Levorol 5 mg/ml Oral Solution

Oral Solution Clear, colourless to slightly pinkish-orangish solution with orange odour.

4.1 Therapeutic indications Levomepromazine is a neuroleptic with indications in psychiatry and general medicine, particularly in terminal illness. Clinically it is more sedative and more potent than chlorpromazine in the management of psychotic conditions and in the relief of severe chronic pain and possesses anti-emetic effects. Levorol 5 mg/ml Oral Solution is indicated: For the suppression of psychomotor restlessness and agitation within the context of psychotic disorders. For acute agitation states in manic episodes. ***General medicine – Palliative care*** As an adjunct therapy for the treatment of severe and/or chronic pain. As second or third line treatment of adults with refractory nausea unassociated with chemotherapy, where other agents have failed to give adequate control.4.2 Posology and method of administration **Posology** Dosage varies with the condition under treatment and the individual response of the patient. The daily dose is usually split into three to four individual doses. *Adults* **Ambulant patients**: 15-30 mg levomepromazine/day (3-6 ml of Levorol oral solution) up to 75 – 150 mg levomepromazine/day (15-30 ml of Levorol oral solution). **Bed Patients with psychosis**: Initially the total daily oral dosage is 75-100 mg (5 ml, 3 to 4 times), increased to 150 mg/day (10 ml, 3 times) up to 300 mg/day (20 ml, 3 times) and for severe psychoses up to 600 mg levomepromazine/day. For doses higher than 300 mg Levomepromazine should be taken in the form of Tablets. **Bed Patients with severe pain**: Initially the total daily oral dosage is 25-50-75 mg/day (5-10-15 ml), gradually increased, if necessary, up to 300 mg/day (60 ml). Note: If therapy with analgesics has been initiated before levomepromazine treatment, the dose of levomepromazine can be reduced. If hypnotic drugs are used concomitantly, the dose of levomepromazine should be reduced at least by half. For treatment of nausea: 1.2 mL (6 mg) once daily, taken at bedtime, increased if necessary to 2.5 mL – 5 mL (12.5-25 mg) twice daily. *Elderly and patients with renal or hepatic impairment* In elderly patients and patients with hepatic and renal impairment the dose must be adjusted with special caution, as there is an increased incidence of side effects. *Paediatric population* The use of Levorol oral solution in children and adolescents under 16 years is not recommended (see Section 4.3). **Method of administration** Levorol 5 mg/ml oral solution is for oral use only. A 5 ml graduated oral syringe with intermediate graduations of 0.1 ml and a “Press- In” Bottle Adapter (PIBA) are provided with the product.

