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Reg. no.: 6397291.00.00
Product characteristics
1.
NAME OF THE DRUG
Proneurin 25 mg coated tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient: Promethazine hydrochloride
1 coated tablet contains 25 mg promethazine hydrochloride.
Other ingredients with known effect:
Lactose and sucrose
For a complete list of all other ingredients, see section 6.1.
PHARMACEUTICAL FORM
Coated tablet
Appearance: white, convex
CLINICAL INFORMATION
4.1 Areas of use
 Anxiety and excitation states in the scope of psychiatric primary diseases Proneurin 25 can be indicated if therapeutic alternatives are not practicable or have not been successful for:  Nausea and vomiting  Sleeping disorders in adults 4.2 Dosage and mode of administration
The dosage, pharmaceutical form and duration of use must be adapted to the individual re-
action situation, indication and severity of the illness. The basic principle applies to keep
the dose as small as possible and the duration of treatment as short as possible.
After longer use, promethazine shouldn't be discontinued abruptly but tapered off.
For anxiety and excitation states in the scope of psychiatric primary diseases
For anxiety and excitation states, the use of Proneurin 25 should be reduced to single ad-
ministrations or a few days.
For adults, the treatment is normally started with 20-30 mg promethazine hydrochloride be-
fore sleeping.
If this dose does not have the desired effect, increase the dose to 40-100 mg promethazine
hydrochloride per day while taking into account the required precautions; the daily dose
should be administered in several single doses.
Higher doses are only required in rare cases and are normally given in the hospital.
For severe anxiety and excitation states, the dose can be increased temporarily to max.
200 mg promethazine hydrochloride per day.
Reg. no.: 6397291.00.00 Older or weak patients and patients with organic brain mutations, circulatory and respirato-
ry insufficiencies and a functional liver and kidney disorder will normally receive half of the
indicated daily dose.
Children and adolescents up to 18 years will initially receive 10 mg promethazine hydro-
chloride before sleeping.
Treatment is normally continued with 3 times 10 mg promethazine hydrochloride per day. A
total daily dose of 0.5 mg promethazine hydrochloride/kg body weight must not be exceed-
ed.
Children younger than 2 years may not be treated with Proneurin 25.
For vomiting, if therapeutic alternatives are not practicable or have not been suc-
cessful
Adults will initially receive generally 20-30 mg promethazine hydrochloride. Treatment is
generally continued with 3 times 10-20 mg promethazine hydrochloride per day.
Older or weak patients and patients with organic brain mutations, circulatory and respirato-
ry insufficiencies and a functional liver and kidney disorder will receive normally half of the
indicated daily dose.
Children and adolescents up to 18 years will initially receive 10 mg promethazine hydro-
chloride. Treatment is normally continued with 3 times 10 mg promethazine hydrochloride.
A total daily dose of 0.5 mg promethazine hydrochloride/kg body weight must not be ex-
ceeded.
Children younger than 2 years may not be treated with Proneurin 25.
For sleeping disorders, if therapeutic alternatives are not practicable or have not
been successful
Adults will receive 20-50 mg promethazine hydrochloride before sleeping. The maximum
dose should not exceed 1 mg promethazine hydrochloride/kg body weight.
Older or weak patients and patients with organic brain mutations, circulatory and respirato-
ry insufficiencies and a functional liver and kidney disorder will receive normally half of the
indicated dose.
Children and adolescents younger than 18 should not be treated with Proneurin 25 for
sleeping disorders.
The coated tablets should be swallowed whole with sufficient fluids.
When treating anxiety and excitation states, take Proneurin 25 mainly in the evening, about
half an hour before going to bed and not on a full stomach to avoid a delayed effect and –
depending on the sleep duration –strong after-effects (such as fatigue, concentration prob-
lems) in the next morning.
