MSD Ireland (Human Health) Limited

Sinemet^®12.5mg/50mg Tablets

Sinemet^®10mg/100mg Tablets

Sinemet^®Plus 25mg/100mg Tablets

Sinemet^®25mg/250mg Tablets

Each tablet of Sinemet 12.5mg/50mg contains carbidopa (equivalent to 12.5 mg of anhydrous carbidopa) and 50 mg levodopa.

Each tablet of Sinemet 10mg/100mg contains carbidopa (equivalent to 10 mg of anhydrous carbidopa) and 100 mg levodopa.

Each tablet of Sinemet Plus 25mg/100mg contains carbidopa (equivalent to 25 mg of anhydrous carbidopa) and 100 mg levodopa.

Each tablet of Sinemet 25mg/250mg contains carbidopa (equivalent to 25 mg of anhydrous carbidopa) and 250 mg levodopa.

For a full list of excipients, see section 6.1.

Tablets.

Sinemet 12.5mg/50mg, yellow, half scored, oval tablets, marked '520' on one side and plain on the other side.

Sinemet 10mg/100mg, dapple-blue, oval tablets, one side plain and the other scored and marked '647'.

Sinemet Plus 25mg/100mg, yellow, oval tablets, one side plain and the other scored and marked '650'.

Sinemet 25mg/250mg, light dapple-blue, oval tablets, one side plain and the other scored and marked '654'.

The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Antiparkinsonian agent.

For treatment of Parkinson's disease and syndrome. 'Sinemet' is useful in relieving many of the symptoms of parkinsonism, particularly rigidity and bradykinesia. It is frequently helpful in the management of tremor, dysphagia, sialorrhoea, and postural instability associated with Parkinson's disease and syndrome.

When response to levodopa alone is irregular, and signs and symptoms of Parkinson's disease are not controlled evenly throughout the day, substitution of 'Sinemet' usually reduces fluctuations in response. By reducing some of the adverse reactions produced by levodopa alone, 'Sinemet' permits more patients to obtain adequate relief from the symptoms of Parkinson's disease.

'Sinemet' may be given to patients with Parkinson's disease and syndrome who are taking vitamin preparations that contain pyridoxine hydrochloride (Vitamin B6).

To be taken orally.

The optimum daily dosage of 'Sinemet' must be determined by careful titration in each patient.

'Sinemet' Tablets are available as:-

Sinemet 12.5mg/50mg containing carbidopa PhEur equivalent to 12.5 mg of anhydrous carbidopa and 50 mg levodopa.

Sinemet 10mg/100mg containing carbidopa PhEur equivalent to 10 mg of anhydrous carbidopa and 100 mg levodopa.

Sinemet Plus containing carbidopa PhEur equivalent to 25 mg of anhydrous carbidopa and 100 mg levodopa.

Sinemet 25mg/250mg containing carbidopa PhEur equivalent to 25 mg of anhydrous carbidopa and 250 mg levodopa.

Each tablet of 'Sinemet' is designed to divide in half with minimal pressure.

General Considerations

Studies show that the peripheral dopa-decarboxylase is fully inhibited (saturated) by carbidopa at doses between 70 and 100 mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting. The formulations of 'Sinemet' are designed to provide a range of doses with sufficient carbidopa to inhibit peripheral dopa-decarboxylase and thus exert optimal therapy.

Standard antiparkinsonian drugs, other than levodopa alone, may be continued while 'Sinemet' is being administered, although their dosage may have to be adjusted.

Because both beneficial and adverse effects are seen more rapidly with Sinemet than with levodopa, patients should be carefully monitored during the dosage adjustment period. Involuntary movements, particularly blepharospasm, are a useful early sign of excess dosage in some patients.

Patients not receiving levodopa

Dosage may be best initiated with one tablet of 'Sinemet'-Plus three times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may be increased by one tablet of Sinemet 12.5mg/50mg or 'Sinemet'-Plus every day or every other day, as necessary, until a dosage equivalent of eight tablets of 'Sinemet'-Plus a day is reached.