1. Open the bottle and insert the “Press-In” Bottle Adapter (PIBA) when first use.
2. Insert the syringe into the PIBA and draw out the required volume from the inverted bottle.
3. Remove the filled syringe from the bottle in the upright position.
4. Discharge the syringe contents into the mouth. Repeat steps 2 to 4 as needed to achieve the required dose.
5. Rinse the syringe and replace the cap on the bottle (PIBA remains in place).4.3 Contraindications Hypersensitivity to the active substance, levomepromazine hydrochloride, thioxanthenes and phenothiazines or to any of the excipients listed in Section 6.1. Levorol oral solution should not be used in: • acute alcohol-, sleeping medication-, analgesic- and psychopharmaceutical- intoxication • shock (circulatory failure) • coma • impairment of the hematopoietic system The use of Levorol oral solution in children and adolescents under 16 years is not recommended.4.4 Special warnings and precautions for use Levorol oral solution should be avoided or used with caution in the following conditions:

• hepatic failure and end stage renal disease
• previous cardiac disease
• prolactin-dependent tumours, such as breast tumours
• severe hypotension or hypertension, postural hypotension
• history of brain disease or epileptic seizures
• non-drug induced Parkinson's disease
• atherosclerotic cerebrovascular disease
• history of Malignant Neuroleptic Syndrome
• glaucoma
• micturition disorder
• pyloric stenosis
• benign prostatic hyperplasia
• congenital long QT syndrome or other clinically significant cardiac disorders (especially coronary artery disease, conduction disorders, arrhythmias)
• concomitant treatment with drugs that prolong the QT interval in the ECG or cause hypokalaemia (See Section 4.5) Blood count (including platelet and differential count) should be checked before treatment with tricyclic neuroleptics agents. If blood values are outside the normal range, levomepromazine should not be used. Blood count (leukocyte count and differential count) should be performed regularly during levomepromazine therapy. Blood monitoring should be performed weekly within the first four months of treatment initiation and if values are within the normal ranges, a monthly blood monitoring is sufficient. Treatment with levomepromazine should be discontinued if values of leucocytes below 3000/mm3or other changes in blood count occur. If required, intensive care measures should be given. Patients should be advised not to self-medicate in case of fever, mouth and gum inflammation, sore throat or purulent angina, and flu-like symptoms, especially if these occur within the first three months of drug treatment, but to seek medical advice immediately. Initiation of treatment with levomepromazine should be followed by ECG monitoring. Whilst on therapy, liver function should be monitored every 6-12 months. Levomepromazine may prolong the QT interval leading (rarely) to fatal arrhythmias, and Torsade de Pointes (see Section 4.8). In these cases, levomepromazine must be discontinued. Blood pressure lowering effects may occur within 10-20 minutes after intramuscular injection of levomepromazine, lasting 4-6 hours (rarely up to 12 hours). As a rule, the blood pressure-reducing effect of levomepromazine is reduced over longer treatment periods. If the treatment is interrupted for several days, further administration of levomepromazine might again lead to a blood pressure reduction. After parenteral administration as well as at the initiation of administration of higher doses, the patient needs bed rest for 5-6 hours. Hospitalization is recommended for daily doses over 150 mg. If high fever and muscle stiffness occur, the possibility of a malignant neuroleptic syndrome (increase in myoglobin and creatine kinase activity [CK] in the blood) should be considered, which is often misdiagnosed as catatonia. Since the re- administration of neuroleptics can have life-threatening consequences, the differentiation from catatonia is decisive in the differential diagnosis (medical history, examination for rigor, fever, as well as an increase in CK and myoglobin in the blood or urine. The following treatment options are recommended:
• Immediate drug withdrawal
• Cooling employed for hyperthermia
• Treatment for fluid and electrolyte imbalance, cardiovascular manifestations, infections, respiratory and renal complications
