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).

Table 5 : Summary of Patients With Adverse Events After Start of Trial Drug Administration
At Least 1% in Entacapone Group and >Placebo

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 Reactions

No differences were noted in the rate of adverse events attributable to entacapone alone by age or gender.

Drug Abuse And Dependence

Controlled 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.

Caution should be exercised when the following drugs are administered concomitantly with Stalevo.

Anti-hypertensive agents

Symptomatic 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 inhibitors

For 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 antidepressants

There 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 isoniazid

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

Phenytoin and papaverine

The 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 salts

Iron salts may reduce the bioavailability of levodopa, carbidopa and entacapone. The clinical relevance is unclear.

Metoclopramide

Although 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).

Pyridoxine

Stalevo 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 drugs

Inhibition or induction effect of levodopa and carbidopa has not been investigated.

Effect of entacapone in Stalevo on the metabolism of other drugs

Entacapone 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 Levels

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

Bookmark this page: