Summary of Product Characteristics Updated 11-Nov-2014 | Accord Healthcare Limited
Apodespan PR 50/200 mg Prolonged release tablets:Peach to light peach colored with mosaic appearance, oval shaped, biconvex tablets of approximately 13.0 mm in length and approximately 7.0 mm in width debossed with 'L200'on one side and plain on other side.
Patients who have never before received Levodopa therapy* For doses not achievable with Apodespan PR 50/200 mg prolonged release Tablets, other brands of carbidopa and levodopa prolonged-release tablets are available and can be used.Carbidopa and Levodopa 25 mg/100 mg prolonged release tablets* is recommended for use in patients, who have not previously had levodopa treatment or to aid titration in patients who receive Apodespan PR 50/200 mg prolonged release Tablets. The recommended starting dose is one tablet 25/100 mg two times per day. In patients who need more levodopa a daily dose of three to four tablets of Carbidopa and Levodopa 25 mg/100 mg prolonged release tablets* is usually well tolerated. For Apodespan PR 50/200 mg prolonged release Tablets the recommended starting dose is two times per day one tablet. The starting dose should not be higher than 600 mg levodopa per day and the doses should be administered with minimum intervals six hours.Dose adjustments should occur with intervals of at least two to four days.Depending of the severity of the disease, six months of treatment may be required to achieve optimal disease control.A guide to substitution for patients who are treated with the immediate-release combination of levodopa and decarboxylase inhibitor Transferring to Apodespan PR should initially occur in a dose that supplies at most about 10% more levodopa per day when higher doses are indicated (more than 900 mg daily). Levodopa and decarboxylase inhibitor should be discontinued at least 12 hours before the administration of Apodespan PR. The dose interval should be prolonged by 30% to 50% at intervals of ranging from 4-12 hours. If the divided doses are not equal it is recommended to administer the lowest dose at the end of the day. The dose should be adjusted depending on the clinical reaction, as indicated below in Dose Adjustment. It could be that doses which supply maximally 30% more levodopa per day are necessary.A guide for the substitution of Apodespan PR treatment for immediate-release levodopa/carbidopa combinations is shown in the table below:
|Levodopa/carbidopa||Carbidopa and Levodopa 25 mg/100 mg prolonged release Tablets*|
|Daily dose Levodopa (mg)||Daily dose Levodopa (mg)||Dose schedule|
|100-200||200||1 tablet, twice daily|
|300-400||400||4 tablets divided in 3 or more doses|
|* For doses not achievable with Apodespan PR 50/200 mg prolonged release Tablets, other brands of carbidopa and levodopa prolonged-release tablets are available and can be used.|
|Levodopa/carbidopa||Apodespan PR 50/200 mg Prolonged release tablets|
|Daily Dose Levodopa (mg)||Daily Dose Levodopa (mg)||Dose schedule|
|300 - 400||400||1 tablet, twice daily|
|500 - 600||600||1 tablet, 3 times per day|
|700 - 800||800||4 tablets*|
|900 1000||1000||5 tablets*|
|1100 - 1200||1200||6 tablets*|
|1300 - 1400||1400||7 tablets*|
|1500 - 1600||1600||8 tablets*|
Patients who are currently treated with just levodopaLevodopa must be discontinued at least twelve hours before therapy with Apodespan PR is started. In patients with mild to moderate form of the disease, the recommended starting dose is Apodespan PR 50/200 mg prolonged release Tablets twice daily.
Dose AdjustmentAfter the treatment is established the doses and the dose frequency can be increased or decreased depending on the therapeutic response. Most patients are adequately treated with 400 mg Levodopa/100 mg Carbidopa to 1600 mg Levodopa/400 mg Carbidopa per day, administered in divided doses at intervals ranging from four to twelve hours during the waking day. Higher doses (up to 2400 mg Levodopa/600 mg Carbidopa) and shorter intervals (less than four hours) have been used, but are generally not recommended.When doses of Apodespan PR are given at intervals of less than four hours or if the divided doses are not equal, it is recommended to administer the lowest dose at the end of the day.The effect of the first morning dose can be delayed in some patients for up to one hour compared to the usual reaction of the first morning dose of immediate-release Levodopa/Carbidopa.Adjustments of the dosage should occur in intervals of at least three days.
