INBRIJA Inhalation powder, hard capsule Ref.[116049] Active ingredients: Levodopa

Bronchospasm in patients with lung disease

Because of the risk of bronchospasm, use of levodopa inhalation powder in patients with asthma, chronic obstructive pulmonary disease (COPD), or other chronic underlying lung disease is not recommended. There is limited data regarding chronic effect of Inbrija in respiratory compromised patients.

Central Nervous System (CNS) effects and mental disturbances

Somnolence and episodes of sudden sleep onset

Levodopa has been associated with somnolence and episodes of sudden sleep onset (see section 4.7). 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 (see section 4.7). Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dose or termination of therapy may be considered.

Withdrawal-emergent hyperpyrexia and confusion

A symptom complex that resembles neuroleptic malignant syndrome (characterised by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious aetiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in the background dopaminergic therapy. Therefore, any abrupt dose reduction or withdrawal of any levodopa medicinal product should be carefully observed, particularly in patients who are also receiving neuroleptics.

Mental disturbances

Patients may experience new or worsening mental status and behavioural changes, which may be severe, including psychotic-like and suicidal behaviour during levodopa treatment or after starting or increasing the dose of levodopa. This abnormal thinking and behaviour can consist of one or more of a variety of manifestations including anxiety, depression, paranoid ideation, delusions, hallucinations, confusion, psychotic-like behaviour, disorientation, aggressive behaviour, agitation, and delirium. Patients with a major psychotic disorder or a history of psychotic disorder must be treated cautiously with a levodopa/dopa-decarboxylase inhibitor because of the risk of exacerbating psychosis. In addition, certain medicinal products used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of levodopa. Concomitant use of antipsychotics should be monitored carefully for worsening of Parkinson's motor symptoms especially when D2-receptor antagonists are used (see section 4.5).

Impulse control disorders

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, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with levodopa. Review of treatment is recommended if such symptoms develop.

Dyskinesia

Inbrija may cause dyskinesia. Adjustment of levodopa therapy or other medicinal products used for the treatment of Parkinson's disease may be considered.

Cardiovascular ischaemic events

Inbrija should be administered with caution in patients with severe cardiovascular disease. Care should be exercised when Inbrija 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 initiation of treatment with Inbrija.

Peptic ulcer disease

Levodopa should be administered cautiously to patients with a history of peptic ulcer disease (because of the possibility of upper gastro-intestinal haemorrhage).

Glaucoma

Levodopa may cause increased intraocular pressure in patients with glaucoma. Patients with chronic glaucoma may be treated cautiously with levodopa provided the intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular pressure during therapy.

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 medicinal products used to treat Parkinson's disease, is unclear. Periodic skin examinations are recommended to monitor for melanoma in patients receiving Inbrija.

Laboratory monitoring

Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and bilirubin. Abnormalities in blood urea nitrogen (BUN) and positive Coombs test have also been reported.

Interference with test

Levodopa may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.

Cases of falsely diagnosed pheochromocytoma in patients on levodopa/dopa-decarboxylase inhibitor therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or levodopa/dopa-decarboxylase inhibitor therapy.

Orthostatic hypotension

Levodopa can cause orthostatic hypotension. Inbrija should be used with caution in case of concomitant use of medicinal products that may cause orthostatic hypotension, e.g. anti-hypertensive medicinal products.

Intercurrent respiratory infection

There is limited data available on the use of Inbrija during a respiratory infection. Based on individual assessments of the severity of the intercurrent respiratory infection Inbrija may be continued or discontinued until the respiratory symptoms resolve (see section 4.2).

Non-selective Monoamine Oxidase (MAO) inhibitors

The use of non-selective MAO inhibitors with levodopa is contraindicated (see section 4.3). Any non- selective MAO inhibitors should be discontinued at least 14 days prior to initiating levodopa.

Selective Monoamine Oxidase (MAO) inhibitors

The use of selective MAO-B inhibitors (e.g. rasagiline, selegiline, and safinamide) with levodopa may be associated with orthostatic hypotension. Patients who are taking these medicinal products should be monitored closely.

