Levodopa – Benserazide
Action And Clinical Pharmacology: The symptoms of Parkinson’s disease are to a high degree associated with striatal dopamine deficiency and degeneration of the dopamine containing neurons in the nigro-striatal bundle. However, administration of dopamine is ineffective in the treatment of Parkinson’s syndrome, because it does not cross the blood-brain barrier.
Levodopa, which does permeate the blood-brain barrier, appears to correct the akinesia of Parkinson’s disease by the formation of dopamine at nigro striatal dopaminergic sites that remain functional. While rigidity and tremor also improve with levodopa therapy, these symptoms seem to be related to a disturbed balance of neurotransmitters.
When levodopa is given alone, a large proportion of it does not reach the brain, because it is rapidly converted to dopamine by aromatic acid decarboxylase at extracerebral sites. Large doses must therefore be given in order to allow for sufficient levodopa to reach the brain and provide the dopamine needed to correct the deficiency observed in patients with Parkinson’s disease. These large doses of levodopa result in a sharp increase in the levels of circulating dopamine and other dopa metabolites, and the excessive quantities of these substances in extracerebral tissues may explain in part some of the side effects of levodopa, such as nausea and vomiting and cardiac arrhythmias. The high incidence of these adverse effects requires a very slow titration of levodopa and may interfere with the administration of an effective drug dosage.
The decarboxylase inhibitor, benserazide, at the recommended therapeutic doses, does not cross the blood-brain barrier. Thus, administration of this agent makes it possible to inhibit the peripheral decarboxylation of levodopa without significantly affecting its metabolism in the brain. In this way, the formation of circulating dopamine is minimized and the incidence of extracerebral side effects may thereby be reduced while at the same time permitting more levodopa to reach the brain. Combined therapy with levodopa and benserazide reduces the amount of levodopa required for optimum therapeutic benefit and permits an earlier response to therapy.
Nevertheless, combined therapy does not decrease the adverse reactions due to central effects of levodopa. In fact, dyskinesias and oscillations in performance occur at lower dosages of levodopa and earlier in treatment during combined therapy.
Plasma levels of levodopa are markedly increased when the drug is given in combination with benserazide compared to those obtained after levodopa alone. There is also a reduction in the level of dopa metabolites when levodopa is combined with benserazide. Clinical trials have suggested that the combination of levodopa and benserazide in a 4 to 1 ratio is effective in reducing peripheral adverse effects and the amount of levodopa required for therapeutic improvement.
The pharmacokinetics of 4-benserazide administered alone and in combination with levodopa has been studied in 6 patients with Parkinson’s disease. Three of these patients were administered 50 mg of the inhibitor by both i.v. and oral routes. Three additional patients received oral does of 50 mg 4-benserazide alone and also in combination with 200 mg of levodopa.
Comparison of the time-plasma concentration curves of total radioactivity in the patients receiving oral and i.v. 4-benserazide indicated that between 66 and 74% of the administered dose was absorbed from the gastrointestinal tract. Peak plasma concentrations of radioactivity were detected 1 hour after oral administration in 5 of the 6 patients.
Elimination of the 4-label was primarily by urinary excretion with 86 to 90% of an i.v. dose recovered in the urine while 53 to 64% of the oral dose was detected in the urine. The majority of the 4 radioisotope was accounted for in the urine within 48 hours after administration. Fecal recovery studies conducted over 5 to 8 days accounted for the majority (approximately 30%) of the remainder of administered 4-benserazide.
In still another experiment in man, where 4-dopa had been administered either i.v. (0.1 mg/kg) or orally (3 mg/kg), the administration of benserazide (16 to 24 mg orally) enhanced the 4-dopa and 4-methyldopa plasma concentrations 6- to 10-fold over those observed with the administration of 4-dopa alone. Also, the 4-phenolcarboxylic acid concentration was 1/5 to 1/10th that which was observed when 4-dopa was administered alone.
Pyridoxine HCl (vitamin B6) accelerates the decarboxylation of levodopa and is therefore contraindicated in patients on levodopa alone. However, the efficacy of combination therapy is generally unaffected by pyridoxine.
Indications And Clinical Uses: Treatment of Parkinson’s syndrome with exception of drug-induced parkinsonism.
The administration of Prolopa is associated with amelioration of the symptoms of Parkinson’s syndrome with the advantage that combined therapy significantly diminishes the incidence of the levodopa-induced peripheral side effects of nausea, vomiting and possibly cardiac arrhythmias.
This results in an advantage for those patients who previously were unable to tolerate an optimal daily dosage of levodopa. Improved gastrointestinal tolerance also provides for a more rapid induction of therapy, e.g., optimum dosage can in most cases be achieved within 2 to 3 weeks.
However, combined therapy with levodopa and benserazide increases the incidence of centrally mediated abnormal movements earlier in therapy and can lead to an earlier appearance of oscillations in performance. Thus, when combined therapy with levodopa and benserazide is instituted it is important to strive at using and maintaining a dosage regimen which balances efficacy with freedom from dyskinesias.
Despite the dramatic symptomatic improvement it produces in many patients with Parkinson’s disease, levodopa does not arrest the progression of the disease and there is evidence to indicate that drug adverse effects increase with continuing use. Combined therapy, because of the advantages already described, is therefore indicated only when its use is capable of improving the quality of life of the patient. However, there is little to be gained by substituting combined therapy for levodopa in patients already on stable, effective and well tolerated levodopa therapy.
Contra-Indications: As with levodopa, patients in whom sympathomimetic amines are contraindicated should not receive Prolopa.
MAO inhibitors cannot be given concomitantly and should be withdrawn at least 2 weeks prior to initiating therapy with Prolopa.
Prolopa should not be administered to patients with clinical or laboratory evidence of uncompensated cardiovascular, endocrine, renal, hepatic, hematologic or pulmonary disease. Prolopa is also contraindicated in patients with narrow angle glaucoma.
Prolopa is contraindicated in patients with a known sensitivity to levodopa or benserazide.
Manufacturers’ Warnings In Clinical States: Before initiating therapy in patients already receiving levodopa, the levodopa should be discontinued at least 12 hours before Prolopa is started. Prolopa therapy should be instituted at a level that will provide approximately 15% of the previous amount of levodopa (see Dosage).
Prolopa is not indicated in the management of intention tremor, Huntington’s chorea, or drug-induced extrapyramidal effects.
Since Prolopa may induce CNS side effects effects shortly after beginning its use, and at lower doses of levodopa, it is important to administer the dosage in careful increments and to observe patients carefully for the development of abnormal involuntary movements. These movements and oscillations in performance may appear earlier with combination therapy. Should they occur, a dosage reduction is indicated.
All patients should be carefully observed for signs of depression with suicidal tendencies or other serious behavioral changes. Extreme caution should be used in treating patients with a history of psychotic disorders or who are receiving psychotherapeutic agents such as reserpine, phenothiazines or tricyclic antidepressants.
Care should be exercised in administering Prolopa to patients with a history of myocardial infarction or who have atrial, nodal or ventricular arrhythmias. Patients with cardiac abnormalities should have their treatment with Prolopa initiated in a facility with adequate monitoring equipment and provision for intensive care.
Care should be exercised in administering this drug to patients with a history of melanoma or with suspicious undiagnosed skin lesions.
Children and Young Adults: The safety of Prolopa in patients under the age of 18 has not been established. Animal studies have suggested the possibility of skeletal abnormalities when benserazide is administered before ossification is complete.
It should also be borne in mind that Prolopa stimulates human growth hormone secretion.
Pregnancy and Lactation: Although Prolopa’s effects on human pregnancy are unknown, levodopa has caused visceral and skeletal malformations in rabbits. Before prescribing the combination of levodopa and benserazide, physicians should consider the possibility that a woman of childbearing potential may be pregnant and should weigh the anticipated benefits of the drug against its possible hazards to the mother and to the fetus. In the event women of childbearing age become pregnant or wish to become pregnant while taking Prolopa the physician should consider the desirability of discontinuing this drug. Prolopa should not be given to nursing mothers.