4.3 Contraindications
Proneurin 25 may not be used for:  hypersensitivity against the active ingredient, other phenotiazines or one of the oth- er ingredients listed in section 6.1  acute intoxication with centrally dampening drugs (e.g. opiates, hypnotics, antide- pressants, neuroleptics, tranquilizers) or alcohol  severe blood cell or bone marrow defect  circulatory shock or coma  anamnestic known malign neuroleptic syndrome after promethazine Reg. no.: 6397291.00.00 Children younger than 2 may not be treated with promethazine because an increased risk of the so-called "sudden infant death syndrome" cannot be excluded. 4.4 Special warnings and precautions for use
Proneurin 25 may only be used while taking special precautions for:  leucopoenia and other illnesses of the haematopoietic system  functional liver and kidney disorders  pyloric stenosis  prostatic hypertrophy  organic brain diseases and epileptic seizures in the anamnesis  Parkinson syndrome  hypotonia, hypertonia, orthostatic dysregulation, bradycardia, hypokalaemia  congenital long QT syndrome or other clinically significant cardiac disorders (espe- cially coronary cardiac disease, disturbance of conduction, arrhythmias)  simultaneous treatment with drugs which will prolong the QT interval in the ECG as well or which will cause a hypokalaemia (see section 4.5)  suspected or neurologically recognisable subcortical brain damage  chronic dyspnoea and bronchial asthma  photo sensitivity or phototoxic reactions in the anamnesis  Acute narrow angle and angle-block glaucoma and corresponding disposition
Children older than 2 years and adolescents younger than 18 years should only be treated
with promethazine in case of urgent indication.
Increased mortality for older people with dementia illnesses
The data of two big user studies have shown that older people with dementia illnesses
which have been treated with conventional (typical) antipsychotics, have a slightly higher
mortality risk compared to those who have not been treated with antipsychotics. Based on
the existing data from the study, the exact level of risk cannot be indicated and the cause
for the increased risk is not known.
Proneurin 25 has not been approved for treatment of behavioural issues connected to de-
mentia illnesses.

Increased risk for occurrence of undesired cerebrovascular events
In randomised, placebo-controlled clinic trials with people suffering from dementia who
have been treated with some atypical antipsychotics, the risk for undesired cerebrovascular
events was increased threefold. The mechanism causing this increased risk is unknown. It
cannot be excluded that this effect can occur when using other antipsychotics or with other
patient groups. Therefore, Proneurin 25 should be used with care on patients with an in-
creased stroke risk.
Thromboembolism risk
In connection with the use of antipsychotics, cases of venous thromboembolism (VTE)
have been reported. Since patients treated with antipsychotics have often acquired risk fac-
tors for VTE, all possible risk factors for VTE before and during the treatment with Proneu-
rin 25 must be identified and preventive measures must be taken.
Note
When treating over a longer period of time, the cardiac function and the haemogram must
be monitored carefully.
Reg. no.: 6397291.00.00 Patients with the rare hereditary galactose and/or fructose intolerance, lactase deficiency, glucose-galactose-malabsorption or sucrase-isomaltase deficiency should not take Proneu-rin 25. 4.5 Interaction with other drugs and other interactions
For simultaneous use with other centrally dampening drugs (hypnotics, sedatives, analge-sics, other psychotropic drugs, antihistamines) or alcohol, the effects and adverse effects might be mutually increased (especially for sedation and blood pressure decrease). A combination of promethazine with other anticholinergic working drugs such as anti-depressants or atropine, might increase the anticholinergic effects additively and phar-macogenic delirant syndromes might occur increasingly. The plasma concentration of tricyclic anti-depressants and their metabolites is increased strongly by simultaneous administration of promethazine and other phenothiazines, so that an increased toxicity of both active ingredients (anticholinergic effect, reduction of the sei-zure threshold and first and foremost with cardiac effects [QT interval prolongation]) must be assumed. Therefore, this combination is not advisable. Due to indications to hypertension and increase of extrapyramidal motoric adverse effects in connection with MAO inhibitors, a combination of promethazine with MAO inhibitors is not advisable. Promethazine should not be combined with epinephrine due to a possible paradox blood pressure drop ("reverse epinephrine response"). The effect of antihypertonics can be influenced; normally an increased blood pressure re-ducing effect (e.g. orthostatic circulatory dysregulation) has clinical relevance. In case of a simultaneous use of anticonvulsives, an increased decomposition of the phe-nothiazines will occur. Avoid simultaneous use of drugs also prolonging the QT interval (e.g. antiarrhythmics class IA or III, macrolide antibiotics, malaria drugs, antihistamines, antidepressants), causing an hypokaliaemia (e.g. certain diuretics) or inhibiting the hepatic decomposition of prometha-zine. 4.6 Fertility, pregnancy and lactation
In the experiences documented so far for the use during pregnancy with approx. 800 moth-er-child-pairs, approx. 170 thereof in the first trimester, no unambiguous conclusions for an increased risk for deformity. Proneurin 25 penetrates the placenta and will still be traceable up to four hours after birth of the baby in its blood. The possibility of a respiratory depres-sion and temporary EEG and behavioural changes in the baby cannot be excluded. Pro-neurin 25 can affect the thrombocyte aggregation for mother and child. However, so far no cases of increased bleeding tendency after administering the active ingredient while giving birth have been reported. There are no adequate animal studies concerning the reproduc-tive toxicity of Proneurin 25 (see section 5.3). New-borns, exposed to antipsychotics (including promethazine) during the third pregnancy trimester, are at risk due to adverse effects, including extrapyramidal symptoms and/or withdrawal symptoms, where the severity and duration might vary after giving birth. There are reports of agitations, increased or decreased tonicity, tremor, somnolence, dysp-noea or trouble taking in food. Therefore, the new-born should be monitored carefully. Reg. no.: 6397291.00.00 Although there has been no indication for an increased deformity risk by Proneurin 25, the drug should only be used in the early pregnancy if absolutely necessary. For the possibility of a respiratory depression and temporary EEG and behavioural changes in the baby, the drug should be used in the end of the pregnancy and in the lactation period with special care. There are no studies if Proneurin 25 will be transferred into breast milk. 4.7 Impact on the fitness to drive and the ability to operate machines
Proneurin 25 can change the responsiveness even the following day in as much that the capacity to participate in road traffic and to operate machines is impaired. This is even more so in combination with alcohol. Therefore, driving vehicles, operating machines and other dangerous activities – at least in the first phase of the treatment – should be completely avoided. The decision will be taken by the treating doctor in each individual under consideration of the individual reaction and the corresponding dosage. 4.8 Adverse effects
In order to evaluate the adverse effects, the following frequency is used: Very often (≥ 1/100 to < 1/10) (≥ 1/1,000 to < 1/100) (≥ 1/10,000 to < 1/1,000) (frequency is not assessable on the basis of available data) Very often, sedation, dry mouth and thickening of mucus with disorder of mucus secretion might occur. Especially in the beginning of the treatment, blood pressure changes (hypotonia or orthos-tatic dysregulation) and a sudden acceleration of the heart rate might occur. Especially under higher doses, the following might occur: The feeling of a constipated nose, increase of the internal eye pressure, accommodation disturbance, sweating, in-creased thirst feeling and weight gain. In addition, voiding disorders, obstipation and effects on the sexual function (e.g. impairment of the sexual responsiveness, sexual appetence, erection and ejaculation disorders) might occur. Promethazine might prolong the QT interval in the ECG and lead to disturbances of con-duction; very rarely, torsade de pointes have occurred. In these cases, stop the treatment with Proneurin 25. For patients with neurological deficiencies, existing respiratory problems, for children or in combination with other drugs with respiratory depressing effect, a respiratory depression might occur depending on the dose. In addition, leucopoenia, cholestasis and increased temperature as well as cutaneous pho-tosensitisations and allergic skin appearances might occur. There have been reports about galactorrhoea and porphyria. In addition, the following symptoms and syndromes have been reported: Insomnia, disorientation and general