CARBIDOPA, LEVODOPA AND ENTACAPONE (Page 3 of 8)

5.10 Interaction with Drugs Metabolized by COMT

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.

5.11 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 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.

5.12 Peptic Ulcer Disease

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

5.13 Hepatic Impairment

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.

5.14 Laboratory Tests

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 carbidopa, levodopa and entacapone tablets than with levodopa.

Carbidopa, levodopa and entacapone tablets 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.

6 ADVERSE REACTIONS

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

6.1 Clinical Trials Experience

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.

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.

Adverse Reaction Incidence in Controlled Clinical Studies of Entacapone

Table 2 lists treatment emergent adverse reactions that occurred in at least 1% of patients treated with carbidopa/levodopa and 200 mg of entacapone who participated in the double-blind, placebo-controlled studies, and that were numerically more common in this group than in the carbidopa/levodopa plus placebo group. In these studies, either entacapone or placebo was added to carbidopa/levodopa (or benserazide/levodopa).

Table 2: Summary of Patients With Adverse Reactions After Start of Trial Drug Administration At Least 1% in Entacapone Group and Greater Than Placebo
SYSTEM ORGAN CLASS Adverse Reaction Carbidopa/levodopa plus Entacapone (n=603) % of patients Carbidopa/levodopa plusPlacebo (n=400) % of patients
SKIN AND APPENDAGES DISORDERS
Sweating Increased 2 1
MUSCULOSKELETAL SYSTEM DISORDERS
Back Pain 5 3
CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS
Dyskinesia 25 15
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 AND CLOTTING DISORDERS
Purpura 2 1
URINARY SYSTEM DISORDERS
Urine Discoloration 10 0
BODY AS A WHOLE-GENERAL DISORDERS
Fatigue 6 4
Asthenia 2 1
RESISTANCE MECHANISM DISORDERS
Infection Bacterial 1 0

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