalevo® is contraindicated in patients with narrow-angle glaucoma.
Because levodopa may activate malignant melanoma, Stalevo® should not be used in patients with suspicious, undiagnosed skin lesions or a history of melanoma.