Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with Levomed. These inhibitors must be discontinued at least two weeks before starting Levomed. Levomed may be administered concomitantly with the manufacturer’s recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g. selegiline hydrochloride) (See section 4.5).
Levomed 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 section 4.6).
Use in patients with severe psychoses.
Levomed is not recommended for the treatment of drug-induced extrapyramidal reactions.
Levomed 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 or 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 concomitant suicidal tendencies, and other serious antisocial behaviour. Patients with past or 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 Levomed is substituted.
These reactions are thought to be due to increased brain dopamine following administration of levodopa, and use of Levomed may cause a recurrence. Dosage reduction may be required.
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, patients should be observed carefully when the dosage of Levomed is reduced abruptly or discontinued especially if the patient is receiving neuroleptics.
Patients 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 and 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 Levomed. Review of treatment is recommended if such symptoms develop.
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.
Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with carbidopa/levodopa. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS (see also section 4.8).
As with levodopa, periodic evaluation of hepatic, haematopoetic, cardiovascular and renal function is recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with Levomed, 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 Levomed 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 Levomed for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).
If general anaesthesia is required, therapy with Levomed 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.
Transient abnormalities in laboratory test results may occur, but have not been associated with clinical evidence of disease. These include elevated levels of blood urea nitrogen, AST (SGOT), ALT (SGPT), LDH, bilirubin, creatinine, uric acid and alkaline phosphatase.
Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of Levomed 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 Levomed and levodopa alone, but haemolytic anaemia is extremely rare.
Levomed may cause a false positive result for ketonuria when a dipstick is used to test for urinary ketone bodies; and this reaction is not altered by boiling the urine specimen. The use of glucose oxidase methods may give false negative results for glycosuria.
Levomed 100/25mg tablets contains tartrazine. May cause allergic reactions.
Caution should be exercised when the following drugs are administered concomitantly with Levomed.
Symptomatic postural hypotension has occurred when Levomed is added to the treatment of patients receiving some antihypertensive drugs. Therefore, when therapy with levomed is started, dosage adjustment of the antihypertensive drug may be required.
Rarely, reactions including hypertension and dyskinesia have been reported with the concomitant use of tricyclic antidepressants. (For patients receiving monoamine oxidase inhibitors, see first paragraph of section 4.3).
Studies demonstrate a decrease in the bioavailability of carbidopa and/or levodopa when it is ingested with ferrous sulphate or ferrous gluconate.
Dopamine D2 receptor antagonists (e.g. phenothiazines, butyrophenones, and risperidone, thioxanthenes) and isoniazid may reduce the therapeutic effects 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 Levomed should be carefully observed for loss of therapeutic response.
Use of Levomed with dopamine-depleting agents (e.g. reserpine and tetrabenazine) or other drugs known to deplete monoamine stores is not recommended.
Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone (See section 4.3)
Since levodopa competes with certain amino acids, the absorption of Levomed may be impaired in some patients on a high protein diet.
The effect of simultaneous administration of antacids with Levomed on the bioavailability of levodopa has not been studied.
Although the effects of Levomed 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 Levomed in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards should pregnancy occur.
Use of Levomed is contraindicated in pregnancy.
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 Levomed, 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 section 4.4).
Side effects that occur frequently with Levomed 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: The frequencies of adverse events are ranked according to the following: Very common (≥1/10), Common (≥1/100, <1/10), Uncommon (≥1/1000, <1/100), Rare (≥1/10,000, <1/1000), Very Rare (<1/10,000) including isolated reports, not known (cannot be estimated from the available data).
Common: Anorexia
Common: Dream abnormalities, hallucinations, depression with or without development of suicidal tendencies, confusion.
Uncommon: Agitation.
Rare: Psychotic episodes including delusions and paranoid ideation, increased libido.
Not known: Dopamine dysregulation syndrome.
Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated with carbidopa/levodopa. Affected patients show a compulsive pattern of dopaminergic drug misuse above doses adequate to control motor symptoms, which may in some cases result in severe dyskinesias (see also section 4.4).
Common: Bradykinetic episodes (the “on-off” phenomenon), dizziness, somnolence including very rarely excessive daytime somnolence and sudden sleep onset, paresthesia.
Uncommon: Syncope
Rare: Dementia, neuroleptic malignant syndrome (see 4.4 ‘Special warnings and precautions for use’). Rarely convulsions have occurred; however, a causal relationship with Levomed has not been established.
Common: Palpitation.
Rare: Cardiac irregularities.
Common: Orthostatic effects including hypotensive episodes.
Rare: Hypertension, phlebitis.
Common: Chest pain.
Common: Diarrhoea, vomiting.
Rare: Gastrointestinal bleeding, development of duodenal ulcer, dark saliva.
Rare: Leukopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia, agranulocytosis.
Common: Dyspnoea.
Uncommon: Urticaria.
Rare: Angioedema, pruritis, Henoch-Schönlein purpura, alopecia, rash, dark sweat.
Rare: Dark urine.
Neoplasms, benign, malignant and unspecified (including cysts and polyps): Malignant melanoma (see section 4.3).
Gastro-intestinal disorders: Dry mouth, sialorrhoea, dysphagia, hiccups, dyspepsia, abdominal pain and distress, constipation, flatulence, burning sensation of the tongue.
Metabolism and nutrition disorders: Weight gain or loss.
Psychiatric disorders: Anxiety, disorientation, euphoria, insomnia, bruxism.
Nervous system disorders: Bitter taste, decreased mental acuity, ataxia, numbness, increased hand tremor, activation of latent Horner’s syndrome, extrapyramidal and movement disorders, faintness, headache, sense of stimulation. Impulse control disorders: Pathological (compulsive) 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 Levomed (see section 4.4).
Skin and subcutaneous disorders: Increased sweating.
Musculoskeletal, connective tissue and bone disorders: Muscle cramps, trismus.
Eye disorders: Diplopia, blurred vision, dilated pupils, oculogyric crises.
Vascular disorders: Hot flashes, flushing.
Respiratory, thoracic and mediastinal disorders: Hoarseness, bizarre breathing patterns.
Renal and urinary disorders: Urinary retention, urinary incontinence.
Reproductive system and breast disorders: Priapism.
General disorders: Weakness, asthenia, fatigue, malaise, oedema, gait abnormalities.
Injury, poisoning and procedural complications: Falling.
Reporting 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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.
Not applicable.
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