Dopamine D2 receptor antagonists and isoniazid

Dopamine D2 receptor antagonists (e.g. phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce the effectiveness of levodopa. Patients who are taking these medicinal products should be monitored for worsening Parkinson's symptoms (see section 4.4).

Antihypertensives

Symptomatic postural hypotension has occurred when combinations of levodopa and a dopa-decarboxylase inhibitor are added to the treatment of patients already receiving certain antihypertensives. Dose adjustment of the antihypertensive medicinal products may be required during concomitant use of Inbrija.

Anticholinergics

Anticholinergic medicinal products can work synergistically with levodopa, in order to improve tremor. Concurrent use can, however, cause a worsening of involuntary motor disorders. Anticholinergic medicinal products may impair the effect of oral levodopa medicinal products, due to a delayed absorption. A dose adjustment of levodopa may be required.

COMT inhibitors

The addition of entacapone to a levodopa/dopa-decarboxylase inhibitor has been demonstrated to increase the levodopa bioavailability by 30%. A dose adjustment of levodopa may be required with concomitant use of COMT inhibitors.

Tricyclic antidepressants

There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and a levodopa/dopa-decarboxylase inhibitor.

Amantadine

Concurrent administration of levodopa and amantadine may increase confusion, hallucinations, nightmares, gastro-intestinal disturbances, or other atropine-like side effects. Psychotic reactions have been observed in patients receiving amantadine and levodopa.

Local or systemic pulmonary medicinal products

Interactions of Inbrija with local or systemic pulmonary medicinal products were not investigated because Inbrija is not recommended in patients with asthma, chronic obstructive pulmonary disease (COPD), or other chronic underlying lung disease (see section 4.4).

Pregnancy

There are no or limited amount of data from the use of levodopa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Inbrija is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Levodopa is excreted in human milk. There is insufficient information on the effects of levodopa in newborns/infants. Breast-feeding should be discontinued during treatment with Inbrija.

Fertility

There are no data on the effects of levodopa on human fertility. Animal studies indicated no effect on fertility (see section 5.3).

Levodopa may have a major influence on the ability to drive and use machines. Certain side effects such as sleepiness and dizziness, that have been reported with other forms of levodopa medicinal products, may affect some patients' ability to drive or use machines.

Patients being treated with levodopa medicinal products 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. use machines), until such recurrent episodes and somnolence have resolved (see also section 4.4).

Summary of safety profile

The most frequent adverse reactions reported in the Inbrija clinical studies were cough (15.6%), fall (8.7%), upper respiratory tract infection (5.8%), dyskinesia (5.7%) and sputum discoloured (2.8%). Serious adverse reactions of allergic oedema have been reported with levodopa medicinal products but not in clinical studies with Inbrija. A symptom complex resembling neuroleptic malignant syndrome and rhabdomyolysis may occur with levodopa/dopa-decarboxylase inhibitor medicinal products, although no cases have been identified in clinical studies with Inbrija. Gastrointestinal haemorrhage has been reported with levodopa medicinal products and was observed once in Inbrija clinical studies.

Tabulated list of adverse reactions

Adverse reactions are presented by system organ class and frequency in Table 1 below. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), not known (cannot be estimated from the available data).

Table 1. Adverse reactions:

^a Cardiac rhythm disorder here is a combined term representing atrial fibrillation, atrial flutter, atrioventricular block, bundle branch block, sick sinus syndrome, bradycardia, and tachycardia.

Description of selected adverse reactions

Sudden sleep onset

Levodopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

Impulse control disorders

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 (see section 4.4).

Coughing

Most cough reported in the clinical studies with Inbrija were mild to moderate in intensity, and usually reported within the first 30 days of the treatment. Due to cough, 2% of subjects withdrew from the clinical studies with Inbrija.

Sensation of choking

In post-marketing experience, there have been reports of the sensation of choking associated with the drug powder impacting the back of the throat, immediately following administration.

Reporting of suspected adverse reactions

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 via the national reporting system listed in Appendix V.

Not applicable.