Precautions: General: Regular assessments of cardiovascular, hepatic, hematopoietic and renal function should be performed in all patients during extended therapy. Patients with a history of convulsive disorders should be treated cautiously if Prolopa is incorporated into their regimen. The possibility of upper gastrointestinal hemorrhage occurring in patients with a history of peptic ulcer must be borne in mind when treating them with Prolopa.
Physical Activity: Patients with severe parkinsonism who improve on Prolopa therapy should be advised to resume normal activities gradually and with caution as rapid mobilization may increase the risk of injury, especially in those patients with osteoporosis or phlebothrombosis. Physiotherapy and appropriate safeguards may be useful during this phase.
Patients with Wide-Angle Glaucoma: Patients with chronic wide-angle glaucoma can be treated cautiously with Prolopa, provided the intraocular pressure is well controlled. The intraocular pressure should be monitored carefully during therapy. Rarely pupillary dilatation and activation of later Horner’s syndrome have been reported during levodopa treatment.
Drug Interactions: (a) Cardiovascular Drugs: Postural hypotensive episodes have been reported; therefore, Prolopa should be administered cautiously and blood pressure monitored in patients on antihypertensive medication. It may be necessary to adjust the dosage of the latter particularly during the initial stages of therapy with Prolopa. (b) Psychoactive Drugs: If concomitant administration of psychoactive drugs is necessary, they should be administered with great caution. Patients should be carefully observed for unusual untoward drug effect (see Contraindications and Warnings). (c) Anesthetics: If general anesthesia is required, Prolopa can be discontinued the night before surgery and therapy recommended as soon as the patient is able to receive oral medication.
Adverse Reactions: The most common serious adverse reactions occurring with Prolopa are the abnormal involuntary movements. Dosage reduction can diminish those reactions though often at the expense of increasing parkinsonism. Other serious adverse reactions are oscillations in performance, psychiatric disorders and, less frequently, cardiovascular effects.
Involuntary movements: choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm occur less often and may be taken as early signs of overdosage. The appearance of these reactions should prompt a reduction in the dose administered. The incidence of involuntary movements reported by several investigators was 30 to 40% in the first month and 50 to 60% or more by 6 to 9 months.
Oscillations in Performance: Periodic oscillations in performance constitute the most serious problem encountered after prolonged levodopa therapy and appear earlier with combined therapy than when levodopa is used alone. Three types have been described:
End of Dose Akinesia: episodic re-emergence of Parkinsonian symptoms 3 or more hours after each dose of levodopa, often following a period of dyskinesia. This type of akinesia tends to occur progressively earlier after each dose during prolonged therapy and is regarded as resulting from a temporary insufficiency of dopamine at the appropriate receptor sites.
On-off Phenomenon: a rapid alternation between a state of satisfactory motility, usually with oral-facial dyskinesias, and a rigid akinetic state without dyskinesias. This oscillation of performance is also regarded as being associated with a temporary insufficiency of dopamine.
Akinesia Paradoxica (Hypotonic Freezing): irregular episodes of sudden freezing, usually of short duration, with the patient unable to move, accompanied by hypotonia and postural instability. These episodes are at times accompanied by autonomic symptoms. Hypotonic freezing is regarded as possibly associated with a severe temporary deficiency in norepinephrine in progressively depleted and damaged norepinephrine pathways.
Psychiatric Disorders: paranoid ideation, psychotic episodes, depression (with or without development of suicidal tendencies) and dementia. In depressed patients, levodopa may give rise to an improvement in mood in a small number of individuals. However, when administered to patients with bipolar depression, it tends regularly to produce hypomania. Various psychiatric disturbances have been reported in about 20% of patients.
Other adverse reactions that occur less frequently during treatment with Prolopa are:
Cardiovascular: arrhythmias and orthostatic hypotensive episodes, hypertension, nonspecific ECG changes, flushing, phlebitis and angina pectoris have also been reported.
Neurologic: ataxia, faintness, impairment of gait, headache, increased hand tremor, akinetic episodes, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism and convulsions.
Intellectual function: progressive impairment of intellectual and autonomic functions has been described, particularly in akinetic patients, after prolonged levodopa therapy.
