CARBIDOPA, LEVODOPA AND ENTACAPONE: Package Insert and Label Information

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.

5.1 Falling Asleep During Activities of Daily Living and Somnolence

Patients with Parkinson’s disease treated with carbidopa, levodopa and entacapone tablets 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, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with carbidopa, levodopa and entacapone tablets.

Before initiating treatment with carbidopa, levodopa and entacapone tablets, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase this risk such as use of concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), carbidopa, levodopa and entacapone tablets should ordinarily be discontinued [see Dosage and Administration (2.5) and Warnings and Precautions (5.7)]. If the decision is made to continue carbidopa, levodopa and entacapone tablets, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2 Hypotension, Orthostatic Hypotension and Syncope

Reports of syncope were generally more frequent in patients in both treatment groups who had had a prior episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement). Hypotension, orthostatic hypotension, and syncope are observed in patients treated with drugs that increase central dopaminergic tone including carbidopa, levodopa and entacapone tablets.

5.3 Dyskinesia

Dyskinesia (involuntary movements) may occur or be exacerbated at lower dosages and sooner with carbidopa, levodopa and entacapone tablets than with preparations containing only carbidopa and levodopa. The occurrence of dyskinesias may require dosage reduction.
In pivotal trials, the treatment difference incidence of dyskinesia was 10% and for carbidopa-levodopa plus 200 mg entacapone. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The treatment difference incidence of study withdrawal for dyskinesia was 1% for carbidopa-levodopa-entacapone.

5.4 Depression and Suicidality

All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or current psychoses should be treated with caution.

5.5 Hallucinations and/or Psychotic-Like Behavior

Dopaminergic therapy in patients with Parkinson’s disease has been associated with hallucinations. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with carbidopa, levodopa, entacapone and carbidopa, levodopa, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the carbidopa, levodopa, entacapone and carbidopa, levodopa, groups, respectively. Agitation occurred in 1% of patients treated with carbidopa, levodopa, entacapone and 0% treated with carbidopa, levodopa.

5.6 Impulse Control and/or Compulsive Behaviors

Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications generally used for the treatment of Parkinson’s disease and which increase central dopaminergic tone, including entacapone taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with entacapone. Physicians should consider dose reduction or stopping carbidopa, levodopa and entacapone tablets if a patient develops such urges while taking carbidopa, levodopa and entacapone tablets [see Dosage and Administration (2.5), Warnings and Precautions (5.7)].

5.7 Withdrawal-Emergent Hyperpyrexia and Confusion

Cases of hyperpyrexia and confusion resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reduction or withdrawal of therapy with carbidopa, levodopa and entacapone. However, in some cases, hyperpyrexia and confusion were reported after initiation of treatment with entacapone. Hyperpyrexia and confusion are uncommon but they may be life-threatening with a variety of features, including hyperpyrexia/fever/hyperthermia, muscle rigidity, involuntary movements, altered consciousness/mental status changes, delirium, autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension, and abnormal laboratory findings (e.g., creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin). If a patient needs to discontinue or reduce their daily dose of carbidopa, levodopa and entacapone tablets, the dose should be decreased slowly, with supervision from a health care provider [see Dosage and Administration (2.5) ]. Specific methods for tapering entacapone have not been systematically evaluated.

5.8 Diarrhea and Colitis

In clinical trials of entacapone, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg of entacapone or placebo in combination with levodopa and dopa decarboxylase inhibitor, respectively. In patients treated with entacapone, diarrhea was generally mild to moderate in severity (8.6%) but was regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of entacapone. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 to 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment. Diarrhea may be associated with weight loss, dehydration, and hypokalemia.

Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases diarrhea has usually been moderate to severe, watery and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when entacapone treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of entacapone but recurred after retreatment with entacapone.

If prolonged diarrhea is suspected to be related to carbidopa, levodopa and entacapone tablets, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered.

5.9 Rhabdomyolysis

Cases of severe rhabdomyolysis have been reported with entacapone when used in combination with carbidopa and levodopa. Severe prolonged motor activity including dyskinesia may possibly account for rhabdomyolysis. Most of the cases were manifested by myalgia and increased values of creatine phosphokinase (CPK) and myoglobin. Some of the reactions also included fever and/or alteration of consciousness. It is also possible that rhabdomyolysis may be a result of the syndrome described in Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7) ].

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