Maintenance doseBecause Parkinson's disease is progressive, periodic clinical check-ups are recommended and an adjustment of the dose schedule of Apodespan PR may be needed.
Addition of other antiparkinson medicationAnticholinergic agents, dopamine agonists and amantadine can be administered concomitantly with Apodespan PR or Carbidopa. It might be necessary to adjust the dose Apodespan PR when these medications are added to an ongoing treatment of Apodespan PR.
Interruption of therapyPatients should be carefully observed in case of a sudden reduction of the dose or if it is necessary to discontinue treatment with Apodespan PR, particularly in the patient who is receiving antipsychotics (see 4.4 'Special warnings and precautions for use'). If an anaesthetic is necessary, the administration of Apodespan PR can be continued as long as the patient is allowed to take oral medications. In case of a temporary interruption of the therapy, the usual dose can be administered as soon as the patient is able to take the oral medications.
Use in ChildrenThe safety in patients under 18 years of age has not been established and its use in patients below the age of 18 is not recommended.
Use in the elderlyThere is a wide experience in the use of combinations of levodopa and carbidopa in elderly patients. The recommendations set out above reflect the clinical data derived from this experience.
Use in renal/hepatic impairmentRenal impairmentNo particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal insufficiency, therefore Levodopa/Carbidopa should be administered cautiously to patients with severe renal impairment including those receiving dialysis therapy. The dose should be titrated individually.Hepatic impairmentLevodopa/Carbidopa is contraindicated in patients with severe hepatic impairment (see section 4.3). For patients with mild to moderate hepatic impairment caution is advised. The dose should be titrated individually.
Impulse control disordersPatients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Apodespan PR. Review of treatment is recommended if such symptoms develop.Patients with Parkinson's disease show a possible increased risk of melanoma but no confirmed association with levodopa therapy has been established.Therefore caution should be exercised during treatment.
Laboratory TestsCarbidopa/levodopa preparations have given rise to abnormalities in several laboratory tests and these can also occur with Apodespan PR. These include elevations of liver function tests such as alkaline phosphatase SGOT (AST), SGPT (ALT), lactic acid dehydrogenase, bilirubin, blood urea nitrogen, creatinine, uric acid and positive Coombs test. Decreased haemoglobin and haematocrit, elevated serum glucose and white blood cells, bacteria and blood in the urine have been reported with Levodopa/Carbidopa.When a test strip is used to determine ketonuria, carbidopa/levodopa preparations can show a false positive result for urinary ketone bodies. This reaction is not altered by boiling the urine sample. False negative results can also occur in the examination of glycosuria with the use of glucose oxidase methods.Lactose: Apodespan PR contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Anti-hypertensivesSymptomatic orthostatic dysregulation has occurred when levodopa is added with a decarboxylase inhibitor to certain antihypertensives. Dose adjustment of antihypertensives may be necessary during the titration phase of treatment with Apodespan PR.
AntidepressantsThere have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant administration of tricyclic antidepressants and carbidopa/levodopa preparations. (see section 4.3 for patients receiving mono-amine oxidase inhibitors).
AnticholinergicsAnti-cholinergics may act synergistically with levodopa to decrease tremor. However combined use may exacerbate abnormal involuntary movements. Anticholinergics may decrease the effects of levodopa by delaying its absorption. An adjustment of the dose of Levodopa/Carbidopa may be needed.