unrest, respiratory disorder, agranulocytosis, for-mation of a thrombose, phototoxic reaction and occurrence of seizures. Reg. no.: 6397291.00.00 Very rarely the treatment with neuroleptics might cause a life-threatening malign neurolep-tic syndrome with fever above 40°C and muscular rigidity (increase of myogobines and the creatine kinase activity in the blood). Treatment of this syndrome is difficult, the following measures are recommended:  stop taking the medication immediately  treat the hyperthermia by cooling because antipyretics might not be effective with  treat electrolyte and water balance disorders, cardiovascular manifestations, infec- tions and respiratory and renal complications  therapy attempt with dantrolene infusions (3-10 mg/kg body weight and day) in combination with bromocriptine (7.5-30 mg/day orally) Neuroleptics might cause extrapyramidal motoric adverse effects, especially when highly dosed and if the treatment is continued over a longer period of time. Basically, early dyskinesia (spastic protruding of the tongue, spasms of the pharyngeal muscles, eye spasms, wry neck, stiffening of the back muscles, jaw muscle spasms) or a pharmacogenetic Parkinson syndrome (trembling, rigidity, lack of motion) might occur. When early dyskinesia or Parkinson symptoms occur, reduction of the dose and treatment with anticholinergic antiparkinsonian drugs is required. After longer use, tardive dyskinesia (especially for older patients and for female patients) might occur, especially in the mouth area which might stay after treatment and which might be irreversible. For a promethazine mono therapy in individually adapted and the lowest doses possible over a longer period of time, tardive dyskinesia has not yet been reported or its causal connection to promethazine is questionable. Basically, tardive dyskinesia can be masked under the neuroleptic therapy and will only be realised after terminating the treat-ment. Pregnancy, puerperium and perinatal illnesses Not known: Drug withdrawal syndrome of the new-born (see section 4.6) For long-term treatment with high doses, incorporation or pigmentation in cornea and lens of the eye are possible. Especially in children and older patients, paradox CNS stimulation with tremor, irritability, insomnia and affective disorders might occur. Feverish illnesses and dehydration have a predisposing effect. Frequency not known: Cases of thromboembolisms (including cases of lung embolisms and cases of deep venous thrombosis) 4.9 Overdose
Phenothiazines are characterised by a significant acute toxicity; children and toddlers have
an increased risk.
Symptoms of an overdose
Overdoses with promethazine are first and foremost – depending on the used amount –
characterised by the different stages of a CNS impairment (somnolence to coma, respirato-
ry depression up to apnoea, anxiety state, hallucinations, excitation states up to seizures)
as well as cardiac circulatory symptoms (blood pressure reduction, tachycardia, cardiac ar-
rhythmias such as QT interval prolongation whereby torsades de pointes cannot be ex-
cluded). In addition, anticholinergic symptoms (fever, dry mucous membranes, mydriasis,
obstipation, urine retention) and a metabolic acidosis will occur.
Especially in children, the exciting CNS effects can be dominant.
Reg. no.: 6397291.00.00 Measures in case of an overdose
Intensive medical care must be started as fast as possible.
Gastro lavage might be effective if it is carried out at an early stage (preferably within one
hour), followed by the administration of activated charcoal. A provocation of vomiting does
not seem to be reasonable considering the antiemetic effect of promethazine and the low
efficiency of this measure.
Any further therapy will be symptomatic: Volume substitution, anti-convulsant, vasocon-
strictive drugs, (norepinephrine, no epinephrine!) and for cardiac complication anti-
arrhythmics and/or sodium hydrogen carbonate or lactate should be used, for extrapyrami-
dal symptoms, anticholinergics (biperiden) could be sensible.
ECG and vital functions must be monitored until the ECG has normalised. Analeptics are
contraindicated because reducing the seizure threshold with promethazine leads to a pre-
disposition to cerebral seizures. Even beta blockers should be avoided because they in-
crease the vasodilatation.
For severe poisoning or occurrence of an anticholinergic syndrome there is physostigmine
salicylate as antidote for use under intensive care (ECG check!).
Due to the big distribution volume and the strong plasma protein binding, forced diuresis or
haemodialysis for pure promethazine poisoning are not helpful.