Psychiatric: increased libido with serious antisocial behavior, euphoria, lethargy, sedation, stimulation, fatigue and malaise, confusion, insomnia, nightmares, hallucinations and delusions, agitation and anxiety.
Gastrointestinal: nausea and vomiting, constipation, diarrhea, epigastric and abdominal distress or pain, flatulence, eructation, hiccups, sialorrhea, difficulty in swallowing, bitter taste, dry mouth, duodenal ulcer, gastrointestinal bleeding, burning sensation of the tongue.
Dermatologic: dark sweat, sweating, edema, hair loss, pallor and rash.
Hematological: hemolytic anemia, leukopenia, agranulocytosis.
Musculoskeletal: low back pain, muscle spasm and twitching, musculoskeletal pain.
Respiratory: cough, hoarseness, bizarre breathing pattern, postnasal drip.
Genitourinary: dark urine, hematuria, nocturia and urinary frequency, retention or incontinence and changes in libido.
Ophthalmologic: blurred vision, diplopia, dilated pupils, activation of latent Horner’s syndrome.
Miscellaneous: fever, weight variation.
Laboratory abnormalities: Elevations of BUN, serum uric acid, AST, ALT, LDH, bilirubin, alkaline phosphatase or PBI have been observed. Positive Coombs’ tests have been observed during extended therapy, both with Prolopa and with levodopa alone but hemolytic anemia is extremely rare.
Overdose: Symptoms: Symptoms of acute overdosage may be qualitatively similar to those listed under Adverse Effects and to those observed in patients overdosed with levodopa alone, but will possibly be of greater magnitude.
Treatment: General supportive measures should be employed, along with immediate gastric lavage. I.V. fluids should be administered judiciously and an adequate airway maintained. ECG monitoring should be instituted and the patient carefully observed for the development of arrhythmias and if required appropriate antiarrhythmic therapy should be provided. To date, the value of dialysis in the treatment of Prolopa overdosage is not known. Consideration should be given to the possibility of multiple drug ingestion by the patient. Pyridoxine is ineffective in reversing the effects of Prolopa overdosage.
Dosage And Administration: In order to achieve maximal benefit and reduce the incidence of adverse reactions, therapy with Prolopa must be individualized and drug administration must be continuously matched to the needs and tolerance of the patient. Because of the increased availability of levodopa to the CNS when administered in combined therapy, titration and adjustments of dosage should be made in small steps and the dosage ranges recommended should usually not be exceeded. The appearance of involuntary movements should be regarded as a sign of levodopa toxicity and as an indication of overdosage, usually requiring a reduction in dosage. Treatment should aim at maximal benefit without dyskinesias.
Levodopa should be discontinued for at least 12 hours before initiating therapy with Prolopa.
Capsules should be swallowed whole and not opened or dissolved in liquid.
Initiation of treatment in patients not on levodopa therapy: The initial recommended dose is 1 capsule of Prolopa 100-25 once or twice a day. This dose may be carefully increased by 1 capsule every third or fourth day until an optimal therapeutic effect is obtained without dyskinesias. Near the upper limits of dosage, the increments should be made slowly, say at 2- to 4-week intervals. The dosage should be divided, aiming at a frequency of dosing of at least 4 times daily taken with or immediately after meals.
The optimal dosage for most patients is usually 4 to 8 capsules of Prolopa 100-25 daily (400 to 800 mg of levodopa) divided into 4 to 6 doses. Most patients require no more than 6 capsules of Prolopa 100-25 (600 mg of levodopa)/day.
Individual patient response varies. Some patients, e.g., post encephalitic Parkinson patients, may only tolerate a slower rate of increase in dosage, e.g., 1 capsule of Prolopa 100-25 at weekly intervals, since these patients are more sensitive to levodopa and usually only tolerate lower dosages.
Prolopa 200-50 capsules are intended only for maintenance therapy once the optimal dosage has been determined using Prolopa 100-25 capsules. No patient should receive more than 5 to 6 capsules of Prolopa 200-50 daily (1 000 to 1 200 mg of levodopa in combined therapy) during the first year of therapy.
Treatment should be continued for at least 3 to 6 weeks before it is concluded that Prolopa therapy has not benefited the patient.