• Treatment with dantrolene infusions (3 to 10 mg/kg/day) in combination with bromocriptine (7.5 to 30 mg/day orally) **Increased mortality in elderly people with dementia** Data from two clinical studies indicated that elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of mortality. The extent to which this association is attributable to the medicinal product, as opposed to being confounded by patient characteristics, has not yet been elucidated. Levorol oral solution is not indicated for the treatment of dementia-related behavioural disturbances. **Increased risk of adverse cerebrovascular events** In randomised, placebo-controlled clinical studies in the dementia population, there was an approximately 3-fold increased risk of cerebrovascular adverse events with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other patient populations. Levorol oral solution must be used with caution in patients with risk factors for stroke. **Venous thromboembolism risk** Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with levomepromazine solution and preventive measures should be undertaken. **Note**: Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight (see Section 4.8). **Propylene glycol** This medicine contains 150.95 mg propylene glycol in each 1 ml of oral solution. Medical monitoring is required in patients with impaired renal or hepatic functions because various adverse events attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction. While propylene glycol has not been shown to cause reproductive or developmental toxicity in animals or humans, it may reach the foetus and was found in milk. As a consequence, administration of propylene glycol to pregnant or lactating patients should be considered on a case by case basis. **Sodium** This medicine contains less than 1 mmol sodium (23 mg) per 40 ml of oral solution, that is to say essentially 'sodium-free'. **Sodium benzoate** This medicine contains 0.3 mg sodium benzoate in each 1 ml of oral solution. **Benzyl alcohol** This medicine contains 0.03 mg benzyl alcohol in each 1 ml of oral solution. Benzyl alcohol may cause allergic reactions. High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).4.5 Interaction with other medicinal products and other forms of interaction **Effects of other medicinal products on levomepromazine** Concomitant administration of carbamazepine and barbiturates can induce the CYP enzyme activity resulting in decreased levomepromazine plasma concentrations. The effects of levomepromazine can be inhibited by anticholinergic medicinal products, such as biperiden. The moderate anticholinergic effects of levomepromazine can be enhanced by other anticholinergic agents or other medicinal products with anticholinergic effects. Concomitant administration of drugs known to inhibit hepatic metabolism of levomepromazine, might lead to enhanced therapeutic effects of levomepromazine. **Effects of levomepromazine on other medicinal products** The concomitant use of levomepromazine with analgesics, hypnotic agents, sedatives or other Central Nervous System antidepressants can lead to increased sedation and respiratory depression. Levomepromazine is an inhibitor of cytochrome P450 2D6 (CYP2D6). Co- administration of levomepromazine and drugs primarily metabolised by the CYP2D6 enzyme system may result in increased plasma concentrations of these drugs (risperidone, haloperidol, amitriptyline, captopril, ondansetron, codeine, celecoxib, flecainide and amphetamine derivatives). Concomitant use of levomepromazine may affect the metabolism of phenytoin, resulting in toxic plasma concentrations of phenytoin. Levomepromazine can enhance the respiratory depression after concomitant administration with polypeptide antibiotics (Capreomycin, Colistin, Polymyxin B). Levomepromazine can affect the hepatic metabolism of tricyclic antidepressants (TCAs) resulting in increased plasma levels of TCAs. Caution should be exercised if levomepromazine is combined with MAO inhibitors. Patients undergoing surgical repair should be carefully monitored for potential hypotension. The dose of anaesthetics may need to be reduced. The effects of antihypertensive drugs can be enhanced with the concomitant use of levomepromazine. The hypotensive effects of guanethidine, clonidine and alpha- methyldopa can, however, be depressed. The combined use of levomepromazine with dopamine agonists (e.g. levodopa) may result in diminished effects of dopamine agonists. The alpha-adrenergic effects of adrenaline are also diminished. The response to gonadorelin can be diminished by phenothiazines due to the enhanced levels of prolactin. **Other drug interactions** The combined use of levomepromazine and propranolol may result to increased levels of both drugs. The concomitant use of levomepromazine and piperazine anthelmintics and metoclopramide can result to an increased risk of extrapyramidal symptoms. The absorption of other drug substances can be affected by the inhibition of gastrointestinal motility. Treatment with levomepromazine may affect the PKU Test for Phenylketonuria (false-positive result). The concomitant use of medicinal products that prolong the QT interval (class IA or III antiarrhythmics, cisapride, certain antibiotics, antimalarials, antihistamines, antidepressants) or lead to hypokalaemia (e.g. certain diuretics) should be avoided.4.6 Fertility, pregnancy and lactation **Pregnancy** There have been isolated case reports and one controlled study of different congenital malformations with the use of phenothiazines. Any correlation could not be confirmed by clinical studies. There are insufficient data on the effects of