CARBIDOPA, LEVODOPA AND ENTACAPONE

CARBIDOPA, LEVODOPA AND ENTACAPONE — carbidopa, levodopa and entacapone tablet, film coated
Rising Pharma Holdings, Inc.

1 INDICATIONS AND USAGE

Carbidopa, levodopa and entacapone tablets, are indicated for the treatment of Parkinson’s disease.

Carbidopa, levodopa and entacapone tablets 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

Carbidopa, levodopa and entacapone tablets 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 carbidopa, levodopa and entacapone tablets 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 carbidopa, levodopa and entacapone tablets 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 carbidopa, levodopa and entacapone tablets depends on the strength used. The maximum number of tablets to be used in a 24-hour period is less with the highest strength (carbidopa, levodopa and entacapone tablets 50 mg/200 mg/200 mg) 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 Carbidopa, Levodopa and Entacapone Tablets in a 24-hour Period

Carbidopa, Levodopa and Entacapone Tablets Dosage Strength	Maximum Number of Tablets in a 24-hour Period
12.5 mg per 50 mg per 200 mg, 18.75 mg per 75 mg per 200 mg, 25 mg per 100 mg per 200 mg, 31.25 mg per 125 mg per 200 mg, 37.5 mg per 150 mg per 200 mg	8
50 mg per 200 mg per 200 mg	6

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

Patients currently treated with entacapone 200 mg with each dose of non-extended release carbidopa/levodopa tablet, can switch to the corresponding strength of carbidopa, levodopa and entacapone tablets 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 carbidopa, levodopa and entacapone 25 mg/100 mg/200 mg 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 Carbidopa, Levodopa and Entacapone Tablets

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 carbidopa, levodopa and entacapone.

When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa either by decreasing the strength of carbidopa, levodopa and entacapone tablets 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 carbidopa, levodopa and entacapone tablets is being administered; however, dosage adjustments of the concomitant medication or carbidopa, levodopa and entacapone tablets may be required.

2.5 Decrease or Interruption of Dosing

Avoid interruption of carbidopa, levodopa and entacapone tablets 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 carbidopa, levodopa and entacapone tablets. Administer only one tablet at each dosing interval. All strengths of carbidopa, levodopa and entacapone tablets 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 carbidopa, levodopa and entacapone tablets 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 carbidopa, levodopa and entacapone tablet, provided in 6 single-dose strengths, contains carbidopa and levodopa in a 1:4 ratio and a 200 mg dose of entacapone. Carbidopa, levodopa and entacapone tablets are supplied as film-coated tablets for oral administration in the following 6 strengths:

Carbidopa, levodopa and entacapone film-coated tablets 12.5 mg/50mg/ 200mg containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone. The unscored, round, biconvex shaped tablets are brownish and debossed “S 50” on one side and plain on other side.

Carbidopa, levodopa and entacapone film-coated tablets 18.75 mg/75 mg/200 mg containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone. The unscored, oval, biconvex shaped tablets are light brownish and debossed “S75” on one side and plain on other side.

Carbidopa, levodopa and entacapone film-coated tablets 25 mg/100 mg/200 mg containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone. The unscored, oval, biconvex shaped tablets are brownish and debossed “S100” on one side and plain on other side.

Carbidopa, levodopa and entacapone film-coated tablets 31.25 mg/125 mg/200 mg containing 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone. The unscored, oval, biconvex shaped tablets are light brownish and debossed “S125” on one side and plain on other side.

Carbidopa, levodopa and entacapone film-coated tablets 37.5 mg/150 mg/200 mg containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone. The unscored, elongated ellipse shaped tablets are brownish and debossed “S150” on one side and plain on other side.

Carbidopa, levodopa and entacapone film-coated tablets 50 mg/200 mg/200 mg containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone. The unscored, oval shaped tablets are brownish red and debossed “S200” on one side and plain on other side.

4 CONTRAINDICATIONS

Carbidopa, levodopa and entacapone tablets are 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 carbidopa, levodopa and entacapone tablets.
• 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 carbidopa, levodopa and entacapone tablets (i.e., levodopa, carbidopa, and/or entacapone) based upon the safety experience in clinical trials (especially pivotal trials) or in postmarketing reports.