Initiation of treatment in patients on levodopa therapy: Allow at least 12 hours or more to elapse between the last dose of levodopa and the first dose of Prolopa. A dosage of Prolopa should be used that will provide approximately 15% of the previous levodopa daily dosage. For example, if a patient is receiving 4 000 mg of levodopa/day, the dosage of Prolopa 100-25 should not exceed 6 capsules/day (600 mg of levodopa) divided into 4 to 6 doses.
Adjustment and maintenance of therapy in all patients: Prolopa 200-50 capsules may be used for maintenance therapy once the optimal dosage has been determined using Prolopa 100-25 capsules. Prolopa 50-12.5 capsules should be used when frequent dosing is required to minimize adverse effects. During the first year of treatment the total daily dosage should not exceed 1 000 to 1 200 mg of levodopa in combined therapy.
The variability in dosage response of patients is considerable. Some individuals may experience oscillations in performance with a diurnal rhythm of periods of symptomatic control alternating with periods of akinesia (end of dose), with return of Parkinson’s symptoms, which can frequently be corrected by rescheduling individual doses. A low protein diet tends to potentiate and stabilize the effects of levodopa, whereas a high protein diet may decrease the effect of levodopa, although with combined therapy this effect may be less prominent. The predominant limiting factor in treatment with Prolopa is the occurrence of involuntary movements. These frequently can be controlled by reducing the dosage of levodopa and varying the frequency of individual doses. A progressive decrease in the threshold for dyskinetic manifestations and an increase in the incidence of oscillations in performance have been reported after a certain time on levodopa therapy. These appear earlier in the course of combined treatment with Prolopa than with levodopa alone.
In an attempt to avoid the emergence, or decrease the incidence of these manifestations, it is recommended that, after the initial period, the daily maintenance dosage of levodopa as combined therapy should be reduced slowly (at a rate of about 50 mg a month) over a period of a few months, to a maintenance level without dyskinesias. After 1 year of therapy, the patient should usually receive not more than 6 capsules of Prolopa 100-25 daily (600 mg of levodopa) divided into at least 4 to 6 doses.
Other antiparkinson agents, e.g., anticholinergics, may be continued during Prolopa therapy, and should not be abruptly withdrawn. However, as treatment proceeds, their dosage may need to be altered.
Interruption of therapy: If Prolopa therapy is interrupted for a brief period, the previous dosage may be administered as soon as the patient is again able to take oral medication. If, however, therapy is interrupted for a longer period, a lower dosage should be given and the dosage should be adjusted gradually. In many cases, patients can be returned rapidly to their previous therapeutic dosage.
Availability And Storage: Prolopa 50-12.5: Each light grey and blue capsule, imprinted (black ink) alternating between cap and body, contains: levodopa 50 mg and benserazide base 12.5 mg in the form of benserazide HCl. Nonmedicinal ingredients: gelatin, indigotine, iron oxide, magnesium stearate, mannitol, microcrystalline cellulose, povidone, talc and titanium dioxide. Energy: 0.7 kJ (0.2 kcal). Gluten-, lactose-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100.
Prolopa 100-25: Each blue and flesh colored capsule, imprinted (black ink) alternating between cap and body, contains: levodopa 100 mg and benserazide base 25 mg in the form of benserazide HCl. Nonmedicinal ingredients: gelatin, indigotine, iron oxide, magnesium stearate, microcrystalline cellulose, povidone, talc and titanium dioxide. Energy-, gluten-, lactose-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100.
Prolopa 200-50: Each blue and caramel colored capsule, imprinted (black ink) alternating between cap and body, contains: levodopa 200 mg and benserazide base 50 mg in the form of benserazide HCl. Nonmedicinal ingredients: gelatin, indigotine, iron oxide, magnesium stearate, microcrystalline cellulose, povidone, talc and titanium dioxide. Energy-, gluten-, lactose-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100.
Keep in a tightly closed, light-resistant container. Store at 15 to 30°C. (Shown in Product Recognition Section)
PROLOPA® Roche Levodopa – Benserazide Antiparkinsonian Agent