levomepromazine on human embryo or foetus and animal studies are insufficient with respect to reproductive toxicity (see Section 5.3). Levorol oral solution should not be used in the first trimester of pregnancy. Levomepromazine should be avoided in the second and third trimesters, unless considered essential by the physician. The lowest effective dose should be used. Neonates exposed to antipsychotics (including Levorol oral solution) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be carefully monitored. Levorol oral solution should not be used during the last 10 days of pregnancy to prevent extrapyramidal and/or withdrawal symptoms in the neonate. Levorol oral solution is not recommended during pregnancy. If Levorol is prescribed to a female patient of child-bearing age, she should be advised to contact her doctor immediately if she would like to become pregnant or suspects that she is pregnant. **Breast-feeding** Levomepromazine and its metabolites are excreted to human milk. If treatment cannot be avoided, breast-feeding should be discontinued. **Fertility** There are no human data available on fertility.4.7 Effects on ability to drive and use machines Levomepromazine may cause tiredness, dizziness and fatigue which may affect the patient's ability to drive or operate machinery. Patients should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery, at any time when affected. Simultaneous intake of alcohol may further affect the ability to drive and use machines.4.8 Undesirable effects Adverse effects have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100; <1/10); uncommon (≥1/1,000; <1/100); rare (≥1/10,000; <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data). | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | **System organ class** | **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)** | **Very Rare (<1/10,000)** | **Not known (cannot be estimated from available data)** | | Blood and lymphatic system disorders | | | | | Blood dyscrasias | | | Immune system disorder | | | Anaphylactic reaction | | | | | Metabolism and nutrition disorders | | Weight gain | | | | | | Nervous system disorders | Fatigue | Extrapyramidal symptoms such as dyskinesia, Parkinson's disease, akathisia | Restlessness, agitation, drowsiness, depressed mood, lethargy, dizziness, headache, exacerbation of psychotic symptoms, confusion, seizures, disturbance of temperature regulation | Malignant neuroleptic syndrome | Delirium | | | Pregnancy, puerperium and perinatal conditions | | | | | | Withdrawal syndrome | | Eye disorders | | Eye dystonia, blurred vision, ocular hypertension | Anterior corneal pigmentations | | | | | Cardiovascular disorders | Orthostatic hypotension, Tachycardia, ECG changes | | | | Torsade de Pointes | Thromboembolism | | Respiratory, thoracic and mediastinal disorders | | Nasal congestion | | | | | | Gastrointestinal disorders | | Constipation, nausea, vomiting, diarrhoea, loss of appetite, xerostomia | | Paralytic ileus | Ulcerative colitis | | | Hepatobiliary disorders | | | Liver dysfunction, bile drainage problems, jaundice | | | | | Skin and subcutaneous tissue disorders | | | Skin hypersensitivety reactions, photosensitivity | | | | | Renal and urinary disorders | | Micturition disorder | | | | | | Reproductive system and breast disorders | | | | | Gynecomastia, menstrual disorders, galactorrhoea, sexual dysfunction | | **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.4.9 Overdose **Signs and symptoms** Somnolence to coma, confusion and agitation, cardiac failure, arrhythmia, hypotension, tachyarrhythmia, dry mucous membranes, constipation, paralytic ileus, urinary retention, mydriasis, convulsions, hypo- or hyperthermia, parkinsonism. **Management and treatment** Initial treatment consists of induction of emesis. Gastric lavage can be attempted many hours after ingestion of a toxic dose by using high amounts of lubricant due to the existing dry mucous membranes. Activated charcoal and Glauber's salt should be administered repeatedly to inhibit the absorption and accelerate the elimination of levomepromazine. Dialysis does not offer significant benefits. The antidote for the anticholinergic symptoms is physostigmine. The risk with physostigmine treatment should be weighed against its benefit on the management of levomepromazine overdose. Due to the enterohepatic circulation of tricyclic substances, treatment with cholestyramine may be attempted (3 × 4 g daily). Symptomatic treatment such as controlled ventilation and intubation may be considered, as well as general intensive medical care for restoring electrolyte balance, serum tonicity, through intravenous infusion of positive inotropic agents, ECG and intraocular pressure monitoring. Infusion of alpha sympathomimetics such as norfenefrine or noradrenaline may be considered. Do not use adrenaline. Severe dystonic reactions usually respond to biperiden (adults: 2.5-5 mg IM or slow IV) or diphenhydramine (50 mg orally every 6 hours) or diazepam (3-10 mg slow IV).