If Sinemet 10mg/100mg or Sinemet 12.5mg/50mg is used, dosage may be initiated with one tablet three or four times a day. Titration upward may be required in some patients to achieve optimum dosage of carbidopa. The dosage may be increased by one tablet every day or every other day until a total of eight tablets (two tablets q.d.s.) is reached.

For patients starting with Sinemet 25mg/250mg, the initial dose is one-half tablet taken once or twice daily. However, this may not provide the optimal amount of carbidopa needed by many patients. If necessary, add one-half tablet every day or every other day until optimal response is reached.

Response has been observed in one day, and sometimes after one dose. Fully effective doses usually are reached within seven days as compared to weeks or months with levodopa alone.

Sinemet 12.5mg/50mg or Sinemet 10mg/100mg may be used to facilitate dosage titration according to the needs of the individual patient.

Patients receiving levodopa

Discontinue levodopa at least 12 hours (24 hours for slow-release preparations) before starting therapy with 'Sinemet'. The easiest way to do this is to give 'Sinemet' as the first morning dose after a night without any levodopa. The dose of 'Sinemet' should be approximately 20% of the previous daily dosage of levodopa.

Patients taking less than 1,500 mg levodopa a day should be started on one tablet of 'Sinemet'-Plus three or four times a day dependent on patient need. The suggested starting dose for most patients taking more than 1,500 mg levodopa a day is one tablet of Sinemet 25mg/250mg three or four times a day.

The dosage may then be adjusted gradually, but should not exceed eight tablets a day of Sinemet 25mg/250mg.

Maintenance

Therapy with Sinemet should be individualised and adjusted gradually according to response. When a greater proportion of carbidopa is required, each tablet of Sinemet 10mg/100mg may be replaced with a tablet of 'Sinemet'-Plus or Sinemet 12.5mg/50mg.

'Sinemet'-Plus may be helpful, especially for patients with nausea and vomiting.

Most patients can be maintained on divided doses of three to six tablets of Sinemet 25mg/250mg a day. Tablets are scored for easy division should the frequency of daily dosage need to be increased. During the titration period, 'Sinemet'-Plus may be more convenient.

When more levodopa is required, Sinemet 25mg/250mg should be substituted at a dosage of one tablet three or four times a day. If necessary, the dosage of Sinemet 25mg/250mg may be increased by half to one tablet every other day to a maximum of eight tablets a day. Experience with a total daily dosage greater than 200 mg carbidopa is limited.

Sinemet 10mg/100mg can be used as an alternative to 'Sinemet'-Plus.

Patients receiving levodopa with another decarboxylase inhibitor

When transferring a patient to 'Sinemet' from levodopa combined with another decarboxylase inhibitor, its dosage should be discontinued at least 12 hours before 'Sinemet' is started. Begin with a dosage of 'Sinemet' that will provide the same amount of levodopa as contained in the other levodopa/decarboxylase inhibitor combination.

Use with other antiparkinsonian agents

Current evidence indicates that other antiparkinsonian agents such as anticholinergics and amantadine may be continued when 'Sinemet' is introduced, although dosage may have to be adjusted in line with manufacturers recommendations.

Use in children

The safety of 'Sinemet' 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 elderly

In the elderly, dosage should generally be low with slow and minimal increments.

Non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with 'Sinemet'. These inhibitors must be discontinued at least two weeks before starting therapy with 'Sinemet'. 'Sinemet' may be administered concomitantly with the manufacturer's lowest recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline hydrochloride). (See 4.5 'Interactions with other medicinal products and other forms of interaction').

'Sinemet' is contraindicated in patients with narrow-angle glaucoma and in patients with known hypersensitivity to any component of this medication.

Since levodopa may activate a malignant melanoma, it should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

Use during pregnancy or lactation and in women breast-feeding infants (see 4.6 'Pregnancy and lactation').