Other medicinesDopamine D2 receptor antagonists (for instance phenothiazines, butyrophenons, risperidone), benzodiazepines and isoniazide can reduce the therapeutic effect of levodopa. The beneficial effects of levodopa in Parkinson's disease may be reduced by phenytoin and papaverine. Patients taking these medications together with Apodespan PR should be observed carefully for loss of therapeutic response. Concomitant use of selegiline and levodopa-carbidopa may be associated with severe orthostatic hypotension (see section 4.3 'Contraindications').
COMT inhibitors (tolcapone, entacapone)Concomitant use of COMT (Catechol-O-Methyl Transferase) inhibitors and Apodespan PR can increase the bioavailability of levodopa. The dose of Levodopa/Carbidopa may need adjusting. Amantadine has a synergistic effect with levodopa and may increase levodopa-related side events. An adjustment of the dose of Levodopa/Carbidopa may be needed.Metoclopramide increases gastric emptying and may increase the bioavailability of Apodespan PR.Sympathomimetics may increase cardiovascular side events related to levodopaConcomitant use of ferrous sulphate and levodopa-carbidopa can lead to a reduction in the bioavailability of levodopa.As levodopa competes with certain amino acids, the absorption of levodopa can be impaired in some patients who are on a protein rich diet. Concurrent administration of iron sulphate and levodopa/carbidopa reduces the bioavailability of levodopa with approximately 50 %, most likely because of chelate formation. The bioavailability of carbidopa is also decreased by approximately 75 %. Products containing iron sulphate and levodopa/carbidopa should be administered separately with the longest possible time interval.The effect of administration of antacids and Levodopa/Carbidopa retard on the bioavailability of levodopa has not been studied.
PregnancyThere are insufficient data on the use of levodopa/carbidopa in pregnant women. The results of animal studies have shown reproduction toxicity (See 5.3 'Preclinical Safety Data'). The potential human risk to the embryo or the foetus is not known.Apodespan PR should not be used during pregnancy. Any woman of childbearing potential who is receiving Apodespan PR must practise effective contraception.
LactationIt is not known whether carbidopa is excreted in human milk. Carbidopa was excreted in small amounts in milk of rats. Levodopa is secreted in breast milk. While using Apodespan PR women should not breast feed. Carbidopa and levodopa are known to suppress prolactin production.FertilityThere are no data regarding potential effects of levodopa and carbidopa on fertility.
Blood and lymphatic system disordersRare (≥ 1/10,000 to < 1/1,000): Leukopenia, haemolytic and non-haemolytic anaemia, thrombocytopeniaVery rare (< 1/10,000): Agranulocytosis
Metabolism and nutrition disordersCommon (≥ 1/100 to < 1/10): AnorexiaUncommon (≥ 1/1,000 to < 1/100): Loss of weight, increased weight
Psychiatric disordersCommon (≥ 1/100 to < 1/10): Hallucinations, confusion, dizziness, nightmares, sleepiness, fatigue, sleeplessness, depression with very rare suicide attempts, euphoria, dementia, feeling of stimulation, dream abnormalitiesRare (≥ 1/10,000 to < 1/1,000): Agitation, fear, reduced thinking capacity, disorientation, headache, increased libido, numbness and convulsions, psychotic episodes including delusions and paranoid ideation
Impulse control disordersPathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Apodespan PR.(see section 4.4 'Special warning and precautions for use).
Nervous system disordersCommon (≥ 1/100 to < 1/10): Dyskinesia (a higher frequency of dyskinesia was seen with Apodespan PR than with the immediate-release formulation of Levodopa/Carbidopa), chorea, dystonia, extrapyramidal and movement disorders, the on-off-appearanceBradykinesia (on-off episodes) may appear some months to years after the beginning of treatment with levodopa and is probably related to the progression of the disease. The adaptation of dose schedule and dose intervals may be required.Uncommon (≥ 1/1,000 to < 1/100): Ataxia, increased tremor of the handsRare (≥ 1/10,000 to < 1/1,000): Malignant neuroleptic syndrome, paraesthesia, falling, walking defects, trismusLevodopa/carbidopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.Not known: Muscle twitching
Eye disordersRare (≥ 1/10,000 to < 1/1,000): Hazy vision, blepharospasm, activation of a latent Horner's syndrome, double vision, dilated pupils, and oculogyric crisesBlepharospasm can be an early sign of overdosage.