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antihistamines for systematic use, phenothiazine derivate ATC-Code: R06AD02 Promethazine, a phenothiazine derivate with a branched aliphatic side chain, is a potent H1 antihistamine with strongly sedating effect which has only few antipsychotic properties. It has an antihistaminergic, anticholinergic and antiserotonergic effect and acts as membrane stabiliser. Further, it blocks alpha receptors. In animal experiment, it does not act antago-nistic on dopamine receptors and shows in vitro a very low affinity to (3H) haloperidol marked dopamine receptors. Therefore, the prolactin secretion is not increased, the apo-morphine and amphetamine induced hyperactivity not reduced, there is no catalepsy and no inhibition of the induced flight reflex. Promethazine works antiemetic. Clinically, promethazine is currently used primarily as sedative for anxiety and excitation states; under certain conditions for its antiemetic and hypnotic properties. According to cur-rent level of medical knowledge, the use as antihistaminic drug has only a positive risk-benefit-balance when used parenteral (see section 4.1). 5.2 Pharmacokinetic properties
Absorption Promethazine is completely resorbed after oral use. Due to a strong first-pass-effect, the systemic bioavailability is low (approx. 25%). Distribution The plasma concentration is subject to strong fluctuations. The maximum plasma concen-tration has been determined after 1.5-3 h with 2-18 ng/ml (after 25 mg single dose per os) and with 8-39 ng/ml (after 50 mg single dose per os). After intramuscular injection of 25 mg, maximum plasma concentrations of 22.4±5.9 ng/ml have been measured after 4h which decreased to 3 ng/ml after 12 hours. Promethazine will distribute over all organs, the highest concentrations are in lung, liver and kidneys. The substance gets over the blood cerebral barrier, is transplacental and will be transferred quickly to the foetuses. Foetal plasma concentrations correspond to the ones of the mother. There are no data concerning transfer into breast milk. Reg. no.: 6397291.00.00 Plasma protein binding is up to 90%. The distribution volume is big; the values in the litera-ture range from 171-1,346 litres. Metabolism/Elimination The metabolisation is carried out primarily in the liver, mainly by S-oxidation, in smaller vol-umes also by N demethylation and ring hydroxylation. The main metabolite is the pharma-cological inactive promethazine sulfoxide. Promethazine induces the microsomal enzymes. Excretion is mainly renal, 10% thereof as sulfoxide and in smaller amount biliary. Only a very small part of promethazine is excreted unchanged (0.2%). Total clearance is at 1.1 l/min and is nearly exclusively hepatically induced. 5.3 Pre-clinical data for safety
The repetitive oral application of promethazine over a period of 13 weeks has caused an increased liver weight in rats and in a long-term study (2 years), fat accumulations in the liver of male animals have been reported. In-vivo- and in-vitro examinations to verify genetic and chromosome mutations and DNA reparations have been negative with promethazine. Long-term studies with rats and mice have delivered no evidence to any tumour creating potential. Oral doses up to 250 mg/kg/day did not have any adverse effect on the implantation and embryonic development in rats. In vitro, promethazine blocks expressed HERG channels in micromolar concentrations which are in the upper range of therapeutic plasma concentration. These channels are re-sponsible for repolarisation in the heart. Therefore, promethazine has the potential to cause certain forms of ventrical cardiac arrhythmia (torsade de pointes). PHARMACEUTICAL INFORMATION
6.1 List of other ingredients
 Calcium carbonate  Microcrystalline cellulose  Lactose-monohydrate  Macrogol 6000  Magnesium stearate (Ph.Eur.)  Maize starch  Poly(O-carboxymethyle) starch sodium salt  Highly disperse silicon dioxide  Colorant titanium dioxide (E 171) 6.2 Incompatibilities
6.3 Shelf life
Reg. no.: 6397291.00.00 The drug should not be used anymore after having expired. 6.4 Special precautions for storage
No special storage precautions required for this drug. 6.5 Type and contents of the container
Original packaging with 20, 50 and 100 coated tablets. Possibly, not all packaging sizes are marketed. 6.6 Special precautions for disposal
No specific requirements. HOLDER OF THE MARKETING AUTHORISATION OF PHARMACEUTICALS
HEXAL AG
Industriestraße 25
83607 Holzkirchen, Germany
Telephone: (08024) 908-0
Telefax: (08024) 908-1290
E-mail: [email protected]
REGISTRATION NUMBER
6397291.00.00
DATE OF REGISTRATION / PROLONGATION OF THE REGISTRATION
06/04/1999 / 23/09/2004 / 21/07/2009

10: INFORMATION AS OF

11. SELLING RESTRICTIONS
On prescription only

Source: https://healthcms.gov.mt/en/poyc/Documents/213329-001_Proneurin%2025mg%20SPC%20GER_English.pdf