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Phenothiazines with aliphatic side-chain, Psycholeptics, ATC code: N05AA02 **Mechanism of action** Levomepromazine belongs to the group of phenothiazines. Levomepromazine antagonizes dopamine receptors in the Central Nervous System, depressing the cerebral cortex, hypothalamus and limbic system. The clinical effects produced by this action include: a depressant action on conditioned responses and emotional responsiveness; a sedative action useful for the treatment of restlessness and confusion; an anti-emetic effect through blockade of the chemoreceptor trigger zone (CTZ), which is useful to treat vomiting; and antihistamine activity. **Pharmacodynamic effects** Levomepromazine has a broad receptor binding profile covering antagonist actions at D1–D4, 5-HT1 and 5-HT2, noradrenergic (including, unlike chlorpromazine, a2 as well as a1), histamine H1, and muscarinic M1 and M2 sites. **Clinical efficacy and safety** The clinical efficacy of levomepromazine for the suppression of psychomotor restlessness and agitation within the context of psychotic disorders and agitation states in manic episodes has been evaluated in clinical studies and has been compared to other medications. The results of clinical studies indicate that levomepromazine is effective in these episodes when compared to other medications, such as haloperidol and olanzapine. The results of clinical studies support also the use of levomepromazine in combination with other medications for the treatment of serious or chronic pain. The most common adverse events occurring after levomepromazine administration are gastrointestinal disorders and nervous system disorders. The effect of levomepromazine, along with other antipsychotic medications, on QTc prolongation is well known and monitoring after levomepromazine administration is recommended.5.2 Pharmacokinetic properties **Absorption** Following oral administration, maximum plasma concentration is observed after 2-3 hours. The maximum plasma concentration after a single intramuscular administration is reached in 30-90 minutes. Due to the extensive first-pass effect, bioavailability is approximately 50 %. Considerable fluctuations are possible. **Distribution** The volume of distribution is 20-40 L/kg. After therapeutic doses of 50-375 mg/day, plasma concentrations of 15-60 ng/ml are observed. Plasma concentration of levomepromazine is not affected by dialysis. Phenothiazines penetrate the placental barrier and can enter breast milk. **Biotransformation** Levomepromazine is metabolized by the liver. CYP3A4 is the main isoenzyme responsible for levomepromazine 5-sulfoxidation and N-demethylation at a therapeutic concentration of the drug. **Elimination** The mean total clearance of levomepromazine is 2.8 L/min.5.3 Preclinical safety data Acute toxic effects of levomepromazine mainly occur in Central Nervous System and Cardiovascular system (see Section 4.9). Pre-clinical chronic toxicity studies are not available. Levomepromazine showed no evidence of mutagenicity in *in vitro* studies. Long-term studies on a carcinogenic potential of levomepromazine are not available. Long term studies of phenothiazines in mice have shown to induce breast tumours, which may be attributed to the increased prolactin blood levels. Numerous neuroleptics also cause hyperprolactinaemia in humans. Reproduction toxicity studies have not been performed. Various phenothiazines*,* in micromolar concentration which is in the upper range of the therapeutic plasma levels, block *in vitro* the expression of hERG potassium channels, which are responsible for the cardiac repolarization process. The phenothiazines-induced block may result to ventricular arrhythmias (Torsades de Pointes). This effect has not been studied with levomepromazine.

6.1 List of excipients Propylene glycol (E1520) Glycerol (E422) Sodium benzoate (E211) Saccharin sodium (E954) Orange flavour (including propylene glycol, E1520 and benzyl alcohol, E1519) Hydrochloric acid, concentrated (E507) (for pH adjustment) Purified water6.2 Incompatibilities Not applicable6.3 Shelf life 36 months After first opening use within 3 months.6.4 Special precautions for storage This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light.6.5 Nature and contents of container Amber, type III glass bottle safely closed with a child-resistant HDPE screw cap with tamper evident closure. Each bottle contains 100 ml of this medicinal product. A 5 ml graduated oral syringe with intermediate graduations of 0.1 ml and a “press- in” syringe/bottle adapter are also provided.6.6 Special precautions for disposal and other handling No special requirements.