Entacapone (Page 5 of 5)

Effects of Gender and Age on Adverse Reactions

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

Postmarketing Reports

The following spontaneous reports of adverse events temporally associated with Entacapone Tablets have been identified since market introduction and are not listed in Table 4. 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 Tablets exposure.

Hepatitis with mainly cholestatic features has been reported.

DRUG ABUSE AND DEPENDENCE

Entacapone is not a controlled substance. Animal studies to evaluate the drug abuse and potential dependence have not been conducted. Although clinical studies have not revealed any evidence of the potential for abuse, tolerance or physical dependence, systematic studies in humans designed to evaluate these effects have not been performed.

OVERDOSAGE

The postmarketing data include several cases of overdose. The highest reported dose of entacapone was at least 40,000 mg. The acute symptoms and signs commonly seen in these cases included somnolence and decreased activity, states related to depressed level of consciousness (e.g., coma, confusion and disorientation) and discolorations of skin, tongue, and urine, as well as restlessness, agitation, and aggression.

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

The highest daily dose given to humans was 2,400 mg, administered in one study as 400 mg six times daily with levodopa and carbidopa 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 minutes, compared to 1.0 mcg per mL and 1.2 mcg per mL with 200 mg entacapone at 45 minutes). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2,000 mg Entacapone Tablet have been administered as 200 mg 10 times daily with levodopa and carbidopa or levodopa and benserazide 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.

The range of lethal plasma concentrations of entacapone based on animal data was 80 mcg per mL to 130 mcg per mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses.

Management of Overdose

Management of Entacapone Tablets overdose is symptomatic; there is no known antidote to Entacapone Tablets. Hospitalization is advised, and general supportive care is indicated. There is no experience with hemodialysis or hemoperfusion, but these procedures are unlikely to be of benefit, because Entacapone Tablets are highly bound to plasma proteins. An immediate gastric lavage and repeated doses of charcoal over time may hasten the elimination of Entacapone Tablet by decreasing its absorption and reabsorption from the gastrointestinal (GI) tract. The adequacy of the respiratory and circulatory systems should be carefully monitored and appropriate supportive measures employed. The possibility of drug interactions, especially with catechol-structured drugs, should be borne in mind.

DOSAGE AND ADMINISTRATION

The recommended dose of Entacapone Tablets is one 200 mg tablet administered concomitantly with each levodopa and carbidopa dose to a maximum of 8 times daily (200 mg x 8 = 1,600 mg per day). Clinical experience with daily doses above 1,600 mg is limited.

Entacapone Tablets should always be administered in association with levodopa and carbidopa. Entacapone has no antiparkinsonian effect of its own.

In clinical studies, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been greater than or equal to 800 mg or if patients had moderate or severe dyskinesia before beginning treatment.

To optimize an individual patient’s response, reductions in daily levodopa dose or extending the interval between doses may be necessary. In clinical studies, the average reduction in daily levodopa dose was about 25% in those patients requiring a levodopa dose reduction. (More than 58% of patients with levodopa doses above 800 mg daily required such a reduction.)

Entacapone Tablets can be combined with both the immediate and sustained-release formulations of levodopa and carbidopa.

Entacapone Tablets may be taken with or without food (see CLINICAL PHARMACOLOGY).

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 and 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).

Withdrawing Patients from Entacapone Tablets: Rapid withdrawal or abrupt reduction in the Entacapone Tablets dose could lead to emergence of signs and symptoms of Parkinson’s disease (see CLINICAL PHARMACOLOGY, Clinical Studies), and may lead to hyperpyrexia and confusion, a symptom complex resembling NMS (see PRECAUTIONS, Other Events Reported With Dopaminergic Therapy). This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. If a decision is made to discontinue treatment with Entacapone Tablets, patients should be monitored closely and other dopaminergic treatments should be adjusted as needed. Although tapering Entacapone has not been systematically evaluated, it seems prudent to withdraw patients slowly if the decision to discontinue treatment is made.

HOW SUPPLIED

Entacapone Tablets are supplied as 200 mg film-coated tablets for oral administration. The oval-shaped tablets are brownish-orange, unscored and embossed “W 781” on one side. Tablets are provided in HDPE containers as follows:

Bottle of 100 tablets NDC 64679-781-02

Bottle of 500 tablets NDC 64679-781-03

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

[See USP Controlled Room Temperature.]

Manufactured by:

Orion Corporation

ORION PHARMA

Orionintie 1,

FIN-02200 Espoo,

Finland.

Distributed by:

Wockhardt USA LLC.

20 Waterview Blvd.

Parsippany, NJ 07054

USA.

Rev. July 17, 2014

Repackaging Information

Please reference the How Supplied section listed above for a description of individual tablets. This drug product has been received by Aphena Pharma — TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:

Count200mg
360043353-996-83
420043353-996-05

Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:
Aphena Pharma Solutions -- TN
Cookeville, TN 38506
20180211JH

PRINCIPAL DISPLAY PANEL

NDC 43353-996 — Entacapone 200mg — Rx Only

Bottle Label 200mg
(click image for full-size original)

ENTACAPONE entacapone tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43353-996(NDC:64679-781)
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ENTACAPONE (ENTACAPONE) ENTACAPONE 200 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE
CROSCARMELLOSE SODIUM
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
GLYCERIN
HYDROGENATED COTTONSEED OIL
HYPROMELLOSE 2910 (6 MPA.S)
MAGNESIUM STEARATE
MANNITOL
POLYSORBATE 80
SUCROSE
TITANIUM DIOXIDE
Product Characteristics
Color BROWN (brownish-orange) Score no score
Shape OVAL Size 17mm
Flavor Imprint Code W781
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:43353-996-83 3600 TABLET, FILM COATED in 1 BOTTLE None
2 NDC:43353-996-05 4200 TABLET, FILM COATED in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020796 09/30/2012
Labeler — Aphena Pharma Solutions — Tennessee, LLC (128385585)
Establishment
Name Address ID/FEI Operations
Aphena Pharma Solutions — Tennessee, LLC 128385585 REPACK (43353-996)

Revised: 12/2019 Aphena Pharma Solutions — Tennessee, LLC

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