Levodopa and Carbidopa

Foscarbidopa has been identified as a potential inducer of CYP1A2 in vitro. Care should be taken when prescribing 24-hour subcutaneous infusions containing foscarbidopa in combination with sensitive CYP1A2 substrates (e.g., fluvoxamine, clozapine, caffeine, theophylline, duloxetine and melatonin). No clinical DDI studies have been conducted to assess the clinical relevance of this finding.

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

Although the effects of levodopa/carbidopa 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 levodopa/carbidopa in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards should pregnancy occur.

It is not known whether carbidopa or levodopa is excreted in human milk. In a study of one nursing mother with Parkinson's disease, excretion of levodopa in human 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 breastfeeding or discontinue the use of levodopa/carbidopa, taking into account the importance of the drug to the mother.

Fertility

In reproduction studies, no effects on fertility were observed in rats receiving levodopa/carbidopa.

Individual responses to medication may vary and certain side effects that have been reported with levodopa/carbidopa may affect some patients' ability to drive or operate machinery. Patients 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.

Oral administration

Side effects that occur frequently with levodopa/carbidopa 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 serious 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 palpitations, orthostatic effects including hypotensive episodes, hypertension, phlebitis.

Gastro-intestinal: Vomiting, gastro-intestinal bleeding, development of duodenal ulcer, diarrhoea, dark saliva.

Hematologic: Leucopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia, agranulocytosis.

Hypersensitivity: Angioedema, urticaria, pruritus, Henoch-Schonlein purpura.

Nervous System/Psychiatric: Neuroleptic malignant syndrome, bradykinetic episodes (the "on-off" phenomenon), dizziness, paraesthesia, psychotic episodes including delusions, hallucinations and paranoid ideation, depression with or without development of suicidal tendencies, dementia, dream abnormalities, agitation, confusion, increased libido. Levodopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

Respiratory: Dyspnoea.

Skin: Alopecia, rash, dark sweat.

Urogenital: Dark urine.

Rarely convulsions have occurred; however, a causal relationship with levodopa/carbidopa has not been established.

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

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

Frequency "not known": Dopamine dysregulation syndrome.

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

Metabolic: Weight gain or loss, oedema.

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 including levodopa/carbidopa.

Skin: Flushing, increased sweating.

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

Urogenital: Urinary retention, urinary incontinence, priapism.

Infections and Infestations: Urinary tract infections (frequency: very common)

Miscellaneous: Weakness, faintness, fatigue, headache, hoarseness, malaise, hot flushes, sense of stimulation, bizarre breathing patterns, malignant melanoma.

Description of selected adverse reactions: 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.

Subcutaneous administration

Summary of the safety profile

The most frequent adverse reactions (≥10%) reported in all Phase 3 studies in patients exposed to solution for infusion were infusion site events (infusion site erythema, infusion site cellulitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction, and infusion site infection), hallucination, fall, and anxiety.

Tabulated list of adverse reactions

Adverse reactions reported in all Phase 3 studies in patients exposed to levodopa/carbidopa solution for infusion (379 patients with total exposure of 414.3 person‑years, 230 subjects exposed for ≥6 months, 204 subjects exposed for ≥12 months) or data from levodopa/carbidopa intestinal gel based on treatment emergent frequencies, regardless of causality assigned are presented in Table 1, listed by MedDRA system organ class. Adverse reaction frequencies are based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); and very rare (<1/10 000).

Table 1. List of adverse reactions:

^a Common adverse reactions pertaining to infusion site events included if ≥2%.
^b These adverse reactions were identified with levodopa/carbidopa intestinal gel as drug-related events. However, these events were not considered adverse reactions for levodopa/carbidopa solution for infusion.
^c Hallucination includes hallucination, hallucination visual, hallucination auditory, hallucination olfactory, hallucinations tactile, and hallucinations mixed.
^d Polyneuropathy includes neuropathy peripheral, polyneuropathy, decreased vibratory sense, peripheral sensory neuropathy, sensory disturbance, and sensory loss.
^e Based on post-marketing data

