Signs and symptoms of overdosage may include drowsiness, sweating, hypotension and hypothermia.
Treatment is symptomatic.
Not applicable
The following undesirable effects are ranked according to system organ class and to their frequency:
Very common (>1/10)
Common (>1/100 and <1/10)
Uncommon (>1/1000 and <1/100)
Rare (>1/10,000 and <1/1000)
Very rare (<1/10,000)
Not known (it is not possible to estimate the incidence from available data).
| System/Organ categories | Frequency | Event |
| Psychiatric disorders | Very common | Depression |
| Common | Anxiety, insomnia, confusion | |
| Not known | Disorientation, nervousness | |
| Nervous system disorders | Very common | Drowsiness (with higher dosages), Parkinson-like syndrome (with higher dosages) |
| Metabolism and nutrition disorders | Not known | Increased appetite |
| Uncommon | Altered levels of consciousness | |
| Rare | Neuroleptic malignant syndrome (NMS) | |
| Not known | Ataxia, akathisia, dystonia, dizziness, amnesia | |
| Vascular disorders | Common | Hypotension |
| Not known | Bradycardia, epigastric pain, dry mouth | |
| Gastro-intestinal disorders | Common | Dysphagia, nausea, vomiting, diarrhoea, constipation |
| Musculoskeletal and connective tissue disorders | Uncommon | Severe extrapyramidal symptoms including muscular rigidity, autonomic dysfuntion |
| Very rare | Skeletal muscle damage | |
| General disorders and administration site conditions | Uncommon | Hyperhermia |
| Investigations | Not known | Weight increase |
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In repeated dose toxicity studies, the effects observed with orally administered Andriol were related to depletion of central stores of monoamines. Common symptoms were hypoactivity, lethargy, strabismus, or closed eyes. Primarily pharmacological effects such as sedation were observed and considered dose limiting.
The genotoxic potential of Andriol has been studied using a series of conventional tests. In vitro, Andriol was negative for point mutations and positive for chromosomal aberrations in Chinese hamster ovary cells, at cytotoxic concentrations only. Andriol was not genotoxic in an in vivo chromosomal aberration test.
Andriol did not reveal any carcinogenic potential when administered for 26 weeks in the transgenic p53 heterozygous mouse model at doses up to 30 mg/kg/day and in a limited study in male rats Andriol was noncarcinogenic when administered for 94 weeks at doses up to 12 mg/kg/day.
In a fertility and early embryonic development study at systemic exposures below those observed clinically there was no evidence of effect on pregnancy or in utero survival in rats. Length of the estrous cycle was increased and a delay in fertility was seen in female rats. Reproduction was unaffected in male rats.
In embryo-fetal developmental toxicity studies there was no evidence of embryotoxicity or teratogenicity in either rats or rabbits. In a perinatal and postnatal study in rats, neonatal deaths and delayed pup maturation were observed at systemic exposures below those observed clinically. These effects could either be indirect effects due to inadequate maternal care or a direct effect of Andriol on the pups.
Pharmacotherapeutic group: Other nervous system drugs, ATC Code: NO7XX06
The central effects of Andriol closely resemble those of reserpine, but it differs from the latter in having less peripheral activity and being much shorter acting.
Mechanism of action
Animal studies have shown that Andriol disturbs the metabolism of biogenic amines, for instance that of serotonin and noradrenaline, and that this activity is limited to the brain. The supposition is that this effect of Andriol on amines in the brain explains the clinical effects in the brain.
Andriol inhibits the re-uptake of monoamines in the neuroterminal of the presynaptic neurons of the central nervous system. This results in a depletion of monoamines, including dopamine. Dopamine depletion results in hypokinesis leading to a reduction in chorea severity.
Andriol inhibits the re-uptake of monoamines in synaptic nerve terminals by a reversible and short-term binding to the vesicular monoamine transporter (VMAT). VMAT2 transports monoamines especially in peripheral and central neurons, while VMAT1 regulates the transport in peripheral chromaffine tissues. Andriol has a higher affinity for VMAT2 than for VMAT1. Thus, Andriol has a short, hardly peripheral effect.
Andriol has a low and erratic bioavailability. It appears to be extensively metabolised by firstpass metabolism. The major metabolite, hydroxyAndriol, is formed by reduction. Little unchanged Andriol can be detected in the urine. Since hydroxyAndriol is reported to be as active as Andriol in depleting brain amines, it is likely that this is the major therapeutic agent.
Special populations
Hepatic impairment
Mild and moderate hepatic impairment increases the exposure and prolongs the half-lives of Andriol and hydroxyAndriol (4 patients with Child Pugh score 5-6 and 1 patient with Child Pugh score 9.) Severe hepatic impairment has not been studied.
Patients should be advised that Andriol may cause drowsiness and therefore may modify their performance at skilled tasks (driving ability, operation of machinery, etc.) to a varying degree, depending on dose and individual susceptibility.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