Use in patients with severe psychoses.

'Sinemet' is not recommended for the treatment of drug-induced extrapyramidal reactions.

'Sinemet' should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease (because of the possibility of upper gastro-intestinal haemorrhage).

Levodopa has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of sleep during daily activities, in some cases without awareness of warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with levodopa. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of dosage or termination of therapy may be considered.

All patients should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients with current psychoses should be treated with caution.

Dyskinesias may occur in patients previously treated with levodopa alone because carbidopa permits more levodopa to reach the brain and, thus, more dopamine to be formed. The occurrence of dyskinesias may require dosage reduction.

Patients with a history of severe involuntary movements or psychotic episodes when treated with levodopa alone should be observed carefully when 'Sinemet' is substituted. These reactions are thought to be due to increased brain dopamine following administration of levodopa, and use of 'Sinemet' may cause a recurrence. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, mental changes and increased serum creatine phosphokinase has been reported with the abrupt withdrawal of antiparkinsonian agents. Therefore, any abrupt dosage reduction or withdrawal of 'Sinemet' should be carefully observed, particularly in patients who are also receiving neuroleptics.

Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease.

If concomitant administration of psycho-active drugs such as phenothiazines or butyrophenones is necessary, such drugs should be administered with caution, and the patient carefully observed for loss of antiparkinsonian effect.

Patients with a history of convulsions should be treated with caution.

As with levodopa, periodic evaluation of hepatic, haematopoetic, cardiovascular and renal function are recommended during extended therapy.

Patients with chronic wide-angle glaucoma may be treated cautiously with 'Sinemet', provided the intra-ocular pressure is well controlled and the patient monitored carefully for changes in intra-ocular pressure during therapy.

Care should be exercised when 'Sinemet' is administered to patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. Cardiac function should be monitored with particular care in such patients during the period of initial dosage adjustment.

Melanoma: Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using SINEMET for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

If general anaesthesia is required, therapy with 'Sinemet' may be continued for as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the usual daily dosage may be administered as soon as the patient is able to take oral medication.

Laboratory Tests

Transient abnormalities in laboratory test results may occur, but have not been associated with clinical evidence of disease. These include elevated blood urea, AST (SGOT), ALT (SGPT), LDH, bilirubin, and alkaline phosphatase.

Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of Sinemet than with levodopa.

Decreased haemoglobin, haematocrit, elevated serum glucose and white blood cells, bacteria and blood in the urine have been reported.

Positive Coombs' tests have been reported, both with 'Sinemet' and levodopa alone, but haemolytic anaemia is extremely rare.

'Sinemet' may cause a false positive result when a dipstick is used to test for urinary ketone; and this reaction is not altered by boiling the urine. The use of glucose oxidase methods may give false negative results for glycosuria.

Caution should be exercised when the following drugs are administered concomitantly with 'Sinemet'.

Antihypertensive agents

Symptomatic postural hypotension has occurred when 'Sinemet' is added to the treatment of patients receiving some antihypertensive drugs. Therefore, when therapy with 'Sinemet' is started, dosage adjustment of the antihypertensive drug may be required.

Antidepressants

Rarely, reactions including hypertension and dyskinesia have been reported with the concomitant use of tricyclic antidepressants. (For patients receiving monoamine oxidase inhibitors, see 4.3 'Contraindications'.)

Iron

Studies demonstrate a decrease in the bioavailability of carbidopa and/or levodopa when it is ingested with ferrous sulphate or ferrous gluconate.

Other drugs

Dopamine D₂ receptor antagonists (eg. phenothiazines, butyrophenones and risperidone) thioxanthenes, tetrabenazine, reserpine and isoniazid, may reduce the therapeutic effect of levodopa. The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with 'Sinemet' should be carefully observed for loss of therapeutic response.

Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone (see 4.3 'Contraindications').

Since levodopa competes with certain amino acids, the absorption of levodopa may be impaired in some patients on a high protein diet.

The effect of simultaneous administration of antacids with 'Sinemet' on the bioavailability of levodopa has not been studied.

Pregnancy

Although the effects of 'Sinemet' on human pregnancy are unknown, both levodopa and combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits. Therefore, the use of 'Sinemet' in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards should pregnancy occur.

Use of 'Sinemet' is contraindicated in pregnancy.

Breast-feeding mothers

It is not known whether carbidopa is excreted in human milk. In a study of one nursing mother with Parkinson's disease, excretion of levodopa in breast milk was reported. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in infants, a decision should be made whether to discontinue breast-feeding or discontinue the use of 'Sinemet', taking into account the importance of the drug to the mother.

No data are known about the effect on the ability to drive. If side effects such as dizziness or somnolence occur, they may affect the ability to drive and to operate machinery.

Patients being treated with levodopa and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also 4.4 'Special warnings and precautions for use').

Side effects that occur frequently with 'Sinemet' are those due to the central neuropharmacological activity of dopamine. These reactions can usually be diminished by dosage reduction. The most common are dyskinesias including choreiform, dystonic and other involuntary movements and nausea. Muscle twitching and blepharospasm may be taken as early signs to consider dosage reduction.

Other side effects reported in clinical trials or in post-marketing experience include:

Body as a whole: syncope, chest pain, anorexia.

Cardiovascular: cardiac irregularities and/or palpitation, orthostatic effects including hypotensive episodes, hypertension, phlebitis.

Gastrointestinal: vomiting, gastrointestinal bleeding, development of duodenal ulcer, diarrhoea, dark saliva.

Haematologic: leukopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia, agranulocytosis.

Hypersensitivity: angioedema, urticaria, pruritis, Henoch-Schoenlein purpura.

Nervous System/Psychiatric: neuroleptic malignant syndrome (see 4.4 'Special warnings and precautions for use'), bradykinetic episodes (the “on-off” phenomenon), dizziness, somnolence including very rarely excessive daytime somnolence and sudden sleep onset episodes, paresthesia, psychotic episodes including delusions, hallucinations and paranoid ideation, depression with or without development of suicidal tendencies, dementia, dream abnormalities, agitation, confusion, increased libido.

Respiratory: dyspnoea.

Skin: alopecia, rash, dark sweat.

Urogenital: dark urine.

Rarely convulsions have occurred; however, a causal relationship with 'Sinemet' has not been established.

Other side effects that have been reported with levodopa or levodopa/carbidopa combinations and may be potential side effects with 'Sinemet' include:

Body as a whole: muscle cramps.

Gastro-intestinal: dry mouth, bitter taste, sialorrhoea, dysphagia, bruxism, hiccups, dyspepsia, abdominal pain and distress, constipation, flatulence, burning sensation of the tongue.

Metabolic: weight gain or loss, oedema.

Nervous System/Psychiatric: asthenia, decreased mental acuity, disorientation, ataxia, numbness, increased hand tremor, trismus, activation of latent Horner's syndrome, insomnia, anxiety, euphoria, extrapyramidal and movement disorders, falling, gait abnormalities.

Patients treated with dopamine agonists for treatment of Parkinson's disease, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.

Skin: flushing, increased sweating.

Special senses: diplopia, blurred vision, dilated pupils, oculogyric crises.

Urogenital: urinary retention, urinary incontinence, priapism.

Miscellaneous: weakness, faintness, fatigue, headache, hoarseness, malaise, hot flushes, sense of stimulation, bizarre breathing patterns, malignant melanoma (see 4.3 'Contraindications').

Management of acute overdosage with 'Sinemet' is basically the same as management of acute overdosage with levodopa; however pyridoxine is not effective in reversing the actions of 'Sinemet'. ECG monitoring should be instituted, and the patient carefully observed for the possible development of arrhythmias; if required, appropriate anti-arrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as 'Sinemet' should be taken into consideration.

To date, no experience has been reported with dialysis, and hence its value in the treatment of overdosage is not known.

Levodopa is a precursor of dopamine, and is given as replacement therapy in Parkinson's disease.

Carbidopa is a peripheral dopa decarboxylase inhibitor. It prevents metabolism of levodopa to dopamine in the peripheral circulation, ensuring that a higher proportion of the dose reaches the brain, where dopamine acts. A lower dose of levodopa can be used, reducing the incidence and severity of side effects.

Following oral dosing levodopa, in the absence of decarboxylase inhibitor, is rapidly but variably absorbed from the gastrointestinal tract. It has a plasma half life of about 1 hour and is mainly converted by decarboxylation to dopamine, a proportion of which is converted to noradrenaline. Up to 30 % is converted to 3-O-methyldopa which has a half life of 9 to 22 hours. About 80 % of levodopa is excreted in the urine within 24 hours mainly as homovanillic acid and dihydroxyphenylactic acid. Less than 1 % is excreted unchanged.

Once in the circulation it competes with other neutral amino acids for transport across the blood brain barrier. Once it has entered the striatal neurones it is decarboxylated to dopamine, stored and released from presynaptic neurones. Because levodopa is so rapidly decarboxylated in the gastrointestinal tract and the liver very little unchanged drug is available for transport into the brain. The peripheral decarboxylation reduces the therapeutic effectiveness of levodopa but is responsible for many of its side effects. For this reason levodopa is usually administered together with a peripheral decarboxylase inhibitor such as carbidopa so that lower doses may be given to achieve the same therapeutic effect.

Carbidopa is rapidly but incompletely absorbed from the gastrointestinal tract following oral dosing. Following an oral dose approximately 50% is recorded in the urine with about 30 % of this as unchanged drug. It does not cross the blood brain barrier but crosses the placenta and is excreted in breast milk. Turnover of the drug is rapid and virtually all unchanged drug appears in the urine within 7 hours.

Carbidopa inhibits the peripheral decarboxylation of levodopa to dopamine but as it does not cross the blood brain barrier, effective brain levels of dopamine get produced with lower levels of levodopa therapy reducing the peripheral side effects noticeably nausea and vomiting and cardiac arrhythmias.

'Sinemet' is well established in medical use. Preclinical data is broadly consistent with clinical experience. For reproductive toxicity, see 4.6 'Pregnancy and lactation'.

Sinemet 12.5mg/50mg & 'Sinemet'-Plus tablets: quinoline yellow (E104), maize starch, pregelatinised maize starch, microcrystalline cellulose, magnesium stearate

Sinemet 10mg/100mg & Sinemet 25mg/250mg tablets: indigo carmine (E132), maize starch, pregelatinised maize starch, microcrystalline cellulose, magnesium stearate.

Not applicable.

3 years.

Bottles: Do not store above 25°C. Keep the bottle tightly closed. Store in the original package.

Blisters: Do not store above 25°C. Store in the original package in order to protect from light.

HDPE bottle of 84 or 100 tablets.

PVC/AL blister packs of 30 or 90 tablets.

Not all pack sizes are marketed.

Not applicable.

Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom

Sinemet 12.5mg/50mg Tablets: PA 35/47/4

Sinemet 10mg/100mg Tablets: PA 35/47/1

Sinemet Plus 25mg/100mg Tablets: PA/35/47/3

Sinemet 25mg/250mg Tablets: PA 35/47/2

Sinemet 12.5mg/50mg Tablets: 8 February 1990 / 1 April 2009

Sinemet 10mg/100mg Tablets: 1 April 1979 / 1 April 2009

Sinemet Plus 25mg/100mg Tablets: 2 March 1981 / 1 April 2009

Sinemet 25mg/250mg Tablets: 1 April 1979 / 1 April 2009

September 2009.

® Registered trademark of Merck & Co Inc., Whitehouse Station, New Jersey, USA