Description of selected adverse reactions

Infusion site events

In the Phase 3 studies, the most common AEs related to levodopa/carbidopa solution for infusion were infusion site reactions 77.6% (N=294) and infusion site infections 41.4% (N=157). Infusion site events including infusion site reactions and infections, commonly seen with subcutaneous infusions were observed with levodopa/carbidopa solution for infusion in the clinical studies. The majority of the infusion site events were non-serious, were mild or moderate in severity, and resolved spontaneously or with treatment such as antibiotics and/or incision and drainage. Three subjects with infusion site infections had a complication of sepsis resulting in hospitalisation. Monitor for any skin changes at the infusion site that could indicate a potential infection, such as redness associated with warmth, swelling, pain, and discolouration when you apply pressure to it. Aseptic techniques should be followed while using this medication and consider rotating the infusion site more frequently than every 3^rd day, using a new infusion set if you see these skin changes. It is recommended that new infusion sites be at least 2.5 cm from sites used within the previous 12 days.

Laboratory values: The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should, therefore, be acknowledged when treating patients with levodopa/carbidopa solution for infusion: elevated urea nitrogen, alkaline phosphatases, S-AST, S-ALT, LDH, bilirubin, blood sugar, creatinine, uric acid and positive Coomb's test, and lowered values of haemoglobin and haematocrit. Leucocytes, bacteria and blood in the urine have been reported. Levodopa/carbidopa, and thus levodopa/carbidopa solution for infusion, may cause a false positive result when a dipstick is used to test for urinary ketone; this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may give false negative results for glucosuria.

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 HPRA Pharmacovigilance; website: www.hpra.ie.

Continuous intestinal administration

Drug-related undesirable effects that occur frequently with the continuous intestinal administration system include nausea and dyskinesia.

Device- and procedure related undesirable effects that occur frequently with the continuous intestinal administration system include abdominal pain, complications of device insertion, excessive granulation tissue, incision site erythema, postoperative wound infection, post procedural discharge, procedural pain, and procedural site reaction.

Most of these adverse reactions were reported early in the studies, subsequent to the percutaneous endoscopic gastrostomy procedure and occurred during the first 28 days.

Undesirable effects reported with levodopa/carbidopa intestinal gel

The safety of levodopa/carbidopa intestinal gel was compared to the standard oral formulation of levodopa/carbidopa (100 mg/25 mg) in a total of 71 advanced Parkinson's disease patients who participated in a randomized, double-blind, double-dummy, active controlled study of 12 weeks duration. Additional safety information was collected in an open-label, 12-month study in 354 patients with advanced Parkinson's disease and open-label extension studies.

An analysis was performed for patients who received levodopa/carbidopa intestinal gel in all studies, regardless of the study design (double-blind or open-label) to allow for a summary of drug-related adverse reactions. Another analysis was performed for patients who received levodopa/carbidopa intestinal gel or placebo gel through a PEG-J to allow for a summary of procedure-related and device-related adverse reactions in all studies, regardless of the study design (double-blind or open-label).

Drug-, Procedure- and device-related adverse reactions based on treatment emergent frequencies, regardless of causality assigned, in addition to adverse reactions identified during post-approval use of levodopa/carbidopa intestinal gel are presented in Table 2.

Table 2. Adverse Reaction Data Derived From Clinical Trials and Post-marketing Experience:

Dislocation of the intestinal tube backwards into the stomach or an obstruction in the device leads to reappearance of the motor fluctuations.

The following additional adverse reactions (listed in MedDRA preferred terms) have been observed with oral levodopa/carbidopa and could occur with levodopa/carbidopa intestinal gel:

Table 3. Adverse Reaction Observed with Oral Levodopa/Carbidopa:

Laboratory values: The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should, therefore, be acknowledged when treating patients with levodopa/carbidopa intestinal gel: elevated urea nitrogen, alkaline phosphatases, S-AST, S-ALT, LDH, bilirubin, blood sugar, creatinine, uric acid and positive Coomb's test, and lowered values of haemoglobin and haematocrit. Leucocytes, bacteria and blood in the urine have been reported. Levodopa/carbidopa, and thus levodopa/carbidopa intestinal gel, may cause a false positive result when a dipstick is used to test for urinary ketone; this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may give false negative results for glucosuria.