Stalevo

Uses

Each 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). For example-

• 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)

This medicine is used for the treatment of adult patients with Parkinson's disease and end-of-dose motor fluctuations not stabilized on levodopa/dopa decarboxylase (DDC) inhibitor treatment.

Stalevo is also used to associated treatment for these conditions: Parkinson's Disease (PD), Postencephalitic parkinsonism, Symptomatic Parkinson Disease, Levodopa-driven nausea and vomitingParkinson's Disease (PD)Paralysis agitans, Parkinson's Disease (PD), Parkinsonism, Postencephalitic parkinsonism, Restless Legs Syndrome (RLS), Advanced Motor fluctuations

How Stalevo works

Carbidopa is an inhibitor of the DDC which in order, inhibits the peripheral metabolism of levodopa. DDC is very important in the biosynthesis of L-tryptophan to serotonin and the modification of L-DOPA to dopamine.

DDC can be found in the body periphery and in the blood-brain barrier. The action of carbidopa is focused on peripheral DDC as this drug cannot cross the blood-brain barrier. Hence, it will prevent the metabolism of levodopa in the periphery but it will not have any activity on the generation of dopamine in the brain.

The mechanism of action of entacapone is believed to be through its ability to inhibit COMT in peripheral tissues, altering the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to a greater reduction in the manifestations of parkinsonian syndrome.

Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors.

Dosage

Stalevo dosage

Adults: The optimum daily dose must be determined by careful titration of levodopa in each patient. Patients should be instructed to take only 1 (one) tablet per dose administration. The maximum recommended daily dose of entacapone is 2,000 mg. Usually this combination is to be used in patients who are currently treated with corresponding doses of standard release Levodopa or Dopa Decarboxylase (DDC)inhibitor and entacapone.

May be taken with or without food. Keep a consistent diet. A change in diet to foods high in protein may delay levodopa absorption & reduce amount taken up in circulation. Excessive acidity also delays stomach emptying & thus delays levodopa absorption. Iron salts may also reduce amount of levodopa available to the body. Swallow whole.

Side Effects

Common side effects include dyskinesia, nausea, hyperkinesia, change in urine color, diarrhea and stomach pain. Other side effects may include diarrhea, sometimes severe; colitis; hallucinations; other mental disturbances; orthostatic hypotension; rhabdomyolysis; and symptoms resembling neuroleptic malignant syndrome (a condition characterized by high fever, muscle stiffness, and confusion); fibrosis; skin cancer, etc.

Toxicity

The LD50 of carbidopa is reported to be in the rat of 4810 mg/kg. In animal studies, carbidopa showed no incidences on neoplasia and showed no effect on the fertility status and development.

No reports of overdosage have been registered with the carbidopa-only product. In the event of overdosage, immediate gastric lavage is recommended as well as intravenous fluid administration. Continuous electrocardiographic monitoring is required.

Side effect include increase the occurrence of orthostatic hypotension, severe rhabdomyolysis, dyskinesia, hallucinations, hyperkinesia, hypokinesia, dizziness, fatigu,e gastrointestinal effects including abdominal pain constipation diarrhea nausea

There is no readily available data for the use of levodopa in pregnancy. Rabbits treated with levodopa and carbidopa produced smaller litters and their offspring developed visceral and skeletal deformities. Levodopa may lower prolactin and interfere with lactation but there is limited human data to demonstrate this effect. Levodopa is present in human breast milk and so the potential effects of nursing while taking levodopa should be considered before prescribing levodopa to nursing mothers. There is currently a lack of data on the safety and effectiveness of using levodopa in pediatric patients. Patients over 65 years of age are more likely to experience adverse effects associated with taking levodopa, however this generally is not sufficient to exclude this patient group from treatment.

Precaution

Levodopa, carbidopa and entacapone together may cause dizziness and symptomatic orthostatism. Therefore, caution should be exercised when driving or using machines. As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function are recommended during extended therapy.

Interaction

Symptomatic postural hypotension may occur when levodopa is added to the treatment of patients already receiving antihypertensive. Dose adjustment of the antihypertensive agent may be required. Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics), phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these medicinal products with levodopa/ carbidopa/ entacapone combination should be carefully observed for loss of therapeutic response. Since levodopa competes with certain amino acids, the absorption of Levodopa, Carbidopa & Entacapone may be impaired in some patients on high protein diet.

Volume of Distribution

The volume of distribution reported for the combination therapy of carbidopa/levodopa is of 3.6 L/kg. However, carbidopa is widely distributed in the tissues, except in the brain. After one hour, carbidopa is found mainly in the kidney, lungs, small intestine and liver.

• 20 L

168L for orally inhaled levodopa.

Elimination Route

When levodopa/carbidopa is administered orally, 40-70% of the administered dose is absorbed. Once absorbed, carbidopa shows bioavailability of 58%. A maximum concentration of 0.085 mcg/ml was achieved after 143 min with an AUC of 19.28 mcg.min/ml.

Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.

Orally inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide.

Half Life

The reported half-life of carbidopa is of approximately 107 minutes.

0.4-0.7 hour

2.3 hours for orally inhaled levodopa. Oral levodopa has a half life of 50 minutes but when combined with a peripheral dopa decarboxylase inhibitor, the half life is increased to 1.5 hours.

Clearance

The reported clearance rate for the combination therapy of levodopa/carbidopa is 51.7 L/h.

• 850 mL/min

Intravenously administered levodopa is cleared at a rate of 14.2mL/min/kg in elderly patients and 23.4mL/min/kg in younger patients. When given carbidopa, the clearance of levodopa was 5.8mL/min/kg in elderyly patients and 9.3mL/min/kg in younger patients.

Elimination Route

In animal studies, 66% of the administered dose of carbidopa was eliminated via the urine while 11% was found in feces. These studies were performed in humans and it was observed a urine excretion covering 50% of the administered dose.

Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug.

After 48 hours, 0.17% of an orally administered dose is recovered in stool, 0.28% is exhaled, and 78.4% is recovered in urine

Pregnancy & Breastfeeding use

Pregnancy category C. The combination of levodopa/ carbidopa/ entacapone should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. The safety of this combination in the infant is not known. Women should not breast-feed during treatment with this combination.

Contraindication

Narrow-angle glaucoma, phaeochromocytoma, history of neuroleptic malignant syndrome (NMS) and/ or non-traumatic rhabdomyolysis. Severe hepatic impairment. Concurrent use of or within 14 days of discontinuing non-selective MAOIs.

Special Warning

Children: Safety and effectiveness in pediatric patients have not been established.

Elderly: No dose adjustment is required for elderly patients.

Hepatic impaired patients: Should be administered cautiously to patients with mild to moderate hepatic impairment. Dose reduction may be needed.

Renally impaired patients: Should be administered cautiously to patients in severe renal impairment including those receiving dialysis therapy

Acute Overdose

The acute symptoms and signs of overdose include agitation, confusional state, coma, bradycardia, ventricular tachycardia, Cheyne Stokes respiration, discolorations of skin, tongue and conjunctiva, and chromaturia. Management of acute overdose with levodopa/ carbidopa/ entacapone combination is similar to acute overdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of levodopa/ carbidopa/ entacapone combination. Hospitalization is advised and general supportive measures should be employed with immediate gastric lavage and repeated doses of charcoal over time.

Storage Condition

Store in a cool and dry place. Protect from light.

Innovators Monograph

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