Cardiac disordersCommon (≥ 1/100 to < 1/10): Palpitations, irregular heartbeat
Vascular disordersCommon (≥ 1/100 to < 1/10): Orthostatic hypotension, inclination to faint, syncopeUncommon (≥ 1/1,000 to < 1/100): HypertensionRare (≥ 1/10,000 to < 1/1,000): Phlebitis
Respiratory, thoracic and mediastinal disordersUncommon (≥ 1/1,000 to < 1/100): Hoarseness, chest painRare (≥ 1/10,000 to < 1/1,000): Dyspnoea, abnormal breathing pattern
Gastrointestinal disordersCommon (≥ 1/100 to < 1/10): Nausea, vomiting, dry mouth, bitter tasteUncommon (≥ 1/1,000 to < 1/100): Constipation, diarrhoea, sialorrhoea, dysphagia, flatulenceRare (≥ 1/10,000 to < 1/1,000): Dyspepsia, gastrointestinal pain, dark saliva, bruxism, hiccups, gastrointestinal bleeding, burning sensation of the tongue, duodenal ulceration
Skin and subcutaneous tissue disordersUncommon (≥ 1/1,000 to < 1/100): OedemaRare (≥ 1/10,000 to < 1/1,000): Angioedema, urticaria, pruritus, facial redness, hair loss, exanthema, increased perspiration, dark perspiration fluid and Schönlein-Henoch purpura
Musculoskeletal, connective tissue and bone disordersUncommon (≥ 1/1,000 to < 1/100): Muscle spasms
Renal and urinary disordersUncommon (≥ 1/1,000 to < 1/100): Dark urineRare (≥ 1/10,000 to < 1/1,000): Urinary retention, urinary incontinence, priapism
General disorders and administration site conditionsAsthenia Uncommon (≥ 1/1,000 to < 1/100): Weakness, malaise, flare ups
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
AbsorptionThe pharmacokinetics of levodopa after administration of levodopa+carbidopa 200+50 mg in retard form compared to an immediate release levodopa+carbidopa 200+50 mg tablet has been studied in young healthy volunteers. After administration of levodopa+carbidopa 200+50 mg retard it took approximately two hours before maximal levodopa plasma levels were reached in comparison to 0.75 hours for the immediate-release tablet. The mean maximal levodopa plasma levels were reduced 60% in levodopa+carbidopa 200+50 mg retard compared in immediate-release tablets. The absorption of levodopa after the administration of levodopa+carbidopa 200+50 mg retard occurred continuously for four to six hours. In these studies the levodopa plasma concentrations fluctuated within closer margins than with the immediate-release tablet of levodopa and carbidopa. As the bio-availability of levodopa from levodopa+carbidopa 200+50 mg retard in comparison to an immediate-release tablet with a combination of levodopa and carbidopa is approximately 70%, the daily dose of levodopa in the modified release formulation should as a rule be higher than that of the immediate-release product.Intake of food had no influence on the absorption of levodopa. With regard to carbidopa the simultaneous intake of food resulted in a 50% AUC reduction and a 40% Cmax reduction. The reduced plasma levels of carbidopa have no clinical relevance.
DistributionLevodopa is widely distributed to most body tissues, but not to the central nervous because of extensive metabolism in the periphery. Levodopa is not bound to proteins.Levodopa crosses the blood-brain barrier by an active but saturable transport system for large neutral amino acids. Carbidopa does not cross the blood brain barrier. Both Levodopa and carbidopa cross the placenta and are excreted in breast milk.
Metabolism and eliminationIn the presence of carbidopa, levodopa is mainly metabolised to aminoacids and, to a less extent, to catecholamine derivates. All metabolites are excreted renally.Following an oral dose approximately 50% is recorded in the urine.
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