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STALEVO (carbidopa, levodopa and entacapone) tablets,

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use STALEVO safely and effectively. See full prescribing information for STALEVO.

STALEVO ® (carbidopa, levodopa and entacapone) tablets, for oral use
Initial U.S. Approval: 2003

INDICATIONS AND USAGE

Stalevo, a combination drug consisting of levodopa (aromatic amino acid), carbidopa (aromatic amino acid decarboxylation inhibitor), and entacapone (catechol-O-methyltransferase (COMT) inhibitor) is indicated for the treatment of Parkinson's disease. Stalevo is to be used:

To substitute (with equivalent strengths of each of the three components) for carbidopa/levodopa and entacapone previously administered as individual products (1)
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 (1)

DOSAGE AND ADMINISTRATION

The optimum daily dosage of Stalevo must be determined by careful titration in each patient (2.1)
Individual tablets should not be split or fractionated. Administer only one tablet at each dosing interval (2.6)

DOSAGE FORMS AND STRENGTHS

Each Stalevo tablet contains a 1:4 ratio of carbidopa to levodopa and 200 mg of entacapone (mg of carbidopa per mg of levodopa per mg of entacapone) (3)

Stalevo 50 (12.5 mg per 50 mg per 200 mg)
Stalevo 75 (18.75 mg per 75 mg per 200 mg)
Stalevo 100 (25 mg per 100 mg per 200 mg)
Stalevo 125 (31.25 mg per 125 mg per 200 mg)
Stalevo 150 (37.5 mg per 150 mg per 200 mg)
Stalevo 200 (50 mg per 200 mg per 200 mg)

CONTRAINDICATIONS

Concomitant use of nonselective monoamine oxidase (MAO) inhibitors (4)
Narrow-angle glaucoma (4)

WARNINGS AND PRECAUTIONS

May cause falling asleep during activities of daily living without apparent warning, and daytime drowsiness and somnolence (5.1)
May cause syncope and hypotension/orthostatic hypotension (5.2)
May cause or exacerbate dyskinesia (5.3)
May cause depression and suicidality (5.4)
May cause hallucinations and/or other psychotic-like behavior (5.5)
May cause problems with impulse control and compulsive behaviors (5.6)
Abrupt discontinuation may cause hyperpyrexia and confusion (5.7)
May cause diarrhea and/or drug-induced colitis (5.8)
May cause rhabdomyolysis (5.9)
Increased risk of melanoma (5.10)

ADVERSE REACTIONS

The most common adverse reactions (incidence 3% or higher than placebo incidence) are dyskinesias, urine discoloration, diarrhea, nausea, abdominal pain, vomiting, and dry mouth (6)

To report SUSPECTED ADVERSE REACTIONS, contact NOVARTIS PHARMACEUTICAL CORPORATION at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

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)

USE IN SPECIFIC POPULATIONS

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

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 7/2014

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

2.2 Converting Patients from Carbidopa, Levodopa, and Entacapone to Stalevo

2.3 Converting Patients from Carbidopa and Levodopa Products to Stalevo

2.4 Concomitant Use with Other Anti-Parkinson's Disease Drugs

2.5 Decrease or Interruption of Dosing

2.6 Important Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Falling Asleep During Activities of Daily Living and Somnolence

5.2 Hypotension, Orthostatic Hypotension and Syncope

5.3 Dyskinesia

5.4 Depression and Suicidality

5.5 Hallucinations and/or Psychotic-Like Behavior

5.6 Impulse Control and/or Compulsive Behaviors

5.7 Withdrawal-Emergent Hyperpyrexia and Confusion

5.8 Diarrhea and Colitis

5.9 Rhabdomyolysis

5.10 Melanoma

5.11 Interaction with Drugs Metabolized by COMT

5.12 Fibrotic Complications

5.13 Peptic Ulcer Disease

5.14 Hepatic Impairment

5.15 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 MAO Inhibitors

7.2 Drugs Metabolized by Catechol-O-Methyltransferase (COMT)

7.3 Antihypertensive Agents

7.4 Tricyclic Antidepressants

7.5 Dopamine D2 Receptor Antagonists

7.6 Isoniazid

7.7 Phenytoin

7.8 Papaverine

7.9 Iron Salts

7.10 Drugs Known to Interfere with Biliary Excretion, Glucuronidation, and Intestinal Beta-glucuronidase

7.11 Drugs Metabolized via CYP2C9 (e.g., coumadin)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment or Biliary Obstruction

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdosage

10.2 Management of Overdosage

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.6 Hormone Levels

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*: Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

Stalevo, a combination drug consisting of levodopa, carbidopa (dopa decarboxylase inhibitor), and entacapone (catechol-O-methyltransferase-COMT inhibitor) 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.

2 DOSAGE AND ADMINISTRATION

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.

2.1 Dosing Information

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.

Table 1: Maximum Recommended Dose of Stalevo in a 24-hour Period
Stalevo Dosage Strength	Maximum Number of Tablets in a 24-hour Period
Stalevo 50, Stalevo 75, Stalevo 100, Stalevo 125, Stalevo 150	8
Stalevo 200	6

2.2 Converting Patients from Carbidopa, Levodopa, and Entacapone to Stalevo

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).

2.3 Converting Patients from Carbidopa and Levodopa Products to Stalevo

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.

2.4 Concomitant Use with Other Anti-Parkinson's Disease Drugs

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.

2.5 Decrease or Interruption of Dosing

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)].

2.6 Important Administration Instructions

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)].

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

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.

5.1 Falling Asleep During Activities of Daily Living and Somnolence

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